CVJA Volume 29 Issue 1 by Clinics Cardive Publishing

JANUARY/FEBRUARY 2018 VOL 29 NO 1

ß RESTORE cardiac function CARVEDILOL: - is indicated twice daily for mild to moderate stable symptomatic congestive heart failure

www.cvja.co.za

- is indicated once daily for essential mild to moderate hypertension

CardioVascular Journal of Africa (official journal for PASCAR)

• Proportion of patients living within 60 and 120 minutes of a PCI facility

- has a positive effect on metabolic parameters.1

• Effects of age on systemic inflammatory response syndrome after CABG • Cardiac diastolic function after recovery from pre-eclampsia • Cardiac morphology and vertical jump height of competitive footballers • Atherosclerotic disease the predominant aetiology of acute coronary syndrome • Rehospitalisation or death after admission for acute heart failure in Nigeria • Left ventricular remodelling in chronic primary mitral regurgitation

6,25 mg 12,5 mg

25 mg

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing information, refer to the package insert approved by the Medicines Control Council, December 2014. 1) Panagiotis C Stafylas, Pantelis A Sarafidis. Carvedilol in hypertension treatment. Vascular Health and Risk Management 2008;4(1):23-30. CDD328/01/2018.

Cardiovascular Journal of Africa . Vol 29, No 1, January/February 2018

CARVEDILOL

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689 For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za BILOCOR 5, 10. Each tablet contains 5, 10 mg bisoprolol fumarate respectively. S3 A38/5.2/0053, 0051. NAM NS2 06/5.2/0061, 0062. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 23 July 2010. BILOCOR CO 2,5/6,25, 5/6,25, 10/6,25. Each tablet contains 2,5, 5, 10 mg bisoprolol fumarate respectively and 6,25 mg hydrochlorothiazide. S3 A44/7.1.3/1010, 1011, 1012. NAM NS2 13/7.1.3/0260, 0261, 0262. For full prescribing information, refer to the package insert approved by the Medicines Control Council, 2 November 2012. 1) IMS MAT UNITS Sept 2017. BRF344/01/2018.

ISSN 1995-1892 (print) ISSN 1680-0745 (online)

Vol 29, No 1, JANUARY/FEBRUARY 2018

CONTENTS

Cardiovascular Journal of Africa

www.cvja.co.za

EDITORIAL 4

Appropriate strategies for South Africa for the management of acute myocardial infarction in patients presenting with ST-segment elevation R Delport

The proportion of South Africans living within 60 and 120 minutes of a percutaneous coronary intervention facility Willem Stassen • Lee Wallis • Craig Vincent-Lambert • Maaret Castren • Lisa Kurland

Reinforcement of suture lines with aortic eversion in aortic replacement E Kaya

Value of transluminal attenuation gradient of stress CCTA for diagnosis of haemodynamically significant coronary artery stenosis using wide-area detector CT in patients with coronary artery disease: comparison with stress perfusion CMR HY Kim • HS Yong • EJ Kim • E-Y Kang • BK Seo

Effects of age on systemic inflammatory response syndrome and results of coronary bypass surgery O Gokalp • NK Yesilkaya • S Bozok • Y Besir • H Iner • H Durmaz • Y Gokkurt • B Lafci • G Gokalp • L Yilik • A Gurbuz

Cardiac diastolic function after recovery from pre-eclampsia P Soma-Pillay • MC Louw • AO Adeyemo • J Makin • RC Pattinson

A comparative study on the cardiac morphology and vertical jump height of adolescent black South African male and female amateur competitive footballers PJ-L Gradidge • D Constantinou

Atherosclerotic disease is the predominant aetiology of acute coronary syndrome in young adults AK Pillay • DP Naidoo

CARDIOVASCULAR TOPICS

INDEXED AT SCISEARCH (SCI), PUBMED, PUBMED CENTRAL AND SABINET

Editors

SUBJECT Editors

Editorial Board

Editor-in-Chief (South Africa) Prof Pat Commerford

Nuclear Medicine and Imaging DR MM SATHEKGE

prof PA Brink Experimental & Laboratory Cardiology

PROF A LOCHNER Biochemistry/Laboratory Science

PROF R DELPORT Chemical Pathology

PROF BM MAYOSI Chronic Rheumatic Heart Disease

Assistant Editor Prof JAMES KER (JUN) Regional Editor DR A Dzudie Regional Editor (Kenya) Dr F Bukachi Regional Editor (South Africa) PROF R DELPORT

Heart Failure Dr g visagie Paediatric dr s brown Paediatric Surgery Dr Darshan Reddy Renal Hypertension dr brian rayner Surgical dr f aziz Adult Surgery dr j rossouw Epidemiology and Preventionist dr ap kengne Pregnancy-associated Heart Disease Prof K Sliwa-hahnle

PROF MR ESSOP Haemodynamics, Heart Failure DR MT MPE Cardiomyopathy & Valvular Heart Disease DR OB FAMILONI Clinical Cardiology DR V GRIGOROV Invasive Cardiology & Heart Failure

International Advisory Board PROF DAVID CELEMAJER Australia (Clinical Cardiology) PROF KEITH COPELIN FERDINAND USA (General Cardiology) DR SAMUEL KINGUE Cameroon (General Cardiology)

PROF DP NAIDOO Echocardiography

DR GEORGE A MENSAH USA (General Cardiology)

PROF B RAYNER Hypertension/Society

PROF WILLIAM NELSON USA (Electrocardiology)

PROF MM SATHEKGE Nuclear Medicine/Society PROF J KER (SEN) Hypertension, Cardiomyopathy, PROF YK SEEDAT Cardiovascular Physiology Diabetes & Hypertension

DR ULRICH VON OPPEL Wales (Cardiovascular Surgery)

DR J LAWRENSON Paediatric Heart Disease

PROF ERNST VON SCHWARZ USA (Interventional Cardiology)

PROF H DU T THERON Invasive Cardiology

PROF PETER SCHWARTZ Italy (Dysrhythmias)

CONTENTS Vol 29, No 1, JANUARY/FEBRUARY 2018

Coronary stent restenosis and the association with allergy to metal content of 316L stainless steel D Slodownik • C Danenberg • D Merkin • F Swaid • S Moshe • A Ingber • H Lotan • R Durst

Short-term rehospitalisation or death and determinants after admission for acute heart failure in a cohort of African patients in Port Harcourt, southern Nigeria MR Akpa • O Iheji

Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy K McCutcheon, P Manga

PUBLISHED ONLINE (Available on www.cvja.co.za and in PubMed)

Risk assessment of the occurrence of sudden death related to hypertrophic cardiomyopathy in Dakar [Evaluation du risque de mort subite lié à la cardiomyopathie hypertrophique à Dakar] K Babaka • SA Sarr • B Dodo • F Aw • M Bodian • MB Ndiaye • A Kane • M Diao • SA Ba

REVIEW ARTICLE

CARDIOVASCULAR TOPICS

CASE REPORTS e6

Coronary artery bypass grafting and paraparesis; is there a correlation? I Samiotis • NG Baikoussis • V Patris • M Argiriou • P Dedeilias • C Charitos

Acute type A aortic dissection involving the iliac and left renal arteries, misdiagnosed as myocardial infarction PN Tolefac • A Dzudie • S Mouliom • L Aminde • R Hentchoya • MH Abanda • CM Mvondo • VD Wanko • HN Luma

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Michael Meadon (Design Connection) Tel: 021 976 8129 Fax: 0866 557 149 e-mail: michael@clinicscardive.com

GAUTENG CONTRIBUTOR PETER WAGENAAR Cell 082 413 9954 e-mail: skylark65@myconnection.co.za The Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published 10 times a year, the publication date being the third week of the designated month. Copyright: Clinics Cardive Publishing (Pty) Ltd.

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Results were consistent across patients with or without previous hospitalisations4 For any Entresto® product related enquiries, please contact the Novartis Customer Contact Centre on 0861 929 929 CV=cardiovascular; HF=heart failure References: 1. Krim SR, Campbell PT, Desai S, et al. Management of patients admitted with acute decompensated heart failure. Oschner J. 2015;15:284-289. 2. Entresto® package insert. Novartis, South Africa; September 2017. 3. McMurray JJV, Packer M, Desai AS, et al; for PARADIGM-HF Committees Investigators. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825. 4. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 5. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248. SCHEDULING STATUS: S3 ENTRESTO® 50 mg film-coated tablets Reg. No. 50/7.6/1016; ENTRESTO® 100 mg film-coated tablets Reg. No. 50/7.6/1017; ENTRESTO® 200 mg film-coated tablets Reg. No. 50/7.6/1018 COMPOSITION: ENTRESTO® 50 mg filmcoated tablets contain 24 mg sacubitril and 26 mg valsartan. ENTRESTO® 100 mg film-coated tablets contain 49 mg sacubitril and 51 mg valsartan. ENTRESTO® 200 mg film-coated tablets contain 97 mg sacubitril and 103 mg valsartan. PHARMACOLOGICAL CLASSIFICATION: A7.6 Vascular medicines Others INDICATIONS: ENTRESTO® is indicated as a second-line therapy, replacing ACE inhibitors or ARB for treatment of symptomatic heart failure (NYHA class II-IV) in patients with systolic dysfunction. ENTRESTO® is administered in combination with other heart failure therapies as appropriate. DOSAGE AND DIRECTIONS FOR USE: Adults: • The target dose of Entresto® is 200 mg twice daily. • The recommended starting dose of Entresto® is 100 mg twice daily. • A starting dose of 50 mg twice daily is recommended for patients taking low doses of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). • Dose up titration by resembling the dose every 3 – 4 weeks is recommended until a dose of 200 mg twice daily is achieved of tolerance. Geriatric patients: Patients over the age of 65 years may have impaired renal function, therefore a lower starting dose is recommended. Pediatric patients: The safety and efficacy in paediatric patients aged below 18 years has not been established. Renal impairment: contraindicated in patients with severe impaired renal function. Hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment use of Entresto® is not recommended. METHOD OF ADMINISTRATION: for oral use. May be administered with or without food. CONTRAINDICATIONS: • Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the excipients. • Concomitant use with ACE inhibitors. Entresto® must not be administered until 36 hours after discontinuing ACE inhibitor therapy. • Known history of angioedema related to previous ACE inhibitor or ARB therapy. • Hereditary or idiopathic angioedema. • Hypertrophic obstructive cardiomyopathy. • Bilateral renal artery stenosis. • Renal artery stenosis in patients with a single kidney. • Aortic valve stenosis. • Concomitant therapy with potassium sparing diuretics such as spironolactone, triamerene, amiloride • Porphyria • Lithium therapy • Concomitant use with renin antagonists • Pregnancy and lactation • Severe renal impairment • Concomitant use with aliskiren-containing products WARNINGS AND SPECIAL PRECAUTIONS: Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Entresto® must not be administered with an ACE inhibitor or another ARB due to the risk of angioedema. Entresto® must not be initiated until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. If treatment with Entresto® is stopped, ACE inhibitor or ARB therapy must not be initiated until 36 hours after the last dose of Entresto®. • Entresto® must not be used concomitantly with aliskiren. Hypotension: If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive medicines, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Entresto® should be reduced or the product should be temporarily discontinued. Sodium and/or volume depletion should be corrected before starting treatment with Entresto®. Impaired renal function: Down titration of Entresto should be considered in patients who develop a clinically significant decrease in renal function. Hyperkalemia: Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should not be used with ENTRESTO®. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as diabetes mellitus, hypoaldosteronism or receiving a high potassium diet. Angioedema: If angioedema occurs, Entresto® should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Entresto® must not be re-administered. Patients with a prior history of angioedema were not studied. Black patients may have increased susceptibility to develop angioedema. Patients with renal artery stenosis: is contraindicated. Interactions with statins: Caution should be exercised upon co-administration with statins Pregnancy and lactation: Entresto should not be used during pregnancy or lactation. INTERACTIONS: ◊ Concomitant use contraindicated: Aliskiren, Use with ACE inhibitors. Entresto® must not be started until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto®. ◊ Caution when used concomitantly with statins, sildenafil, lithium, potassium-sparing diuretics including mineral corticoid antagonists (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium, non-steroidal anti-inflammatory agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors), inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporin) or MPR2 (e.g. ritonavir). Side effects: Very common (≥10%): Hyperkalaemia, hypotension, renal impairment. Common (1 to 10%): Anaemia, Cough, dizziness, renal failure, diarrhoea, hypokalaemia, fatigue, headache, syncope, nausea, asthenia, orthostatic hypotension, vertigo, hypoglycaemia, gastritis Uncommon (0.1 to 1%): Angioedema, postural dizziness, pruritis, rash Packs: 14, 28 or 56 tablets packed in PVC/PVDC blister packs. Note: Before prescribing consult full prescribing information

Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, 2090. Tel +27 11 3476000. Company Reg No: 1946/020671/07 For any product related enquiries, please contact the Novartis Customer Contact Centre on 0861 929 929 ZA1802773289 Exp 06/02/2019

CARDIOVASCULAR JOURNAL OF AFRICA â&#x20AC;˘ Volume 29, No 1, January/February 2018

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Editorial Appropriate strategies for South Africa for the management of acute myocardial infarction in patients presenting with ST-segment elevation Rhena Delport

Timely reperfusion Both patient and health-system delays contribute to delays in restoring myocardial perfusion. Patient-related delays constitute the time from onset of symptoms to the call for help, and onset of symptoms to first medical contact. These will not be discussed here. Of relevance are time metrics relating to â&#x20AC;&#x2DC;symptom onset to initiation of fibrinolysis or first balloon or device, and hospital door to either onset of fibrinolytic therapy (door-to-needle time) or to first balloon or device (door-to-balloon time)â&#x20AC;&#x2122;, as well as strategies that may be considered if circumstances are not ideal, as elegantly interrogated by Gershlick et al.1 Evidence-based guidelines provide clear time targets and recommendations for reperfusion therapy, as discussed in the report by Ibanez et al.,2 but in essence, primary percutaneous coronary intervention (PCI) is advocated as the primary strategy, and if not anticipated to be achievable within 120 minutes of ST-elevation myocardial infarction (STEMI) diagnosis, fibrinolysis should be initiated immediately. The study by Stassen et al., published in this edition (page 6), reports on the feasibility of PCI within the proposed time frame, while considering driving times and distances to public and private PCI facilities in different regions of South Africa.

Mortality data In the 2015 list of the 10 leading underlying natural causes of death in each province, the Western Cape (WC) ranks third, with ischaemic heart diseases (ICD-10: I20-I25) as cause of death (5.8% of all-cause deaths), followed by Gauteng (GP) ranking seventh (3% of all-cause deaths), and KwaZulu-Natal (KZN) ranking ninth (2.6% of all-cause deaths).3 Despite 100% of the inhabitants of GP living within 120 minutes of a PCI facility, calculated from mid-year population estimates for 2015,4 the proportionate mortality rate of 0.22/1 000 was higher than the mortality rate of 0.19/1 000 for KZN and markedly lower than that of 0.47/1 000 for the WC region, the respective proportions of inhabitants living within 120 minutes of a PCI facility for ST-Elevation Myocardial Infarction South Africa: National Project Manager, SA Heart Association; Department of Chemical Pathology, University of Pretoria, Pretoria, South Africa Rhena Delport, PhD, rhena.delport@up.ac.za

the latter two regions being 64.7 and 87.6%. These findings suggest that factors other than proximity to PCI facilities explain ischaemic heart disease mortality rates for South Africa.

Disparities Statistics South Africa (2011)5 reports a total medical aid coverage of 16% for the total population, the respective population covered by medical aid or medical benefit schemes or other private health insurance, and for the three aforementioned regions it is 23.7% for GP, 12.2% for KZN and 25% for WC. Access to healthcare facilities includes means of transport to reach the health facility normally used (walking: 47.4%, public transport: 29.1%, or own transport: 22.1%) and time taken to reach the health facility normally used (80% of households take less than 30 minutes to reach the health facility normally used). Information relating to type of health facility used first when household members fell ill and decided to seek medical help may be relevant when interpreting the report of Stassen et al. on the proportion of the South African population living within 60 and 120 minutes of a public PCI facility. The authors calculated that 32.6 million (63%) of the total population lived within 120 minutes of a public PCI facility, whereas in reality only 9.5% of the population purportedly used public hospitals and 2.0% used private hospitals when household members fell ill. Public sector services are sourced by 70.6% of the total population (mainly public clinic services: 61.2%) and private sector services by 27.9% (mainly private doctor services: 24.3%). Coming back to PCI services in particular, Stassen et al. previously reported that 48 (77%) PCI facilities are privately owned, whereas the 14 state-owned facilities are tasked with providing services to the population with no medical aid coverage (79.9%) and a high poverty rate (59.6%).6

Recommendations Given all these disparities, compounded by population dispersion across metropolitan and rural regions, equitable healthcare related to PCI services may be deemed questionable for South Africa. The White Paper on Management of STEMI in Lowand Middle-Income Countries by Baliga et al. 7 provides muchneeded insight into the challenges experienced in countries such as South Africa, relating, among others, to lack of essential resources and services. Clear strategies are proposed, as in the

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

contribution of Gershlick et al.,1 which may be recommended for the formulation of solutions to enable prevention or reduction in STEMI-related mortality and morbidity in South Africa.

http://www.statssa.gov.za/publications/P03093/P030932015.pdf P0302.

https://www.statssa.gov.za/publications/P0302/

P03022015.pdf 5.

Use of health facilities and levels of selected health conditions in South

ST-segment elevation myocardial infarction 1: reperfusion therapy for

Africa: Findings from the General Household Survey, 2011. Statistics

STEMI: is there still a role for thrombolysis in the era of primary percu-

South Africa. Report no. 03-00-05 (2011). http://www.statssa.gov.za/

taneous coronary intervention? Lancet 2013; 382(9892): 624–632. DOI: 10.1016/S0140-6736(13)61454-3. 2.

Mid-year population estimates 2015. Statistics South Africa. Statistical release

References Gershlick AH, Banning AP, Myat A, Verheugt FW, Gersh BJ.

Mortality and causes of death in South Africa, 2015: Findings from death notification. Statistics South Africa. Statistical release P0309.3.

publications/Report-03-00-05/Report-03-00-052011.pdf 6.

Stassen W, Wallis LA, Lambert C, Castren M, Kurland L. Percutaenous

Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the

coronary intervention still not accessible for many South Africans.

management of acute myocardial infarction in patients presenting

Afr J Emerg Med 2017; 7: 105–107. http://dx.doi.org/10.1016/j. afjem.2017.04.009.

with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation

Baliga RR, Bahl VK, Alexander T, Mullasari A, Manga P, Dec GW,

of the European Society of Cardiology (ESC). Eur Heart J 2018; 39:

Narula J. Management of STEMI in low- and middle-income countries.

119–177. https://doi.org/10.1093/eurheartj/ehx393.

Glob Heart 2014; 9(4): 469–510. doi: 10.1016/j.gheart.2014.11.001.

Conﬁdence Through Clinical and Real World Experience1-3 #1 Scripted Non-VKA Oral Anticoagulant by Cardiologists* Millions of Patients Treated Worldwide Across Multiple Indications4 REFERENCES: 1. Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fi brillation. N Engl J Med. 2011;365(10):883–91. 2. Tamayo S., Peacock W.F., Patel M.R., et al. Characterizing major bleeding in patients with nonvalvular atrial fi brillation: A pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8. 3. Camm A.J., Amarenco P., Haas S. et al. XANTUS: A Real-World, Prospective, Observational Study. 4. Calculation based on IMS Health MIDAS, Database: Monthly Sales January 2017. S4 Xarelto 15: Each film-coated tablet contains rivaroxaban 15 mg. Reg. No: 46/8.2/0111; Namibia NS2 : 12/8.2/0006; S2 Botswana: BOT1302296; Zimbabwe: PP10 Reg. 2017/10.2/5363 S4 Xarelto 20: Each film-coated tablet contains rivaroxaban 20 mg. Reg. No: 46/8.2/0112;Namibia NS2 : 12/8.2/0007; S2 Botswana: BOT1302297; Zimbabwe: PP10 Reg. 2017/10.2/5364 PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants. INDICATIONS: (1) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF); (2) Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE); (3) Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT). For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC). HCR: Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041. L.ZA.MKT.GM 06.2017.1808 © Bayer June 2017 *Impact RX Data 2016 NOAC: Non Vitamin K Oral Anticoagulant

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

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Cardiovascular Topics The proportion of South Africans living within 60 and 120 minutes of a percutaneous coronary intervention facility Willem Stassen, Lee Wallis, Craig Vincent-Lambert, Maaret Castren, Lisa Kurland

Abstract Introduction: Timely reperfusion, preferably via percutaneous coronary intervention (PCI) following myocardial infarction, improves mortality rates. Emergency medical services play a pivotal role in recognising and transporting patients with ST-elevation myocardial infarction directly to a PCI facility to avoid delays to reperfusion. Access to PCI is, in part, dependant on the geographic distribution of patients around PCI facilities. The aim of this study was to determine the proportion of South Africans living within 60 and 120 minutes of a PCI facility. Methods: PCI facility and population data were subjected to proximity analysis to determine the average drive times from municipal ward centroids to PCI facilities for each province in South Africa. Thereafter, the population of each ward living within 60 and 120 minutes of a PCI facility was extrapolated. Results: Approximately 53.8 and 71.53% of the South African population live within 60 and 120 minutes of a PCI facility. The median (IQR, range) drive times and distances to a PCI facility are 100 minutes (120.4 min, 0.7–751.8) across 123.6 km (157.6 km, 0.3–940.8).

Department of Clinical Research and Education, Karolinska Institute, Stockholm, Sweden; and Division of Emergency Medicine, Stellenbosch University, Stellenbosch, South Africa Willem Stassen, BTEMC, MPhil, stassen88@gmail.com

Division of Emergency Medicine, Stellenbosch University, Stellenbosch, South Africa Lee Wallis, MB ChB, FRCEM, MD

Department of Emergency Medical Care, University of Johannesburg, Johannesburg, South Africa Craig Vincent-Lambert, BTEMC, MEd, PhD

Department of Clinical Research and Education, Karolinska Institute, Stockholm, Sweden; and Department of Emergency Medicine and Services, Helsinki University, Helsinki, Finland Maaret Castren, MD, PhD,

Department of Clinical Research and Education, Karolinska Institute, Sweden; and Department of Medical Sciences, Örebro University, Örebro, Sweden Lisa Kurland, MD, PhD

Conclusion: Based on the proximity of South Africans to PCI facilities, it seems possible that most patients could receive timely PCI within 120 minutes of first medical contact. However, this may be unlikely for some due to a lack of medical insurance, under-developed referral networks or other system delays. Coronary care networks should be developed based on the proximity of communities to 12-lead ECG and reperfusion therapies (such as PCI facilities). Public and private healthcare partnerships should be fortified to allow for patients without medical insurance to have equal accesses to PCI facilities. Keywords: myocardial infarction, healthcare disparities, percutaneous coronary intervention, South Africa Submitted 18/5/17, accepted 14/1/18 Cardiovasc J Afr 2018; 29: 6–11

www.cvja.co.za

DOI: 10.5830/CVJA-2018-004

Ischaemic heart disease (IHD) is projected to double in incidence within sub-Saharan Africa within the next few years.1,2 For a variety of reasons, African healthcare services may not be prepared to manage these lifestyle diseases.3 ST-elevation myocardial infarction (STEMI), a time-sensitive consequence of cardiovascular disease progression, should be managed emergently in order to decrease morbidity and mortality rates.4-8 According to the American and South African Heart Associations, percutaneous coronary intervention (PCI) is the preferred method of reperfusion for STEMI, and should be performed within 120 minutes of first medical contact.4,9,10 Despite this recommendation, only 61.3% of patients who present with STEMI in South Africa receive reperfusion via PCI within 24 hours. In 34.8% of patients, the indication for PCI was failed thrombolysis.11 For patients who cannot reach a PCI facility within 120 minutes, it is recommended that reperfusion be obtained by means of thrombolytic therapy within 30 minutes of first medical contact. This could be initiated by pre-hospital emergency care providers.4 Delayed reperfusion can be attributed to: late patient presentation, protracted pre-hospital response and scene times, delays in 12-lead ECG acquisition and STEMI diagnosis, transport to non-PCI facilities requiring secondary interfacility transfer, and PCI preparation time.12-14

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To minimise these delays, it has been suggested that 12-lead ECG and STEMI diagnosis should become standard practice in the pre-hospital setting. This would allow for patients to be transported directly to a PCI facility.4 However, as outcome is linked to the time to reperfusion, the outcome benefit gained of initial transport to a PCI facility may be offset by protracted transport times to such facilities. The geographic distribution of patients and PCI facilities and their relative proximity will therefore impact on the feasibility of these recommendations, and the successful development and implementation of regional coronary care networks for patients with STEMI. The aim of this study was to determine the proportion of South Africans who live within 60 and 120 minutes of a PCI facility. To this end, we determined the driving times and distances from each municipal ward to the closest PCI facility. This can be used as a measure of access and as a guide for future development of coronary care and referral networks.

Methods We assessed timely access to PCI facilities by a series of geospatial analyses. Firstly, we determined the driving times and distances to the closest (private and/or public) PCI facility of each of the municipal wards within South Africa. Hereafter, we determined the proportion of the South African population who live within 60 and 120 minutes of these facilities, based on the

average driving times. We purposefully selected these time frames as they are in line with local and international PCI reperfusion guidelines.4,10 PCI facility availability data from a previously published cross-sectional study were utilised.15 We plotted public and private PCI facilities in turn, using the physical address of each. From here we used ArcGIS 10 and ArcGIS Online (Esri, California, United States) to plot a 60- and 120-minute drive-time polygon around each of the PCI facilities. ArcGIS calculates the drivetime polygons around created points (PCI facilities, in this case) that can be accessed within a specified time of travel from that point. These drive times are calculated using predicted typical traffic trends. Typical traffic trends for each road are determined within ArcGIS by averaging a weekâ&#x20AC;&#x2122;s real-time travel speeds in five-minute intervals. Using ArcGIS, a join was created between the current South African ward boundary lines and the 2011 population census data.16 Ward (district)-level data were used as this is the smallest geographical area available with population data, which improves accuracy of results. Ward-level data were not available for the 2016 community survey. The mathematical mid-point (centroid) of each ward was calculated and the population was added to this point on the map datasets. Proximity analysis was used to determine the projected driving time from each ward centroid to the closest PCI facility in all provinces. These driving times were again calculated

Cath labs Wards within 60 min of cath lab Wards within 120 min of cath lab Wards (2011)

Fig. 1. D rive-time polygons and wards within 60 and 120 minutes of PCI facilities (ArcGIS 10, Esri, California, United States).

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

based on the typical traffic trends for each area. These data are presented descriptively. Medians and interquartile ranges are reported as the data showed heterogeneity between provinces. Using the drive-time polygons and the ‘Select by Location’ feature of ArcGIS 10, it was possible to extract those wards whose centres fell within the 60- and 120-minute drive-time polygons.17 Integrity of the data was ensured by performing a series of manual verifications. We extracted the specific wards and their populations that fell within these polygons to determine the population who live within these referral areas. Ethical approval was obtained from the Human Research Ethics Committee of the University of Stellenbosch (HREC Ref Nr: M14/07/027).

Results

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minutes while the shortest drive is in the Free State province (0.7 minutes). Nationally, the median driving time to PCI is 100 minutes (IQR: 120.4). The closest public PCI facility (Table 4) is a median of 123.7 minutes (IQR 164.1) away. The shortest time to the closest public PCI facility is in KwaZulu-Natal (1.5 minutes away) while the furthest is in the Northern Cape (900.1 minutes away). Just over half of the population (53.8%) of South Africa live within 60 minutes of a PCI facility while 71.53% of the country’s population can reach a PCI facility within two hours (Table 5). Practically all inhabitants of the Gauteng province live within 60 minutes of PCI while 2.5% of the Northern Cape’s inhabitants are within two hours of the closest PCI facility, whether public or privately owned. When only considering public PCI facilities (Table 6), only 47.8 and 63% of the population can access these facilities within 60 and 120 minutes, respectively.

PCI facilities are concentrated around major cities and along the coastal areas of South Africa. Wards within the 60- and 120-minute drive-time polygons to PCI facilities are presented in Fig. 1. Table 1 displays the driving distances to PCI facilities in South Africa. The median driving distance to the closest PCI facility nationally is 123.6 km (IQR: 157.6 km). The Northern Cape has the longest driving distance to a PCI facility, of 940.8 km, while the shortest distance is 0.3 km in the Eastern Cape and the Free State provinces, jointly. The median driving distance to the closest public PCI facility (Table 2) is 100 km (IQR: 157.6 km), while the shortest median driving distances are in the Free State and the Gauteng provinces, jointly (0.9 km), and the furthest is in the Northern Cape (1 085 km). Table 3 displays the driving times to the PCI facilities in South Africa. The longest drive to PCI is in the Northern Cape at 751

Approximately 53.8 and 71.5% of the South African population live within 60 and 120 minutes of a PCI facility, respectively. The median distance from a PCI facility nationally is 123.6 km while the median driving time to a PCI facility is 100 minutes. In the United States, 79% of the adult population live within one hour of a PCI facility. For those living further away, 74% would be able to access a PCI facility with an additional drive of less than 30 minutes,18 well within the recommendations.4 There is currently one PCI facility for every 887 096 people in South Africa,15 which would be sufficient if every patient could access this facility within 120 minutes of first medical contact.19 This is however only achievable for 71.53% of the population. More PCI facilities are therefore needed.

Table 1. Driving distances to a PCI facility (public or private) in South Africa

Table 3. Driving times to a PCI facility (public or private) in South Africa

Province

Minimum drive distance (km)

Median drive distance (km) (IQR)

Gauteng

0.5

15.1 (15.9)

Western Cape

0.8

52.9 (110.3)

Maximum drive distance (km)

Discussion

Province

Minimum drive time (min)

Median drive time (min) (IQR)

Maximum drive time (min)

Gauteng

0.8

18.3 (13.8)

59.6

363

Western Cape

1.6

43.8 (79.3)

277.9

71.5

155.5

406.9 (305.4)

940.8

Northern Cape

300.4 (640.1)

751.8

Eastern Cape

0.3

206.9 (157.2)

395

Eastern Cape

0.8

164 (137.5)

318.6

North West

1.1

144 (162.6)

573.3

North West

3.1

115.4 (117.3)

453.6

KwaZulu-Natal

1.6

137.5 (166.6)

413.8

KwaZulu-Natal

3.0

109.8 (133.6)

345.1

Free State

0.3

140.1 (118.1)

278

Free State

0.7

103.1 (79.9)

227.0

Mpumalanga

2.0

109.7 (51.7)

313.1

Mpumalanga

4.2

94.4 (54.6)

249.2

Limpopo

2.3

132 (73.9)

342.9

Limpopo

3.5

114.1 (63.2)

344.3

South Africa

0.3

123.6 (157.6)

940.8

South Africa

0.7

100 (120.4)

751.8

Northern Cape

Table 2. Driving distances to a public PCI facility in South Africa

Table 4. Driving times to a public PCI facility in South Africa

Province

Minimum drive distance (km)

Median drive distance (km) (IQR)

Gauteng

0.9

28.7 (28.5)

90.6

Gauteng

1.7

29.1 (20.6)

68.3

Western Cape

1.4

93 (227.8)

495.6

Western Cape

3.0

77.8 (160.4)

328.7

Northern Cape

105.4

298.1 (210.9)

900.1

4.3

238.6 (127.2)

432.6

10.5

134.2 (125.8)

486.7

Northern Cape

Maximum drive distance (km)

111.7

Province

Minimum drive time (min)

Median drive time (min) (IQR)

Maximum drive time (min)

155.5

406.8 (311.6)

1085.8

Eastern Cape

2.4

302.3 (140.4)

551.7

Eastern Cape

North West

7.0

172.3 (173.9)

653.7

North West

KwaZulu-Natal

2.4

146.3 (173.8)

434.8

KwaZulu-Natal

1.5

90.9 (108)

270.2

Free State

0.9

158.3 (107.8)

301.8

Free State

1.7

112.5 (79.1)

242.9

Mpumalanga

7.4

125.5 (52.5)

320.4

Mpumalanga

12.6

102.6 (53.4)

257.8

77.0

289.2 (158.1)

607.8

Limpopo

80.8

230 (88.3)

515.2

0.9

170.7 (22.35)

1085.8

123.7 (164.1)

900.1

Limpopo South Africa

South Africa

1.5

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Table 5. Proportion of South African population living within 60 and 120 minutes of a public or private PCI facility Province Gauteng

PCI within 60 minutes n (% per province)

PCI within 120 minutes n (% per province)

Table 6. Proportion of South African population living within 60 and 120 minutes of a public PCI facility Province

12.3 mil (100)

4.44 mil (76.1)

5.1 mil (87.6)

Western Cape

4.19 mil (71.9)

4.78 mil (82)

Northern Cape

0 (0)

29 000 (2.5)

Northern Cape

0 (0)

Eastern Cape

1.96 mil (29.9)

2.68 mil (40.8)

Eastern Cape

1.22 mil (18.6)

1.48 mil (22.6)

North West

1.28 mil (36.4)

2.13 mil (60.6)

North West

0.66 mil (18.8)

1.93 mil (55)

KwaZulu-Natal

4.89 mil (47.6)

6.64 mil (64.7)

KwaZulu-Natal

4.78 mil (46.6)

6.72 mil (65.4)

Free State

0.99 mil (36.4)

1.9 mil (69.3)

Free State

0.82 mil (29.9)

1.81 mil (65.9)

Mpumalanga

0.95 mil (23.5)

3.19 mil (78.9)

Mpumalanga

0.73 mil (18.1)

3.13 mil (77.5)

Limpopo

1.06 mil (19.8)

3.04 mil (56.3)

Limpopo

37.0 mil (71.5)

mil: million.

Despite living in close proximity to PCI facilities, only 61.3% of STEMI patients receive PCI within 24 hours.11 This might suggest that larger system problems contribute to further delays.12-14 Access is not simply a product of proximity, but also of socio-economic status and other demographic factors.3,15,20-22 Low-income patients living in rural areas and those without medical insurance experience the greatest barriers to accessing healthcare services.20 In South Africa, 77% of all the PCI facilities are owned by the private healthcare sector and can therefore only be utilised by 18.1% of the population,15 unless upfront payment of up to $3500 (~R50Â 000) is made.15 When we consider this, the proportion of South Africans who can access PCI within 60 (53.8%) and 120 minutes (71.53%) is an over-estimation, as access is often limited to insurance status. In South Africa, the median driving times for uninsured patients to the closest public PCI facility are 123.7 minutes across 170.7 km, while only 47.8% and 63.0% of the population can access these facilities in 60 and 120 minutes respectively. It is recommended that patients who experience symptoms of myocardial infarction be transported to hospital via emergency medical services (EMS) so that suitably qualified pre-hospital emergency care providers can start treatment and manage any complications that might arise.4 Locally, the majority of patients seem to be transported privately.12-13 Reasons for this include unfamiliarity with emergency numbers, poor and unreliable response times of EMS, or lack of understanding of the value of EMS use in myocardial infarction.12 Mistrust in the EMS is not unfounded as up to 95% of urban and 68% of rural high-acuity responses are not serviced within 15 and 40 minutes, respectively.23 One study has shown that in 16.7% of responses, public ambulances may take more than 12 hours to arrive in certain rural areas of the country.24 In Africa, EMS systems are often informal with unreliable coverage.25 Ambulance transport may not always be feasible for Africans with STEMI,25 and pre-hospital delays can have significant effects on the reperfusion times of patients regardless of their proximity to a PCI facility.26 For patients who cannot reach a PCI facility timeously, pre-hospital thrombolysis is recommended.4 At present, only emergency care practitioners who hold a bachelor degree qualification can administer pre-hospital thrombolysis in South Africa.27,28 Recommendations are that, should pre-hospital thrombolysis be considered, it should be performed within a well-developed coronary care network that can manage failed

Total, n (% SA)

12.27 mil (99.7)

PCI within 120 minutes n (% per province)

12.27 mil (99.7)

27.86 mil (53.8)

Gauteng

PCI within 60 minutes n (% per province)

Western Cape

Total, n (% SA)

12.27 mil (99.7)

6 000 (0.1)

0.26 mil (4.9)

24.6 mil (47.8)

32.6 mil (63.0)

mil: million.

thrombolysis and other complications.28 We found that most PCI facilities are concentrated in the urban areas. Unfortunately, within our setting, there is misdistribution of advanced life support (ALS) paramedics, with most practicing in urban areas.29 Steps should be taken to promote recruitment, deployment and retention of paramedics in these rural areas. The utilisation of helicopter emergency medical services (HEMS) has been suggested to improve the reperfusion times30 of STEMIs and to deliver ALS care to patients in rural areas.31 Considering the shortage of ground-based ALS, HEMS may be a feasible option for delivering pre-hospital thrombolysis to many remote communities, however, the benefit of this resource should be offset by its cost burden in the context of low- and middle-income countries such as South Africa.31 Further to this, activation of HEMS should be subject to confirmed STEMI diagnosis by on-scene providers. Until now, 12-lead ECG acquisition and interpretation has been a skill reserved only for ALS providers.27 Pre-hospital 12-lead ECG acquisition and interpretation has also been extended to the mid-level EMS worker (emergency care technicians), which may expedite STEMI diagnosis and decrease reperfusion times.32 Upskilling in this regard may be required, as studies have shown that a delay in reperfusion may occur when inexperienced providers doubt the ECG diagnosis.12 Pre-hospital 12-lead ECG telemetry has been applied in developed countries and may be used to expedite reperfusion.33 A randomised, controlled trial was undertaken in 2016 in South Africa to determine the application of 12-lead ECG telemetry in this context (pers commun).

Limitations This study has some important limitations. Drive-time polygons were generated based on typical (average) driving times and traffic conditions. Response and ambulance scene times, which may prolong the pre-hospital time, were not taken into consideration. In addition, for patients not utilising ambulance transport to hospital, time to access private or public transport was not taken into consideration. Census data from 2011 was used as the 2016 community survey data from Statistics South Africa provide population data only up to municipal level, as the sample size does not allow for analysis at ward level. Again it is essential to reiterate that expressing access in this study assumes that any patient can be treated at any facility.

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However, in practice most facilities (77%) are only accessible to the 18% of patients with medical insurance.15,34 Using epidemiological and geospatial data, formal referral networks and guidelines could be developed that are contextual to each specific region within South Africa (and Africa), and that take into consideration the specific resources available and the proximity to these resources. In addition, it is essential to establish what the capacity and role of EMS is within the African context to improve reperfusion times for patients suffering myocardial infarctions.

Conclusion

11. Schamroth C, ACCESS South Africa Investigators. Management

McNamara RL, Wang Y, Herrin J. Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2006; 47: 2180–2186. PMID: 16750682, DOI: 10.1016/j. jacc.2005.12.072.

De Luca G, Suryapranata H, Ottervanger J, Antman E. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 2004; 109(10): 1223– 1225. PMID: 15007008, DOI: 10.1161/01.CIR.0000121424.76486.20.

10. SAMA/Acute Coronary Syndrome Working Group. Management of acute coronary syndromes clinical guideline. S Afr Med J 2001; 91(10.2):879–895.

Up to 72% of South Africans live within two hours of a PCI facility, but timely access may not be possible because of insurance status or other system delays. The incidence of ischaemic heart disease is on the increase in South Africa. In order to prepare for this epidemiological transition, there is a pressing need to develop coronary care networks to provide emergency care for these patients. Development of coronary care networks should be prioritised by policy makers and tailored to the specific proximity to 12-lead ECG, thrombolysis or PCI of each community.

of acute coronary syndrome in South Africa: insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry. Cardiovasc J Afr 2012; 23(7): 365–370. PMCID: PMC3721828, DOI: 10.5830/CVJA-2012-017. 12. Meel R, Gonçalves R. Time to fibrinolytics for acute myocardial infarction: Reasons for delays at Steve Biko Academic Hospital, Pretoria, South Africa. S Afr Med J 2015; 106(1): 92–96. PMID: 26792315, DOI:10.7196/SAMJ.2016.v106i1.9801. 13. Snyders A, Delport R. Referral pathways for reperfusion of STEMI – developing strategies for appropriate intervention. SA Heart 2015; 12(2): 74–80. 14. Peterson MC, Syndergaard T, Bowler J, Doxey R. A systematic review

The authors acknowledge Matthew Rosenberg for his expert consultation

of factors predicting door to balloon time in ST-segment eleva-

with ArcGIS on this project.

tion myocardial infarction treated with percutaneous intervention. Int J Cardiol 2012; 157(1): 8–23. PMID: 21757243, DOI: 10.1016/j.

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Nutrition advice aimed at children also improves parents’ diets Nutrition advice aimed at children also improves parents’ diets, according to research published recently in the European Journal of Preventive Cardiology. ‘Diets high in unsaturated fat and low in saturated fat have been associated with a reduced risk of cardiovascular events and death in adults,’ said lead author Dr Johanna Jaakkola, a postdoctoral researcher at the University of Turku, Finland. ‘Very little is known about the long-term effects of nutrition advice for children on the diets and health of parents.’ The longitudinal randomised Special Turku Coronary Risk Factor Intervention Project (STRIP) decreased the saturated fat intake and improved the cardiovascular health of children by recommending foods rich in unsaturated instead of saturated fat. The current study examined whether the long-term dietary intervention focused on children was also associated with parental dietary intake and cardiometabolic risk factors over two decades of follow up. The primary results of the STRIP study have been previously reported. Briefly, the study included 1 107 infants and their parents who were recruited from well-baby clinics in Turku, Finland, between 1989 and 1992. Families were randomly assigned to the dietary intervention (562) or control (545) groups. The intervention group received dietary counselling at least once a year by a nutritionist from the child’s age of eight months to the age of 20 years. Counselling was first given only to the parents, and from the age of seven years, the children were also met alone. The main focus of the dietary intervention was to reduce the child’s intake of saturated fat and concomitantly increase the child’s unsaturated fat intake. As previously reported, the repeated dietary counselling led to decreased saturated fat intake in the intervention children, and lower serum low-density lipoprotein (LDL) cholesterol concentration from infancy until 19 years of age. For the current study, parental dietary intake was assessed

by a one-day food record biennially from the child’s age of nine to 19 years. Weight and height, and blood pressure, serum lipid, glucose and insulin levels of the parents were measured repeatedly from the child’s age of seven months until 20 years. The investigators found that the child-oriented dietary counselling increased the intake of polyunsaturated and monounsaturated fats and decreased the saturated fat intake of intervention mothers and fathers compared to control parents between the child’s ages of nine and 19 years. In addition, the child-oriented dietary counselling tended to decrease serum total and LDL concentrations in intervention mothers compared to control mothers. There was a similar trend in fathers but it was not statistically significant. Dr Jaakkola said: ‘The child-oriented dietary intervention contributed advantageously to the parental diet in the long term and tended to reflect lipid concentrations, particularly in mothers. Presumably all family members eat the same foods and therefore child-oriented dietary counselling also affects parents’ diets.’ ‘“Dietary intake may have been more strongly associated with maternal than paternal serum lipid levels because mothers might have more actively participated in the study and complied better with the diet,’ she continued. ‘There is also the possibility that the improvement in the fathers’ diets was not strong enough to cause a statistically significant difference in serum lipid levels.’ Dr Jaakkola concluded: ‘Our study emphasises that long-term dietary counselling directed at children may be an efficient way to also improve the diets of parents. These findings could be used to plan public health counselling programmes.’ Source: European Society of Cardiology Press Office

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Reinforcement of suture lines with aortic eversion in aortic replacement Erhan Kaya

Abstract Background: In this study, we describe the technique of eversion of the native aortic tissue to prevent suture line complications, and report on our results with this technique. Methods: A total of 42 patients who were operated on due to aortic aneurysm were retrospectively assessed. In all patients, an aortic segment of approximately 2 cm, which was left both distally and proximally, was everted to form a doublelayer lumen and the grafts were anastomosed. Postoperative outcomes and long-term follow-up results were assessed. Results: Aortic root replacement was done in 14 cases and eight subjects underwent concurrent coronary artery bypass surgery. Postoperatively, the average volume of the drainage was 375 ± 75 ml, and there were no re-operations. Twentyseven patients required blood transfusion. Conclusion: Reinforcement of the anastomosis line via eversion of the native aortic tissue reduced peri-operative blood loss and pseudo-aneurysm and infection, with the advantage of using viable tissue. Keywords: suture technique, ascending aortic aneurysms, dissection, pledgetted Submitted 4/5/16, accepted 12/1/17 Published online 16/1/18 Cardiovasc J Afr 2018; 29: 12–15

www.cvja.co.za

DOI: 10.5830/CVJA-2017-008

Bleeding at the suture line may be severe enough to necessitate re-do cardiopulmonary bypass in patients undergoing surgical prosthetic graft replacement due to aortic dissection or aneurysm. Various techniques have been reported in an effort to prevent this complication, including the use of pledgetted stitches and/ or bands during anastomosis, placement of additional sutures, use of interrupted pledgetted sutures in the posterior region, use of pledgetted sutures together with aortic inversion, use of bands, inclusion of the graft within the graft, or the use of tissue fibrinogen activators after anastomosis.1-4 The inflammatory response to foreign pledgetted material or adhesions associated with the use of fibrin tissue adhesives may increase the risk of infection in the long term or may complicate dissection when re-operation is necessary. On the other hand, external eversion of the aortic tissue at the site of anastomosis to obtain a double-layered lumen to reinforce the suture line may offer an alternative to pledgetted sutures or bands, allowing minimal use of foreign material, preservation of tissue viability Private Pendik Regional Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey Erhan Kaya, MD, drerhankaya@yahoo.com

at the suture line, and reducing the early risk of bleeding and long-term risk of infection. In this study, we present our results of a group of patients who underwent ascending aortic tube graft replacement with eversion of the aortic tissue in the stump and minimal or no use of pledgetted sutures/bands to avoid postoperative bleeding, pseudo-aneurysm and infection.

Methods Patients undergoing surgery due to ascending aortic aneurysm between 1 May 2014 and 31 December 2015 in our unit were included in this retrospective study. Forty-two patients with a diagnosis of ascending aortic aneurysm underwent surgery in this period. During surgery, aortic tissue was everted without the use of pledgetted sutures or bands in all patients undergoing distal anastomosis, as well as in all patients undergoing proximal anastomosis with tube graft interposition only. In those undergoing aortic root surgery, aortic tissue was everted on the non-coronary site of the proximal anastomosis, while Teflon band reinforcement was done on the right and left coronary sides in those subjects lacking adequate tissue for eversion. All procedures were performed under general anaesthesia and cardiopulmonary bypass with a median sternotomy. The right axillary artery was used for cannulation in all patients. During surgery, arterial cannulation was performed through the right axillary artery in all patients, while antegrade cerebral perfusion and the open-anastomosis technique were used during distal anastomosis. Except for one patient who had mitral valve repair with bicaval venous cannulation, and another who underwent atrial septal defect (ASD) closure, venous cannulation was performed with a single venous cannula from the right atrium in all patients. Left heart decompression was achieved via the right superior pulmonary vein and left atrial vent. After cross-clamping at the distal ascending aorta, cardiac arrest was achieved with blood cardioplegia through the aorta in patients with aortic sufficiency, while in those with aortic valve insufficiency, initial cardioplegia was achieved with the retrograde coronary sinus route, followed by selective coronary ostia after aortotomy. In all patients, myocardial protection was maintained continuously via the coronary sinuses after antegrade cardioplegia. After opening the aneurysmal sac, it was transected proximally and distally, while care was taken to leave approximately 2 cm of aortic tissue, allowing eversion at both ends. Similarly, in patients undergoing coronary re-implantation, aortic tissue adequate for eversion was left intact proximally on the non-coronary side. In our unit, we perform re-implantation of the coronary ostia by leaving a wide margin of aortic tissue around the coronary ostia, using the eversion technique. A proximal anastomosis was then performed by placing the sutures first through the double-

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Fig. 1. A : We left 2 cm of aortic tissue to allow for eversion of the aorta. B: Double-layered aortic tissue is prepared by everting and suturing 2 cm of aortic tissue. C: Proximal anastomosis is performed using continuous 4/0 prolene sutures. D: View of the ascending aorta after proximal anastomosis. E: In the aortic root replacement, double-layered aortic tissue is prepared at the coronary buttons. F: View of the aorta after coronary anastomosis.

layered aortic tissue, then through the graft, using continuous 4/0 prolene sutures without pledgetted sutures or band. In those undergoing aortic root replacements, adequate native aortic tissue was left in the non-coronary sinus area, allowing eversion, while the anastomosis in the right and left coronary sinus area was performed with reinforcement from a Teflon band, since there was insufficient aortic tissue to allow for eversion. After proximal aortic anastomosis, the coronary arteries were anastomosed to the graft by eversion of the excess aortic tissue in the button (Fig. 1). Subsequently, cardioplegia was administered through a needle over the graft to check bleeding at the proximal anastomosis line and the coronary implantation suture lines (Fig. 2). A clamp was then placed on the innominate artery and the cross-clamp was removed. The aortic tissue was everted to accomplish the distal anastomosis of the graft under antegrade cerebral perfusion and mild hypothermia. In patients with additional cardiac pathologies, aortic replacement was completed after the surgical procedure for the cardiac pathology had been carried out. In patients undergoing aortic root replacement with a valved conduit, a modified Bentall procedure with flanged graft was used, as we believe that this approach may help reduce the risk of tissueâ&#x20AC;&#x201C;prosthesis incompatibility as well as the risk of bleeding, in addition to shortening the duration of anastomosis.5 When simultaneous coronary bypass surgery was done, proximal anastomoses were

Fig. 2. Control of bleeding with administration of cardioplegia via a needle over the graft.

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performed during the warming phase after ascending aortic tube graft implantation. After cardiopulmonary bypass (CPB) was terminated, the surgery was completed with haemostatic control.

Statistical analysis Statistical assessments were performed using Microsoft Excel software. All numerical data are presented as mean ± standard error, while categorical variables are presented as percentages.

Results The mean age of the patient group was 58 ± 2 years and 54.8% of the study population was male. Demographic characteristics and pre-operative data of the study patients are shown in Table 1. Aortic root replacement was performed in 14 patients. Four received surgical valvular repair, and a total of 18 patients underwent aortic valve replacement, including a modified Bentall procedure with flanged grafts in 10 patients (Table 2). The mean CPB and cross-clamp times were 80 ± 18 and 53 ± 18 minutes, respectively. The mean postoperative drainage volume was 375 ± 75 ml. The mean transfusion rate of erythrocyte suspension was 1.1 ± 0.3 units (Table 3). No patient required revision surgery and the average duration of hospital stay was 7.9 ± 1.4 days.

Discussion Among cardiac operations, aortic surgery is generally associated with higher volumes of blood loss due to a number of factors, including thinned, atherosclerotic, calcific or fragile aortic tissue, and also due to re-implantation of the coronary arteries. Following an anastomosis, bleeding occurring posteriorly poses a particular challenge since it may require re-initiation of CPB. Different methods have been reported to reduce the risk of postoperative bleeding in these patients.1-4 In our practice, autogenous aortic tissue is generally used to reduce the risk of bleeding based on the advantage of tissue continuity. Also, easier control of bleeding with additional sutures on the native aortic tissue represents an additional benefit of this approach. We therefore perform anastomosis after obtaining double-layered aortic tissue with eversion of the autogenous aorta. Among our 42 patients undergoing ascending aorta replacement using this technique, no complications occurred and Table 1. Pre-operative demographical data of the patients Variable Age (mean ± SD)

Value

there were no cases requiring re-operation. The average drainage volume was 375 ml. No cases of postoperative morbidity/ mortality associated with pseudo-aneurysms, complications due to the use of foreign materials, or bleeding were recorded. Prolonged CPB, hypothermia and administration of heparin are associated with an increased risk of postoperative bleeding in patients undergoing cardiac surgery,6 leading to increased requirement for transfusion, with a subsequent increase in the risk of infection, anaphylaxis and renal/pulmonary injury.6 With this technique as described above, an average of 1.1 ± 0.3 units of erythrocyte suspension were transfused in approximately two-thirds of our patients. Pseudo-aneurysms may arise at the suture line after ascending aorta graft replacement, or infections may cause dehiscence at the suture line,7-10 elevating the risk of mortality and need for re-operation. Higuchi et al.11 reported lower risk of bleeding using continuous sutures for anastomosis after the inclusion of a 7-cm segment of Dacron tube graft, folded with three sutures to achieve a double-layered structure. However, this approach may be expected to increase the early risk of thrombosis formation in the graft as well as embolic risk, since the contact surface between the synthetic graft material and the aorta is increased. On the other hand, the method described above, involving eversion of the autogenous aortic tissue would not only reduce the amount of intra-luminal tissue, but would also exploit the advantage of using autogenous tissue. Use of as much viable tissue as possible during graft replacement may also hasten the postoperative healing process at the suture lines, reducing the risk of pseudo-aneurysm. Ohata et al.3 reported the use of a graft interposition technique in which the aortic tissue is folded inside, leaving a felt band in the outer layer. In this technique, continuous prolene sutures were preferred, and in contrast with our approach, the Table 2. Surgical procedures Variable

Value

Ascending aortic repair without valve procedure

Ascending aortic repair with valve procedure

Bentall procedure

David operation

Separated graft interposition

Concomitant surgical intervention AVR

CABG

Mitral valve repair

ASD repair

AVR: aortic valve replacement, CABG: coronary artery bypass grafting, ASD: atrial septal defect.

58.2 ± 13.9

Male, n (%)

23 (54.8)

Hypertension, n (%)

21 (50)

Diabetes, n (%)

1 (2.3)

Chronic renal failure, n (%)

0 (0)

COPD, n (%)

6 (14.2)

Coronary artery disease, n (%)

8 (19)

History of CVA, n (%)

2 (4.8)

Re-operation, n (%)

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1 (2.3)

Pre-operative EF (%) (mean ± SD)

58.2 ± 13.8

Aortic insufficiency, n (%)

22 (52.4)

SD: standard deviation, EF: ejection fraction, COPD: chronic obstructive pulmonary disease, CVA: cerebrovascular accident.

Table 3. Surgical findings Variable

Value

Duration of cross clamp, min (mean ± SD)

52.9 ± 17.7

Duration of cardiopulmonary bypass, min (mean ± SD)

79.8 ± 18.5

Drainage, ml (mean ± SD)

375 ± 75

Revision, n Erythrocyte replacement, units (mean ± SD) Duration of intubation, hours (mean ± SD) Postoperative EF, % (mean ± SD) Duration of hospitalisation, days (mean ± SD) SD: standard deviation, EF: ejection fraction.

0 1.1 ± 0.3 5.3 ± 1.1 54.8 ± 6.3 7.9 ± 1.4

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graft was approximated to the aorta using four mattress sutures. Use of Surgicel to prevent bleeding at the suture line during surgery may lead to a pressure effect on the coronary artery, while tissue adhesives may compress coronary ostia from the outer surface and lead to ischaemia, embolism, necrosis of the aortic tissue and prosthetic valve dysfunction.3,12 Wrapping with bovine pericardium has also been proposed for bleeding control at the suture lines.12 Graft infection in the ‘dead space’ has been reported, even with wrapping using autogenous aortic tissue in ascending aortic grafting.13 The infection risk due to the formation of a potential dead space between the two grafts, as well as the degree of inflammation caused by the wrapping of a synthetic graft using a second biological graft are currently unknown. When there is no adequate space for cross-clamping in ascending aortic lesions, antegrade perfusion with axillary artery cannulation may be reliably used.14 In order to achieve better exposure of the distal anastomosis and to perform aortic tissue eversion, we prefer an open anastomosis technique for the distal anastomosis, using selective cerebral perfusion via the axillary artery in all cases. Using this approach, there were no postoperative complications. This study has the obvious limitations of retrospective studies. All data were obtained from medical records. Since we routinely perform reinforcement of suture lines with aortic eversion in ascending aortic surgery, there was no control group. Prospective, randomised studies are needed to improve our results.

References 1.

Pratali S, Milano A, Codecasa R, De Carlo M, Borzoni G, Bortolotti U. Improving hemostasis during replacement of the ascending aorta and aortic valve with a composite graft. Tex Heart Inst J 2000; 27: 246–249.

Schäfers HJ, Kunihara T. Towards safer reoperations: special aspects in aortic dissection. Eur J Cardiothorac Surg 2008; 33: 700–702.

Ohata T, Miyamoto Y, Mitsuno M, Yamamura M, Tanaka H, Ryomoto M. Modified sandwich technique for acute aortic dissection. Asian Cardiovasc Thorac Ann 2007; 15: 261–263.

Tamura N, Komiya T, Sakaguchi G, Kobayashi T. ‘Turn-up’ anastomotic technique for acute aortic dissection. Eur J Cardiothorac Surg 2007; 31: 548–549.

Kirali K, Mansuroğlu D, Omeroğlu SN, Erentuğ V, Mataraci I, Ipek G, et al. Five-year experience in aortic root replacement with the flanged composite graft. Ann Thorac Surg 2002; 73: 1130–1137.

Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thorac Surg 2009; 88: 1377–1383.

Isik O, Ertugay S, Akyuz M, Ayık MF, Atay Y. An unusual late complication associated with the Bentall procedure: pseudoaneurysm caused by button total detachment and aorto-right atrial fistula. Turk Gogus Kalp Dama 2014; 22: 636–638.

Mohammadi S, Bonnet N, Leprince P, Kolsi M, Rama A, Pavie A, et al. Reoperation for false aneurysm of the ascending aorta after its prosthetic replacement: surgical strategy. Ann Thorac Surg 2005; 79: 147–152.

Luciani N, De Geest R, Lauria G, Farina P, Luciani M, Glieca F, et al. Late reoperations after acute aortic dissection repair: single-center experience. Asian Cardiovasc Thorac Ann 2015; 23: 787–794.

10. Ikizler M, Gultekin B, Sezgin A, Tasdelen A. Ruptured pseudoaneurysm into the right ventricle outflow tract after ascending aorta replace-

Conclusion In ascending aortic surgery, the thin, fragile aorta is subjected to eversion to obtain a double-layered tissue. In this technique using viable aortic tissue, the risk of bleeding, pseudo-aneurysms and dehiscence are reduced. The ascending aortic anastomosis technique with aortic eversion is a simple procedure that may be reliably preferred in aortic surgery, with reduced postoperative complication rates.

ment. Turk Gogus Kalp Dama 2004; 12: 271–273. 11. Higuchi K, Takamoto S. Graft anastomosis technique in the fragile aorta. Asian Cardiovasc Thorac Ann 2013; 21: 628–630. 12. Keshavamurthy S, Mick SL, Damasiewicz H, Sabik JF 3rd. Bovine pericardial wrap for ıntractable bleeding after graft replacement of the ascending aorta. Ann Thorac Surg 2015; 100: 735–737. 13. Altarabsheh SE, Deo SV, Berbari E, Park SJ. Prosthetic graft infection, five years after ascending aortic replacement. J Card Surg 2012; 27: 220–221. 14. Sanioglu A, Sokullu O, Yapici F, Yilmaz M, Arslan Y, Hastaoglu O, et

The authors gratefully acknowledge the assistance provided by Temucin

al. Axillary artery cannulation in surgery of the ascending aorta and the

Noyan OGUS in drawing the figures.

aortic arch. Turk Gogus Kalp Dama 2007; 15: 197–201.

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Value of transluminal attenuation gradient of stress CCTA for diagnosis of haemodynamically significant coronary artery stenosis using wide-area detector CT in patients with coronary artery disease: comparison with stress perfusion CMR Hee Yeong Kim, Hwan Seok Yong, Eung Ju Kim, Eun-Young Kang, Bo Kyoung Seo

Abstract Introduction: This study aimed to evaluate the value of transluminal attenuation gradient (TAG) of stress coronary computed tomography angiography (CCTA), using a widearea detector CT in patients with coronary artery disease, compared to stress perfusion cardiac magnetic resonance (CMR) imaging. Methods: This prospective study from May 2012 to January 2015 included 21 patients with moderate coronary stenosis on invasive coronary angiography. All patients underwent adenosine stress single-shot CCTA with a rest CCTA scan using a wide-area detector CT. Coronary artery stenosis was evaluated on both stress and rest CCTA images, and TAG was manually obtained for all vessels. Stress perfusion CMR was used as a reference standard. A TAG cut-off value of –15.1 HU/10 mm was applied for diagnosing haemodynamically significant stenosis. The diagnostic accuracies of TAG and CMR were estimated and compared. Results: TAG of stress CCTA in all coronary arteries had a sensitivity, specificity, and positive and negative predictive values of 90.5, 90.0, 86.4 and 93.1%, respectively. Corresponding values for TAG of rest CCTA in all coronary arteries were 42.9, 83.3, 64.3 and 67.6%, respectively, whereas those for TAG of coronary arteries with moderate stenosis on stress CCTA were 93.3, 100, 100 and 92.3%, respectively. Mean effective radiation doses for stress and rest CCTA were 10.6 ± 2.6 mSv and 2.3 ± 1.3 mSv, respectively.

Department of Radiology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea Hee Yeong Kim, MD, PhD

Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea Hwan Seok Yong, MD, PhD, yhwanseok@naver.com Eun-Young Kang, MD, PhD

Division of Cardiology, Cardiovascular Centre, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea Eung Ju Kim, MD, PhD

Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea Bo Kyoung Seo, MD, PhD

Conclusions: TAG of CCTA provided high diagnostic accuracy for detecting haemodynamically significant coronary artery stenosis. TAG of stress CCTA was more diagnostically accurate, especially in coronary arteries with moderate stenosis. Keywords: coronary artery disease, transluminal attenuation gradient, computerised tomography, magnetic resonance imaging Submitted 25/4/16, accepted 1/5/17 Cardiovasc J Afr 2018; 29: 16–21

www.cvja.co.za

DOI: 10.5830/CVJA-2017-026

Coronary computed tomography angiography (CCTA) is increasingly used as a non-invasive diagnostic imaging tool for the detection and exclusion of coronary artery disease (CAD).1,2 However, a well-recognised limitation of CCTA is its moderate ability to assess the haemodynamic significance of a given coronary stenosis.3 Other modalities, such as singlephoton emission computerised tomography (SPECT), cardiac magnetic resonance (CMR) imaging, invasive fractional flow reserve (FFR), CT-derived computed fractional flow reserve (CT-FFR), or CT myocardial perfusion (CTP) can predict haemodynamically significant coronary artery stenosis or myocardial ischaemia. However, CTP imaging may require additional iodinated contrast and radiation exposure,4,5 and the analysis of CT-FFR data requires a large amount of time on a parallel supercomputer,6 even though these modalities were developed in an attempt to improve the diagnostic accuracy of CCTA. Recently, the transluminal attenuation gradient (TAG), defined as the contrast opacification gradient along the length of a coronary artery on CCTA, has been suggested as a tool for detecting haemodynamically significant coronary artery stenosis. TAG combines anatomical and functional information to enable appropriate therapeutic decisions regarding CAD. Preliminary data suggest that TAG provides additional functional information to CCTA.7,8 This method may represent a simple and useful test to differentiate individuals who will or will not benefit from revascularisation. Choi et al.8 reported that TAG could provide information about the functional significance of coronary artery stenosis. However, that study was performed with a 64-slice multi-detector row scanner. Although a subsequent study was performed with a

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320-detector row CT scanner, rest CCTA was performed without stress CCTA.7 A further study performed both stress and rest CCTA scans with a 320-detector row CT scanner,9 but the rest CCTA scan was followed by a stress CCTA scan. All of these studies used invasive FFR as the reference standard. Invasive FFR is a well-established and highly accurate method for assessing the functional significance of coronary artery stenosis; however, it is limited by its invasive nature. Stress perfusion CMR is a well-established and highly accurate non-invasive method used to assess the functional significance of coronary artery stenosis. Therefore, we designed a study protocol based on CCTA using a wide detector in which a stress scan was followed by a rest scan, and stress perfusion CMR was used as a reference standard. The aim of this study was to determine whether TAG could be valid for detecting haemodynamically significant coronary artery stenosis using wide-area detector CT, compared to the reference standard of stress perfusion CMR as a reference standard.

Methods This prospective study was approved by the institutional review board. Informed consent was obtained from all subjects prior to examination. From May 2012 to January 2015, all patients with moderate coronary artery stenosis (50–70%) detected on invasive coronary angiography (ICA), who were required to undergo haemodynamic significance testing were enrolled, and underwent adenosine stress CCTA and stress perfusion CMR. Exclusion criteria included a history of coronary artery bypass graft surgery or other cardiac surgery, myocardial infarction (MI) or heart failure, atrial fibrillation, second- or third-degree atrioventricular block, impaired renal function, symptomatic asthma, pregnancy or any contra-indications to iodinated contrast agents, or other any MR imaging contra-indication.

Stress CCTA protocol All patients were scanned on a wide-area detector CT scanner (Aquilion ONE, Toshiba Medical System, Otawara, Japan) with 320-detector rows (each 0.5-mm wide) and a gantry rotation time of 350 ms. The entire heart was imaged in a single heart beat with a maximum of 16-cm coverage in the Z direction. After intravenous adenosine infusion (140 µg/kg/min for three minutes; Denosin injection 90 mg/30 ml; BC World Pharm Co, Ltd, Seoul, Korea), stress CCTA was performed using the biphasic injection method (Fig. 1). A 60-ml bolus of iodinate contrast (lobitridol, Xenetics 350; Guerbet, Paris, France) was

Pre-scan

3 min 2 min 45 sec

Beta blockade, ECG monitoring

Scout images

Adenosine infusion

15 sec

IV contrast

injected intravenously, followed by a 50-ml saline chaser at a flow rate of 5 ml/s. To identify the optimal phase of contrast enhancement for adenosine stress CCTA, we performed a 10-second dynamic scan 15 seconds after initiating contrast injection.10 All scans used prospective electrocardiogram (ECG) gating that covered phases 30–50% of the R-R interval. Rest CCTA was performed 10 min after adenosine stress CCTA. The rest scan was acquired during the injection of 50 ml of iodinate contrast, followed by 50 ml of saline at a flow rate of 5.0 ml/s. The phase window was set at 30–50% of the R-R interval in patients with a heart rate (HR) ≥ 75 beats per minute (bpm), and 65–85% of the R-R interval in patients with a HR < 75 bpm. For most cases, prospective ECG gating covering 65–85% of the R-R interval was used.

Stress perfusion CMR protocol CMR was performed using a 3.0-T unit (Magnetom Skyra; Siemens, Erlangen, Germany) with an 18-channel body coil. The imaging protocol consisted of three parts: ciné imaging for ventricular volume and function; first-pass contrast-enhanced myocardial perfusion imaging during adenosine-induced stress and under resting conditions; and myocardial delayed enhancement imaging. For the perfusion study, adenosine was injected as described for the CCTA protocol, after which 0.05 mmol/kg of gadoliniumbased contrast material (gadoterate meglumine, Dotarem; Guerbet, Villepinte, France) was injected intravenously at an injection rate of 3 ml/s, followed by a 25-ml saline flush. Firstpass stress myocardial perfusion imaging of three short-axis imaging planes positioned in the base, mid and apical myocardial segments of the left ventricle was performed using a saturationrecovery turbo-fast low-angle shot (FLASH) gradient echo sequence. Fifteen minutes after stress perfusion imaging, rest perfusion images were acquired after a second bolus of 0.1 mmol/kg gadolinium-based contrast was injected.

Analysis of CCTA and CMR imaging Adenosine stress CCTA data and stress perfusion CMR images were reviewed by two experienced readers (six and 16 years of experience with CCTA and CMR), blinded to the ICA results. Three major coronary arteries per patient were evaluated. TAG was manually obtained for each vessel using an image postprocessing workstation (Vitrea 6.4; Vital Images, A Toshiba Medical Systems Group, Minnetonka, MN, USA), following the method described by Wong et al.7

Dynamic stress scan

Waiting for HR to baseline

Rest scan

10 sec

10 min

Coronary CTA

Adenosine infusion ceased

IV contrast

Time

Fig. 1. C CTA protocol. After a 3-min intravenous adenosine infusion, contrast-enhanced stress CCTA was acquired, followed by a rest CCTA after 10 minutes. CCTA = coronary computed tomography angiography.

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The centre line was determined for each major coronary artery, and cross-sectional images perpendicular to the vessel centre line were subsequently reconstructed. The region of interest (ROI) contour (size = 1 mm2) was positioned in the centre of each crosssectional image. The mean luminal radiological attenuation (in Hounsfield units, HU) was measured at 5-mm intervals from the ostium to a distal level where the vessel cross-sectional area fell below 2.0 mm2. TAG was determined from the change in HU per 10-mm length of the coronary artery and defined as the linear regression coefficient between intraluminal radiological attenuation (HU) and distance from the ostium (mm).7,8 A TAG cut-off value of –15.1 HU/10 mm was defined as significant, as previously described.7 The TAGs of all coronary arteries and of coronary arteries with moderate stenosis were calculated on stress and rest CCTA scans, and the TAG results were compared with perfusion defects detected on CMR images.

Radiation dose estimation of coronary CTA The effective radiation dose of CCTA was calculated by multiplying the dose–length product (DLP) by the conservative constant k (k = 0.014 mSv/mGy/cm), according to standard methodology outlined in the European guidelines on quality criteria for computed tomography.11

Statistical analysis All continuous variables are expressed as means ± standard deviations, whereas categorical data are expressed as percentages. The diagnostic accuracy of CT-TAG for the detection of perfusion defects was assessed using CMR as the reference standard. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated and 95% confidence intervals (CI) were reported for each parameter, which were bias-adjusted by bootstrap resampling with replacement 200 times from the sample. Calculations were performed on both an individual coronary vessel and individual patient basis. All reported diagnostic values were based on consensus between the two observers. A p-value < 0.05 was considered to indicate statistical significance. Statistical analysis was performed using MedCalc software (Mariakerke, Bergium).

Results A total of 21 patients were included in this study. Of these, two declined to undergo stress perfusion CMR after stress CCTA because of chest discomfort during the CCTA scan, and another two patients were excluded because of poor CT image quality that was unsuitable for analysis. Three major coronary arteries per patient were evaluated; therefore, a total of 17 patients (mean age: 60.2 ± 9.5 years; 52.9% men) and 51 coronary arteries successfully underwent the evaluation, with good diagnostic image quality. Patient characteristics are summarised in Table 1. The mean estimated radiation effective doses for stress and rest CCTA were 10.6 ± 2.6 and 2.3 ± 1.3 mSv, respectively. The mean HR values were 85.5 ± 25.4 bpm during stress and 64.6 ± 10.5 bpm at rest (p = 0.018). The CT scan parameters are summarised in Table 2.

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Table 1. Baseline characteristics in 17 patients 60.2 ± 9.5

Age (years) Men/women

9/8

BMI (kg/m2)

25.0 ± 4.9

Family history of CAD, n (%)

3 (17.6)

Diabetes, n (%)

5 (29.4)

Hypertension, n (%)

8 (47.1)

Hypercholesterolaemia, n (%)

6 (35.3)

Current smoker, n (%)

4 (23.5)

Data are presented as the mean ± standard deviation or frequency (%). BMI = body mass index; CAD = coronary artery disease.

Accuracy of TAG compared with stress perfusion CMR On ICA, all patients had at least one segment containing ≥ 50% stenosis. Six patients (6/17; 35.3%) had single-vessel disease, seven (7/17; 41.2%) had two-vessel disease, and four (4/17; 23.5%) had three-vessel disease. Overall, five vessels (5/51; 9.8%) in three patients (3/17; 17.6%) were found to have at least one segment with ≥ 70% stenosis; these patients had three-vessel disease. Of the 51 vessels, 19 (19/51; 37.3%) were classified as having mild stenosis [three left anterior descending arteries (LAD), seven left circumflex arteries (LCX) and nine right coronary arteries (RCA)], 27 (27/51; 52.9%) were classified as having moderate stenosis (13 LAD, eight LCX and six RCA), and five vessels (5/51; 9.8%) were classified as having severe stenosis (one LAD, two LCX and two RCA). The mean degree of coronary stenosis in all coronary arteries was 55.1 ± 17.3%. Regarding TAG of stress CCTA, 22 vessels (22/51; 43.1%) were classified as functionally significant stenosis with a TAG less than –15.1 HU/10 mm, whereas 29 vessels (29/51; 56.9%) had a TAG greater than –15.1 HU/10 mm, indicating functionally non-significant stenosis. In a patient-based analysis, the sensitivity, specificity, PPV and NPV for TAG of stress CCTA in all patients were 90.0% (9/10; 95% CI, 55.5–98.3%), 71.4% (5/7; 95% CI, 29.3–95.5%), 81.8% (9/11; 95% CI, 48.2–97.2%) and 83.3% (5/6; 95% CI, 36.1–97.2%), respectively. The corresponding values for TAG of rest CCTA in all patients were 66.7% (6/9; 95% CI, 30.1–92.1%), 57.1% (4/7; 95% CI, 18.8–89.6%), 66.7% (6/9; 95% CI, 30.1– 92.1%) and 57.1% (4/7; 95% CI, 18.8–89.6%), respectively. The diagnostic accuracy of the per-vessel analysis was slightly higher than that of the per-patient analysis (Table 3). In a vessel-based analysis, the sensitivity, specificity, PPV and NPV for TAG of stress CCTA in all coronary arteries were 90.5% (19/21; 95% CI, 69.6–98.5%), 90.0% (27/30; 95% CI, 73.4–97.8%), 86.4% (19/22; 95% CI, 65.1–96.9%) and 93.1% (27/29; 95% CI, 77.2–99.0%), respectively. The corresponding Table 2. Stress and rest CCTA imaging parameters Age (years)

60.2 ± 9.5

Men/women

9/8

BMI (kg/m2)

25.0 ± 4.9

Family history of CAD, n (%)

3 (17.6)

Diabetes, n (%)

5 (29.4)

Hypertension, n (%)

8 (47.1)

Hypercholesterolaemia, n (%)

6 (35.3)

Current smoker, n (%)

4 (23.5)

Data are presented as the mean ± standard deviation or frequency (%). CCTA = coronary computed tomography angiography, bpm = beats per minute.

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values for TAG of rest CCTA in all coronary arteries were 42.9% (9/21; 95% CI, 21.9–65.9%), 83.3% (25/30; 95% CI, 65.3–94.3%), 64.3% (9/14; 95% CI, 35.2–87.1%) and 67.6% (25/37; 95% CI, 49.5–82.6%), respectively. In five (5/51; 9.8%) vessels (one LAD, two LCX and two RCA), TAG of stress CCTA was not consistent with the findings of stress perfusion CMR. Because two RCAs were hypoplastic and one LCX exhibited diffuse atherosclerotic changes that could not influence the HU gradient, the TAG values of these coronary arteries met the criteria for functionally significant stenosis, but no perfusion defects were observed on stress perfusion CMR. On the other hand, one LCX had stenosis in the far distal portion of the coronary artery, and one LAD had stenosis of the coronary ostium. TAG values of these vessels met the criteria of functionally non-significant stenosis, but CMR images acquired during stress and at rest showed a complete, reversible sub-endocardial perfusion defect. In coronary arteries with moderate stenosis on ICA, the sensitivity, specificity, PPV and NPV for TAG of stress CCTA were 93.3% (14/15; 95% CI, 68.0–98.9%), 100% (12/12; 95% CI, 73.4–100%), 100% (14/14; 95% CI, 76.7–100%) and 92.3% (12/13; 95% CI, 63.9–98.7%), respectively. The sensitivity, specificity and PPV for TAG of coronary arteries with moderate stenosis were higher than the corresponding values for all vessels on both stress and rest CCTA (Table 3).

A 1000

stress

1000

800

600

400

200 0

rest

200 y = –23.173x + 771.36 0

8 10 12

y = –16.353x + 616.12 0

708 746 765 618 692 670 580 600 594 498

Discussion Our data show that the TAG of stress CCTA for the detection of haemodynamically significant coronary artery stenosis yielded an excellent diagnostic performance, and higher accuracy was observed in the coronary arteries with moderate stenosis than for all vessels (Fig. 2). This indicates that TAG could facilitate decisions regarding which coronary arteries would benefit from revascularisation in patients with CAD. It is widely known that anatomical measures of stenosis are not good predictors of functionally significant stenosis. The high sensitivity of CCTA has been validated in prospective multi-centre studies, although specificity is a known limitation of CCTA.12 Invasive FFR was shown to reduce the rate of the composite end-point of death, non-fatal MI and repeat revascularisation in patients with multi-vessel coronary artery Table 3. Overall sensitivity, specificity, PPV and NPV of TAG of the coronary arteries with moderate stenosis, all coronary arteries and per-patient analysis on stress and rest CCTA scans Stress CCTA

Rest CCTA

Moderate stenosis (n = 27)

All vessels (n = 51)

Per patient (n = 17)

Moderate stenosis (n = 27)

All vessels (n = 51)

Per patient (n= 17)

Sensitivity

93.3 (14/15)

90.5 (19/21)

90 (9/10)

46.7 (7/15)

42.9 (9/21)

66.7 (6/9)

Specificity

100.0 (12/12)

90.0 (27/30)

71.4 (5/7)

83.3 (10/12)

83.3 (25/30)

57.1 (4/7)

PPV

100.0 (14/14)

86.4 (19/22)

81.8 (9/11)

77.8 (7/9)

64.3 (9/14)

66.7 (6/9)

NPV

92.3 (12/13)

93.1 (27/29)

83.3 (5/6)

55.6 (10/18)

67.6 (25/37)

57.1 (4/7)

All data are percentages. The absolute numbers used to calculate the percentages are in parentheses. PPV = positive predictive value, NPV = negative predictive value, TAG = transluminal attenuation gradient, CCTA = coronary computed tomography angiography.

Fig. 2. A 47-year-old woman with chest pain. (A) TAG of the LAD was –23 HU/10 mm on stress CCTA and –16 HU/10 mm on rest CCTA. (B) Invasive coronary angiography, and (C) curved multi-planar reformatted images of stress CCTA show significant stenosis in the mid-LAD. (D) Axial multi-planar reformatted image shows corresponding luminal attenuation of CCTA. (E) CMR imaging with stress perfusion imaging shows low signal intensity, indicating a subendocardial perfusion defect in the anterior septum and anterior wall at the mid-ventricular level (LAD territory). (F) No low-signal intensity lesion was visible with rest perfusion imaging. TAG = transluminal attenuation gradient, LAD = left anterior descending artery, CCTA = coronary computed tomography angiography, CMR = cardiac magnetic resonance.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

disease in the FAME [Fractional Flow Reserve (FFR) versus Angiography in Multivessel Evaluation)] study.13 However, FFR is limited by its invasive nature, and non-invasive approaches such as CT-FFR, SPECT and CMR are needed. More recently, CT-FFR was described in the DISCOVERFLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study.6 Although the study results have been encouraging, this technique requires much time as well as analysis on a parallel supercomputer. By contrast, TAG can be applied to any CCTA study in daily practice. This technique does not require any modification of CCTA protocols and involves a relatively simple analysis without the need for complicated software, therefore suggesting the possibility of a non-invasive functional assessment of coronary stenosis.7 Contrast opacification on single-shot CCTA with wide-area detector CT is homogenous along the length of a normal coronary artery, but exhibits a linear drop-off in luminal HU along the length of the artery in the presence of haemodynamically significant coronary artery stenosis.14 Choi et al. reported a low sensitivity but high specificity for TAG measured in 64-detector row CCTA that, when added to CCTA percentage stenosis information, significantly increased the area under the receiver operating characteristic curve for the detection of an abnormal invasive FFR < 0.8.15 However, an earlier study of TAG was performed using a 64-slice multi-detector row scanner,8,15 which had a limitation of temporal heterogeneity in coronary artery opacification. Wong et al.7 reported that TAG independently predicted FFR < 0.8 and increased both the sensitivity and specificity of information on CCTA percentage stenosis. That study used a 320-detector row CT scanner, but performed rest CCTA without stress CCTA. Thereafter, another study compared the diagnostic accuracy of combined CTP and TAG320.9 Both stress and rest CCTA were performed using 320-detector row CT scanner, but an initial rest CCTA scan was followed by a stress CCTA scan. As a result, cross-contamination of contrast during the second acquisition (stress CCTA) might have led to false negatives. We used a CCTA protocol in which the stress phase is followed by the rest phase during a single examination, which differs from the protocols used in previous studies. Performing a stress phase acquisition first could allow a ‘clean’ acquisition, thus optimising the detection of haemodynamically significant coronary artery stenosis by avoiding contrast contamination.16 This protocol is suitable for patients with an intermediate to high pre-test probability of CAD, patients with high calcium scores (> 400 mg/dl), and patients with known CAD. We used a CT protocol in which the stress phase was followed by the rest phase because our patients had exhibited moderate coronary artery stenosis during ICA. Interpretation of TAG may be limited by multiple heartbeat acquisition algorithms and coronary calcification. The use of a wide-area detector allows a longitudinal axis of 16 cm, which in most instances enables the entire heart volume to be imaged in a single gantry rotation with a short breath-hold time. This is ideal for TAG functional assessments of coronary arterial stenosis because this modality would enable non-invasive quantitative assessment of coronary contrast changes with temporal uniformity,7,14 and eliminate step registration artifacts. Radiation dose is a major issue concerning the clinical application of stress CCTA. To determine the optimal

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enhancement time, a 10-s stress CCTA scan was performed, causing a relative increase in the radiation dose of our protocol (10.6 ± 2.6 mSv) relative to the doses of previous studies. The radiation dose may decrease with a static scan or dynamic stress CCTA with a shorter scan duration. Although dynamic scanning results in higher radiation doses, its advantages includes the ability to determine the optimal enhancement time or to generate dynamic data sets for the visual analysis of serial dynamic images. Further studies are needed to reduce the radiation doses from dynamic CT scans before implementing widespread use. To our knowledge, we have compared for the first time the diagnostic accuracy of TAG of stress CCTA using a wide-area detector CT with that of stress perfusion CMR as a reference standard. In many studies, invasive FFR is becoming more widely accepted and is selected as the reference standard, but FFR has disadvantages such as its invasive nature, the associated radiation exposure, and high costs.17 Stress perfusion CMR has been established as a non-invasive diagnostic modality with a high diagnostic accuracy for inducible perfusion defects. This modality has the advantage of no radiation exposure or attenuation artifacts. The diagnostic accuracy of stress perfusion CMR is significantly greater than that of SPECT,18 and a qualitative visual analysis of CMR versus FFR identified an excellent diagnostic accuracy for the detection of functionally significant CAD, using a FFR cut-off value < 0.75 for discriminating haemodynamically significant from non-significant stenosis.19,20 CMR has become an important non-invasive diagnostic modality for the clinical work-up of patients with significant coronary artery stenosis. In five (9%) coronary arteries (one LAD, two LCX and two RCA), the TAGs of stress CCTA were not consistent with the findings of stress perfusion CMR. Two RCAs were hypoplastic, and one LCX exhibited diffuse atherosclerotic changes. On the TAGs of these vessels, the transverse graph axis, which represents the distance from the ostium to the distal coronary artery, was relatively short, and the diameters of the coronary arteries were small, and TAG indicated a false positive. On the other hand, the TAG of one LCX and one LAD indicated a false negative. The LCX had stenosis of the far distal portion of the coronary artery, and the LAD had stenosis of the coronary ostium. The stenotic portion of the coronary artery was the beginning or end-point on the transverse graph axis, and therefore the intraluminal attenuation gradient of these vessels was not affected by HU in the stenotic portions of the coronary arteries.

Limitations This study has some limitations. First, this was a single-centre study with a small sample of patients who underwent ICA. Larger, multi-centre studies are needed to provide further functional information and confirmation, using stress perfusion CMR as a reference. Second, the radiation dose incurred during stress CCTA was relatively high. A 10-s scan duration was used to determine the optimal enhancement time for dynamic stress CCTA. Therefore, a shorter dynamic stress CCTA scan duration should be adopted to reduce the radiation dose. Third, the TAG is influenced by the scanner hardware and the measurement technique. There is no standardised measurement method, and obtaining TAG remains time consuming. Although a semi-automated programme has been introduced, currently

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available software requires manual correction near branch vessels. Further refinements to the software are expected to reduce the time burden and facilitate applications in daily practice. Fourth, we did not measure the TAG cut-off value in our study; we considered that a TAG cut-off value of –15.1 HU/10 mm, as previously described, would be significant.7 This value could have been influenced by the use of iodine contrast material, the CT protocol, or TAG calculation method. However, the value of –15.1 HU/10 mm is generally accepted, and therefore our data do not conflict with the results of other studies.

in coronary computed tomography angiography is a novel noninvasive approach to the identification of functionally significant coronary artery stenosis: a comparison with fractional flow reserve. J Am Coll Cardiol 2013; 61(12): 1271–1279. 8.

Choi JH, Min JK, Labounty TM, et al. Intracoronary transluminal attenuation gradient in coronary CT angiography for determining coronary artery stenosis. J Am Coll Cardiol Cardiovasc Imaging 2011; 4(11): 1149–1157.

Wong DT, Ko BS, Cameron JD, et al. Comparison of diagnostic accuracy of combined assessment using adenosine stress computed tomography perfusion + computed tomography angiography with transluminal

Conclusion This study found that the TAG of stress CCTA using a widearea detector CT yielded a high diagnostic performance as well as high sensitivity and specificity for the detection of haemodynamically significant coronary artery stenosis when compared with stress perfusion CMR. We believe that the addition of TAG to CCTA could allow for comprehensive anatomical and functional assessments of CAD, but this remains to be proven in appropriately designed prospective trials.

attenuation gradient + computed tomography angiography against invasive fractional flow reserve. J Am Coll Cardiol 2014; 63(18): 1904–1912. 10. Kim SM, Kim YN, Choe YH. Adenosine-stress dynamic myocardial perfusion imaging using 128-slice dual-source CT: optimization of the CT protocol to reduce the radiation dose. Int J Cardiovasc Imaging 2013; 29(4): 875–884. 11. Shrimpton PC, Hillier MC, Lewis MA, Dunn M. National survey of doses from CT in the UK: 2003. Br J Radiol 2006; 79(948): 968–980. 12. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 57(10):

References 1.

Vanhoenacker PK, Heijenbrok-Kal MH, Van Heste R, et al. Diagnostic performance of multidetector CT angiography for assessment of coronary artery disease: meta-analysis. Radiology 2007; 244(2): 419–428.

opacification gradients in normal coronary arteries imaged with prospectively ECG-gated single heart beat 320-detector row computed

coronary gradient-based methods by coronary computed tomography

Meijboom WB, Van Mieghem CA, van Pelt N, et al. Comprehensive

angiography for the evaluation of physiologically significant coronary

assessment of coronary artery stenoses: computed tomography coro-

artery stenoses: a validation study with fractional flow reserve. Eur

lation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008; 52(8): 636–643. Ko BS, Cameron JD, Meredith IT, et al. Computed tomography stress myocardial perfusion imaging in patients considered for revascularization: a comparison with fractional flow reserve. Eur Heart J 2012; 33(1):

future perspective. JACC Cardiovasc Imaging 2011; 4(8): 905–916. 17. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31(20): 2501–2555. 18. Greenwood JP, Motwani M, Maredia N, et al. Comparison of cardiovascular magnetic resonance and single-photon emission computed

Nasis A, Ko BS, Leung MC, et al. Diagnostic accuracy of combined

tomography in women with suspected coronary artery disease from the

coronary angiography and adenosine stress myocardial perfusion imag-

Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart

2013; 23(7): 1812–1821.

Disease (CE-MARC) Trial. Circulation 2014; 129(10): 1129–1138. 19. Watkins S, McGeoch R, Lyne J, et al. Validation of magnetic resonance

Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coro-

myocardial perfusion imaging with fractional flow reserve for the detec-

nary stenoses by noninvasive fractional flow reserve computed from

tion of significant coronary heart disease. Circulation 2009; 120(22):

coronary computed tomographic angiograms. Results from the prospec-

Heart J Cardiovasc Imaging 2012; 13(12): 1001–1007. 16. Techasith T, Cury RC. Stress myocardial CT perfusion: an update and

67–77.

ing using 320-detector computed tomography: pilot study. Eur Radiol 6.

tomography. Circ Cardiovasc Imaging 2010; 3(2): 179–186. 15. Choi JH, Koo BK, Yoon YE, et al. Diagnostic performance of intra-

48(9): 1896–1910.

nary angiography versus conventional coronary angiography and corre-

New Engl J Med 2009; 360(3): 213–224. 14. Steigner ML, Mitsouras D, Whitmore AG, et al. Iodinated contrast

Valgimigli M. Diagnostic performance of multislice spiral computed sive coronary angiography: a meta-analysis. J Am Coll Cardiol 2006;

versus angiography for guiding percutaneous coronary intervention.

Hamon M, Biondi-Zoccai GG, Malagutti P, Agostoni P, Morello R, tomography of coronary arteries as compared with conventional inva-

1237–1247. 13. Tonino PAL, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve

2207–2213.

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20. Lockie T, Ishida M, Perera D, et al. High-resolution magnetic resonance

Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J

myocardial perfusion imaging at 3.0-Tesla to detect hemodynamically

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Effects of age on systemic inflammatory response syndrome and results of coronary bypass surgery Orhan Gokalp, Nihan Karakas Yesilkaya, Sahin Bozok, Yuksel Besir, Hasan Iner, Huseyin Durmaz, Yasar Gokkurt, Banu Lafci, Gamze Gokalp, Levent Yilik, Ali Gurbuz

Abstract Background: Coronary artery bypass (CAB) surgery triggers systemic inflammatory response syndrome (SIRS) via several mechanisms. Moreover, age is directly correlated with SIRS. We evaluated the effect of age on SIRS and postoperative outcome after CAB surgery. Methods: We retrospectively reviewed the records of 229 patients who had undergone CAB surgery. The patients were divided into three groups according to age: group 1, < 40 years (n = 61); group 2, 40–75 years (n = 83); and group 3, > 75 years old (n = 85). Pre- and peri-operative data were assessed in all patients. SIRS was diagnosed according to the criteria established by Boehme. Results: The average pre-operative EuroSCORE value in group 3 was higher than in the other groups and body surface areas were significantly lower in group 3 than in the other groups (p < 0.05). The postoperative SIRS rates were 68.9% in group 1, 84.3% in group 2 and 91.8% in group 3 (group 1 vs group 3; p < 0.05). Mortality rates were not significantly different between the groups (p > 0.05). The predictive factors for SIRS were age, EuroSCORE rate, on-pump CAB surgery and intra-aortic balloon pump use. Conclusion: Age was an important risk factor for SIRS during the postoperative period after CAB. Keywords: systemic, inflammation, coronary, bypass

Department of Cardiovascular Surgery, Faculty of Medicine, İzmir Katip Celebi University, İzmir, Turkey Orhan Gokalp, MD Yuksel Besir, MD Levent Yilik, MD Ali Gurbuz, MD

Department of Cardiovascular Surgery, Ataturk Training and Research Hospital, İzmir Katip Celebi University, İzmir, Turkey Nihan Karakas Yesilkaya, MD Hasan Iner, MD Huseyin Durmaz, MD Yasar Gokkurt, MD Banu Lafci, MD

Department of Cardiovascular Surgery, Bahcesehir University, İstanbul, Turkey

Submitted 21/3/17, accepted 16/5/17 Published online 23/5/17 Cardiovasc J Afr 2018; 29: 22–25

www.cvja.co.za

DOI: 10.5830/CVJA-2017-030

Coronary artery bypass grafting (CABG) is the conventional treatment for coronary artery disease (CAD). Previously, CABG was primarily performed in patients between the ages of 60 and 75 years. However, because of increased life expectancy and the need to re-perform the procedure, CABG is now commonly performed in patients over 75 years of age.1–3 As a result of this age-related shift in CABG recipients, some postoperative outcome parameters have changed. Systemic inflammatory response syndrome (SIRS) is an inflammatory process that can be triggered during openheart surgery. SIRS is produced by the release of several pro-inflammatory mediators and affects postoperative outcome after open-heart surgery.3,4 The recent marked increase in SIRS after CABG may be due to age-related changes in the immune system.5,6 We therefore investigated the correlation between age and SIRS after CABG.

Methods Ethics committee approval was obtained for the study. Patient medical records were obtained from the hospital automation system and archived files. We retrospectively evaluated 229 patients who had undergone CABG. The patients were divided into three groups according to age: group 1 patients were under 40 years old (n = 61), group 2 were 40–75 years (n = 83), and group 3 were over 75 years old (n = 85). We compared the incidence of SIRS and several clinical parameters among the groups. SIRS was diagnosed by the criteria used by Boehme.7 According to these criteria, the existence of two of the following symptoms was sufficient for the diagnosis of SIRS: fever < 36°C or > 38°C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg, leukocytes < 4 000 cells/μl or > 12 000 cells/μl or > 10% polymorphonuclear leukocytes for at least 24 hours. All patients were cooled to 32°C during cardiopulmonary bypass (CPB). Patients who underwent emergent CABG or simultaneous valve/vascular surgery were excluded from the study. In addition, patients given postoperative anti-inflammatory drugs were also excluded from the study.

Sahin Bozok, MD, sahinboz@yahoo.com

Department of Pediatric Emergency, İzmir Tepecik Training and Research Hospital, İzmir, Turkey Gamze Gokalp, MD

Statistical analysis All of the statistical tests were conducted using the Statistical Package for the Social Sciences for Windows version 22 (SPSS

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Table 3. Postoperative data

Table 1. Demographic data

Group 1 (n = 61) n (%)

Group 2 (n = 83) n (%)

Group 3 (n = 85) n (%)

Parameters

Group 1 (n = 61) n (%)

Group 2 (n = 83) n (%)

Group 3 (n = 85) n (%)

Age (years)

36.7

61.3

77.9

Male gender

49 (80.3)

63 (75.9)

55 (64.7)

0.083

ICU stay (day)

2.92 ± 1.45

3.2 ± 2.69

3.52 ± 2.42

0.346

Diabetes mellitus

14 (23)

36 (43.4)

21 (24.7)

0.937

Hospital stay (day)

7.41 ± 3.96

8.59 ± 12.22

7.32 ± 3.12

0.736

3 (3.6)

6 (7.1)

0.107

Neurological complications

1 (1.6)

2 (2.4)

0.786

54 (63.5)

0.000

Mortality

3 (4.9)

5 (6.0)

12 (14.1)

0.083

42 (68.9)

70 (84.3)

78 (91.8)

0.000

COPD

1 (1.6)

Hypertension

17 (27.9)

CRF Smoking Redo surgery EuroSCORE Pre-operative Hb BSA

49 (59)

p-value

Weaning period (h)

0.000

3 (3.6)

1 (1.2)

0.082

SIRS

35 (57.4)

42 (50.6)

24 (28.2)

0.001

ICU: intensive care unit, SIRS: systemic inflammatory response syndrome.

2 (2.4)

0.107

3.69 ± 2.24

5.2 ± 1.7

0.000

13.02 ± 1.89

12.57 ± 1.71

11.93 ± 1.49

0.000

1.88 ± 0.18

1.77 ± 0.16

1.68 ± 0.16

0.000

COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure, Hb: haemoglobin, BSA: body surface area.

Inc, Chicago, IL, USA). Group comparisons of categorical data were assessed using Pearson’s chi-squared and Fisher’s exact tests and chi-squared trend analysis. Because the permanent variables did not have normal distributions (Kolmogorov–Smirnov test, p < 0.05), the Mann–Whitney U-test was used to compare the two groups, and the Kruskal–Wallis H-test (post hoc Bonferroni corrected Mann–Whitney U-test) was used to compare multiple groups. The associations between SIRS and other variables were evaluated using Spearman’s rho correlation analysis.

Results We found no statistically significant differences among the groups regarding gender, incidence of diabetes, chronic obstructive lung disease, chronic renal failure or prior open-heart surgery (p > 0.05). Smoking rates, pre-operative haemoglobin levels, and body surface area were significantly lower in group 3 than in the other groups, and the incidence of hypertension was significantly lower in group 1 compared to the other groups (p < 0.05). The average EuroSCORE value was higher in group 3 than in the other groups (p < 0.05; Table 1). Comparisons of off-pump bypass surgery rates, CPB time, cross-clamping time, intra-aortic balloon pump use and revision ratios revealed no statistically significant differences among the groups (p > 0.05). However, the amount of postoperative drainage and peri-operative blood transfusions were significantly higher in group 2 than in the other groups (p < 0.05; Table 2). We found no significant differences in length of intensive care unit or hospital stay, incidence of neurological complications, and mortality rates among the groups (p > 0.05). However, Table 2. Peri-operative data

Parameters

Group 1 (n = 61) n (%)

Group 2 (n = 83) n (%)

Group 3 (n = 85) n (%)

p-value

Off-pump CABG

15 (24.6)

20 (24.1)

19 (22.4)

0.745

CPB time (min) Cross-clamping time (min)

82.21 ± 49.45 88.05 ± 29.05 83.58 ± 29.76

0.105

45.9 ± 30.62 46.53 ± 19.17 43.72 ± 18.78

0.536

5 (8.2)

8 (9.6)

11 (12.9)

0,343

Drainage (ml)

581 ± 294

480 ± 268

670 ± 501

0.004

Blood transfusion (IU)

2.25 ± 1.45

1.7 ± 0.95

3.26 ± 3.38

0.045

6 (7.2)

15 (17.6)

0.321

IABP

p-value

10.67 ± 7.55 13.9 ± 10.01 14.28 ± 10.25

4 (6.6)

1.95 ± 2.07

Revision

Parameters

8 (13.1)

CABG: coronary artery bypass graft, CPB: cardiopulmonary bypass, IABP: intra-aortic balloon pump.

the incidence of SIRS was significantly higher in group 3 than in group 1 (p < 0.05; Table 3), and the weaning period was significantly shorter in group 1 than in the other groups (p < 0.05). Analysis of the predictive factors for SIRS revealed a statistically significant but weak positive correlation of SIRS with age, EuroSCORE value, on-pump CABG and intra-aortic balloon pump use. By contrast, we found a statistically significant but weak negative correlation of SIRS with pre-operative haemoglobin levels and off-pump CABG (p < 0.05). No other statistically significant relationships were found between SIRS and the other variables (p > 0.05; Table 4).

Discussion CPB itself may trigger systemic inflammation; however its role is controversial because inflammation may be induced by several factors other than CPB. Tissue damage, endotoxaemia and contact of blood with a non-endothelial surface during CBP are thought to trigger systemic inflammation during open-heart surgery,8,9 which may lead to SIRS. The reported incidence of SIRS during the 24-hour postoperative period widely varies from 27 to 96%; this variability

Table 4. Predictive factors for SIRS following CABG SIRS r

p-value

Age

0.254

0.000

Diabetes mellitus

0.103

0.121

–0.017

0.799

0.028

0.672

–0.040

0.544

Hypertension

0.103

0.119

Redo surgery

–0.082

0.216

EuroSCORE

0.179

0.007

–0.037

0.580

0.068

0.308

Hospital stay

–0.015

0.837

Pre-operative haemoglobin level

–0.164

0.013

Body surface area

–0.073

0.272

Off-pump CABG

–0.186

0.005

On-pump CABG

0.208

0.002

CPB period

0.140

0.062

Cross-clamping period

0.138

0.065

Intra-aortic balloon pump use

0.138

0.037

Drainage amount

0.048

0.471

Blood transfusion

0.060

0.531

–0.035

0.602

Parameters

COPD Smoking CRF

Ejection fraction Neurological complications

Revision

COPD: chronic obstructive pulmonary disease, CRF: chronic renal failure, CABG: coronary artery bypass grafting, CPB: cardiopulmonary bypass, SIRS: systemic inflammatory response syndrome.

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may be explained by the different diagnostic criteria, such as clinical parameters versus the measurement of pro-inflammatory mediators,7 used in the various studies. For instance, Sasse et al.10 found a SIRS incidence of 39% in paediatric patients with a history of prior cardiac surgery, whereas MacCallum et al.11 reported that the incidence of SIRS was 96.2% in an adult cardiothoracic intensive care unit. Our finding that the incidence of SIRS was 83% in all age groups is consistent with that of MacCallum et al.11 Given the wide range in age of the patients undergoing CABG, marked differences in postoperative outcomes have been observed in the different age groups. Several studies have reported widely varying results, particularly those including octogenarians. Therefore, although some studies have found a poor postoperative outcome in older compared to younger adult patients, others found that CABG was a safe procedure for octogenarian patients. For example, Sumin et al.12 assessed postoperative outcomes according to age in patients who underwent CABG. The authors found that the rates of hospital mortality and postoperative complications were significantly higher in patients older than 70 years compared to those younger than 60 years. Similarly, Wilson et al.13 reported that the rates of mortality and postoperative complications were higher in patients older than 75 years than in younger patients. In a similar study, Arıtürk et al.14 reported that advanced age was a risk factor for 30-day mortality in patients who underwent CABG and mitral valve repair as a result of ischaemic mitral regurgitation. Moreover, an investigation of risk factors predicting neurological complications following CABG found that advanced age was a significant risk factor.15 Conversely, several investigators have reported that age had no effect on postoperative outcomes after CABG. In a study of 8 890 patients, Karimi et al.16 found that age was not a predictive factor for mortality. A meta-analysis of 12 697 older patients found that the CABG postoperative outcomes were satisfactory.17 An investigation of arterial graft use for CABG in patients older than 70 years found that CABG was safe and effective for older individuals.18 We found no significant differences in mortality or neurological complication rates among the age groups in our study. Our finding that the average EuroSCORE value was higher in older (group 3) than younger (groups 1 and 2) patients is noteworthy because high EuroSCORE values predict poor early and late postoperative outcomes.19 Aging is associated with increased inflammatory activity;20 however, the role of aging on the immune response to various stimuli is controversial. Krabbe et al.20 reviewed studies investigating the role of gene polymorphisms in inducing inflammation. Some studies found no association between age and systemic inflammatory mediators,21,22 whereas others reported a marked increase in inflammatory cytokines; in particular, interleukin-1 (IL1), IL6 and tumour necrosis factoralpha (TNF-α) levels were higher in older than in younger patients.23,24 We used clinical parameters but not markers of inflammation to evaluate the effects of age on SIRS. We found that the incidence of SIRS was significantly higher in patients older than 75 years than in those younger than 40 years. Few studies have used clinical parameters to investigate the correlation between age and SIRS in the postoperative period after CABG.

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Previous investigations of predictive factors for SIRS have yielded important findings both in terms of identifying and preventing risk factors; however, it is surprising that so few studies have investigated the risk factors associated with SIRS in open-heart surgery, and of those, none have focused on CABG. A study investigating the correlation between intraoperative blood transfusion and SIRS found that intra-operative blood transfusion, low pre-operative functional capacity, liver dysfunction, chronic obstructive pulmonary disease, male gender, pre-operative steroid therapy, history of pre-operative haemodialysis and being older than 74 years were risk factors for postoperative SIRS.25,26 An investigation of SIRS in patients who had undergone transaortic valve implantation found that the predictive factors for SIRS were contrast amount, major bleeding, major vascular trauma and blood transfusion.27 A study of patients who underwent paediatric heart surgery found that predictive factors for SIRS were age, low body weight, and CBP and cross-clamping times.8 A similar study in a paediatric population found that CPB time, low body weight (< 10 kg) and right-to-left shunt were predictive factors for SIRS. Our findings that age, pre-operative haemoglobin levels, EuroSCORE value, on-pump CABG and intra-aortic balloon pump use were predictive factors for SIRS are consistent with those of previous studies. Our sample size was adequate; however, a limitation of our study is that pro-inflammatory mediators were not used to diagnose SIRS.

Conclusion We found that age was a risk factor for SIRS in patients undergoing CABG. For this reason, it should be borne in mind that the risk of developing SIRS in elderly patients increases, and accordingly, precautionary measures must be taken. Nevertheless, larger randomised clinical studies in patients undergoing CABG are needed to clarify the relationship between age and SIRS.

References 1.

Kirsch M, Guesnier L, LeBesnerais P, Hillion L, Debauchez M, Seguin J, et al. Cardiac operations in octogenarians: Perioperative risk factors for death and impaired autonomy. Ann Thorac Surg 1998; 66(1): 60–67.

Fruitman DS, MacDougall CE, Ross DB. Cardiac surgery in octogenarians: Can elderly patients benefit? Quality of life after cardiac surgery. Ann Thorac Surg 1999; 68(6): 2129–2135.

Gümüş F, Erkalp K, Kayalar N, Alagöl A. Cardiac surgery and anesthesia approach in an elderly patient population. Turk Gogus Kalp Dama 2013; 21(1): 250–255.

Sürer S, Bolat A, Koç M, Gülbahar O, Kutsal A. Investigation of the effects of leukocyte filtration in congenital heart surgery. Turk Gogus Kalp Dama 2014; 22(2): 298–304.

Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006; 34(1): 15.

Walley KR. Aging and the intramyocardial inflammatory response. Crit Care 2014; 18(6): 638.

Boehme AK, Hays AN, Kicielinski KP, Arora K, Kapoor N, Lyerly MJ, et al. Systemic ınflammatory response syndrome and outcomes in ıntracerebral hemorrhage. Neurocrit Care 2016; 25(1): 133–140.

Soares LC, Ribas D, Spring R, Silva JM, Miyague NI. Clinical profile of systemic inflammatory response after paediatric cardiac surgery with

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cardiopulmonary bypass. Arq Bras Cardiol 2010; 94(1): 127–133. 9.

Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 2002; 97: 215–252.

18. Medalion B, Mohr R, Ben-Gal Y, Nesher N, Kramer A, Eliyahu S, et al. Arterial coronary artery bypass grafting is safe and effective in elderly patients. J Thorac Cardiovasc Surg 2015; 150(3): 607–612. 19. O’Boyle F, Mediratta N, Fabri B, Pullan M, Chalmers J, McShane J, et

10. Sasse M, Dziuba F, Jack T, Köditz H, Kaussen T, Bertram H, et al.

al. Long-term survival after coronary artery bypass surgery stratified by

In-line filtration decreases systemic inflammatory response syndrome,

EuroSCORE. Eur J Cardiothorac Surg 2012; 42(1): 101–106; discussion

renal and hematologic dysfunction in paediatric cardiac intensive care patients. Pediatr Cardiol 2015; 36(6): 1270–1278. 11. MacCallum NS, Finney SJ, Gordon SE, Quinlan GJ, Evans TW.

106–107. 20. Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol 2004; 39(5): 687–699.

Modified criteria for the systemic inflammatory response syndrome

21. Roubenoff R, Harris TB, Abad LW, Wilson PF, Dallal GE, Dinarello

improves their utility following cardiac surgery. Chest 2014; 145(6):

CA. Monocyte cytokine production in an elderly population: Effect of

1197–1203.

age and inflammation. J Gerontol Med Sci 1998; 53(1): M20–M26.

12. Sumin AN, Gaĭfulin RA, Bezdenezhnykh NA, Ivanov SV, Barbarash

22. Wang XY, Hurme M, Jylhä M, Hervonen A. Lack of association

OL, Barbarash LS. Factors affecting results of coronary bypass surgery

between human longevity and polymorphisms of IL-1 cluster, IL-6,

in elderly patients. Kardiologia 2013; 53(1): 56–64.

IL-10 and TNF-alpha genes in Finnish nonagenarians. Mech Ageing

13. Wilson MF, Baig MK, Ashraf H. Quality of life in octagenarians after coronary artery bypass grafting. Am J Cardiol 2005; 95(6): 761–764. 14. Aritürk C, Ökten M, Gülllü U, Şenay Ş, Buturak A, Görmez S, et al. Mitral valve repair for ischemic mitral insufficiency: An increased early postoperative risk for the elderly. Turk Gogus Kalp Dama 2015; 23(2): 239–244. 15. Coskun I, Colkesen Y, Demirturk OS, Tunel HA, Giray S, Gulcan O. Pre- and perioperative risk factors predicting neurologic outcomes after coronary artery bypass surgery in patients with pre-existing neurologic events. J Stroke Cerebrovasc Dis 2013; 22(8): 1340–1349. 16. Karimi A, Ahmadi H, Davoodi S, Movahedi N, Marzban M, Abbasi K, et al. Factors affecting postoperative morbidity and mortality in isolated

Dev 2001; 123(1): 29–38. 23. Gabriel P, Cakman I, Rink L. Overproduction of monokines by leukocytes after stimulation with lipopolysaccharide in the elderly. Exp Gerontol 2002; 37(2–3): 235–247. 24. Born J, Uthgenannt D, Dodt C, Nünninghoff D, Ringvolt E, Wagner T, et al. Cytokine production and lymphocyte subpopulations in aged humans: An assessment during nocturnal sleep. Mech Ageing Dev 1995; 84(2): 113–126. 25. Ferraris VA, Ballert EQ, Mahan A. The relationship between intraoperative blood transfusion and postoperative systemic inflammatory response syndrome. Am J Surg 2013; 205(4): 457–465. 26. Gunes T, Bozok S, Kestelli M, Yurekli I, Ilhan G, Ozpak B, et al.

coronary artery bypass graft surgery. Surg Today 2008; 38(10): 890–898.

α-Tocopherol and ascorbic acid in early postoperative period of cardio-

17. Dhurandhar V, Saxena A, Parikh R, Vallely MP, Wilson MK, Butcher

pulmonary bypass. J Cardiovasc Med (Hagerstown) 2012; 13(11): 691–699.

JK, et al. Comparison of the safety and efficacy of on-pump (ONCAB)

27. Sinning JM, Scheer AC, Adenauer V, Ghanem A, Hammerstingl C,

versus off-pump (OPCAB) coronary artery bypass graft surgery in the

Schueler R, et al. Systemic inflammatory response syndrome predicts

elderly: A review of the ANZSCTS database. Heart Lung Circ 2015;

increased mortality inpatients after transcatheter aortic valve implanta-

24(12): 1225–1232.

tion. Eur Heart J 2012; 33(12): 1459–1468.

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Cardiac diastolic function after recovery from pre-eclampsia P Soma-Pillay, MC Louw, AO Adeyemo, J Makin, RC Pattinson

Abstract Background: Pre-eclampsia is associated with significant changes to the cardiovascular system during pregnancy. Eccentric and concentric remodelling of the left ventricle occurs, resulting in impaired contractility and diastolic dysfunction. It is unclear whether these structural and functional changes resolve completely after delivery. Aims: The objective of the study was to determine cardiac diastolic function at delivery and one year post-partum in women with severe pre-eclampsia, and to determine possible future cardiovascular risk. Methods: This was a descriptive study performed at Steve Biko Academic Hospital, a tertiary referral hospital in Pretoria, South Africa. Ninety-six women with severe preeclampsia and 45 normotensive women with uncomplicated pregnancies were recruited during the delivery admission. Seventy-four (77.1%) women in the pre-eclamptic group were classified as a maternal near miss. Transthoracic Doppler echocardiography was performed at delivery and one year post-partum. Results: At one year post-partum, women with pre-eclampsia had a higher diastolic blood pressure (p = 0.001) and body mass index (p = 0.02) than women in the normotensive control group. Women with early onset pre-eclampsia requiring delivery prior to 34 weeks’ gestation had an increased risk of diastolic dysfunction at one year post-partum (RR 3.41, 95% CI: 1.11–10.5, p = 0.04) and this was irrespective of whether the patient had chronic hypertension or not. Conclusion: Women who develop early-onset pre-eclampsia requiring delivery before 34 weeks are at a significant risk of developing cardiac diastolic dysfunction one year after delivery compared to normotensive women with a history of a low-risk pregnancy.

Cardiac Obstetric Unit, Department of Obstetrics and Gynaecology, University of Pretoria, Steve Biko Academic Hospital, Pretoria, South Africa P Soma-Pillay, FCOG, Cert (Maternal and Foetal Med) SA, priya. soma-pillay@up.ac.za AO Adeyemo, MB BS, MCFP (SA), FCP (SA), Cert Cardiol (SA)

Department of Cardiology, University of Pretoria, Steve Biko Academic Hospital, Pretoria, South Africa MC Louw, N Dip Clin Technol, B Tech Clin Technol; Cardiology

MediClinic Heart Hospital, Pretoria, South Africa AO Adeyemo, MB BS, MCFP (SA), FCP (SA), Cert Cardiol (SA)

South African Medical Research Council Maternal and Infant Health Care Strategies Unit, Department of Obstetrics and Gynaecology, University of Pretoria, Pretoria, South Africa P Soma-Pillay, FCOG, Cert (Maternal and Foetal Medicine) SA J Makin, MB BCh, MSc (Epidemiology and Biostatistics) RC Pattinson, MD, FRCOG, FCOG (SA)

Keywords: pre-eclampsia, diastolic function, left ventricular remodelling, pregnancy Submitted 23/3/17, accepted 10/7/17 Published online 31/8/17 Cardiovasc J Afr 2018; 29: 26–31

www.cvja.co.za

DOI: 10.5830/CVJA-2017-031

Pre-eclampsia is a pregnancy-specific disorder characterised by new-onset hypertension and proteinuria after 20 weeks’ gestation. Hypertensive disorders in pregnancy have been one of the top five causes of maternal mortality in South Africa for more than a decade.1 It was previously believed that the complications of pre-eclampsia ended with the delivery of the foetus and placenta, however it is now well established that pre-eclampsia is a risk for future hypertension, ischaemic heart disease, stroke and venous thromboembolism.2 Pregnancy is associated with significant haemodynamic and hormonal changes affecting the cardiovascular system. There is a 20% increase in cardiac output by eight weeks’ gestation.3 Peripheral vasodilatation leads to a 20 to 30% fall in systemic vascular resistance and a 40% increase in cardiac output. The heart undergoes remodelling, with an increase in left ventricular wall thickness and mass.4 Despite these changes, the left ventricular contractile function is maintained and any changes in cardiac geometry are rapidly reversible within three months post-partum in normotensive women.4 By contrast, vascular reactivity is augmented in pregnancies affected by pre-eclampsia.5 Pre-eclampsia results in a state of increased vascular stiffness, generalised vasoconstriction and a high total vascular resistance and low cardiac output compared to the changes seen in a normal pregnancy. 5 Cardiac changes classically associated with pre-eclampsia are diastolic dysfunction and an after-load-mediated left ventricular remodelling of the maternal heart.6-8 The heart remodelling is a response to the increased systemic afterload in order to minimise myocardial oxygen demand and preserve left ventricular function. About 20% of women with pre-term pre-eclampsia and severe disease undergo severe left ventricular hypertrophy with advanced cardiac dysfunction.9 Typically there is preservation of both left atrial geometry and function, and left ventricular systolic function.4,10 The right ventricle is also usually unaffected.10 Levels of brain naturetic peptide (BNP) increase in pregnancies complicated by pre-eclampsia, and Fayers et al. have shown that the increase in BNP is accompanied by changes in left ventricular diastolic function.11 Elevated BNP levels are possibly the result of myocardial remodelling and sub-clinical ventricular dysfunction that accompanies the severe vasoconstriction observed in pre-eclampsia.11 Diastolic dysfunction is described as impaired left ventricular filling and may be present in the setting of normal or abnormal systolic function. Pre-clinical diastolic dysfunction is associated with the development of future heart failure and is a predictor

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of all-cause mortality.12 Diastolic filling abnormalities may also play a significant role in the pathogenesis of pulmonary oedema, complicating hypertensive crises in pregnancy.13 Desai et al. found that diastolic filling abnormalities were demonstrated in a significant proportion of pre-eclamptic pregnancies complicated by pulmonary oedema compared to control groups of women who were hypertensive and normotensive in pregnancy.13 The authors of this study postulated that the diastolic filling abnormalities demonstrated in the study occurred within a short time frame of severe pre-eclampsia in pregnancy or could represent pre-eclampsia superimposed on established hypertension. Whether diastolic dysfunction persists after delivery is uncertain. Identifying factors that may affect future cardiovascular risk may identify a group of women requiring increased postpartum vigilance and lifestyle modification. The aim of this study was to determine cardiac diastolic function at delivery and one year post-partum in women with severe pre-eclampsia and to further determine possible future cardiovascular risk.

Methods This was a descriptive study of women with severe pre-eclampsia, performed at Steve Biko Academic Hospital from 1 April 2013 to 30 March 2016. The Cardiology Department at Steve Biko Academic Hospital reserved echocardiographic appointments every Wednesday during the study period. Post-partum women with severe pre-eclampsia were identified on a Wednesday morning and if fit to be transported to the cardiology clinic,

were informed of the study. Echocardiographic studies were performed on patients who consented to the procedure and were agreeable to follow-up studies. One hundred and six women with severe pre-eclampsia and 45 normotensive, low-risk women who served as the control group were identified and recruited shortly after delivery. Women with structural heart disease or pulmonary embolus were excluded from the study. Women diagnosed with maternal metabolic syndrome were not recruited to the control group. Echocardiograms of the maternal heart were performed between day two and seven post-delivery and follow-up scans were done after one year. Hypertensive disorders were classified according to the classification and diagnosis of the International Society for the Study of Hypertension in Pregnancy (ISSHP).14 Doppler echocardiography was carried out by the Department of Cardiology at Steve Biko Academic Hospital. The following echocardiographic parameters were assessed in the evaluation of diastolic dysfunction: left ventricular ejection fraction (LVEF), mitral E-wave (E) and mitral A-wave velocities (A), E/A ratio, mitral E-velocity deceleration time (DT), lateral early diastolic (e′) velocity tissue Doppler and E/e′ ratio. The diagnosis of diastolic dysfunction was made by a clinician in the cardiac-obstetric unit. All women diagnosed with diastolic dysfunction had the following minimum positive criteria: average E/e′ > 14 and lateral e′ velocity < 10 cm/s. The American Society of Echocardiography and the European Association of Cardiovascular Imaging have described the advantages and limitations used to assess left ventricular diastolic function15 (Table 1).

Table 1. Utility, advantages and limitations of variables used to assess left ventricular diastolic function15 (reproduced with permission) Variable

Physiological background

Mitral E velocity Reflects the LA–LV pressure gradient during early diastole and is affected by alterations in the rate of LV relaxation and LAP

Advantages

Limitations

Feasible and reproducible

Directly affected by alterations in LV volumes and elastic recoil. Age dependent

Mitral A velocity Reflects the LA–LV pressure gradient during Feasible and reproducible late diastole, which is affected by LV compliance and LA contractile function

Sinus tachycardia, first-degree AV block and paced rhythm can result in fusion of the E and A waves. If mitral flow velocity at the start of the atrial contraction is > 20 cm/s, A velocity may be increased. Age dependent

Mitral E/A ratio

Feasible and reproducible. Provides diagnostic and prognostic information. A restrictive filling pattern in combination with LA dilatation in patients with normal EFs is associated with a poor prognosis similar to a restrictive pattern in dilated cardiomyopathy

The U-shaped relationship with LV diastolic function makes it difficult to differentiate normal from pseudonormal filling, particularly with normal LVEF, without additional variables. If mitral flow velocity at the start of atrial contraction is > 20 cm/s, E/A ratio will be reduced due to fusion. Age dependent

Mitral E-velocity DT is influenced by LV relaxation, LV diastolic DT pressures following mitral valve opening, and LV stiffness

Feasible and reproducible. A short DT in patients with reduced LVEF indicates increased LVEDP with high accuracy both in sinus rhythm and in AF

DT does not relate to LVEDP in normal LVEF. Should not be measured with E and A fusion due to potential inaccuracy. Age dependent

Pulsed-wave TDI-derived mitral annular early diastolic velocity: e′

A significant association is present between e′ and the time constant of LV relaxation shown in both animals and humans. The haemodynamic determinants of e′ velocity include LV relaxation, restoring forces and filling pressure

Feasible and reproducible. LV filling pressures have a minimal effect on e′ in the presence of impaired LV relaxation. Less load dependent than conventional bloodpool Doppler parameters

Need to sample at least two sites with precise location and adequate size of sample volume. Different cut-off values depending on the sampling site for measurement. Age dependent

Mitral E/e′ ratio

e′ velocity can be used to correct for the effect of LV relaxation on mitral E velocity, and E/e′ ratio can be used to predict LV filling pressures

Feasible and reproducible. Values for average E/e’ ratio < 8 usually indicate normal LV filling pressures, values > 14 have high specificity for increased LV filling pressures

E/e′ ratio is not accurate in normal subjects, patients with heavy annular calcification, mitral valve and pericardial disease. ‘Gray zone’ of values in which LV filling pressures are indeterminate. Different cut-off values depending on the sampling site for measurement

Mitral inflow E/A ratio and DT are used to identify the filling patterns

LV, left ventricular; LA, left atrial; LAP, left atrial pressure; LVEF, left ventricular ejection fraction; DT, mitral E-velocity deceleration time; e′, lateral early diastolic velocity; AF, atrial fibrillation.

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Descriptive statistics in the form of means and standard deviations in the case of continuous data, and frequencies and percentages in the case of categorical data were calculated. A p-value of < 0.05 was considered significant. Ethical approval for the study was obtained from the University of Pretoria Ethics Committee (No. 125/2013).

Results There were 6 536 deliveries at our hospital during the recruitment phase of the study (1 April 2013 – 30 March 2015). Four hundred and sixty-three (7.1%) women presented with severe pre-eclampsia and 106 women were recruited to the study. Ten women were lost to follow up. Data were therefore recorded for 96 women with severe pre-eclampsia and 45 controls. Seventy-four (77.1%) women in the study group for whom data were available fulfilled the World Health Organisation (WHO) criteria for the classification of a maternal near miss. Of the 96 women with severe pre-eclampsia, 14 were diagnosed with chronic hypertension and four with diabetes prior to pregnancy. At one year, the mean diastolic blood pressure and mean body mass index was significantly higher among the women who had pre-sclampsia during pregnancy compared to the normotensive control group. Table 2 describes the demographic data of the study population. Twenty women (20.83%) with pre-eclampsia were diagnosed with diastolic dysfunction at delivery compared with six (13.3%) of the controls (p = 0.26). Of the 20 women who were diagnosed with diastolic dysfunction at delivery, 13 (65%) had early-onset pre-eclampsia, requiring delivery prior to 34 weeks. At one year, 11 (11.46%) women with pre-eclampsia were diagnosed with diastolic dysfunction compared with three (6.67%) in the control group (RR = 1.67; p = 0.27). Table 2. Demographic data of the study population

Characteristics

Pre-eclamptic group (n = 96)

Control group (n = 45)

p-value

28.9 (6.83)

27.2 (7.14)

0.66

18–46

20–42

Age, years Mean (SD) Range Race 86 (89.58)

38 (84.44)

Caucasian, n (%)

African, n (%)

5 (5.20)

3 (6.67)

Coloured, n (%)

4 (4.17)

4 (8.89)

Indian, n (%)

1 (1.04)

0 (0)

1.3 (0–4)

1.6 (0–5)

< 34 weeks, n (%)

44 (45.83)

0 (0)

34–37 weeks, n (%)

25 (26.04)

5 (11.11)

> 37 weeks, n (%)

27 (28.13)

40 (88.89)

6 (6.25)

0 (0)

52 (54.17)

2 (4.44)

12.02 (1.46)

12.42 (1.13)

0.15

Systolic, mean (SD)

128.01 (14.17)

115.08 (9.89)

0.08

Diastolic, mean (SD)

80.91 (14.47)

72.45 (9.16)

0.001

BMI at 1 year, mean (SD)

30.27 (7.55)

28.04 (3.64)

0.02

p = 0.04

p = 0.27

10 5 0

Delivery

1 year Pre-eclamptic

Haemoglobin at 1 year (g/dl) Mean (SD)

p = 0.26

Medical conditions Hypertensive at 1 year, n (%)

Heart failure is a progressive condition, which begins with risk factors for left ventricular dysfunction and progresses further to asymptomatic changes in cardiac structure and function, finally evolving into heart failure.16 Myocardial remodelling starts before the onset of symptoms. Diastolic dysfunction precedes the onset of systolic dysfunction in 50% of cardiac diseases, which further precedes the onset of heart failure.5 The American College of Cardiology has highlighted the importance of identifying asymptomatic cardiac dysfunction for early intervention and improvement of outcome.17 The risk for left ventricular diastolic dysfunction is significantly associated with higher age, body mass index (BMI), heart rate and systolic blood pressure.16 The prevalence of diastolic dysfunction in a general population aged less than 49 years was found to be 6.8%, and 27.3% for the total population, which included study subjects older than 70 years.16 Zanstra et al. found that 24% of women with the metabolic syndrome during pregnancy had diastolic dysfunction at six months post-partum, compared to 6.3% of women with low-risk pregnancies.18 Obesity and diastolic hypertension were strong correlates to diastolic dysfunction. The rate of diastolic dysfunction at one year in the two groups of women with early-onset pre-eclampsia (22.7%) and low-risk pregnancies (6.7%) in our study were similar to rates

Timing of delivery

Diabetic at 1 year, n (%)

Discussion

Obstetric history Parity mean (range)

Women with early-onset pre-eclampsia requiring delivery prior to 34 weeks’ gestation had an increased risk of diastolic dysfunction at one year post-partum (RR 3.41, 95% CI: 1.11– 10.5, p = 0.04) (Fig. 1). Delivery prior to 34 weeks was associated with an increased risk of diastolic dysfunction even if patients with chronic hypertension at one year were excluded from the analysis (p = 0.02, 95% CI: 1.43–97.67) There was no significant association between diastolic dysfunction and chronic hypertension at one year (RR = 2.02, p = 0.33, 95% CI: 0.57– 7.13). Echocardiographic measurements of diastolic function after one year are shown in Table 3. Left ventricular systolic function was normal and similar in both groups, suggesting preservation of systolic function in both pre-eclamptics and controls. There was a significant decrease in lateral e′ and a significant increase in A velocity between the pre-eclamptic and control group at one year.

Blood pressure at 1 year (mmHg)

Delivery <34 weeks Control

Fig. 1. Risk of diastolic dysfunction at delivery and at one year, and at one year for sub-group of women with early-onset pre-eclampsia requiring delivery prior to 34 weeks.

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Table 3. Cardiac diastolic function at one year Pre-eclamptic group, mean (SD)

Control group, mean (SD)

p-value

Left ventricular ejection fraction, %

60.54 (7.62)

63.43 (4.88)

0.08

E velocity, m/s

0.98 (0.20)

0.95 (0.14)

0.90

A velocity, m/s

0.70 (0.24)

0.64 (0.05)

0.01

E/A ratio

1.42 (0.39)

1.46 (0.12)

0.74

224.57 (51.00)

225.43 (35.09)

0.08

Lateral e′ (cm/s)

10.83 (2.86)

11.80 (1.99)

0.02

E/e′ ratio

10.11 (5.32)

9.96 (2.25)

0.11

E-deceleration time (ms)

reported by Zanstra et al.16 Although our study did not find associations between diastolic blood pressure and obesity with diastolic dysfunction, women in the pre-eclamptic group had a significantly higher BMI and diastolic blood pressure than those in the control group. Additionally, diastolic dysfunction is also a risk factor for future death. The Olmsted study described the predictive significance of left ventricular diastolic dysfunction using multivariableadjusted analyses.19 The hazard ratio for all-cause mortality was 8.31 (p < 0.001) for mild diastolic dysfunction and 10.17 for moderate to severe diastolic dysfunction (p < 0.001). At one year post-delivery, diastolic dysfunction was present in 11.5% of women with pre-eclampsia, in 22.7% of women with early-onset pre-eclampsia and in 1.9% of women whose pre-eclampsia developed after 34 weeks. Women with early-onset pre-eclampsia requiring delivery prior to 34 weeks, irrespective of the presence of chronic hypertension, were at risk of developing diastolic dysfunction at one year post-delivery. Chronic hypertension, therefore, was not an additional risk factor for diastolic dysfunction at one year in women with earlyonset pre-eclampsia. This study found that early-onset pre-eclampsia was a risk factor for diastolic dysfunction, while women who developed pre-eclampsia after 34 weeks had a risk similar to that of low-risk parous women (RR 3.41, 95% CI: 1.11–10.5, p = 0.04). This may be explained by the proposed differences in pathophysiology between early- and late-onset pre-eclampsia. Redman et al. have suggested that pre-eclampsia could be the result of intrinsic or extrinsic placental causes.20 In early-onset pre-eclampsia, factors extrinsic to the placenta affect the uteroplacental circulation via incomplete spiral artery remodelling, while in late-onset disease, intrinsic factors affect the size of the placenta, restricting intervillous perfusion.20 The placentas of women with early-onset disease differ significantly from those who develop pre-eclampsia at term.21 The former group demonstrate placental findings consistent with insufficiency and vascular lesions, while late-onset disease is characterised by placental hyperplasia and unimpaired foetal growth.21-24 Further evidence suggesting that pre-eclampsia is more than one disease comes from differences in biochemical markers, Doppler studies and clinical features of the disease.25-30 Pre-eclampsia is a known risk factor for future chronic hypertension. Hypertension and hypertensive heart disease are one of the key contributors to the burden of non-communicable cardiovascular disease in Africa. Young African women are bearing the brunt of this increasing public health problem.31,32 Several studies have found that women from sub-Saharan Africa have the greatest risk of developing pre-eclampsia and eclampsia.33,34

Nakimuli et al., in a study of pre-eclampsia in women of African ancestry, found that African ancestry was the second strongest risk factor for pre-eclampsia after chronic hypertension.35 African ancestry was also a risk factor for earlyonset pre-eclampsia and poor obstetric outcomes such as foetal growth restriction and stillbirth.35 Pregnancy-related deaths from pre-eclampsia are also three times higher in women of African ancestry compared with Europeans.36 Almost 90% of women in our study were of African origin. It is estimated that for every woman who dies during pregnancy or childbirth, 20 others will suffer severe morbidity.37 Most maternal mortality and morbidity datasets record information for up to 42 days post-partum. However women who develop pre-eclampsia during pregnancy, especially those with early-onset disease, may develop heart failure several years after pregnancy, resulting in the problem not being adequately identified and addressed. The prognosis of women with compromised cardiac function is poorer than that of men.18 Women often present with atypical symptoms, resulting in delayed presentation, delayed diagnosis and suboptimal care compared to men.38,39 These factors highlight the need to identify women at risk of future cardiovascular disease, with the aim of reducing potential modifiable risk factors. Blood pressure control, weight loss and a low-sodium diet are important measures that have been identified with favourable changes in ventricular diastolic function.18 The American Heart Association Guideline on Lifestyle Management to reduce cardiovascular risk for adults who would benefit from blood pressure lowering include dietary modification appropriate to calorie requirements, reduction in salt intake and three to four sessions of aerobic activity per week lasting on average 40 minutes per session.40 This is the first study to evaluate diastolic function in a pre-eclamptic group of predominantly African population. Although we did not look at other risk factors for cardiovascular disease in this population, the study provides valuable information in identifying a potential group of women at risk of disease at an early stage. This would provide opportunities for screening and lifestyle modification. The strength of this study is that it is one of the first to look at cardiac diastolic function in an African population where the rates of hypertension both during and outside of pregnancy were high. A possible limitation is that most patients were seen for the first time during pregnancy, with severe acute hypertension. Only 14.6% of women were known to have chronic hypertension. It is possible that some women had undiagnosed chronic hypertension – this is especially likely as the rate of chronic hypertension postpartum at one year was 54.2%. Some of the women with undiagnosed chronic hypertension may have had pre-existing diastolic dysfunction that could have been worsened by the superimposed pre-eclampsia. A further limitation is that only a select group of pre-eclamptic women were recruited to the study.

Conclusion Women who develop early-onset pre-eclampsia requiring delivery prior to 34 weeks’ gestation have an increased risk of cardiac diastolic dysfunction one year after delivery. Diastolic dysfunction precedes the onset of systolic dysfunction and

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

clinical heart failure. A strategy to screen and treat women with cardiovascular risk, particularly in lower- and middle-income countries should be explored further.

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topic.htm). 18. Zanstra M, Stekkinger E, van der Vlugt MJ, van Dijk AP, Lotgering FK, Spaanderman MEA. Cardiac diastolic dysfunction and metabolic syndrome in young women after placental syndrome. Obstet Gynecol

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in late-onset preeclampsia. J Perinatal Med 2011; 39: 641–652. 25. Gupta AK, Gebhardt S, Hillerman R, Holzgreve W, Hahn S. Analysis of plasma elastase levels in early and late onset preeclampsa. Arch Gynecol Obstet 2006; 273: 239–242. 26. Crispi F, Llurba E, Dominguez C, Martin-Gallan P, Cabero L, Gratacos

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11. Fayers S, Moodley J, Naidoo DP. Cardiovascular haemodynamics in pre-eclampsia using brain naturetic peptide and tissue Doppler studies. Cardiovasc J Afr 2013; 24(4): 130–136. 12. Wan SH, Vogel MW, Chen HH. Pre-clinical diastolic dysfunction. J Am Coll Cardiol 2014; 63: 407–416. 13. Desai DK, Moodley J, Naidoo DP, Bhorat I. Cardiac abnormalities in pulmonary oedema associated with hypertensive crises in pregnancy. Br J Obstet Gynaecol 1996; 103: 523–528. 14. Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al.

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35. Nakimuli A, Chazara O, Byamugisha J, Elliott AM, Kaleebu P, Mirembe F, et al. Pregnancy, parturition and preeclampsia in women of African ancestry. Am J Obstet Gynecol 2014; 207: 510–520 36. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol 2001; 97: 533–538. 37. Health Canada. Special Report on Maternal Mortality and Severe

myocardial infarction in women: contribution of treatment variables to adverse outcome. Am Heart J 2000; 140: 740–746. 39. Daly C, Clemens F, Lopez Sandon JL, Tavizzi L, Boersma E, Danchin N, et al. Euro Heart Survey Investigators. Gender differences in the management of acute myocardial infarction, 1994 through 2002. N Engl J Med 2005; 353: 671–682.

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arterial coupling in hypertensive heart failure with reserved ejection

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fraction. Circulation: Heart Fail 2013; 6:1165–1171.

Ten-year fall in blood cholesterol of Malaysia heart attack patients suggests statin impact A 10-year decline in the blood cholesterol of heart attack patients in Malaysia suggests that statins are having a positive impact, according to an observational study in nearly 49 000 patients presented at the ASEAN Federation of Cardiology Congress 2017 (AFCC2017). AFCC2017 was hosted by the Brunei Cardiac Society, with the support of the ASEAN Federation of Cardiology, on 3 to 5 November in Brunei Darussalam. Experts from the European Society of Cardiology (ESC) presented a special programme. ‘Lifestyle changes appear to be responsible for falls in blood cholesterol in the general populations of developed nations while statins have reduced cholesterol in patients with heart disease,’ said lead author Dr Sazzli Kasim, Chair, Malaysian Society of Atherosclerosis and Associate Professor of Medicine, University Technology MARA, Shah Alam, Malaysia. ‘Blood cholesterol is still on the rise in the general population of developing countries like Malaysia,’ he continued. ‘This study investigated trends in cholesterol levels in Malaysian patients with acute coronary syndromes.’ The study included 48 851 patients who had an acute coronary syndrome between 2006 and 2015 in Malaysia and were enrolled in the National Cardiovascular Disease Database Acute Coronary Syndrome (NCVD-ACS) registry. This ongoing registry is maintained by the National Heart Association Malaysia with the support of the Ministry of Health Malaysia. Total cholesterol was assessed on entry to the registry. The researchers examined trends in cholesterol levels of ACS patients over the 10-year period and compared them to previously published values for the entire population. They found a significant trend for declining total cholesterol from 2006 to 2015 in the ACS population (p = 0.012). This was opposite to the total cholesterol trend in the Malaysian population. ACS patients with a history of coronary heart disease had almost twice the declining rate in cholesterol as those with

no history of coronary heart disease. When the researchers examined total cholesterol by type of ACS, they found that patients with unstable angina had the lowest total cholesterol level but the steepest rate of decline, followed by patients with non-ST-elevation myocardial infarction and then patients with ST-elevation myocardial infarction. Dr Kasim said: ‘We found that blood cholesterol levels have been falling in Malaysian patients with acute coronary syndromes, which is the opposite of the national trend.’ ‘Since cholesterol levels have increased significantly in the Malaysian population as a whole, it is highly doubtful that lifestyle change is the reason for the declining cholesterol trend we observed in the ACS population,’ he continued. Dr Kasim said: ‘While this was an observational study and we cannot infer causality, it seems likely that cholesterol levels decreased as a result of lipid-lowering medication such as statins. ACS patients with a history of coronary heart disease, who were more likely to be taking statins, had a more rapid decline in cholesterol levels than those without a history of coronary heart disease.’ He concluded: ‘These results appear to mimic findings from developed countries in previous years and show that the Malaysian population is reaching similar health milestones. The findings also highlight the need to increase awareness of the harm of raised lipid values and the treatment available.’ Dr Ezam Emran, scientific chair of AFCC 2017, said: ‘This large study suggests that statins are being effectively used by heart attack patients in Malaysia. Rising lipid levels in the general population need to be tackled by promoting healthier lifestyles.’ Professor Michel Komajda, a past president of the ESC and course director of the ESC programme in Brunei, said: ‘The benefits of statins for preventing a second heart attack are unequivocal, as highlighted by the 2017 ESC guidelines. Patients should also be encouraged to quit smoking, adopt a healthier diet and be physically active.’ Source: European Society of Cardiology Press Office

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

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A comparative study on the cardiac morphology and vertical jump height of adolescent black South African male and female amateur competitive footballers Philippe Jean-Luc Gradidge, Demitri Constantinou

Abstract Objective: The aim of this comparative study was to determine the gender differences in cardiac morphology and performance in adolescent black South African footballers. Methods: Anthropometry, electrocardiography and echocardiography data were measured in 167 (85 males and 82 females) adolescent black South African footballers (mean age: 14.8 ± 1.3 years). Vertical jump height was used as a performance measure of explosive lower-limb power. Results: The males had less body fat compared with the females (12.1 ± 3.6 vs 16.8 ± 4.1%, p < 0.05), while females had higher left ventricular end-diastolic diameters compared with males (48.7 ± 3.7 vs 40.7 ± 8.1, p < 0.05). Vertical jump height was higher in males (37.2 ± 10.3) compared with females (31.2 ± 8) and was inversely associated with body fat (β = –0.2, p < 0.05) and positively associated with lean mass (β = 0.5, p < 0.05). Conclusion: The findings showed that adolescent black South African male footballers had a performance advantage over females for explosive lower-limb power, which was explained by differences in body composition and not cardiac morphology. Keywords: adolescent, black South African, footballers, cardiac morphology, vertical jump height

Methods

Submitted 25/7/16, accepted 13/7/17 Published online 15/8/17 Cardiovasc J Afr 2018; 29: 32–35

Although such cardiac adaptations provide clear physiological advantages for the ability to withstand play during the intermittent nature of football, it is important to distinguish between the physiological and pathological heart. Echocardiography and electrocardiography are therefore important investigative tools in football players, first to screen for and monitor at-risk players, and second to monitor physiological development related to football training.5 Lower-limb dynamic functionality, particularly explosive power during sprinting and jumping activities, is a key characteristic of football.6 These contribute to the speed and strength demands of football performance movements.7 It has been reported that adolescent participants with congenital heart disease produced lower peak jump heights compared with age-matched ‘normal’ controls.6 The converse is unknown, namely whether optimal performance in these activities may depend on the structural cardiac adaptations that follow football training. The aims of this comparative study were: (1) to determine the gender differences in cardiac morphology and performance in competitive adolescent South African footballers; and (2) to determine the factors associated with explosive jump height and measures of cardiac morphology in these footballers.

www.cvja.co.za

DOI: 10.5830/CVJA-2017-032

Football is a popular sport, particularly among adolescents in the developing world.1 Adaptive changes to the heart are assumed with chronic participation in football,2 however little is known of the cardiac morphology of African adolescents who participate in this game.3 Hypertrophy of the cardiac muscle is the main consequence of training, contributing to the higher level of performance compared with the sedentary, age-matched, non-football population.4

Centre for Exercise Science and Sports Medicine (CESSM), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Philippe Jean-Luc Gradidge, MSc (Med), PhD, philippe.gradidge@ wits.ac.za Demitri Constantinou, MB BCh, BSc (Med) (Hons), MSc (Med), MPhil

Data for this comparative study of adolescent black South African footballers were collected from seven of the nine provinces (the Eastern Cape, Free State, Gauteng, KwaZuluNatal, Limpopo, Mpumalanga and Western Cape). Participants included were within the age range of 12 to 18 years, without injury and actively involved in competitive amateur-level football. Ethical clearance for the study was granted by the University of the Witwatersrand (M140513). Participants dressed with minimal clothing on the testing day. No shoes were worn for the anthropometric measurements. Height (m) was measured using a stadiometer (Seca 217, UK) and weight (kg) was measured using a digital scale (Seca 844, UK). Body mass index (BMI) was calculated as weight (kg)/ height (m2) and presented using BMI for age guidelines.8 The Omron sphygmomanometer (Canada) and accompanying stethoscope were used to measure systolic and diastolic blood pressure (BP) with the participant in a seated position after five minutes’ rest period. Three measurements were taken and the average of the second and third BP measurements was recorded. Skinfold measurements were used to determine proxy measures of body fat and muscle mass using standardised methods.9 Echocardiography was performed and measures of cardiac morphology included interventricular septal (IVS) thickness, ejection fraction percentage and left ventricular end-diastolic

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diameter (LVED) [Mindray DP-6600, Shenzhen, China (using a 2.5–3.5 MHz cardiac transducer)]. Resting and stress electrocardiograms (ECG) were recorded using a Schiller AT 6 ECG machine (Schiller AG, Switzerland) using standardised treadmill protocols.9 Vertical jump height (VJH) was measured as the maximal jump height from a two-legged standing starting position. The best result from three trials was recorded.10 The sit-and-reach test was used to measure truncal flexibility (cm).9

Statistical analysis Statistica 13.2 (StatSoft, Tulsa, USA) was used for all analyses. The Student’s t-test was used to compare anthropometric, cardiac and fitness profiles between male and female participants (p < 0.05). Complete data were not available for all measures as more advanced body composition measuring tools, echocardiography and instruments used for performance were available at only selected regions. The mean of the sample was used for participants who had missing data. To determine whether the sample size was suitable, a null hypothesis of < 5% was rejected. Assuming a standardised difference of 0.58 with 90% power for LVED, the minimum number of participants required in each group is 78 with the alpha value set at 5%.11 The actual sample size was above the minimum required. Bivariate analyses were conducted to determine the correlation between variables using Pearson’s correlation by gender. Multivariable linear regression analyses were conducted to determine whether independent variables were associated with the explosive power outcome (VJH) and the cardiac morphology outcomes (ejection fraction percentage, IVS thickness, and LVED. Based on the outcome of the bivariate analysis, the

Table 1. Characteristics of adolescent South African footballers by gender Variables Proportion (%)

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Total sample (n = 167) 100

Males (n = 85) 50.9

Females (n = 82)

Percentage difference†

49.1

1.8

Age (years)

14.8 ± 1.3

15.5 ± 1.1

14.1 ± 1.1*

Height (m)

1.61 ± 0.1

1.66 ± 0.1

1.56 ± 0.1*

6.2

Weight (kg)

54 ± 8.5

58.3 ± 7.2

49.5 ± 7.3*

16.3

following independent variables were included in the initial multiple regression model for the fitness outcome: age, gender, systolic BP, diastolic BP, body fat, lean muscle mass, IVS thickness, ejection fraction and LVED. The following independent variables were included in the initial multivariable linear regression models for the three cardiac outcomes: age, gender, systolic BP, diastolic BP, body fat, muscle mass, resting heart rate, IVS thickness, ejection fraction, LVED and VJH. Multico-linearity was checked using variance inflation factor (VIF) analysis. All independent variables had VIFs < 2.2, indicating no co-linearity.

Results The participants were from Gauteng (n = 35), Kwa-Zulu Natal (n = 27), Mpumalanga (n = 36), Western Cape (n = 15), Eastern Cape (n = 19), Free State (n = 19) and Limpopo (n = 16). The mean age of the study population was 14.8 ± 1.3 years, with a mean BMI of 20.6 ± 2.4 kg/m2. The female (n = 82) footballers were younger compared with the males (n = 85), and presented with significantly higher body fat measures and lower lean mass (Table 1). Resting BP, IVS thickness and LVED were significantly higher in males compared with females; however end-diastolic volumes were similar. Flexibility did not differ between the males and females, however VJH was significantly higher in males compared with females (Table 2). For those who had cardiac auscultation conducted (79 males and 20 females), none of the females presented with abnormal auscultation, while five of the males had functional systolic ejection murmurs (6.3%) and one had a tricuspid regurgitation murmur (3/6) (1.3%). No resting or stress ECGs showed any pathological abnormalities. Using bivariate analysis, there was a significant positive correlation between VJH and age, and lean mass, while body fat, diastolic BP and trunk flexibility were negatively correlated in males. In females, body fat and resting heart rate were negatively correlated with VJH, while lean mass was positively correlated.

9.5 Table 2. Pearson’s correlations for VJH, ejection fraction, IVS thickness and LVED presented by gender VJH

BMI (kg/m2) by age range

Variables 20.1 ± 1 (4)

Ejection fraction

IVS thickness

LVED

Males Females Males Females Males Females Males Females

12–13 years (n)

19.9 ± 2.3 (26)

19.8 ± 2.5 (22)

1.5

Age

0.4*

0.1

0.2

0.01

–0.2

–0.1

–0.2

14–15 years (n)

20.7 ± 2.1 (92) 20.9 ± 1.4 (35) 20.5 ± 2.5 (57)

1.9

BMI

0.2

–0.1

–0.2

0.1

0.2

–0.1

0.2*

–0.1

16–17 years (n)

21.1 ± 2.2 (49) 21.1 ± 1.9 (46)

20.7 ± 0.2 (3)

1.9

Body fat

–0.3*

–0.4*

–0.5*

0.1

0.4*

–0.2

–0.1

–0.2

Body fat (kg)

14.4 ± 4.5

12.1 ± 3.6

16.8 ± 4.1*

32.5

Lean mass

0.7*

0.1

–0.1

–0.3*

0.1

–0.3*

Lean mass (kg)

51.1 ± 4.9

53.5 ± 3.9

48.7 ± 4.7

9.4

0.2

–0.1

–0.4

0.5

–0.02

0.5*

64.8 ± 7

Ejection fraction IVS thickness

–0.1

–0.2

–0.4*

0.5*

0.1

0.9*

0.1

–0.2

–0.02

0.5*

0.1

0.9*

–0.2

–0.3

0.3

0.1

–0.4

–0.3*

–0.1

–0.3*

–0.004

0.1

–0.02

–0.1

0.04 –0.5*

Ejection fraction (%)

64 ± 7.2

63.1 ± 7.3

2.7

IVS thickness (mm)

9.2 ± 1.7

9.9 ± 1.5

8.4 ± 1.6*

16.4

LVED

44.8 ± 7.5

48.7 ± 3.8

40.7 ± 8.1*

17.9

Resting heart rate (bpm)

68.9 ± 9.8

65.8 ± 10.6

72.2 ± 7.6*

9.3

176.7 ± 8.1

172.8 ± 4.8*

2.2

117.2 ± 10.9

110.3 ± 7.5*

6.1

72.3 ± 8.1

69.3 ± 8*

4.2

Peak heart rate (bpm) 174.8 ± 9 Systolic BP (mmHg) Diastolic BP (mmHg)

113.8 ± 10 71.2 ± 8.2

VJH (cm)

37.2 ± 10.3

43.1 ± 8.9

31.2 ± 8*

Trunk flexibility (cm)

40.3 ± 4.9

40.3 ± 3.7

40.4 ± 5.9

32 0.3

Data presented as mean ± SD; *p < 0.05 versus males; †Percentage difference (male minus female/male). BMI: body mass index; BP: blood pressure; IVS: interventricular septal thickness; VJH: vertical jump height; LVED: left ventricular end-diastolic diameter.

LVED Resting heart rate

Systolic BP –0.1

0.2

0.1

Diastolic BP

–0.3*

0.2

–0.1 0.2

–0.1

–0.3*

0.02

0.1

–0.04

–0.2*

VJH Trunk flexibility

–0.1

0.03 –0.04 –0.1

–0.6*

–0.2

0.1

–0.2

0.1

0.2

Data presented as r coefficient for males (n = 85) and females (n = 82); *p < 0.05. BMI: body mass index; BP: blood pressure; LVED: left ventricular end-diastolic diameter; IVS: interventricular septal thickness; VJH: vertical jump height.

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

Table 3. Multivariable linear regression models for determining the influence of body composition, blood pressure, cardiac morphology and performance on VJH, LVED, IVS thickness and ejection fraction Exposure

VJH

Ejection fraction (%)

IVS thickness

Body fat

–0.2*

–0.1

0.2*

–0.02

0.2*

Ejection fraction

0.04

Lean mass

0.5*

IVS thickness

0.004

0.04

–0.1

–0.04

LVED

–0.1 0.6*

LVED

–0.03

0.5*

0.7*

RHR

–0.1

0.3*

–0.2*

Systolic BP

0.1

0.02

0.1

Diastolic BP

-0.02

-0.04

0.02

–0.2*

0.1

0.01

–0.03

0.66*

0.19*

0.59*

0.67*

VJH R2

–0.001

Data presented as adjusted β; p < 0.05. All models were adjusted for age and gender. LVED: left ventricular end-diastolic diameter; IVS: interventricular septal thickness; VJH: vertical jump height; RHR: resting heart rate. *

In males, body fat and IVS thickness correlated negatively with ejection fraction, while resting heart rate correlated positively. In females, IVS thickness and LVED correlated positively with ejection fraction. In males, IVS thickness was positively associated with body fat, and negatively associated with ejection fraction, resting heart rate and flexibility. In females, IVS thickness was negatively associated with lean mass, ejection fraction, resting heart rate and diastolic BP, while positively associated with LVED. In males, LVED was positively associated with BMI. In females, LVED was positively associated with ejection fraction, resting heart rate and IVS thickness, while negatively associated with diastolic BP and lean mass. Table 3 displays the associations for the fitness and cardiac morphology outcomes of the study population. All models were adjusted for age and gender. The multivariable regression models explained 66, 19, 59 and 67% of the variation in VJH, ejection fraction, IVS thickness and LVED, respectively. VJH was positively associated with lean mass, and negatively associated with body fat. Ejection fraction was positively associated with LVED and resting heart rate. Resting heart rate was inversely associated with IVS thickness, while body fat and LVED were positively associated. LVED was positively associated with ejection fraction, body fat and IVS thickness, while negatively associated with diastolic BP.

Discussion Football is the most popular sport globally, with adolescents making up a large proportion of participants. In most sports that predominantly utilise the aerobic system, regular participation provides significant cardiovascular adaptations as an adaptation to improve performance.2 Our study findings primarily add to the limited body of evidence on the cardiac morphology of adolescent African footballers. The findings also show the gender differences in physiological profile and selected performance outcomes, and that selected cardiac parameters were not associated with dynamic VJH. Males were taller and weighed more than the female study participants, which is likely due to the higher lean muscle mass observed in the male participants.12 These body composition differences are expected in adolescents of this age, but little is known about the differences in cardiac morphology of African populations.

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The higher lower-limb dynamic explosive power values observed in male compared with female footballers supports the well-known notion of gender functional strength differences. In this study population, however, the sociopolitical landscape of South Africa cannot be excluded as an additional source of this discrepancy.13 Despite encouraging participation in sport, policy makers fail to account for the limited resources and lack of accessibility experienced by female athletes in South Africa. There are still barriers even when there are opportunities. For example, most premier league football teams have the capability to allow for the development of adolescent footballers, but the training is often performed in the late afternoons to night-time. With personal safety being a concern, these facilities may not easily be accessible for adolescent female footballers, even if located within walking distance. Therefore female subjects may not fully engage in football training as a consequence. The daily demands of schoolwork and other life stresses can further de-emphasise the central focus on football. In addition, incentives to participate in professional football are currently more favourable for male subjects compared with females; however, gender equality in various sports is being addressed. Although studies have shown that the untrained female can improve cardiovascular function by participating in recreational competitive football,14 males still have a more pronounced physiological advantage over age-matched females. The diameters of the male participants’ left ventricles are similar to those of footballers of African descent living in Europe,15 suggesting some degree of genetic heritability. On the other hand, the female participants seem to be more aligned with the adaptations experienced by volleyball athletes.16 This is evident by the finding that females have smaller heart sizes and lower left ventricular mass compared with males.17 Therefore, even though the cardiovascular adaptations to aerobic sport are similar, the absolute difference in cardiac structure is higher in male subjects. Moreover, the variation in cardiac morphology can also be explained by the fact that height is highly associated with heart size and function,17 and male subjects in our study were taller compared with females. The vertical jump test is not only an indicator of explosive strength, but also of neuromuscular adaptation. Our study findings show that age, gender and body composition have an influence on the difference in results for this variable. Therefore, the lower VJH values in females can be explained by lower muscle mass, younger age and increased body fat. It is worth considering the specificity of training to explain the advantage noted in males. Current knowledge shows that for optimal neuromuscular adaptation, athletes need to engage in a progressive strength-training programme, and actively challenge the neuromuscular system.18 Tendons assist with functional movement by acting as shock absorbers and energy capacitors within the muscle–tendon complex.19 Further research is needed to determine whether female footballers have lower jump height as a result of lower tendon compliance for explosive activities. The findings of this study highlight the interconnected characteristic of the various cardiac muscle components. This points to the complexity involved in trying to comprehend cardiac development in footballers. For example, our study findings show that lean muscle mass was associated with LVED volume in the regression analyses, but football training is

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seasonal, with the pre-season representing a period of strength development, while the competitive phase of the sport is typical of peak performance during match play. This suggests that the training adaptation is non-linear, but rather fluctuates depending on external exercise demand. The level of primary sex hormones also alters during the football seasons and depends on internal (e.g. menstrual cycle in females) and external stresses (e.g. more resistance training in males, often to enhance body image). Serum testosterone levels can influence muscle architecture and function, and it is during times of peak training stress when the advantages of this anabolic hormone are most notable. In football, this usually occurs during the aerobic component of play, when the slow-twitch muscle fibres are most active. The body adapts by improving cardiac output, essentially by increasing left ventricular mass,2 which is more pronounced in male athletes. The main limitation of this study is that causality could not be inferred in this comparative study, indicating the need for longitudinal studies of adolescent African footballers to confirm our findings.

for use in screening. Heart 2001; 85(6): 649–654. 5.

Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010; 121: 445–456.

Fricke O, Witzel C, Schickendantz S, Sreeram N, Brockmeier K, Schoenau E. Mechanographic characteristics of adolescents and young adults with congenital heart disease. Eur J Pediatr 2008; 167(3): 331–336.

Stolen T, Chamari K, Castagna C, Wisloff U. Physiology of soccer: an update. Sports Med 2005; 35(6): 501–536.

Ogden CL, Flegal KM. Changes in terminology for childhood overweight and obesity. Natl Health Stat Rep 2010; 25: 1–5.

American College of Sports Medicine (ACSM). ACSM’s Guidelines for Exercise Testing and Prescription. 9th edn. Philadelphia: Lippincot Williams & Wilkins, 2010.

10. Harman EA, Rosenstein MT, Frykman PN, Rosenstein RM, Kraemer WJ. Estimation of human power output from vertical jump. J Appl Sport Sci Res 1991; 5: 116–120. 11. Whitley E, Ball J. Statistics review 4: sample size calculations. Crit Care 2002; 6(4): 335–341. 12. Plowman S, Smith DS. Exercise Physiology for Health, Fitness and Performance. San Francisco, CA: Benjamin Cummings, 2003.

Conclusion This comparative study demonstrated the gender differences in performance as a result of physiological and cardiovascular advantages in male subjects. In addition, football training can remodel body composition, resulting in enhanced jumping ability, which is essential during competitive match play.

13. Shisana O, Labadarios D, Rehle T, et al. South African National Health and Nutrition Examination Survey (SANHANES–1). Cape Town: HSRC Press, 2013. 14. Bangsbo J, Nielsen JJ, Mohr M, et al. Performance enhancements and muscular adaptations of a 16-week recreational football intervention for untrained women. Scand J Med Sci Sports 2010; 20(Suppl 1): 24–30. 15. Sheikh N, Papadakis M, Carre F, et al. Cardiac adaptation to exercise in adolescent athletes of African ethnicity: an emergent elite athletic

Ms Kendra Dykman and Mr Dane Schaefer captured the collected data.

population. Br J Sports Med 2013; 47(9): 585–592. 16. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remod-

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Green DJ, Naylor LH, George K. Cardiac and vascular adaptations to

18. Sale DJ. Neural adaptation to strength training. In: Komi PV (ed.).

Huston TP, Puffer JC, Rodney WM. The athletic heart syndrome. N Engl J Med 1985; 313(1): 24–32.

114(15): 1633–1644. 17. De Simone G, Devereux RB, Daniels SR, Meyer RA. Gender differ-

cardiac arrest on the football field. Br J Sports Med 2010; 44(8): 540–545. exercise. Curr Opin Clin Nutr Metab Care 2006; 9(6): 677–684. 3.

eling and the risks of sports, including sudden death. Circulation 2006;

Strength and Power in Sport. 2nd edn. Oxford: Blackwell Science, 2003: 27–49. 19. Komi PV, Ishikawa M. In-vivo interaction of fascicles and tendons as

Somauroo JD, Pyatt JR, Jackson M, Perry RA, Ramsdale DR. An

measured by the optic fiber and ultrasound technique. In: Rainoldi A,

echocardiographic assessment of cardiac morphology and common

Minetto MA, Merletti R, (eds). Biomedical Engineering in Exercise and

ECG findings in teenage professional soccer players: reference ranges

Sports. Torino: Edizioni Minerva Medica, 2006: 3–15.

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Atherosclerotic disease is the predominant aetiology of acute coronary syndrome in young adults AK Pillay, DP Naidoo

Abstract Objectives: Few studies have evaluated young adults in their third and fourth decades with coronary artery disease (CAD). This study evaluated the clinical and angiographic profile of young adults (< 35 years) with CAD. Methods: A 10-year (2003–2012) retrospective chart review was performed on patients less than 35 years diagnosed with CAD at Inkosi Albert Luthuli Central Hospital, Durban. Results: Of the 100 patients who met the study criteria, the majority were male (90%), of Indian ethnicity (79%), and presented with acute coronary syndrome (93%). Smoking (82%), dyslipidaemia (79%) and dysglycaemia (75%) were the most prevalent risk factors. Almost half of the subjects (48%) met criteria for the metabolic syndrome. Angiographic findings revealed multi-vessel (42%), single-vessel (36%) and non-occlusive disease (20%); only two subjects had normal epicardial vessels. Disease severity was influenced by dyslipidaemia (p = 0.002) and positive family history (p = 0.002). Non-coronary aetiologies were identified in 19% of subjects. Conclusions: Atherosclerotic disease associated with risk-factor clustering was highly prevalent in young adults with CAD. Keywords: coronary artery disease, young adults, risk factors, metabolic syndrome Submitted 21/1/17, accepted 13/7/17 Published online 12/12/17 Cardiovasc J Afr 2018; 29: 36–42

www.cvja.co.za

DOI: 10.5830/CVJA-2017-035

Coronary artery disease (CAD) is considered premature when it appears in adults under the age of 55 years in males and 65 years in females. Premature coronary artery disease (PCAD) is an emerging problem, frequently presenting as premature myocardial infarction (MI) in recent years.1,2 A recent review of young adults (< 40–45 years)3 with CAD described two forms of the disease, one characterised by limited (single) vessel disease with a favourable outcome, and the other by extensive multi-vessel involvement with a more rapid progression of atherosclerosis. Coronary atherosclerosis, beginning as a fatty streak and raised atheromatous plaque, has been noted to begin early in

Department of Internal Medicine, University of KwaZuluNatal, Durban, South Africa AK Pillay, MB BCh, FCP, asheganp@yahoo.com

Department of Cardiology, University of KwaZulu-Natal, Durban, South Africa DP Naidoo, PhD, naidood@ukzn.ac.za

adolescence,4 the majority of patients remaining asymptomatic until later in life.3 This silent process makes the estimation of disease prevalence a particular challenge in young adults.3 Although a prevalence of four to 10% has been reported among individuals with myocardial infarction under age 40–45 years,5,6 autopsy studies have found advanced coronary atheroma in up to 20% of men and 8% of women between 30 and 34 years of age.7 In a local study by Ranjith et al., 20% (n = 491) of 2 290 patients presenting with MI, between 1996 and 2002 were under the age of 45 years.8 This increased cardiovascular risk in youth has been noted to be particularly high among the South African Indian community in whom risk-factor clustering has been described.8-10 In contrast to older subjects, major cardiovascular risk factors such as hypertension and diabetes mellitus are less commonly observed among young adults with PCAD.11 Subtle forms of dysglycaemia such as insulin resistance and impaired glucose tolerance have been found to be more common than diabetes in this age group and add to the risk of PCAD.12 Risk-factor clustering in the form of the metabolic syndrome has also been reported to be common among young patients.11 Additional, ‘non-conventional’ risk factors may also be more commonly found among younger subjects. These include psychosocial factors such as stress12-14 and anger,15 the use of recreational drugs such as cocaine16 and marijuana,17 connective tissue disease18,19 and HIV infection.20,21 Earlier studies have documented at least one major risk factor in over 90% of young subjects with CAD;22,23 more recently the INTERHEART study24 identified major risk factors in subjects with CAD worldwide among young subjects. A corresponding increase in mortality rate has also been associated with an increasing number of risk factors.25 Little is known about the underlying aetiology and angiographic profile of young subjects presenting with CAD. In this study we analysed the clinical and angiographic profile of young adults (< 35 years) presenting to the Cardiology Unit at Inkosi Albert Luthuli Central Hospital over a 10-year period.

Methods A retrospective chart review was conducted on young patients (< 35 years) with CAD referred to the Cardiology Department at Inkosi Albert Luthuli Central Hospital (IALCH) over a 10-year period between 2003 and 2012. All patients were referred with a diagnosis of acute coronary syndrome (ACS) or stable angina. The diagnosis of ACS was made according to criteria outlined by Braunwald et al. and encompasses unstable angina, non-STsegment elevation (non-Q wave) MI (NSTEMI) and ST-segment elevation (Q wave) MI (STEMI).26 The ethics committee of the Faculty of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZuluNatal granted approval for the study (BE324/13).

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As per unit policy, all young subjects diagnosed with ACS/ CAD undergo coronary angiography. Patients referred for coronary angiography for reasons other than assessment of CAD (such as chest trauma or prior to elective valve replacement) were not included. Patients were identified using the Speedminer software program, which is a Data Warehouse Management software package, used by the hospital to manage, process and categorise the data collected on its database. All patient charts were accessed via the software program and data were extracted on demographics, clinical and biochemical parameters, as well as investigations including SestaMIBI and coronary angiography. Clinical and biochemical parameters were assessed to determine the risk-factor profile as well as factors that could influence the clinical outcome of patients. In addition to the metabolic syndrome criteria (see below), other parameters included in the analysis were: body mass index, total cholesterol > 4.5 mmol/l, low-density lipoprotein cholesterol (LDL-C) > 1.8 mmol/l, glycated haemoglobin (HbA1c) > 6.5%, haemoglobin < 13 g/dl for males, < 12 g/dl for females, microalbuminuria 30–300 mg/l and proteinuria > 300 mg/l. The International Diabetes Federation consensus criteria (harmonised definition) (2006) were used to detect subjects with the metabolic syndrome (MetS)27 when they had at least three of the following factors: central obesity [waist > 94 cm in males (90 cm in Indians) and > 80 cm in females], triglycerides > 1.7 mmol/l, high-density lipoprotein cholesterol (HDL-C) < 1.03 mmol/l in males or < 1.29 mmol/l in females, blood pressure > 130/85 mmHg (or previously diagnosed hypertension) and fasting plasma glucose > 5.6 mmol/l (or previously diagnosed type 2 diabetes mellitus). Coronary stenosis of ≥ 50% in any of the major coronary arteries was designated occlusive CAD, and stenosis of < 50% non-occlusive coronary disease (NOD). For scoring the severity of CAD, luminal stenosis of 50% of the proximal coronary artery was given a score of 1, 50–74% of 2, 75–99% was scored as 3 and total occlusion was scored as 4.28

Among this group, 100 subjects were 35 years or younger, constituting 1.3% of all subjects with coronary disease referred for coronary angiography. These subjects (90 males, 10 females) had a mean age of 31.9 years (median 27.5 years) and 23 were under 30 years of age. The ethnic distribution showed a predominance of Indian subjects (79%) (Table 1). The majority of subjects (n = 93) were referred from their base hospital following a diagnosis of acute coronary syndrome. Most (82%) presented with ‘typical’ acute ischaemic chest pain, while atypical chest pain symptoms (sharp, stabbing pain; symptoms suggestive of dyspepsia or heartburn) were reported in 18 cases (18%). Sixty-six patients (66%) had STEMI, 45 of whom received thrombolytic therapy on admission at the base hospital prior to referral. The reason most often cited for failure to administer thrombolysis in the remaining 21 patients was late presentation (> 24 hours since onset of chest pain). A further 13 patients were referred with NSTEMI, and 14 patients presented with unstable angina. Six subjects presented with chronic stable angina and were referred following positive exercise stress tests. One patient presented with symptomatic bradycardia (complete heart block) (Table 1). Varying combinations of cardiovascular risk factors were present (Table 1) in all but one subject, a 32-year-old black male who presented with chronic stable angina, no cardiovascular risk factors and he had single-vessel disease at angiography. The two most common risk factors identified were smoking (82%) and dyslipidaemia (79%) (Table 1). The dyslipidaemia comprised hypercholesterolaemia (67.4%), hypertriglyceridaemia (63.7%) and low HDL-C (56.5%). In the 87 patients in whom LDL-C could be calculated by the Friedewald formula, 78 (90%) were found to have levels greater than 1.8 mmol/l (Table 2). The atherogenic combination of raised triglycerides (TG) and low HDL-C was found in 30 subjects.

Table 1. Demographic profile of the patients

Statistical analysis

Characteristics

Statistical Package for the Social Sciences (SPSS version 23.0) was used for data analysis. A 95% confidence interval (CI) was estimated and a global significance level of α = 5% was chosen. Simple descriptive analysis was used to identify clinical characteristics and present results as frequencies, means and percentages. The chi-squared test and Mann–Whitney U-test were used for categorical variables to determine the relationship between discontinuous variables or continuous variables in assessing the significance of risk factors between subjects with and without angiographic CAD. Binary logistic regression analysis was used to analyse confounding factors when assessing the independent relationships between risk factors and the outcome variable (CAD). A two-way ANOVA analysis was used to assess the effect of clinical criteria and other risk factors on the presence or absence of the metabolic syndrome and the likelihood of CAD.

Ethnicity

Results During the 10-year study period (January 2003 to December 2012), 7 575 subjects with CAD underwent coronary angiography.

Median age (years)

n = 100 33

Indian

White

Black

Coloured

Presentation STEMI

NSTEMI

Chronic stable angina Unstable angina Symptomatic bradycardia

6 14 1

Risk profile Smoking

Hypertension

Diabetes

Dyslipidaemia

Obesity

Family history

Illicit drug use

Retroviral disease

Systemic lupus erythematosus

NSTEMI: non-ST-segment elevation MI; STEMI: ST-segment elevation MI.

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There were 41 patients who were classified as overweight (BMI > 25 kg/m2, > 23 kg/m2 in Indians) and 30 subjects (30%) were classified as obese (BMI > 30 kg/m2). Increased waist circumference was found in 44 patients (42 males and two females). On applying the ethnic-specific harmonised criteria, 48 subjects (48%) were found to have the MetS. The most prevalent criteria in these subjects were waist circumference, impaired fasting glucose level and hypertriglyceridaemia (Table 3). Among the subjects without the MetS (n = 52), dyslipidaemia was present in over 40% and there was a high prevalence of overweight or obesity (65%), a positive family history for CAD (73%) and smoking (83%). Hypertension and diabetes mellitus were present in 28 and 26% of subjects, respectively. There were 20 known (type 1 diabetes mellitus, n = 1) and six newly diagnosed subjects with type 2 diabetes mellitus. On biochemistry, impaired fasting glucose (> 5.6 mmol/l) was present in a further 49 subjects, yielding a 75% prevalence of dysglycaemia in these subjects (Table 2). The average HbA1c level among subjects with known diabetes was 10.0%, indicating a poor level of glycaemic control in these subjects. Seventy-four (74%) subjects had a family history of CAD. Of these, a history of premature CAD in the immediate family Table 2. Biochemical profile of subjects Biochemical profile

Number

Percentage

Lipids TC > 4.5 mmol/l

62/92

TG > 1.7 mmol/l

58/91

HDL-C < 1 mmol/l (M), 1.2 mmol/l (F)

52/92

LDL-C > 1.8 mmol/l

78/87

Glucose Fasting glucose > 5.6 mmol/l

49/99

49.5

HbA1c > 6.5%

25/97

Hb < 13 g/dl (M), 12 g/dl (F)

10/100

Microalbuminuria

24/32

TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; HbA1c glycated haemoglobin; Hb: haemoglobin.

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[a first-degree relative under age 55 (males) or 65 (females)] was documented in 44 subjects. Non-conventional risk factors were found in 19 subjects. Of these, illicit drug use (n = 8), retroviral disease (n = 2) and alcohol excess (n = 2) were the main factors (Table 4). Of interest, there was one subject with systemic lupus erythematosus and one with hypothyroidism. Two patients had co-existing rheumatic valvular heart disease, but they did not have infective endocarditis or atrial fibrillation as predisposing factors for coronary embolism. Four of the five patients who were ≤ 25 years at the time of presentation, had a positive family history of premature CAD and dyslipidaemia (Table 5). The fifth subject was a 25-year-old black male patient with a history of smoking and illicit drug use who had normal epicardial coronary arteries at angiography. It was suspected that the aetiology in this patient was coronary spasm related to drug use. The youngest subject was a 20-year-old Indian male who presented with an anterior STEMI and was subsequently found to have non-occlusive disease on angiography with a kinked distal left anterior descending (LAD) artery. There was no evidence of hypertrophic obstructive cardiomyopathy (HOCM) in this case. One Indian patient, aged 25 years, had a long history of uncontrolled type 1 diabetes mellitus and hypertension. The remaining two subjects (22-year-old coloured and 24-year-old Indian males) had three-vessel disease at angiography. On clinical examination, signs of heart failure (elevated jugulovenous pressure, lower-limb oedema, pulmonary crepitations) were identified in 5% of subjects on presentation. Arrhythmias were identified in eight subjects, four with tachyarrhythmias [supraventricular tachycardia (n = 1), ventricular tachycardia (n = 1), ventricular fibrillation (n = 2)] and four with bradyarrhythmias [first-degree (n = 1), seconddegree (n = 2) complete heart block (n = 1)]. The admission electrocardiogram (ECG) revealed that the majority of patients (65%) had evidence of anterior ischaemia or infarction; further classified as anterior (n = 9), anterolateral Table 4. Non-conventional risk factors

Table 3. Characteristics of subjects with the metabolic syndrome Characteristics

MetS (n = 48)

No MetS (n = 52)

Total (n = 100)

MetS criteria

Non-coronary risk factors

Number

Drug use

Alcoholism

Valvular heart disease

WC > 94 (90)/80

HIV

BP > 130/80

SLE

FPG > 5.6

Oral contraceptives

TG > 1.7

Hypothyroidism

HDL < 1.0/1.2

Post-operative

Thrombophilia (suspected)

Other factors BMI > 25 (23)

Family history

Smoking

Gender Male Female Race Indian

White

Black

Coloured

WC: waist circumference; BP: blood pressure; FPG: fasting plasma glucose; TG: triglycerides; HDL: high-density lipoprotein; BMI: body mass index.

SLE: systemic lupus erythematosus.

Table 5. Risk-factor comparison across age groups Age range, years (n) Risk factors

20–25 (5)

26–30 (18)

31–35 (77)

Smoking, n (%)

1 (20)

12 (67)

69 (90)

Hypertension, n (%)

1 (20)

7 (39)

20 (26)

Diabetes, n (%)

1 (20)

3 (17)

22 (29)

Dyslipidaemia, n (%)

4 (80)

16 (89)

60 (78)

Obesity, n (%)

8 (44)

22 (29)

Family history, n (%)

4 (80)

12 (67)

58 (75)

Drugs, n (%)

1 (20)

2 (11)

7 (9)

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(n = 32) and anteroseptal (n = 24). Thirty per cent presented with inferior (n = 15), inferolateral (n = 13) or inferoposterior (n = 2) involvement. Fully evolved Q waves were identified in 63% of subjects, likely indicative of late presentation as none had a previous history of coronary events. Echocardiography revealed regional wall motion abnormalities in 83% of subjects; the ejection fraction (EF) was < 50% in 42%, with evidence of left ventricular thrombus in nine patients. Reversible ischaemia was identified in 19/29 (65%) subjects who underwent technetium (99mTC) SestaMIBI scanning. Coronary angiography revealed occlusive CAD (> 50% stenosis) in 78 subjects, while 20% had non-occlusive disease and the remaining two subjects had normal epicardial vessels. Single-vessel disease was present in 36 subjects, with the LAD artery being the most commonly involved vessel (n = 33, 92%). Multi-vessel disease was found in 42 subjects; of whom 27 had two-vessel disease (19 with LAD involvement) and 15 had threevessel disease. Among the 26 subjects with diabetes mellitus, angiography revealed most (n = 12) had multi-vessel disease, followed by singlevessel (n = 7) and non-occlusive disease (n = 6). Atherosclerotic coronary disease was present in five of the eight subjects with a history of illicit drug use. There were two subjects who had normal epicardial vessels at coronary angiography: one was the 25-year-old black male who had a history of illicit drug use including cocaine, and the second was a 34-year-old HIV-positive black male. Both subjects presented with anterior STEMI and received thrombolysis at their base hospitals prior to referral. To determine the association of various risk factors on the severity of stenosis or number of vessels affected, we conducted a Mann–Whitney U-test with stenosis severity or number of vessels as the dependent variable and major risk factors as the independent variable. Dyslipidaemia was associated with severity of stenosis (p = 0.002) as well as the number of vessels involved (p = 0.039). Low HDL-C was particularly associated with disease severity (p = 0.004). A positive family history was also found to be associated with both severity of stenosis (p = 0.002) and number of vessels involved (p = 0.001). Hypertension (p = 0.36), diabetes (p = 0.88), the MetS (p = 0.80) and smoking (p = 0.70) were not associated with disease severity. An association with severity and increased waist circumference (p = 0.08) and generalised obesity (p = 0.08) was shown but this was not significant. To determine the relationship between risk factors and occlusive CAD, a chi-squared test was conducted with dyslipidaemia, obesity, smoking, family history, hypertension, diabetes or the MetS as independent factors and occlusive CAD as the dependent factor. On bivariate analysis, a strong association between dyslipidaemia and occlusive CAD was observed (χ2 = 11.717, p = 0.001, RR = 5.52) while major risk factors such as hypertension (p = 0.30), diabetes (p = 0.59) smoking (p = 0.14), family history (p = 0.16) and the MetS (p = 0.93) were not associated with occlusive CAD. To determine the effect of the MetS in combination with other risk factors on the severity of CAD, a two-way ANOVA analysis was conducted with the coronary artery score as the dependent variable and the MetS as the grouping variable, along with various risk factors. Generalised obesity (BMI > 30 kg/m2) in combination with the MetS appeared to influence severity of stenosis (p = 0.004); however, a strong association was not demonstrated with smoking (p = 0.85) or family history of

CAD (p = 0.591). When assessed independently of the MetS, the combination of raised triglycerides and low HDL-C influenced severity of stenosis (p = 0.05) but not number of vessels involved (p = 0.33). To further assess the association of various risk factors with significant CAD, a binomial regression analysis was conducted with significant CAD as the dependent variable and gender, ethnicity, cardiovascular risk factors and the presence or absence of the MetS as covariates. For ethnicity, three dummy variables were created and compared with Indians as the baseline; similarly with regard to age, an age range of 20−24 years was taken as baseline for comparison, and 25−30 and 31−35 years were assigned dummy variables. Only dyslipidaemia showed a significant association with occlusive CAD (p = 0.008, OR: 0.21, 95% CI: 0.670–0.672).

Discussion In this study, young adults comprised 1.3% of subjects with CAD referred for coronary angiography, and the majority presented with acute coronary syndrome. While often regarded as a disease of advancing age, atherosclerotic changes in the coronary vessels have been documented early in adolescence,29 with changes in lifestyle and dietary habits30-32 contributing to CAD becoming clinically manifest early in the third decade of life,8 particularly among certain ethnic groups such as the Indian population.8-10 The observation that CAD prevalence differs significantly among ethnic groups is in agreement with earlier studies that have shown a 50% higher risk of CAD among expatriate Indians compared to other ethnic groups such as Hispanics and blacks,33 even after adjusting for lifestyle factors.34 The majority of subjects in our study were of Indian origin (79%), of whom 53 (81%) were diagnosed with occlusive CAD. The data are also in agreement with the CADI study, which estimated a higher risk of CAD among Indians.35 Our findings suggest that young patients are less likely to present with symptoms of stable angina,36 their first manifestation of CAD being most often an ACS, which untreated or unrecognised, progressed rapidly to MI, STEMI in particular.37,38 Up to two-thirds of young subjects deny a history of chest pain prior to MI;39 when present, angina symptoms have been reported to occur most often in the week preceding the event.37 A study of 200 subjects under 45 years of age with angiographic CAD found a lower incidence of stable angina (24%) and a higher incidence of ACS (76%) compared to subjects over 60 years, with a higher likelihood of complex lesions on angiogram.38 Similar to previous studies in young subjects,40-43 smoking was highly prevalent in our sample, and conferred a greater risk (OR 2.9) among Indian and white subjects. Our findings also confirm a male preponderance in young subjects with CAD,37,44,45 which has been attributed the higher prevalence of smoking among young men and to non-modifiable factors such as the protective effect of oestrogen in women.25 The 82% prevalence of smoking in our study is in keeping with registry data of patients with STEMI undergoing percutaneous coronary intervention (PCI) where smoking rates were highest among the age range of 18–34 years (78%) compared both to older age groups and the general population of similar age (23%).46 Since other cardiovascular risk factors were also highly prevalent in our study, it is likely that

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smoking acted in concert with these factors to result in CAD. Our study supports the finding that clustering of major cardiovascular risk factors predominates in young patients with CAD.47,48 In addition to smoking, dyslipidaemia (80%) and a positive family history of CAD (74%) were the most frequent risk factors identified. Analysis of the lipid profile showed that elevated LDL-C was present in 90% of the 87 subjects in whom it could be calculated. The atherogenic lipid profile of raised triglycerides and low HDL-C levels was present in 30% of the sample, and 30% were classified as obese. Major risk factors including hypertension and diabetes mellitus (28 and 26%, respectively) were frequently present in this young cohort of subjects with PCAD, compared to previous studies of older subjects in this population.49 Of importance, we have noticed the emergence of illicit drug use (cannabis, heroin, cocaine and the local street drug ‘sugars’ containing a mixture including cocaine residue) as a contributory risk factor in 8% of subjects. The third most prevalent risk factor among our subjects was a positive family history of CAD (74%), which influenced both the extent and severity of CAD (p = 0.045 and p = 0.002, respectively). It is well documented that young subjects with CAD more often have a positive family history than middle-aged or elderly patients,50-53 with contributions to this increased risk from both genetic and environmental factors. In a cohort similar to ours, Ranjith et al. found a family history of premature CAD in 54% of South African Indians with MI.11 Parental CAD was a strong predictor of MI in offspring in the INTERHEART study, suggesting that in addition to possible genetic factors, similar environmental exposure contributed to type 2 diabetes mellitus, hypertension and obesity and the increased cardiovascular risk.46,51 Our findings of high prevalence of visceral obesity, high triglyceride and low HDL-C levels, together with elevated LDL-C and dysglycaemia, suggest environmental factors as a major contributor to the emergence of PCAD in young adults in their third decade of life. The combination of subtle abnormalities of glucose metabolism12 with clustering of other risk factors that comprise the MetS has been recognised as a significant predictor of CAD.54 The prevalence of the MetS has been documented to differ significantly among ethnic groups54 and between age groups, rising from less than 10% in the 20–29-year age group to between 38 and 67% in the 60–69-year age group.55 Almost half the subjects in our study (48%) met the modified IDF criteria27 for the MetS. In a previous study, Ranjith et al. assessed the prevalence of the MetS among young (< 45 years) South African Indian subjects with MI using the NCEP ATP III and IDF criteria, and found between 57 and 60% of subjects met the criteria respectively.56 This study suggested that use of the modified IDF ethnic-specific waist circumference cut-off points as the determinant of abdominal obesity was more useful to accurately identify patients in this population group. Waist circumference was the main driver (44/48) for the MetS in our study, reflecting visceral adipose tissue as a major contributor to the increased risk of hyperinsulinaemia, insulin resistance, diabetes and dyslipidaemia in this population.55 Our finding of higher coronary artery severity (CAS) scores in association with a positive family history of PCAD and

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dyslipidaemia (low HDL-C in particular) is in agreement with earlier observations.57 A strong association has been shown between dyslipidaemia and the presence of occlusive CAD (p = 0.004), as well as severity of disease (p = 0.002). Although type 2 diabetes mellitus is known to be a strong predictor of CAD, particularly among groups usually considered ‘low risk’, such as young patients, women and non-smokers,58 it did not influence the extent (p = 0.56) or severity of disease (p = 0.88) in our study, probably due to the shorter duration of diabetes in our cohort of younger subjects, less than 35 years. In contrast to previous studies that have shown the MetS to be associated with extensive (three-vessel) disease,56 neither smoking nor the presence of the MetS contributed significantly to the severity of CAD. Multi-vessel involvement was a characteristic angiographic pattern in our study, with only a third of subjects having single-vessel disease, in contrast to the findings of the CASS study, which found a higher frequency of non-occlusive and single-vessel disease in young subjects,37 The LAD was the most frequently involved coronary vessel in both groups, as noted in a previous study.59

Limitations Our study was limited to a specific geographical area and, more specifically, to a single tertiary referral centre but cases were referred from throughout the province of KwaZulu-Natal. We found a much higher prevalence of PCAD among Indians, and although this ethnic group does not represent a majority in the province concerned, the community is largely concentrated in the Durban area. Because of a small sample size, we could not undertake age and gender matching across race groups, limiting comparisons on gender and ethnic differences in risk factors. Fewer ‘conventional’ cardiovascular risk factors, common in the older population, were found to have a statistically significant relationship with PCAD in very young patients. Among the factors that may have contributed to this indeterminate result include the age range studied and the sample size, which was not gender matched.

Conclusion This study shows that over two-thirds of young subjects referred to a tertiary centre for coronary angiography due to acute ischaemic chest pain symptoms had atherosclerotic multi-vessel disease. The predominance of major modifiable risk factors suggests high environmental exposure in young adults and calls for early lifestyle changes, beginning at school-going age.

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282–289. 33. Amin AP, Nathan S, Evans AT, et al. The effect of ethnicity on the relationship between premature coronary artery disease and traditional cardiac risk factors among uninsured young adults. Prev Cardiol 2009; 12(3): 128–135. 34. Enas EA. High rates of CAD in Asian Indians in the United States despite intense modification of lifestyle: what next. Curr Sci 1998; 74(12): 1081–1086. 35. Enas EA, Senthilkumar A. Coronary artery disease in Asian Indians: an update and review. Coron Artery Dis 2005; 3: 21–57. 36. Doughty M, Mehta R, Bruckman D, et al. Acute myocardial infarction in the young – The University of Michigan experience. Am Heart J 2002; 143:56. 37. Fournier J, Sanchez A, Quero J, Fernandez CJ, González B. Myocardial infarction in men aged 40 years or less: A prospective clinical angiographic study. Clin Cardiol 1996; 19(8): 631–636. 38. Chen L, Chester M, Kaski JC. Clinical factors and angiographic features associated with premature coronary artery disease. Chest 1995; 108(2): 364–369. 39. Klein LW, Agarwal JB, Herlich MB, et al. Prognosis of symptomatic coronary artery disease in young adults aged 40 years or less. Am J Cardiol 1987; 60: 1269. 40. Christus T, Shukkur A, Rashdan I, et al. Coronary artery disease in patients aged 35 or less – a different beast? Heart Views 2011; 12(1): 7. 41. Rissam H, Kishore S, Trehan N. Coronary artery disease in young

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23. AlKoubaisyl OK, Mehdi RS, Arem FD, Ahmed IT. Cine angiographic

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Study. Am Heart J 1987; 113(4): 1006–1010. 44. McGill HC, McMahan CA, Herderick EE, et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 2002; 105(23): 2712–2718. 45. Chua SK, Hung HF, Shyu KG, et al. Acute ST-elevation myocardial infarction in young patients: 15 years of experience in a single center. Clin Cardiol 2010; 33(3): 140–148. 46. Larsen GK, Seth M, Gurm HS. The ongoing importance of smoking as a powerful risk factor for ST-segment elevation myocardial infarction in young patients. J Am Med Assoc 2013; 173(13): 1261–1262. 47. Ranjith N, Pegoraro R, Rom L, Rajput M, Naidoo D. Lp (a) and apoE polymorphisms in young South African Indians with myocardial infarction. Cardiovasc J S Afr 2003; 15(3): 111–117. 48. Tillin T, Dhutia H, Chambers J, et al. South Asian men have different patterns of coronary artery disease when compared with European men. Int J Cardiol 2008; 129(3): 406–413.

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52. Otaki Y, Gransar H, Berman DS, et al. Impact of family history of coronary artery disease in young individuals (from the CONFIRM registry). Am J Cardiol 2013; 111(8): 1081–1086. 53. Bao W, Srinivasan SR, Wattigney WA, Berenson GS. The relation of parental cardiovascular disease to risk factors in children and young adults: The Bogalusa Heart Study. Circulation 1995; 91(2): 365–371. 54. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002; 287: 356–359. 55. Azizi F, Salehi P, Etemadi A, et al. Prevalence of metabolic syndrome in an urban population: Tehran Lipid and Glucose Study. Diabetes Res Clin Pract 2003; 61: 29–37. 56. Ranjith N, Pegoraro RJ, Naidoo DP, Esterhuizen TM. Metabolic syndrome in young Asian Indians with myocardial infarction. Cardiovasc J Afr 2007; 18: 228–233. 57. Wadhwa A, Avasthi R, Ghambhir J, Dwivedi S. To study the prevalence

49. Seedat YK, Mayet FGH, Khan S, Somers SR, Joubert G. Risk factors

and profile of metabolic syndrome, levels of hs-CRP, LP(a) and serum

for coronary heart disease in the Indians of Durban. S Afr Med J 1990;

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78: 447–454.

infarction. J Assoc Phys India 2013; 61(6): 384–386.

50. Bachmann JM, Willis BL, Ayers CR, Khera A, Berry JD. Association

58. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and

between family history and coronary heart disease death across

long-term cardiovascular and noncardiovascular mortality and life

long-term follow-up in men: the Cooper Center Longitudinal Study.

expectancy: findings for 5 large cohorts of young adult and middle-aged

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men and women. J Am Med Assoc 1999; 282(21): 2012–2018.

51. Chow CK, Islam S, Bautista L, et al. Parental history and myocardial

59. Wolfe M, Vacek J. Myocardial infarction in the young. Angiographic

infarction risk across the world: the INTERHEART Study. J Am Coll

features and risk factor analysis of patients with myocardial infarction

Cardiol 2011; 57(5): 619–627.

at or before the age of 35 years. Chest 1988; 94(5): 926–930.

Stroke history higher in asymptomatic versus symptomatic atrial fibrillation patients Newly diagnosed asymptomatic atrial fibrillation patients have a higher rate of previous stroke than those with symptoms, according to results from the GLORIA-AF registry presented recently at EHRA Europace – CardioSTIM 2017. The findings highlight the need for screening to identify atrial fibrillation patients with no symptoms so that stroke prevention treatment can be given. ‘Patients with non-valvular atrial fibrillation have a fivefold increased risk of stroke compared to those without atrial fibrillation,’ said lead author Dr Steffen Christow, a cardiologist at Hospital Ingolstadt GmbH, Ingolstadt, Germany. ‘Strokes in patients with non-valvular atrial fibrillation tend to be particularly severe and disabling, with about half of patients dying within one year.’ ‘Appropriate anticoagulant therapy substantially reduces the risk of stroke, but in many cases non-valvular atrial fibrillation is only diagnosed after a patient has had a stroke,’ he continued. ‘When patients are unaware of their atrial fibrillation they remain untreated and unprotected from stroke.’ GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a large, multinational, prospective registry programme involving patients with newly diagnosed non-valvular atrial fibrillation. This sub-analysis compared characteristics between symptomatic and asymptomatic patients in Western Europe. The study included 6 011 consecutively enrolled patients with non-valvular atrial fibrillation in Western Europe. Symptom status was defined by the European Heart Rhythm

Association (EHRA) score: I–II asymptomatic/minimally symptomatic; III–IV symptomatic. A total of 4 119 patients (two-thirds) were asymptomatic/ minimally symptomatic (hereafter referred to as ‘asymptomatic’) and one-third (1 892) were symptomatic at the time of diagnosis. A number of differences were observed between the two groups. In terms of medical history, asymptomatic patients were twice as likely to have permanent atrial fibrillation (15.8 vs 8.3%) and more than twice as likely to have had a previous stroke (14.7 vs 6.0%) than patients in the symptomatic group. Asymptomatic and symptomatic patients had a similar number of stroke risk factors, as indicated by a CHA2DS2VASc score of 3.3 in each group. Dr Christow said: The finding of a higher rate of previous stroke in the asymptomatic patients despite no differences in the number of stroke risk factors may be explained by a longer but undiagnosed history of atrial fibrillation.’ ‘Our study found that in Western Europe, two-thirds of patients newly diagnosed with atrial fibrillation were asymptomatic,’ he continued. ‘Without detection, patients may not receive appropriate preventive therapy and remain at increased risk of stroke.’ Dr Christow concluded: ‘These results underline the urgent need for public programmes to detect atrial fibrillation in the general population.’ Source: European Society of Cardiology Press Office

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Coronary stent restenosis and the association with allergy to metal content of 316L stainless steel D Slodownik, C Danenberg, D Merkin, F Swaid, S Moshe, A Ingber, H Lotan, R Durst

Abstract Background: Most intra-coronary stents in use are made of 316 L stainless steel, which contains nickel, chromate and molybdenum. Whether inflammatory and allergic reactions to metals contribute to in-stent restenosis is still a matter of debate. Aim: The aim of this study was to ascertain the relationship between metal allergy and the occurrence of in-stent restenosis. Methods: Ninety-nine adult patients who underwent two cardiac catheterisations, up to two years apart, were included in the study. Seventy patients had patent stents at the second angiogram (patent stent group) and 29 were found to have in-stent restenosis (restenosis group). All patients underwent patch testing with the relevant metals and the 316L stainless steel plate. Results: Twenty-eight (28.3%) patients were found to have an allergy to at least one metal. There was no significant difference in the prevalence of metal allergy between the patent stent group and the restenosis group (28.6 and 27.6%, respectively; p = 0.921). Conclusion: Our data do not support the theory that contact allergy plays a role in the pathogenesis of in-stent restenosis. Keywords: stent restenosis, metal allergy, stainless steel Submitted 14/2/17, accepted 13/7/17 Cardiovasc J Afr 2018; 29: 43â&#x20AC;&#x201C;45

www.cvja.co.za

DOI: 10.5830/CVJA-2017-036

Risk factors for in-stent restenosis, such as diabetes mellitus, diameter of the treated artery, length of the lesion and localisation are well known. In-stent restenosis (ISR) results from excessive

Department of Dermatology, Hadassah Hebrew University Medical Centre, Jerusalem, Israel D Slodownik, MD, dans@tlvmc.gov.il F Swaid, MD A Ingber, MD

Cardiology Division, Hadassah Hebrew University Medical Centre, Jerusalem, Israel C Danenberg, MD D Merkin, MD H Lotan, MD R Durst, MD

Sackler Faculty of Medicine, School of Public Health, Department of Environmental and Occupational Health, Tel Aviv University, Tel Aviv, Israel S Moshe, MD

fibroproliferative and inflammatory responses to the insult on the arterial wall, leading to neo-intimal proliferation. Hypersensitivity reaction to metals may be part of the inflammatory process and one of the triggering factors in ISR.1 Contact allergy is a common health concern worldwide, with an estimated 15 to 20% of Western populations being hypersensitive to at least one metal allergen.2 Recently, much progress has been made regarding the mechanisms underlying inflammatory responses to this unique group of contact allergens, including innate immune activation and T-cell activation by common metal allergens, such as nickel, cobalt, palladium and chromate.3 Koster and co-workers1 were the first to demonstrate a higher incidence of ISR in patients with delayed hypersensitivity to metals, especially to nickel and molybdenum. Two years later, Hillen et al.4 published a study that showed no significant differences in the incidence of restenosis in patients with hypersensitivity to metals, compared to patients without hypersensitivity to metals. Similarly, Iijima5 demonstrated that metal allergy was not associated with restenosis after initial stent implantation. However, metal allergy was frequently observed in patients with ISR recurrence. Given the impact of ISR on coronary patient morbidity and mortality rates, and given the contradictory data available in the current literature, we conducted a caseâ&#x20AC;&#x201C;control study aimed at identifying an association between metal allergy and ISR.

Methods An informed, written consent was obtained from all patients. The study received the approval of the local institutional review board for human research. Ninety-nine patients aged 18 years and older, who underwent at least two coronary artery catheterisations within a period of two years at the Department of Cardiology, Hadassah University Hospital in Jerusalem, were enrolled into the study. A bare-metal stent was implanted in one coronary vessel during the first catheterisation. The second catheterisation was performed to assess the degree of restenosis. Catheterisation was performed, using the Seldinger technique, through the femoral artery with 6F standard catheters. In case of intervention, a guiding catheter was introduced over a wire. Stent implantation was usually performed after balloon predilatation. Patients were divided into two groups as follows. The study group consisted of 29 patients who underwent implantation of at least one stent at the first catheterisation and were found to have ISR during the second catheterisation. The control group consisted of 70 patients who underwent implantation of at least one stent at the first catheterisation and were found to have a patent lumen during the second catheterisation. The presence or absence of ISR was determined by the cardiologists who performed the catheterisation. Significant stenosis was defined as stenosis of 50% or more of the coronary

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Table 1. Characteristics of the study and control group individuals Study group (n = 29)

Control group (n = 70)

p-value

64.7 ± 7.2

62.9 ± 5.8

0.6003

Diabetes

11 (38)

27 (39)

0.827

Hypertension

14 (48)

31 (44)

0.713

Smoking

16 (55)

34 (49)

0.557

8 (28)

17 (24)

0.689

14 (48)

36 (51)

0.778

Characteristic Age

Female Hyperlipidaemia

lumen. Table 1 shows the patients’ characteristics. All stents were made of 316L stainless steel. Exclusion criteria included insertion of drug-eluting stents, immunosuppressive therapy, pregnancy, and marked cutaneous inflammation, especially at the patch testing site. Neither the study nor the control group included HIV-infected patients. Three patients in the study group and five in the control group had a prior history of metal allergies. All patients were tested with the metals listed in Table 2. They were patch tested using allergens from Chemotechnique Diagnostics® (Malmö, Sweden). Patches were applied onto the patient’s upper back using Finn Chambers® on Scanpor® (Epitest OY, Tuusula, Finland). All patients were tested for reactions, which were read at D2/3 and D4/5 using ICDRG criteria.6 We used the chi-squared test in order to determine differences between the groups. Statistical significance was determined at a value of p ≤ 0.05.

Results The two study groups did not display any significant differences in terms of age, gender, diabetes, hypertension, lipid profiles and smoking status (Table 1). The data from the patch test reactions are provided in Table 3. Of the 99 patients included in the study, 28 (28.3%) had at least one reaction to the tested metals. There were a total of 40 positive reactions in both groups. The most common reactions were to nickel, followed by chromate and cobalt. Four of the patients had reactions to both nickel and cobalt. Table 4 shows the distribution of the positive reactions to metals among the two study groups. Metal sensitivity rate between the two groups did not differ significantly (p = 0.921).

Discussion Grade 316 is the standard molybdenum-bearing grade, second in overall volume production to grade 304 among the austenitic stainless steels. The molybdenum gives grade 316 better overall corrosion-resistant properties than grade 304, particularly higher resistance to pitting and crevice corrosion in chloride

Table 3. Distribution of positive reactions Metal

No of positive reactions

% of total positive reactions

Nickel

37.5

% of study and control groups 15.1

Chromate

Cobalt

12.5

Manganese

Molybdenum 0.25%

Molybdenum 0.5%

12.5

Stainless steel

2.5

Total positive reactions

100

40.1

environments. Grade 316L, the low-carbon version of 316, has high resistance to sensitisation.7 Over a decade has passed since Koster suggested metal allergy may play a role in the pathogenesis of ISR. Follow up on studies4,5,8,9 of ISR in patients who had received stainless steel stents did not confirm Koster’s initial observations. A recent report from Turkey showed a correlation between nickel allergy and ISR among patients who were treated with cobalt chromium stents, which have a three times higher concentration of nickel than 316L stainless steel stents.10 It has been speculated that nickel ions may influence expression of the adhesion molecule ICAM-1 in endothelial cells,11 which in turn may trigger local inflammation and lead to ISR. By contrast, Thyssen et al.12 studied a large cohort of patients with pre-existing nickel allergy and found that these individuals did not appear to have a higher risk for ISR. In comparison with the above studies, both our study and control groups had higher positive reaction rates to nickel and chromate. This comes as no surprise as metal allergy is more common in Israel,13,14 compared to Europe and North America.15,16 Legislative and market-related factors result in higher metal sensitisation rates in Israel. There were no significant differences, however, between our study and control groups. Our results are in line with most earlier studies and do not support a role for nickel, cobalt, chromate or molybdenum allergy in ISR. Conversely, recent convincing data demonstrate that gold allergy is a contributing factor to ISR. It is possible that gold, which is a more potent sensitiser than nickel,17 may induce a stronger immunological reaction, resulting in endothelial proliferation. The weaknesses of our study, as of previously published reports, are its relatively small size and its retrospective design. We suggest the need for larger, prospective, confirmatory cohort studies of patients with ISR.

Table 4. Distribution of metal sensitivity in both study groups Table 2. Patch-tested metals in the study

Metal

Study group (n = 29)

Control group (n = 70)

p-value

Nickel

0.641

petrolatum

Chromate

0.383

0.5

petrolatum

Cobalt

0.491

Molybdenum chloride

0.25

petrolatum

Manganese

0.553

Molybdenum chloride

0.5

petrolatum

Molybdenum 0.25%

0.935

petrolatum

Molybdenum 0.5%

0.491

petrolatum

Stainless steel

0.172

0.556

Material

Concentration (%)

Vehicle

Nickel sulphate

Potassium dichromate

Manganese oxide Cobalt chloride 316L stainless steel

–

as is

Total positive reactions

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Conclusion

243–246.

Our data do not support the role of contact allergy in the pathogenesis of in-stent restenosis.

The study was done as part of Dr Swaid’s MD thesis

10. Aliağaoğlu C, Turan H, Erden I, et al. Relation of nickel allergy with

El-Mawardy R, Fuad H, Abdel-Salam Z, et al. Does nickel allergy play a role in the development of in-stent restenosis? Eur Rev Med Pharmacol Sci 2011; 15: 1235–1240. in-stent restenosis in patients treated with cobalt chromium stents. Ann

References 1.

Dermatol 2012; 24: 426–429. 11. Messer RL, Wataha JC, Lewis JB, et al. Effect of vascular stent alloys on expression of cellular adhesion molecules by endothelial cells. J Long

Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact

Term Eff Med Implants 2005; 15: 39–47.

allergies in patients with coronary in-stent restenosis. Lancet 2000: 356: 1895–1897. 2.

12. Thyssen JP, Engkilde K, Menné T, et al. No association between metal allergy and cardiac in-stent restenosis in patients with dermatitis-results

Duarte I, Amorim JR, Perizzio EF, Schmitz R. Metal contact dermati-

from a linkage study. Contact Dermatitis 2011; 64(3): 138–141.

tis: Prevalence of sensitization to nickel, cobalt and chromium. An Bras Dermatol 2005: 80(2): 137–142. 3.

13. Lazarov A, David M, Abraham D, Trattner A. Comparison of reactivity to allergens using the TRUE test and IQ chamber system. Contact

Schmidt M, Goebeler M. Immunology of metal allergies. J Dtsch

Dermatitis 2007; 56: 140–145.

Dermatol Ges 2015: 13: 653–660. 4. 5.

Hillen M, Haude, R Erbel, M Goos. Evaluation of metal allergies in

14. Ingber A, Gaamelgaard B, David M. Detergents and bleaches are

patients with coronary stents. Contact Dermatitis 2002; 47: 353–356.

sources of chromium contact dermatitis in Israel. Contact Dermatitis

Iijima R, Ikari Y, Amiya E, et al. The impact of metallic allergy on stent

1998; 38: 101–104.

implantation. Metal allergy and recurrence of in-stent restenosis. Int J

15. Geier J, Uter W, Lessmann H, Schnuch A. Current contact alergens. Hautarzt 2011; 62: 751–756.

Cardiol 2005; 104: 319–325. 6.

Wilkinson D, Fregert S, Magnusson B, et al. Terminology of contact

Jurczyk M. Bionanomaterials for Dental Applications. Singapore: Pan

16. Zug KA, Warsaw EM, Fowler JF, et al. Patch test results of the North American Contact Dermatitis group 2005–2006. Dermatitis 2009; 20:

dermatitis. Acta Dermatol Venereol 1970; 50: 287–292. Stanford, 2013: 36–37. 8.

149–160. 17. Schneider K, Akkan Z. Quantitative relationship between the local

Norgaz T, Hobikoglu G, Serdar ZA, et al. Is There a link between nickel

lymph node assay and human skin sensitization assays. Regul Toxicol

allergy and coronary stent restenosis? Tohoku J Exp Med 2005; 206:

Pharmacol 2004; 39: 245–255.

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 1, January/February 2018

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Short-term rehospitalisation or death and determinants after admission for acute heart failure in a cohort of African patients in Port Harcourt, southern Nigeria Maclean R Akpa, Okechukwu Iheji

Abstract Background: Heart failure (HF) is a major health burden globally and contributes significantly to morbidity and mortality related to cardiovascular disease. The aim of this study was to determine the outcome, and factors determining these outcomes in patients admitted for acute HF and followed up for six months. Methods: This was a hospital-based, prospective study. Subjects included consecutive patients with a confirmed diagnosis of acute HF admitted to the medical wards of the University of Port Harcourt Teaching Hospital (UPTH) in Nigeria over one year. All had a full physical examination and relevant investigations, including echocardiography. Subjects were followed up for six months and reassessed for outcome/ endpoint, which was rehospitalisation or death. Factors that predicted these outcomes were also determined. Results: There were 160 subjects, 84 females and 76 males, age range 20 to 87 years, mean age 52.49 ± 13.89 years. Sixteen subjects (10.0%) were lost to follow up, 66 (41.3%) showed clinical improvement, 57 (35.6%) were rehospitalised, while 21 (13.1%) died. Determinants of rehospitalisation were New York Heart Association (NYHA) class, heart failure type, haemoglobin level at presentation and estimated glomerular filtration rate (eGFR). Determinants of mortality were NYHA class and haemoglobin level at presentation. Conclusion: Heart failure rehospitalisation and mortality rates of 35.6 and 13.1%, respectively, were high compared to developed countries. Keywords: heart failure, outcomes, rehospitalisation, mortality Submitted 17/8/16, accepted 12/8/17 Cardiovasc J Afr 2018; 29: 46–50

www.cvja.co.za

DOI: 10.5830/CVJA-2017-038

Heart failure (HF) is the end stage of most diseases of the heart and a major cause of morbidity and mortality. Thomas Lewis aptly captured the high premium placed on HF as far back as 1933 Cardiovascular Division, Department of Internal Medicine, Faculty of Clinical Sciences, University of Port Harcourt, Port Harcourt, Nigeria Maclean R Akpa, MB BS, FWACP; FRCP (Lond), akpamac@yahoo. com; macakpa12@gmail.com; maclean.akpa@uniport.edu.ng

Cardiovascular Division, Department of Internal Medicine, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria Okechukwu Iheji, MB BCh, FWACP

when he remarked, ‘The very essence of cardiovascular practice is the early detection of heart failure’.1 The worldwide prevalence and incidence rates of HF are approaching epidemic levels, as evidenced by the increasing number of HF hospitalisations and HF-attributable mortalities, as well as the high costs associated with the care of HF patients.2 Worldwide, HF affects almost 23 million people,2 with nearly five million people in the United States3 and up to three million people in the United Kingdom being affected.4 It is estimated to account for about 5% of admissions to hospital medical wards, with over 100 000 annual admissions in the United Kingdom.1 The financial burden of HF in most countries is very substantial. In the United States about $37.2 billion was spent directly or indirectly on HF management in 2009, with $20.1 billion of the expenditure largely related to hospitalisation.5 In Africa, HF has become a dominant form of cardiovascular disease, with great social and economic consequences due to its high prevalence and mortality rate, and the impact on young, economically active individuals.5 The peak incidence of HF in African patients remains in the fifth decade,6 and hospital case fatality rates range from nine to 12.5%.7 This high death rate ranks HF among the major causes of death of cardiovascular origin in Africa.7 In Port Harcourt, Niger delta region of Nigeria, HF was the third commonest non-communicable cause of admission (next to diabetes and its complications and cerebrovascular disease) and contributed 9.6% of patients admitted to the medical wards over a five-year period.8,9 The prognosis of HF is uniformly poor. The one-year mortality rate in patients with severe HF (NYHA class IV) is between 30 and 70%, and in patients with HF in NYHA classes I–III, the annual mortality rate is five to 10%.10,11 Other important variables that have been found to influence the outcome in HF patients include co-morbidities, estimated glomerular filtration rate (eGFR) and haemoglobin level, left ventricular function, as well as treatment or interventions received.12-15 Identifying the predictors of rehospitalisation and mortality among HF patients is vital in helping physicians to risk stratify their HF patients and chart the best possible post-discharge plan.16 There is however a dearth of data on the outcome profile of patients admitted with HF in the Niger delta region of Nigeria. The aim of this study was to determine the short-term (six-month) outcome and factors influencing these outcomes in patients admitted with acute HF in Port Harcourt, southern Nigeria.

Methods The was a hospital-based, prospective study carried out in the medical wards of the University of Port Harcourt Teaching Hospital (UPTH), Port Harcourt, Niger delta region of Nigeria.

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All the patients admitted to the medical wards with a confirmed diagnosis of acute heart failure (AHF) from 1 January to 31 December 2014 were recruited. The patients were selected if they met the Framingham clinical criteria17 for the diagnosis of HF and confirmed on echocardiography. Demographic data were obtained from all patients aged 18 years and older who gave written, informed consent. The hospital’s ethics committee approved the study. The NYHA functional class, and baseline clinical and demographic characteristics of patients were obtained using a structured questionnaire. All study subjects underwent full clinical examinations, anthropometric measurements and relevant investigations, including chest radiography, electrocardiogram and echocardiogram. Blood pressure was measured with a standard mercury sphygmomanometer (cuff size 12.5 × 40 cm) using standard protocols. Systolic and diastolic blood pressures were taken at Korotkoff phases 1 and 5, respectively, to the nearest 2 mmHg.18 Hypertension was deemed present if systolic blood pressure was 140 mmHg or above and/or diastolic blood pressure was 90 mmHg or above on at least two occasions, or if the patient was receiving anti-hypertensive drug treatment.18 Waist circumference was measured in centimetres at the midpoint between the lower costal margin and the iliac crest, with the patient standing and the feet positioned close together. The value was read at the end of a normal expiration.19 Waist circumference was considered increased if greater than 88 cm in women and 102 cm in men.19 Hip circumference was measured similarly but at the level of the greater trochanter. Waist–hip ratio was calculated using the formula: waist (cm)/hip (cm).19 Weight was measured with a mechanical weighing scale with the subject wearing only light clothing, and height was measured using a stadiometer with the subject standing with feet together, without shoes or head gear. The reading was taken to the nearest 0.5 cm. Body mass index (BMI) was calculated using the formula weight (kg)/height2 (m). BMI status was classified according to the WHO criteria as normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), class I obesity (30.0–34.9 kg/m2), class II obesity (35.0–39.9 kg/m2), and morbid obesity (≥ 40 kg/m2).19 Blood samples were collected from all patients and analysed for haemoglobin level, fasting lipid profile, and serum urea, creatinine and plasma glucose levels. Serum creatinine level was used to calculate the eGFR with the Cockcroft–Gault formula.20 Severity of renal impairment was classified using the National Kidney Foundation-developed criteria as part of its Kidney Disease Outcomes Quality Initiative (NKF KDOQI) to stratify chronic kidney injury.21 Fasting serum cholesterol and triglyceride levels were measured using the enzymatic method with a reagent from Atlas Medical Laboratories. Fasting high-density lipoprotein (HDL) cholesterol was measured with the precipitation method. Low-density lipoprotein (LDL) cholesterol values were calculated using the Friedwald equation when the triglyceride level was less than 4.0 mmol/l: LDL = TC – (HDL + TG /2.2).22 Standard 12-lead elctrocardiography was performed for all patients and the parameters assessed included presence of atrial fibrillation, pathological Q waves, left ventricular hypertrophy, QT prolongation and ST abnormalities. Transthoracic echocardiography was performed on all the subjects and assessments were done according to the recommendations of the American Society of Echocardiography.23

Left ventricular (LV) systolic performance was assessed using fractional shortening (FS) and the ejection fraction (EF) of the left ventricle. These were calculated automatically by the machine using the Teichoiz formula.24 Left ventricular mass (LVM) was calculated using the American Society of Echocardiography recommended formula for estimation of LV mass from LV linear dimensions.25 Left ventricular mass index (LVMI) was calculated by indexing the LVM to the body surface area. Left ventricular hypertrophy (LVH) was defined in absolute terms as LVMI > 115 g/m2 in men and > 95 g/m2 in women.25 LV diastolic function was evaluated by studying the filling dynamics of the left ventricle, the isovolumetric relaxation time (IVRT), pulmonary venous flow and tissue Doppler imaging-derived myocardial wall velocities.26 All the study patients were followed up for six months or until death if the patient died before six months of follow up. They were assessed during follow up by telephone contacts if they did not keep out-patient appointments. The primary endpoints were death due to any cause and rehospitalisation. The duration of follow up was defined as the interval from the date of the index examination at which the echocardiogram was obtained to the date of death or the date of last contact. During six months of follow up, clinical and echocardiographic parameters were obtained and compared with initial values.

Statistical analysis Data were analysed using the Statistical Package for Social Sciences (SPSS) version 20.0. Results are presented as mean ± standard deviation for continuous variables, while categorical variables are expressed as proportions or percentages. Tables are used to illustrate results where appropriate. Continuous variables were compared by the Student’s t-test, while proportions or categorical parameters were compared with the chi-squared test or two-tailed Fisher’s exact test, as appropriate. Logistic regression analysis was done where appropriate. A p-value of less than 0.05 was considered statistically significant.

Results A total of 160 patients, 84 females and 76 males, were studied over the study period. The age range was 20 to 87 years with a mean age of 52.49 ± 13.89 years. A total of 16 subjects (10%) were lost to follow up, 66 subjects (41.3%) improved clinically and continued their regular out-patient clinic attendance for six months, 57 subjects (35.6%) were rehospitalised for worsening of HF symptoms, while 21 subjects (13.1%) died. The socio-demographic profile of the patients did not have any significant effect on rehospitalisation and mortality. There was a significant association between rehospitalisation and NYHA class, type of HF (systolic or diastolic HF), BMI, haemoglobin level, LVEF and eGFR (Table 1). However, when the effects of confounding variables were removed using the logistic regression model, the real determinants of rehospitalisation were NYHA class, type of heart failure, haemoglobin level and eGFR (Table 2). There was a significant association between mortality and NYHA class, haemoglobin level and LVEF (Table 3). However after logistic regression analysis, only NYHA class and haemoglobin level at presentation were the real determinants of mortality (Table 4).

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Table 1. Association of different variables with rehospitalisation Rehospitalisation Variable

No n (%)

Yes n (%)

Total n

Gender

Table 2. Result of logistic regression analysis of some variables with rehospitalisation Variable

Chi (p-value)

NYHA class

1.033 (0.309)

Class II

–

< 0.001

0.296

Male

52 (68.4)

24 (31.6)

Class III

1.022

0.271

Female

51 (60.7)

33 (39.3)

Class IV

2.819

< 0.001*

Type of HF

2.711

0.032*

18–45

26 (52.0)

24 (48.0)

45–65

56 (70.9)

23 (29.1)

< 24.99

> 65

21 (67.7)

10 (32.3)

25–29.99

0.158

0.812

≥ 30

0.635

0.285

1.432

0.012*

Age group (years)

4.95 (0.084)

Level of education

BMI (kg/m2)

0.24 (0.623)

None/primary

29 (67.4)

14 (32.6)

Secondary/tertiary

74 (63.2)

43 (36.8)

117

NYHA class at presentation 39 (90.7)

4 (9.3)

Class III

44 (47.8)

48 (52.2)

Class IV

20 (80.0)

5 (20.0)

Type of HF

< 10 g/dl

14 (93.3)

1 (6.7)

Systolic HF

89 (61.4)

56 (38.6)

145

≤ 24.99

34 (64.2)

19 (35.8)

25–29.99

35 (52.2)

32 (47.8)

≥ 30

34 (85.0)

6 (15.0)

≥ 10

84 (69.4)

37 (30.6)

121

< 10

19 (48.7)

20 (51.3)

BMI (kg/m2)

LVEF (%) ≥ 40

6.05 (0.014)*

Diastolic HF

0.410

Haemoglobin 26.64 (< 0.001)*

Class II

–

0.475

25–39.99

–0.879

0.225

< 25

–0.461

0.435

1.085

0.024*

eGFR < 60 ml/min

NYHA = New York Heart Association; BMI = body mass index; LVEF = left ventricular ejection fraction; eGFR = estimated glomerular filteration rate; *significant p-value.

11.72 (0.003)*

Haemoglobin (g/dl)

5.51 (0.019)*

LVEF (%)

Table 3. Association of some variables with mortality 7.52 (0.023)*

≥ 40

48 (77.4)

14 (22.6)

25–39.99

40 (56.3)

31 (43.7)

< 25

15 (55.6)

12 (44.4)

≥ 60

76 (73.8)

27 (26.2)

103

< 60

27 (47.4)

30 (52.6)

eGFR (ml/min)

class III and 15.6% in class IV. This late presentation is similar to findings from other studies documented by investigators on the African continent.5,15,33 Presentation in an advanced NYHA Mortality No, n (%)

Yes, n (%)

Total No.

Male

63 (82.9)

13(17.1)

Female

76 (90.5)

8 (9.5)

Variables

Chi2 (p-value)

Gender

11.17 (0.001)*

NYHA = New York Heart Association; BMI = body mass index; LVEF = left ventricular ejection fraction; eGFR = estimated glomerular filteration rate; n = number; % = percentage within variable; *significant p-value.

Age group (years) 18–45

43 (86.0)

7 (14.0)

46–65

72 (91.1)

7 (89)

> 65

24 (77.4)

7 (22.6)

The average age of the HF patients in this study was 52.49 ± 13.89 years, which is similar to the pattern seen in other African countries but at variance with that of patients in Western countries where HF remains predominantly a disease of the elderly.27,28 In Spain, Permanyer et al.29 found that almost 40% of HF patients were over 80 years and more than 70% were over 70 years. This is also the pattern in the United States of America where average age was about 70 years for HF patients.30 The lower average age in our study and that of other studies emanating from Africa may be attributable to the fact that the major causes of HF in sub-Saharan Africa, such as hypertension, rheumatic heart disease, idiopathic dilated cardiomyopathy and HIV-related heart disease affect mainly young and middle-aged people.31,32 Also hypertension detection, treatment and control in Nigeria, as in other African countries, is poor and complications such as heart failure is expected to occur earlier. The major aetiologies of heart failure in this study were hypertension, dilated cardiomyopathy and rheumatic valve disease, which is in keeping with studies from other parts of Africa.31,32 Late presentation of patients to hospital was a significant finding in this study; 57.5% of the patients presented in NYHA

3.724 (0.155)

Level of education Nursery/primary

Discussion

2.01 (0.156)

Secondary/tertiary

36 (95.3)

7 (16.3)

103 (88.0)

14 (12.0)

117

0.513 (0.474)

NYHA class Class II

41 (95.3)

2 (4.7)

Class III

88 (95.7)

4 (4.3)

Class IV

10 (40.0)

15 (60.0)

57.10 (< 0.001)*

Type of HF Diastolic HF Systolic HF

15 (100.0) 124 (85.5)

0 (0.0)

21 (14.5)

145

2.501 (0.114)

BMI (kg|m2 ) ≤ 24.99

45 (84.9)

8 (15.1)

25–29.99

55 (82.1)

12 (17.9)

≥ 30

39 (97.5)

1 (2.5)

≥ 10

110 (90.9)

11 (9.1)

121

< 10

29 (74.4)

10 (25.6)

5.49 (0.064)

Haemoglobin (g/dl) 7.09 (0.008)*

LVEF (%) ≥ 40

60 (96.8)

2 (3.2)

25–39.99

57 (80.3)

14 (19.7)

< 25

22 (81.5)

5 (18.5)

8.72 (0.013)*

eGFR (ml/min) ≥ 60

93 (90.3)

10 (9.7)

103

< 60

46 (80.7)

11 (19.3)

2.96 (0.085)

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Table 4. Logistic regression analysis of some variables with mortality Variable

p-value

NYHA class

0.284 < 0.001

Class II Class III

–3.96

0.001*

Class IV

–4.76

< 0.001*

Haemoglobin (g/dl)

0.048

0.950

LVEF (%) ≥ 40

0.018

25–39.99

0.587

0.643

< 25

2.682

0.014*

NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; *significant p-value.

class impacts negatively on the prognosis and outcome of heart failure patients.15 This fact was also shown in our study where the severity of the NYHA functional class of the patient at presentation was found to be a determinant of outcome. In this study, 10% of the patients were lost to follow up and all attempts at location were futile. The reasons were not clear. The rehospitalisation rate for HF in this study was 35.6%, which is higher than figures from the United States where Ross et al.,34 using data from the Medicare, documented 30-day re-admission rates after HF hospitalisation of 23.0% in 2004, 23.3% in 2005 and 22.9% in 2006. Therefore hospitalisation and rehospitalisation of HF patients continues to be a great public heath burden, especially in a developing economy such as Nigeria. The mortality rate of 13.1% in this study is similar to the figures documented for hypertensive HF patients in the same institution about two decades ago, where investigators reported a mortality rate of 13.6%.35 This finding suggests that mortality rate from HF in our environment has remained relatively stable despite advances in treatment modalities. This rate is also comparable to the mortality rate of 10% reported in the northern part of Nigeria.36 It is however much lower than the 30.8% documented from western Nigeria,33 and the 35% documented in Lusaka, Zambia.37 The high mortality rate from western Nigeria may be attributable to late presentation, with more than 90% of patients presenting in NYHA class IV, whereas the Zambian investigators admitted logistic and financial challenges that made it difficult to optimise a patient’s treatment. However Ogah et el.38 in a recent study in the south-west region of Nigeria reported a rehospitalisation rate of 12.2% and mortality rate of 4.2% at six months of follow up. The determinants of rehospitalisation in this study were NYHA class at presentation (higher NYHA class was associated with higher re-admission rate), type of heart failure (systolic heart failure), low haemoglobin level (< 10 g/dl) and low eGFR (< 60 ml/min), while the identified determinants or predictors of six-month mortality were high NYHA class (class III and IV) and low LVEF (< 25%). These findings agree with the results of other studies done within and outside Africa. Falase et al.39 reported the prognostic importance of anaemia in HF patients, Karaye et al.36 noted the poor prognostic value of low LVEF of < 40%, Familoni et al.15 reported factors associated with poor outcome in HF patients to include anaemia, low eGFR, increased age and low haemoglobin level of < 10 g/dl. Nohria et al.3 documented high NYHA class, low LVEF, advanced age, low

eGFR, anaemia and other co-morbid conditions as factors that negatively affect outcome in HF patients. Ogah et al.38 from south-western Nigeria however identified factors associated with six-month rehospitalisation to include presence of mitral regurgitation, age ≥ 60 years, presence of tricuspid regurgitation and atrial fibrillation, and LVEF. Using data from the sub-Saharan African Survey of Heart Failure (THESUS-HF), Sliwa et al.40 also noted that the main predictors of 60-day re-admission or death were a history of malignancy and severe lung disease, admission systolic blood pressure, heart rate and signs of congestion (rales), kidney dysfunction (BUN), anaemia, HIV positivity and echocardiographic ejection fraction. The determinants of mortality in our study were similar to findings from other parts of Nigeria and sub-Saharan Africa. This is probably because the aetiology of heart failure in this region is similar and due mainly to hypertension, cardiomyopathy and rheumatic valvular heart disease.

Conclusion As in other studies of HF patients in sub-Saharan Africa, HF patients in the south-south region of Nigeria were relatively young, being in their fifth to sixth decades of life, and presented in advanced NYHA functional class. The determinants of mortality were high NYHA class, low eGFR and anaemia, while the determinants of rehospitalisation were anaemia, low LVEF, systolic heart failure and impaired renal function.

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Failure of the European Society of Cardiology: Guidelines for the treatment and diagnosis of chronic heart failure: an executive summary (update 2005). Eur Heart J 2005; 26: 1115–1140. 12. Levy W, Mozaffarian D, Linker D, Sutradha S, Anker S, Cropp A, et al. The Seattle Heart Failure Model. Circulation 2006; 113: 1424–1433. 13. Mosterd A, Hoes A. Clinical epidemiology of heart failure. Heart 2007; 93: 1137–1146. 14. Lewis EF, Solomon SD, Jablonski KA, Rice MM, Clemenza F, Hsia J, on behalf of the PEACE investigators. Predictors of heart failure in patients with stable coronary artery disease. Circ Heart Fail 2009; 2: 209–216. 15. Familoni OB, Olunuga TO, Olufemi BW. A clinical study of pattern and factors affecting outcome in Nigerian patients with advanced heart failure. Cardiovasc J Afr 2007; 18: 308–311. 16. Zaya M, Phan A, Schwarz ER. Predictors of re-hospitalization in patients with chronic heart failure. World J Cardiol 2012; 4(2): 23–30. 17. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham Study. N Engl J Med 1971; 285: 1441–1446. 18. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252. 19. Waist circumference and waist–hip ratio: report of a WHO expert consultation, Geneva. 2008; 8–11. 20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

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Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539–2550. 27. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 1995; 26: 1565–1574. 28. Lenzen MJ, Scholte op Reimer WJM, Boersma E, Vantrimpont PJMJ, Follath F, Swedberg K. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 2004; 25(14): 1214–1220. 29. Permanyer Miralda G, Soriano N, Brotons C, Moral I, Pinar J, Cascant P, et al. Baseline characteristics and determinants of outcome in a patient population admitted for heart failure to a general hospital. Rev Esp Cardiol 2002; 55(6): 571–578. 30. Abraham WT, Fonarow GC, Albert NM, Stough GS, Gheorghiade M, Greenberg BH, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2008; 52: 347–356. 31. Ojji DB, Alfa J, Ajayi OS, Mamven MH, Falase AO. Pattern of heart failure in Abuja, Nigeria: an echocardiographic study. Cardiovasc J Afr 2009; 20: 349–352. 32. Carretero OA, Oparil S. Essential hypertension: Part I: definition and etiology. Circulation 2000; 101: 329–335. 33. Kolo PM, Opadijo OG, Omotoso ABO, Katibi IA, Balogun MO, Araoye MA. Prognostic Significance of Qt interval prolongation in adult Nigerians with chronic heart failure. Niger J Clin Pract 2008; 11(4): 336–341.

21. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al.

34. Ross JS, Chen J, Lin Z, Bueno H, Curtis JP, Keenan PS, et al. Recent

National Kidney Foundation practice guidelines for chronic kidney

national trends in readmission rates after heart failure hospitalization.

disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139: 137–147. 22. Friedwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of preparative ultracentrifugation. Clin Chem 1972; 18: 499–502. 23. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in m-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083. 24. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echo-

Circ Heart Fail 2010; 3: 97–103. 35. Agomuoh DI, Odia OJ. A clinical study of 59 Nigerian patients with hypertensive heart failure. Trop Cardiol 1994; 20(79): 99–103. 36. Karaye KM, Sani MU. Factors associated with poor prognosis among patients admitted with heart failure in a Nigerian tertiary medical center: a cross-sectional study. Br Med Coll Cardiovasc Disord 2008; 8: 16. 37. Chansa P, LakhiS,Andrews B, Kalinchenko S, Sakr R. Factors associated with mortality in adults admitted with heart failure at the University Hospital in Lusaka, Zambia. Med J Zambia 2012; 39(1): 1–10.

cardiographic volume determinations: echocardiographic–angiographic

38. Ogah OS, Stewart S, Falase AO, Akinyemi OJ, Adegbite GD, Alabi AA,

correlations in the presence of absence of asynergy. Am J Cardiol 1976;

et al. Predictors of rehospitalisation in patients admitted with heart

37(1): 7–11.

failure in Abeokuta, Nigeria: Data from the Abeokuta Heart Failure

25. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7: 79–108.

registry. J Cardiac Failure 2014; doi: 10.1016/j.cardfail.2014.08.012. 39. Falase AO, Ayeni O, Sekoni GA, Odia OJ. Heart failure in Nigerian hypertensives. Afr J Med Sci 1983; 12(1): 7–15.

26. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA,

40. Sliwa K, Davison BA, Mayosi BM, Damasceno A, Sani M, Ogar OS, et

Rademakers FE, et al. How to diagnose diastolic heart failure: a

al. Readmission and death after an acute heart failure event: predictors

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ventricular ejection fraction by the Heart Failure and Echocardiography

registry. Eur Heart J 2013; 34(40): 3151–3159.

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Review Article Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy Keir McCutcheon, Pravin Manga

Abstract Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

Keywords: mitral regurgitation, left ventricular remodelling, medical therapy, beta-blocker Submitted 30/5/16, accepted 12/1/17 Cardiovasc J Afr 2018; 29: 51–65

www.cvja.co.za

DOI: 10.5830/CVJA-2017-009

Mitral regurgitation (MR) is caused by failure of adequate coaptation of the anterior and posterior mitral leaflets during left ventricular contraction, resulting in various degrees of regurgitation of blood from the left ventricle (LV) into the left atrium (LA). The result of this regurgitation is twofold. Firstly, there is a reduction in forward stroke volume (FSV) into the aorta, with subsequent reduction in perfusion. Secondly, there is an increase in LA blood volume during ventricular systole, which results in an increase in left ventricular preload, the so-called ‘volume overloaded’ state. Division of Cardiology, Department of Internal Medicine, Charlotte Maxeke Johannesburg Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa Keir McCutcheon, BSc (Hons), MSc, MB BCh, FCP (SA), Cert Cardiol (SA), keir_mccutcheon@hotmail.com Pravin Manga, MBBCh, FCP (SA), PhD, FRCP (UK)

MR is classified as either primary (organic) or secondary (functional), and acute or chronic.1 Causes of acute MR include infective endocarditis and spontaneous cordal rupture and will not be discussed further in this review. Chronic secondary MR can be ischaemic and/or non-ischaemic in nature and therapies for secondary MR range from medical to surgical.2 By contrast, chronic primary MR is predominantly caused by degenerative disease in developed countries,3 and rheumatic heart disease (RHD) in developing countries.4 RHD is one of the major contributors to the aetiology of heart failure in Africa, where it remains the most common form of acquired cardiovascular disease in children and adults.4 Current therapy for patients with severe chronic primary MR, as recommended by the European Society of Cardiology guidelines,1 comprises surgical repair or replacement in patients who are surgical candidates, or conservative (i.e. palliative) therapy in patients with very poor left ventricular function who are deemed to be poor surgical candidates. At present, there is no recommendation for drug therapy in patients with any degree of chronic primary MR. However, once heart failure develops, angiotensin converting enzyme inhibitors (ACE inhibitors), beta-blockers and spironolactone may be considered.5 Although there have been several recent reviews focusing on ventricular remodelling in ischaemic heart disease, hypertensive heart disease and aortic stenosis, there have been few recent reviews on pathological left ventricular remodelling in patients with primary MR.6-8 In this review we focus in particular on the pathophysiological changes seen in the myocardium of the LV due to volume overload caused by chronic primary MR. We also discuss medical interventions that may attenuate or reverse the adverse changes seen in chronic primary MR, focusing on data related to the use of beta-blockers in these patients.

Pathophysiological changes in the LV in chronic primary MR Primary MR may present acutely, as a slowly progressive disease, or as chronic progressive MR with sudden deterioration related to acute changes in mitral valve anatomy such as a ruptured cord. Acute MR is usually a medical emergency requiring emergent surgery and is not the focus of this review. Patients with chronic primary MR are often asymptomatic for long periods of time before presenting at a late stage in heart failure. During this period, there is development of progressive left ventricular dysfunction as the LV is remodelled in an attempt to produce an adequate forward stroke volume.9,10 Five- to

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10-year cardiovascular mortality rates vary between 10 and 15%, with a worse prognosis for patients with severe MR.11,12 Alterations in the global structure of the LV in response to primary MR have been reviewed in detail previously.9 Briefly, MR results in increases in LA volume, a reduction in FSV and an increase in left ventricular preload. By mechanisms that are unclear but are discussed in more detail below, the LV responds to the increased preload by eccentric hypertrophy, with a serial increase in myocyte sarcomeres and myofibril slippage (Fig. 1).13-18 Eccentric hypertrophy normalises afterload, as estimated by mean systolic stress, compared to patients with aortic regurgitation, leading to a period of so-called ‘compensation’.19 However, the hypertrophy that develops is actually insufficient to fully compensate for the wall stress that develops. This is due to inadequate protein synthesis triggered by MR compared to pressure overload,16,20 and progressive deterioration in myocardial function.21 There is no clear explanation for this phenomenon but it has been proposed that the lower systolic load in the case of MR may result in a reduced hypertrophic response at a time when there is a marked demand for an increased stroke volume.21 Altered cytoskeletal changes, such as microtubular density, may also play a role.22 With time, in the face of inadequate hypertrophy and a dilating LV, systolic wall stress increases [based on the Laplace effect where wall stress (σ) is directly related to the pressure within the ventricle and its radius (Pr), and inversely related to the wall thickness (2h); σ = Pr/2h] due to the increases in LV dimensions and inadequate hypertrophy.21,23,24 Chronic increases in wall stress are detrimental to the myocardium, resulting in activation of a number of complex inflammatory and apoptotic pathways, in a similar manner to heart failure from other causes. Ultimately, there is myocyte loss and sliding displacement of cardiomyocytes, or cell slippage, A

• • • • •

Normal heart

Normal preload Normal LA volume Normal LV volume and contractility Normal wall stress Normal TSV and FSV

caused by disruption of the myocardial extracellular matrix (ECM)–integrin linkages.7,25 Various lines of evidence point to time-dependent changes in the up- and downregulation of remodelling pathways in chronic primary MR.26 This process is initiated by diastolic mechanical stretch due to an increase in end-diastolic wall stress, leading to an early increase in reactive oxygen species (ROS) generation, inflammatory cytokine expression and neurohormonal activation, with increases in angiotensin II and catecholamine levels. Early in the remodelling process there is interstitial collagen loss and cell slippage but with time there is myocyte apoptosis and pathological ECM fibrosis.27 Chronic decompensated MR ensues, and the LV resembles end-stage dilated cardiomyopathy.

MR causes mechanical stretch, which triggers mechanoreceptors and activates signal-transduction pathways Myocardial mechanoreception is currently poorly understood.28-30 There is no evidence that specialised mechanosensory cells exist in the myocardium and the role of stretch-activated channels in sensing stretch is debatable.29 Two systems appear to be particularly important in mechanoreception in the cardiomyocyte: the collagen–integrin–cytoskeleton connections25,31 and sarcomererelated signalling.30 The contraction–relaxation cycle of the myocyte depends on coordinated interaction between the thin actin filament and the thick myosin filament within the myocyte sarcomere.32 Actin is bound directly to the Z-disc while myosin is bound indirectly to the Z-disc via the giant elastic protein, titin.33,34 In the normal heart, titin is responsible for restoring the stretched sarcomere to its resting length following active contraction.33,34 However, another important role for titin is in mechanoreception and the

Chronic compensated MR

↑ preload ↑ LA volume and pressure ↑ LV volume ↑ contractility Eccentric hypertrophy but normalised wall stress • ↑ TSV • Normal FSV • • • • •

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• • • • • •

Decompensated MR

↑ preload ↑↑ LV volume ↓ contractility ↑↑ wall stress ↓ TSV ↓ FSV

Fig. 1. Left ventricular remodelling in chronic primary mitral regurgitation. A: Normal LV is represented on the left. Wall stress is normal. B: Chronic compensation with eccentric hypertrophy and dilatation. The increase in LV volume is compensated for by the increase in wall thickness. Wall stress appears to be normalised by the eccentric hypertrophy. FSV is normal because of increased LV filling. C: Adversely remodelled LV of decompensated chronic MR. The myocardial wall is thin resulting in an increase in wall stress. The arrow indicates severe MR, which becomes more severe with a dilating LV. LA = left atrium; LV = left ventricle; TSV = total stroke volume; FSV = forward stroke volume; MR = mitral regurgitation.

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activation of a number of signal-transduction pathways when there is chronic myocyte stretch.28,29,33,35-37 It does this by changes in the expression of various genes involved in adaptation to the increased load and, ultimately, to the activation of various maladaptive pathways.38-40 Titin complexes with a number of potential ‘signalosomes’ (a mechanosensative signalling complex), including the Z-disclocalised protein MLP (muscle LIM protein), which has been shown to be responsible for hypertrophy and cardiomyopathy in MLP-deficient animals.41,42 MLP, aside from its structural role in the Z-disk and its interaction with signal transduction proteins, is able to translocate to the nucleus and thereby act as a transcription factor modifying gene expression, depending on mechanical stretch.43 MLP may be responsible for control of other transcription factors coordinating alterations in the expression of genes responsible for ventricular remodelling. Another important titin signalosome that controls muscle gene expression is the sarcomere M-band-associated protein titin kinase (TK), which is activated by myocyte stretch.38,40 TK may primarily respond to diastolic stretch,29 which is particularly relevant in the case of pathological volume overload caused by chronic MR (Fig. 2). Pathological volume overload-induced mechanical stretch has a number of other effects on the cardiomyocyte. For example, in in vitro44 and in vivo45 rat experiments, TNF-α is produced by cardiomyocytes, resulting in an inflammatory response to stretch, suggesting that TNF-α is an important component in the pathophysiological response of the myocardium to volume overload. Mechanical stretch also results in the local production of angiotensin II46 and ROS,47 which, via transcription factors, such as TRAIL (TNF-related apoptosis-inducing ligand) and NFκB,47 result in local increases in pro-inflammatory cytokines, further contributing to activation of remodelling signaltransduction pathways.48,49 Finally, as discussed in more detail below, mechanical stretch is transmitted through the ECM to

cardiomyocyte integrins, which trigger a number of intracellular signal-transduction pathways involved in hypertrophy and apoptosis.31,39

Chronic primary MR increases cardiac reactive oxidative stress ROS play an important role in signal transduction and physiological regulation in vascular and myocardial cells. However, under pathological conditions, such as excessive myocyte stretch or excessive inflammatory signals, ROS have been shown to activate maladaptive remodelling signal-transduction pathways.50,51 These signal-transduction pathways include (but are not limited to) protein phosphorylation pathways leading to cell growth or apoptosis (depending on ROS levels and other factors); matrix metalloproteinase activation;52 cell cycle protein pathways leading to apoptosis; and pathways leading to the activation of inflammatory transcription factors such as NFκB.53 ROS are increased in patients with congestive heart failure,54 and there is evidence of pathological increases in ROS in patients with chronic isolated MR who still have left ventricular ejection fractions (LVEF) above 60%.55 These data suggest that there is an A Mast cells increase early and continue to increase

MMP activity Adrenergic: activated throughout

Inflammation

Interstitial collagen

β-AR responsiveness Myocyte stretch

M-band

Acute MR inflammation

Titin Sarcomere Telethonin

MLP

Regulation of gene expression

‘Compensated’ Laplace criteria met but ongoing myocyte stress

Decompensation

B Activity of regulatory pathways

Z-disc

ROS: increased oxidative stress throughout

Acute MR

Decompensation Time

Ventricular remodelling

Fig. 2. S chematic representation of gene regulation in response to myocyte sarcomere stretch via signal transduction through MLP and TK. MLP = muscle LIM protein; TK = titin kinase. See text for details.

Fig. 3. A. Proposed time-dependent changes in various remodelling pathways including changes in measured prevalence of mast cells. B. Proposed overall timedependent changes in remodelling pathway activation. MMP = matrix metalloproteinases; β-AR = β-adrenergic; ROS = reactive oxidative species. See text for details.

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increase in oxidative stress even before the LV starts to develop systolic dysfunction, which supports the notion that wall stress is present throughout the evolution of left ventricular remodelling in primary MR. This oxidative stress appears to be present as long as the volume overload persists (Fig. 3).56

Chronic primary MR triggers an inflammatory response Tumour necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) are produced by all nucleated cells, including cardiac myocytes.57 Cytokines are responsible for beneficial adaptation to short-term stresses, such as haemodynamic overload, within the myocardium. These molecules may play an important role in protecting the heart from oxidative injury and there are several lines of evidence supporting their beneficial role in short-term stress.58 However, the role of cytokines in remodelling is complicated and not easily predictable. For example, TNF can have both a protective and an adverse effect on the myocardium, depending on which TNF receptors are activated.59 Furthermore, prolonged elevation of tissue cytokines has been found to have deleterious effects on the LV.60,61 Chronic elevation of cytokines has an effect on left ventricular remodelling by blunting of β-adrenergic signalling57 and activation of apoptotic pathways.62-64 TNF-α also increases cardiomyocyte apoptosis63,65 by activating p38 MAP kinase and NFκB and by down-regulating ERK 1/2 MAP kinase.66 Overexpression of TNF has also been shown to increase tissue matrix metalloproteinase (MMP) activity, with the resultant acute loss in myocardial fibrillar collagen and left ventricular dilatation.67-69 However, with continuing TNF overexpression, there is an increase in tissue inhibitors of metalloproteinase (TIMP-1) expression and reduction in MMP expression, leading to abnormal increases in fibrillar collagen,67,68 suggesting a time-dependent effect of chronic exposure to elevated myocardial TNF. Cytokines are elevated in patients with heart failure,70 in patients with pressure and volume overload,71 and in other forms of heart disease.72,73 Several lines of evidence suggest that the myocardial response to TNFα is similar regardless of aetiology. Gene expression analysis by micro-array suggests that there is a time-dependent inflammatory response to volume overload (Fig. 3).26,45 Very early after the initiation of volume overload in aortocaval fistula rats, there is a marked increase in the expression of inflammatory pathway genes, followed by relative normalisation during the chronic ‘compensated’ period of volume overload.26 This is supported by earlier studies that demonstrate that myocyte stretch induces TNFα secretion from myocytes,44,74 and mast cell-deficient rats with volume overload were protected from TNFα-dependent left ventricular remodelling.69 Furthermore, in humans with compensated chronic primary MR and normal LVEF, there is a down-regulation of inflammatory pathways.56 As the LV becomes dilated and dysfunctional, there is an increase in inflammatory pathway gene expression,26 which is supported by clinical work in patients with severe chronic primary MR71,75 and severe rheumatic aortic regurgitation.76 Overall, there appears to be a biphasic elevation in the inflammatory response to mitral regurgitation, with early volume overload activating the expression of numerous inflammatory pathways, and decompensation triggering a second inflammatory response (Fig. 3).

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Myocyte loss in chronic primary MR Apoptosis is activated by several extracellular death signals, including myocyte stretch,77 catecholamines25,78-80 and inflammatory cytokines,57 and various intracellular death signals.81-85 These death signals25 activate transcription factors,86 ultimately resulting in activation of the caspase cascade.87 Loss of myocytes will increase the stress on remaining myocytes. This leads to further increases in ROS,88 cytokine release,44 increases in adrenergic activation,89 perpetuating loss of myocytes in a downward-spiraling process. Time-dependent apoptosis of non-myocyte cells has been described in volume-loaded rats26 and there is evidence that chronic primary MR causes a reduction in contractile elements.21,82,90 Based on this evidence and evidence from studies in myocardial remodelling due to other causes, it is probable that cell loss is an important component in left ventricular dilatation and dysfunction in chronic primary MR.

ECM changes in chronic primary MR Myocyte arrangement and myocardial integrity is highly organised to enable the continuously moving myocardium to produce coordinated contraction, resulting in stroke volume.91 The structural integrity is provided by the ECM, which comprises a basement membrane, proteoglycans and glycosaminoglycans, and ECM proteins such as type I, III and V collagen, of which approximately 85% is type I collagen.7 This collagen framework serves to maintain cardiac myocyte alignment, without which the myocytes would ‘slip’, altering the shape and size of the cardiac chambers.91 The ECM is a highly dynamic part of the myocardium that changes depending on the degree and type of mechanical stress, neurohormonal activation, inflammation and oxidative stress. These stressors on the ECM result in changes in the expression and activation of the proteins responsible for ECM turnover and, ultimately, alterations in collagen deposition and degradation. MMPs are a heterogeous family of enzymes responsible for the proteolysis of various protein-based extracellular substances. They include the collagenases (MMP-1, MMP-8 and MMP-13), stromelysins (MMP-3 and MMP-10) and the gelatinases (MMP2 and MMP-9). They are expressed and secreted into the extracellular space by a variety of cells, including cardiac myocytes, cardiac fibroblasts and macrophages.92 However, the roles of each MMP and the control of their activity are not yet clearly elucidated and this is an area of on-going research.7 Some studies have demonstrated a correlation between MMP expression and cardiomyopathy phenotypes,93-95 and others have demonstrated that serum levels of MMPs have prognostic value in heart failure.96,97 TIMPs are low-molecular-weight proteins that bind to the catalytic domain of active MMPs, preventing substrate binding. There are four species of TIMPs with overlapping functions within the myocardium, which are not restricted to MMP inhibition. Other pleomorphic effects have been described. For example, TIMP-2 increases collagen production by fibroblasts, whereas TIMP-3 is responsible for fibroblast apoptosis.98 Biological and/or mechanical stimuli trigger various signaltransduction pathways, resulting in the production of MMP transcription factors and the secretion of these enzymes into the ECM.92,99-101 Mechanical stimuli, such as stretch,102 are transduced through the ECM, which, via collagen–integrin–cytoskeleton

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connections, are connected to and activate a number of intramyocyte signal-transduction pathways involved in ECM remodelling.31,46,103-106 Local ROS, endothelin-1, angiotensin II and catecholamines, via α- and β-receptors, are also responsible for increases in MMP expression.52,89,107,108 Cytokines, such as TNFα and IL-1, have been found to increase MMP expression,67,102 promoting matrix degradation and ventricular dilatation.7 On the other hand, MMP-9 production can be suppressed by TGF-β-activated NFκB binding in some experiments,109 whereas its expression was up-regulated by angiotensin II-activated NFκB in other experiments.110 Angiotensin II107 and aldosterone both increase ECM remodelling, mainly through TGF-β,111 although the effects of this protein are multiple and often opposing, depending on circumstances.112 TGF-β stimulation induces maturation of fibroblasts to myofibroblasts and enhances ECM protein synthesis via induction of TIMP expression and inhibition of certain MMP expression.111 However, this is dependent on the load on the myocardium and there is clear evidence that volume overload results in reduction in TGF-β level and loss of interstitial collagen,113 whereas pressure overload increases TGF-β.114 The result is increased detection of markers of collagen types I and III turnover in the serum,115 pathological decreases in interstitial collagen15,116,117 and left ventricular dilatation. In response to different haemodynamic overloads (pressure versus volume), the ECM undergoes different patterns of remodelling.27 Volume overload produces a distinctive loss of collagen fibrils surrounding individual myocytes,15,116,118 with the resultant wall thinning and ventricular dilatation changing the geometrical shape of the LV, whereas excess matrix deposition is observed in pressure overload.119,120 Despite similar fibrotic molecular pathways and cellular effectors, the pathophysiological mechanisms leading to fibrotic remodelling are different, depending on the load on the heart.7 For example, ACE inhibitors reduce remodelling and collagen accumulation in pressure overload,121 but not in chronic MR.15,122 Furthermore, the expression of integrins, which are important in ECM–myocyte connectivity and ECM remodelling, are reduced in MR113 but increased in pressure overload.123 Similarly, profibrotic TGF-β expression was increased in mice with pressure overload114 but was decreased in dogs with experimental MR,113 and expression of PAI-1 was increased in a swine model of early pressure overload124 but decreased in chronic MR.113 There appears to be a time-dependent increase and decrease in MMP activity during the evolution of left ventricular remodelling in response to primary MR (Fig. 3).26,117 Myocardial mast cells have been found to be instrumental in increases in MMP activity in early volume overload,69,117,125,126 and are increased in number in response to volume overload-induced increases in myocardial TNFα.45 In animal models there is an early rise in myocardial MMP levels after the volume-loaded state is created but this seems to normalise after the acute phase.127,128 MMP gene expression in dogs with isolated MR has confirmed that, at four months, there was down-regulation of a number of non-collagen genes important in ECM structure, down-regulation of pro-fibrotic connective tissue growth factor and plasminogen activator, and down-regulation of numerous genes in the TGF-β pathway.113 However, MMP-1 and MMP-9 gene expression was still markedly increased in these dogs with

compensated MR compared with controls.113 As the LV started to dilate in dogs with chronic myxomatous mitral valve disease, MMP-9 levels decreased.129 Over time, there are characteristic changes in the MMP/TIMP ratio, enabling the ventricle to initially increase compliance in the acute and compensated phases of MR. However, at some point (the ‘transition’ point) there is excessive degradation of the ECM, leading to the decompensated and dilated LV.27,130 What controls the steady deterioration in the myocardium in response to volume overload is not clear and appears to be complex. In the early stages of volume overload, there are decreases in ECM deposition (which contrasts with the picture in pressure overload),113 but late in the progression of the dilating volumeloaded heart, an increase in perivascular collagen deposition has been noted,26,126 which may reduce ventricular compliance and promote systolic dysfunction.27

Chronic primary MR activates the neurohormonal system: implications for beta-blocker therapy Patients with chronic primary MR demonstrate LV systolic dysfunction even before a reduction in LVEF occurs.131,132 As with heart failure due to any other cause, chronic MR results in activation of the neurohormonal system and inflammatory cascade at both systemic and local levels.133-135 With neurohormonal activation, myocardial angiotensin II plays an important role in the regulation of cell proliferation, apoptosis, inflammation and production of mediators of remodelling such as platelet-derived growth factor and MMPs.136 Persistent angiotensin receptor-1 activation by angiotensin II not only results in the generation of ROS but also alterations in protein synthesis via tyrosine kinase receptor activation and MAP kinase signalling.137 Furthermore, angiotensin II-activated ROS act as second messengers that also have effects on inflammation and cell growth.138 Angiotensin II also acts on the sympathetic nerve endings in the myocardium to facilitate catecholamine release.139,140 Long-term increases in myocardial angiotensin II levels increase local TGF-β, with the resultant increases in activation of genes involved in ECM production via nuclear translocation of NFκB.110,141 Unlike the pressure-overloaded heart where there is progressive fibrosis,142 the increase in myocardial angiotensin II in volume overload results in an increase in ECM turnover with loss of interstitial ECM.143 Despite the clear link between angiotensin and remodelling in heart failure, to date there has been little clinical evidence to support the role of medical therapy directed against angiotensin in subjects with chronic organic MR.15,144-146 This may be explained by the fact that ACE inhibitors reduce the breakdown of bradykinin, which has been implicated in the initial increase in MMP activity and collagen breakdown seen in volume overload.143 Three types of β-adrenergic receptors (β-ARs) are known to exist in the myocardium: β1, β2 and β3, with an approximate ratio of 80:17:3.147 β1 and β2 are important in the regulation of myocyte excitation–contraction coupling.80 β1-AR is the predominant receptor subtype expressed in the heart and, like other β-ARs, its stimulation results in G-protein-coupled activation of the adenyl cyclase–cAMP–protein kinase A (PKA) signalling cascade. This leads to activation of a number of subcellular pathways important in cardiomyocyte contractile function, including

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calcium channel activation and troponin I phosphorylation. By contrast, β2-AR signalling has negative effects on adenyl cyclase activation and the subsequent G-protein-activated ionotropic response.80 β3-AR appears to be important in protection from hypertrophic and fibrotic remodelling by preserving NO/cGMP signalling during cardiac stress.148 The β-adrenergic receptor system plays an important role in the pathogenesis of myocardial remodelling and heart failure.84 The exact mechanisms are unclear but it has been known for decades that chronically increased plasma catecholamines can lead to heart failure.149,150 In dogs with chronic primary MR, there is activation of the adrenergic system,89,108 and recent gene array data in chronic primary MR patients with preserved LVEF demonstrate increased expression of genes involved in β-adrenergic signalling.56 This indicates that the adrenergic system is activated during the compensatory phase of MR and supports the concept that blocking these pathways may reduce their adverse consequences. However, with transition to decompensation there is a reduction in adrenergic responsiveness. In patients with systolic heart failure (HF), several studies in the last three decades show that β1-receptor density151 and its mRNA152,153 are reduced while β2-receptor density remains unchanged.154 Similarly, in animals with HF due to chronic volume overload, β1-AR responsiveness is reduced due to neurohormonal activation (Fig. 3).47,155 These changes in β1-AR expression are caused by sustained adrenergic activity, causing an increase in the expression and activity of GRK 2 (G-proteincoupled receptor kinase; formerly called β-ARK or β-agonist receptor kinase), resulting in β1-AR being phosphorylated and labelled for desensitisation, internalisation and recycling.156 The result is a reduction in the density of β1-ARs and a reduced propensity for myocyte activation by chronic β1-receptor activation, which may protect the myocyte from long-term catecholamine toxicity.80

Beta-blocker therapy improves β1-AR signalling and clinical outcomes in HF Chronic β1-AR activation causes a number of detrimental effects, ultimately resulting in changes in the ECM and cell loss from necrosis and apoptosis,25 which in turn leads to cardiac dilatation and failure.157 However, the intracellular pathways responsible for these final acts are unclear.25 What is clear is that β1-AR antagonists improve clinical outcomes in patients with systolic heart failure and improve cardiac function and myocardial remodelling.158 Most β-adrenergic blockers are antagonistic to β-ARs (whether β-1, β-2 or β-3) by occupying the receptor and preventing signal transduction via G-protein activation. Importantly, there is an up-regulation of β1-AR expression and improvements in receptor sensitivity, resulting in reversal of cardiac remodelling.147 However, the pharmacological and clinical effects of these agents vary quite considerably. Cardioselective beta-blockers (metoprolol, bisoprolol and atenolol, for example) have a greater affinity for β1-ARs than β2-ARs, whereas carvedilol binds β1-ARs more than β2-ARs and has vasodilatory effects, via nitric oxide and α1-receptor blockade. There are other important differences between carvedilol and other beta-blockers. For example, metoprolol upregulates

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cardioprotective β3-AR expression, whereas carvedilol does not.159,160 Carvedilol has antioxidant and antiproliferative properties161-163 and differs from metoprolol in its effects on haemodynamics, left ventricular function and β1-AR expression.164,165 Carvedilol166 and bisoprolol167 have also been shown to improve right ventricular (RV) ejection fraction, attenuate RV dilatation and reduce pulmonary artery hypertension in patients with ischaemic and non-ischaemic dilated cardiomyopathy. Although there are no recent confirmatory studies, these improvements in RV function may be related to reductions in RV afterload and/or improvements in RV contractility.166,167 By contrast, short-term (two-week) metoprolol did not improve RV function in patients with moderate-to-severe degenerative MR.168 Clinical support for β-adrenergic receptor blocker therapy in patients with heart failure is well known,158,169,170 with some data suggesting that patient outcomes are better with carvedilol than the immediate-release form of metoprolol.171 Several mechanisms for the improvement in outcomes with β1-receptor blockade have been proposed,84 including antiarrhythmic properties;172 improved β-adrenergic signalling by cardiac β-AR upregulation;80 free-radical scavenging;161 improvements in calcium cycling by the sarcoplasmic reticulum;83,173 bradycardia reducing myocardial work, mechanical stress,174 and prolonging diastolic calcium uptake and cycling by the sarcoplasmic reticulum; inhibition of the renin– angiotensin–aldosterone system; and there is growing evidence that β-antagonists, in particular carvedilol,162,163 directly reduce apoptosis78,175-177 and collagen loss by MMP activation.178

β1-AR blockade in MR counters adverse adrenergic effects Since MR leads to a reduction in forward stroke volume, it is hypothesised that the adrenergic system is activated to maintain systemic blood pressure and perfusion, and blockade of the adrenergic system should limit adverse left ventricular remodelling. There is evidence that chronic primary MR results in excessive activation of the sympathetic nervous system, with increases in myocardial catecholamine levels,89,118,134 similar to heart failure from other causes.179 Tallaj et al.118 demonstrated that β-AR blockade with extendedrelease metoprolol succinate attenuated angiotensin II-mediated norepinephrine and epinephrine release in the myocardium of dogs with ‘subacute’ (two to four weeks’ duration) isolated MR. Similarly, Hankes et al.89 demonstrated that norepinephrine release into the cardiac interstitium was significantly higher in dogs with subacute MR, which was reduced by β1-AR blockade. In an earlier study by Tsutsui et al.90 in ‘chronic’ (three months) canine MR, the β1- AR blocker atenolol improved left ventricular function, which was associated with improvement in contractile function of isolated cardiocytes and an increase in the number of contractile elements. This was supported by a similar study by Nemoto et al.,145 which showed that only when a β1-AR blocker was added to an ACE inhibitor did forward stroke volume and cardiac contractility return to normal. Recently, Trappanese et al.180 demonstrated an improvement in β3-AR expression and β3-NO-cGMP coupling with chronic therapy with metoprolol in dogs with primary MR. Since β3-AR is cardioprotective, this may partially explain the potential beneficial effects of β1-AR blockade in primary MR.159

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Beta-blockade therapy for chronic primary MR At present there is no proven medical therapy for chronic primary MR. Surgery is the mainstay of treatment for severe MR1 but carries peri-operative risk, and patients are potentially subjected to a life-time risk of anticoagulation if they undergo mitral valve replacement. Many patients in the developing world are from poor and rural backgrounds where access to regular medication and regular anti-coagulation assessment is difficult. A medication that could limit or even reverse left ventricular dysfunction associated with the volume-loaded state of chronic severe MR would be extremely beneficial to these patients, even if only to delay the need for surgical intervention. This would especially be true in women of child-bearing age. Warfarin is teratogenic and many women with prosthetic valves have complicated pregnancies related to the teratogenic effects of warfarin or the risks related to bleeding during pregnancy. Persistent, and often worsened, postoperative left ventricular dysfunction is a major cause of morbidity and mortality in these patients,133 although this is not a universal finding, especially when patients are referred for early surgery.181-183 Nevertheless, a means to improve left ventricular function in the peri-operative period might improve the postoperative morbidity and mortality rates associated with left ventricular dysfunction. Current guidelines1,184 recommend surgery for patients with severe pulmonary hypertension on presentation or a progressively dilating LV, even if they are asymptomatic. However, timing of surgery is uncertain185,186 and there is no clear guideline as to the urgency of the surgery in asymptomatic patients without overt left ventricular systolic dysfunction (LVEF < 60%). Several studies support early surgery for chronic primary MR.187-189 Enriquez-Sarano et al.12 showed that patients with an effective regurgitant orifice area of at least 40 mm2, as assessed by echocardiography, should promptly be considered for cardiac surgery. Barbieri et al.190 found that asymptomatic patients with evidence of pulmonary hypertension (> 50 mmHg at rest) should undergo prompt surgery. However, there is also evidence that asymptomatic patients with severe MR can be followed until they become symptomatic or demonstrate echocardiographic signs of left ventricular dysfunction.132,191 How these patients should be managed in the interim is unclear but it is important that patients are not left untreated until irreversible left ventricular remodelling has taken place. In resource-limited hospitals, patients who do not need emergency surgery often wait several months before they undergo surgery, by which time there has been progressive advancement of ventricular remodelling, leading to permanent impairment of function. Medical therapy that could reverse or at least attenuate LV remodelling may improve outcomes in these patients. To date, there is little evidence to support medical therapy in the treatment of patients with organic valve disease,1,119,192 or in the reversal or attenuation of LV remodelling, which may delay the need for surgery in asymptomatic patients.193 Vasodilator therapy, which reduces peripheral vascular resistance and left ventricular afterload,119 has generally not improved outcomes in patients with MR or in experimental MR canine models.15,122,145,194 Although several small studies from the 1970s to the 1990s showed benefit of vasodilator therapy in acute MR,144 small human studies from the same period failed to show long-term benefit.195 One retrospective study, however, demonstrated an improvement in echocardiographic LVEF in patients treated

with afterload-reducing agents.146 However, there are no large randomised studies assessing long-term vasodilator therapy, including ACE inhibitors, in humans. There is some clinical evidence to support the concept that β-AR blockade may attenuate remodelling in patients with primary MR (Table 1). Stewart et al.196 recruited 25 patients with moderate or severe degenerative MR and randomly assigned the participants to the β1-AR blocker metoprolol, or placebo for approximately two weeks. Left ventricular function was assessed at baseline and on study completion by cardiac magnetic resonance imaging. They found that the β1-AR blocker resulted in a decrease in left ventricular work and an increase in forward stroke volume.196 Mitral annular dimensions also appeared to improve over the two-week period in the same cohort of patients.197 A retrospective observational study involving 895 patients in California showed that participants on β1-AR blocker therapy with severe MR and normal left ventricular function had a significantly lowered mortality hazard, regardless of the presence of hypertension or coronary artery disease.198 Ahmed et al.199 published the results of the first randomised, controlled phase IIb trial of beta-blockade in patients with chronic degenerative MR. Thirty-eight asymptomatic patients with moderate-tosevere isolated MR were randomised to either placebo or longacting metoprolol for two years. Cardiac magnetic resonance analysis showed that patients randomised to the β-AR blocker had significantly better LVEFs after two years of therapy. By contrast, there are several pre-clinical and clinical studies demonstrating that beta-blocker therapy actually worsens left ventricular dimensions and function in chronic primary MR (Table 1).108,146,197,200,201 A recent, longer-term (23 to 35 weeks) study in rats found that echocardiographic measures of left ventricular remodelling were not improved by carvedilol.201 In fact, left ventricular dimensions, ejection fraction and survival were significantly lower with long-term carvedilol use. Similarly, in a four-month dog model, extended-release metoprolol succinate failed to attenuate the adverse global left ventricular remodelling and ECM loss, but did preserve cardiomyocyte function.200 Interestingly, all dogs treated with β-1-receptor blocker (n = 6) survived to four months, whereas only five out of nine of the untreated dogs survived to four months. Similarly, Sabri et al.108 found that, despite reductions in interstitial collagen degradation and reductions in adverse remodelling-related intracellular signalling, extended-release metoprolol succinate failed to attenuate left ventricular dilatation or decline in left ventricular function. A retrospective echocardiographic study in 134 human subjects with moderate-to-severe MR (67% degenerative and 20% ‘non-specific thickening’) found that patients exposed to beta-adrenergic blockade developed worsening of their ejection fraction over a mean of 20 months of follow up.146 Finally, despite improvements in left ventricular work and annular dimensions,197 in patients treated over a short period with metoprolol, there were significant increases in left ventricular end-systolic and end-diastolic volume with no significant change in LVEF or regurgitant volume.196 At the present time, there are no recommendations regarding medical therapy in chronic primary MR. Afterload reduction has not consistently been shown to improve long-term outcomes.15,122,145,146,195 Data from heart failure trials158,169,170 as well as from animal models90 and human trials199 suggest a role for

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Table 1. Studies of beta-blocker therapy and left ventricular function in primary MR Number treated with BB Type of study

Authors

Year Subject Cause of MR

Tsutsui et al.89

1994

Dog

Experimental chordal rupture

n=6

Nemoto et al.144

2002

Dog

Experimental chordal rupture

n = 11

Tallaj et al.117

2003

Dog

Experimental chordal rupture

Hankes et al. 88

2006

Dog

Experimental chordal rupture

Oh et al. 145

2007 Human 71% degenerative

Pat et al. 199

2008

Dog

Sabri et al.107

2008

Dog

Varadarajan et al.197

2008 Human LVEF > 55% + ‘severe MR’

Stewart et al. 195

Duration of BB Outcome measures

Control

Type of BB

Case controlled

n=6

Atenolol 50 mg daily

3 months Cardiocyte contractility, myofibrillar density

Longitudinal

Atenolol 100 mg daily

3 months Haemodynamics, LV + function

Normal: n=8 2 weeks MR: n = 8 4 weeks MR: n = 6

Metoprolol succinate 100 mg daily

4 weeks

RAAS activation

Case controlled

Normal =6 Untreated MR = 6

Metoprolol succinate 100 mg daily

4 weeks

NE release into cardiac interstitium

n = 134

Retrospective cohort

Not ascertained

1–88 months

Echo LVEF

–

Experimental chordal rupture

n = 11

Case controlled

n = 10

Metoprolol succinate 100 mg twice daily

Experimental chordal rupture

n=6

Case controlled

Normal = 6 Metoprolol Untreated succinate 100 mg MR = 6 daily

4 weeks

LV remodelling by echo; interstitial collagen quantification; FAK signalling (integrin signalling)

BB reduced FAK tyrosine phosphorylation but no change in remodeling parameters; BB reduced epicardial collagen loss but not endocardial collagen loss

n = 218

Retrospective observational cohort study

n = 614

Not stated

8 years

Mortality

2008 Human MVP

n = 25

Double-blind cross-over study

Metoprolol to a maximum 190 mg daily

14 days

MRI EF LVEDV LVESV LV ‘work’ (CO)

– – – +

Ahmed et al. 198

2012 Human MVP

n = 19

RCT

n = 19

Toprol XL 25–100 mg daily

Pu et al. 200

2013

Rat

Experimental leaflet disruption

n = 43 ‘Long-term’ BB in 19

RCT

n = 44

Carvedilol (1 200 ppm)

36 weeks Echo only LV dimensions LVESV and mass index FS and EF Survival probability

Trappanese 2015 et al.179

Dog

Experimental chordal rupture

n=8 (MR + BB)

Case controlled

Normal = 10 Untreated MR = 8

Metoprolol succinate 100 mg daily

4 weeks

2 weeks Case MR+BB: n = 6 controlled 4 weeks MR+BB: n = 8

4 weeks of MR+BB = 8

4 months LV remodelling by MRI and echo; cardiomyocyte function

MRI LVEF MRI LVESV LV longitudinal strain rate

Favours BB +

Improved cardiomyocyte function and BB receptiveness but failure to attenuate remodelling

+ – – –

Activation of β3AR/ + NO-cGMP signalling β3-AR expression +

BB = beta-blocker; MVP = mitral valve prolapse; RCT = randomised controlled trial; MR = mitral regurgitation; NE = norepinephrine; + indicates that the study favoured BB therapy in primary MR; – indicates that the study did not favour BB therapy in primary MR; LV = left ventricle; LVEF = left ventricular ejection fraction; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume; CO = cardiac output; RAAS = renin–angiotensin–aldosterone system; echo = echocardiogram; MRI = magnetic resonance imaging; ppm = parts per million.

beta-blockade in MR, however, other studies do not support this.108,146,197,200,201 The reasons for the discrepancies in these findings are unclear but some explanations can be proposed. Firstly, the studies have been performed in different experimental models and at different stages in the evolution of MR-related left ventricular remodelling. Many of the experiments performed thus far have been in animal models with controlled formation of volume overload showing that early introduction of beta-blocker therapy89,90,118 may be beneficial, and this is supported to some extent by the work of Ahmed et al.199 in humans. However, there appears to be a time-dependent pattern during remodelling of the LV in chronic primary MR. Early after the development of MR there is a marked increase in inflammatory and neurohormonal response to the

acute volume overload.26,113 A period of compensation and a relatively normal inflammatory response appears to follow until the late decompensated stage is reached, when adverse pathway activation seems to increase.26 Depending on when in this evolution of left ventricular remodelling the studies to date have been performed, there may be discrepancies in the findings with regard to the impact of beta-blockade on left ventricular remodelling. Beta-blockade may have more impressive effects if used early in the evolution of volume overload-related left ventricular remodelling but it may be less effective later on. Secondly, various beta-adrenergic agents have been tested under different circumstances. Compared to the impressive beneficial results in heart failure patients with the mixed adrenergic blocker, carvedilol,158,202 Pu et al.201 demonstrated

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that this drug caused worsening left ventricular dimensions and function in animal subjects with primary MR. By contrast, treatment of dogs with the selective beta-blocker atenolol improved left ventricular remodelling,90 whereas treatment with metoprolol in animals and humans have had mixed results.108,180,196,197,199,200 Thirdly, an important question is whether patients presenting in more advanced stages of left ventricular remodelling will respond to anti-remodelling therapy or whether the wall stresses determined by the Laplace law will outweigh any potential beta-blocker effect. In this regard, the findings of Pat et al. 200 are interesting because although there were improvements in cardiomyocyte contractility and beta-receptor responsiveness, left ventricular remodelling was not attenuated by metoprolol. It was postulated that β-AR blockade failed to preserve interstitial collagen loss and therefore failed to prevent ongoing myocyte slippage. There appears to be a strong early adrenergic response to chronic primary MR,56 and beta-blocker therapy before onset of left ventricular dilatation may have more benefit. Lastly, in patients with rheumatic mitral valve disease, there is a possibility that rheumatic fever causing rheumatic carditis may have long-lasting effects on the myocardium, attenuating reverse remodelling by beta-blockers.

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Conclusion Left ventricular remodelling in response to the volume load created by chronic primary MR is a complex process that stems from excessive diastolic stretch of myocytes. Excessive stretch triggers activation of numerous signal transduction pathways, resulting in an initial adaptive remodelling process in the form of eccentric hypertrophy. However, chronic activation of these pathways results in abnormal increases in ROS, catecholamines, angiotensin II and inflammatory cytokines. This is followed by a transition to adverse remodelling involving cardiomyocyte apoptosis and interstitial collagen loss, common to all forms of heart failure. Limited data do not support the routine long-term use of afterload-reducing agents for the treatment of chronic primary MR. By contrast, there is pre-clinical data demonstrating that β-AR blockade reverses remodelling caused by the volume overload of chronic primary MR, and there are some recent clinical data to support this hypothesis. However, some studies demonstrated worsening left ventricular remodelling with betablocker therapy. Whether these contrasting outcomes are related to differences in beta-blockers, varying experimental models or differences in timing of therapy will need clarification. Ultimately, further studies are required to elucidate the exact mechanisms involved, and large randomised clinical trials are needed to clarify the role of these agents for patients with chronic primary MR.

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The authors thank Drs Eric Klug and Thomas Kalk for their valuable comments, and Dr Lindsay McCutcheon for help with the artwork.

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2008; 295(6): H2321–2327.

of Cardiology/American Heart Association Task Force on Practice

201. Pu M, Gao Z, Pu DK, Davidson WR Jr. Effects of early, late, and long-

Guidelines (Writing Committee to revise the 1998 guidelines for the

term nonselective beta-blockade on left ventricular remodeling, func-

management of patients with valvular heart disease). Endorsed by the

tion, and survival in chronic organic mitral regurgitation. Circ Heart

Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008; 52(13): e1–142. 185. Hetzer R, Dandel M. Early detection of left ventricular dysfunction in

Fail 2013; 6(4): 756–762. 202. Capomolla S, Febo O, Gnemmi M, et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000; 139(4): 596–608.

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Cardiovascular Topics Risk assessment of the occurrence of sudden death related to hypertrophic cardiomyopathy in Dakar Simon Antoine Sarr, Boubacar Dodo, Kana Babaka, Fatou Aw, Malick Bodian, Mouhamadou Bamba Ndiaye, Adama Kane, Maboury Diao, Serigne Abdou Ba

Abstract Aim: The aim of this study was to assess of the risk of sudden death in a population of hypertrophic cardiomyopathy patients in Dakar. Methods: This was a transverse study at the cardiology clinic of Aristide Le Dantec Hospital from January 2014 to June 2015. We used the European Society of Cardiology risk score to calculate this risk.

Department of Cardiology, Teaching Hospital Aristide Le Dantec, Dakar, Senegal Simon Antoine Sarr, MD Boubacar Dodo, MD Kana Babaka, MD, sokanam@yahoo.fr Fatou Aw, MD Malick Bodian, MD Mouhamadou Bamba Ndiaye, MD Adama Kane, MD Maboury Diao, MD Serigne Abdou Ba, MD

Results: The average age of patients was 53 years. Unexplained syncope was found in two patients and two others had a family history of sudden death. The septal hypertrophy average was 20.9 mm. Seven patients had left intraventricular obstruction. One patient had a high risk of sudden death, three had intermediate risk and 13 had low risk. Competitive sport was not allowed, 13 patients were under medical treatment, one had an implantable cardioverter defibrillator and two had no treatment. Conclusion: Our study highlighted a low and intermediate risk of the occurrence of sudden death at five years. One patient had a high risk of sudden death.

Keywords: hypertrophic cardiomyopathy, HCM, sudden death, implantable cardioverter defibrillator, score Submitted 7/7/16, accepted 12/1/17 Cardiovasc J Afr 2018; 29: e1–e5

www.cvja.co.za

DOI : 10.5830/CVJA-2017-010

Evaluation du risque de mort subite lié à la cardiomyopathie hypertrophique à Dakar Simon Antoine Sarr, Boubacar Dodo, Kana Babaka, Fatou Aw, Malick Bodian, Mouhamadou Bamba Ndiaye, Adama Kane, Maboury Diao, Serigne Abdou Ba Cardiologie, CHU Aristide Le Dantec, Dakar, Senegal Simon Antoine Sarr, MD Boubacar Dodo, MD Kana Babaka, MD, sokanam@yahoo.fr Fatou Aw, MD Malick Bodian, MD Mouhamadou Bamba Ndiaye, MD Adama Kane, MD Maboury Diao, MD Serigne Abdou Ba, MD

Résumé Objectifs: La cardiomyopathie hypertrophique (CMH) est l’une des principales causes de mort subite (MS) du sujet jeune, notamment chez le sportif de moins de 35 ans. Le niveau de risque est variable et nécessite d’être évalué afin d’adopter une stratégie préventive adaptée. Nous avons entrepris ce travail dans le but d’évaluer le risque de survenue de mort subite dans une population de CMH à Dakar.

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Méthode: Il s’agissait d’une étude transversale et descriptive menée à la clinique cardiologique de l’hôpital Aristide Le Dantec de Dakar du 1er Janvier 2014 au 30 Juin 2015. Nous avions évalué sur le plan clinique et paraclinique les facteurs de risque de mort subite et utilisé le score en ligne de l’European Society of Cardiology (ESC) pour le calcul de ce risque. La population étudiée était constituée de patients porteurs de CMH diagnostiquée, suivis dans ledit service. Résultats: Nous avions retrouvé un âge moyen des patients de 53.25 ans et il y avait une prédominance masculine (sexratio de 1.66). La syncope inexpliquée était retrouvée chez 2 patients et 2 autres avaient des antécédents de survenue de mort subite dans leurs familles à des âges de 50 ans et 55 ans. L’hypertrophie septale maximale était en moyenne de 20.9 mm. Quatorze patients présentaient une dilatation auriculaire gauche. Sept patients présentaient une obstruction intra-ventriculaire gauche. Selon le score ESC, 1 patient avait un haut risque de survenue de mort subite dans les 5 ans, 3 un risque intermédiaire et 13 un risque faible. Le sport de compétition était proscrit, 13 patients étaient sous traitement médical, 1 avait eu un défibrillateur automatique implantable (DAI) et 2 n’étaient sous aucun traitement. Conclusion: Notre travail a mis en exergue une prédominance de risque faible et intermédiaire de mort subite à 5 ans. Le haut risque existait dans un cas. Mots clés: cardiomyopathie hypertrophique (CMH), score, mort subite, DAI Submitted 7/7/16, accepted 12/1/17 Cardiovasc J Afr 2018; 29: e1–e5

www.cvja.co.za

DOI : 10.5830/CVJA-2017-010

La cardiomyopathie hypertrophique (CMH) est la plus fréquente des maladies cardiaques d’origine génétique dont la transmission se fait par le mode autosomique dominant.1 Il s’agit d’une affection primitive se caractérisant par une hypertrophie pariétale du ventricule gauche, en règle asymétrique, le plus souvent septale, et s’accompagnant inconstamment d’obstruction ventriculaire.2,3 Elle représente l’une des principales causes de mort subite (MS) du sujet jeune, notamment chez le sportif de moins de 35 ans et, est rencontrée dans environ 0.5% des patients référés à un laboratoire d’échocardiographie en l’absence de toute sélection préalable.2 Il existe une grande hétérogénéité dans l’expression et l’évolution de la maladie, et la majorité des patients reste asymptomatique ou paucisymptomatique pendant très longtemps.4 La mort subite (MS) demeure la complication redoutée de la maladie par sa gravité et son caractère imprévisible. Elle peut constituer la première manifestation de la maladie, son incidence est d’environ 1% par an.4-6 Elle est habituellement en relation avec une tachyarythmie ventriculaire, le stimulus initial pouvant être variable (trouble du rythme supraventriculaire, chute excessive des résistances vasculaires à l’effort, ischémie d’effort, augmentation brutale du gradient intraventriculaire, troubles de conduction). Ce dernier survient volontiers au cours ou au décours immédiat d’un effort physique important.5,6 Le but de notre étude était d’évaluer le risque de survenue

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de mort subite chez les patients porteurs de CMH à Dakar, en procédant à des examens cliniques et paracliniques afin de proposer une prise en charge adaptée.

Méthode Il s’agissait d’une étude transversale et descriptive réalisée du 1er Janvier 2014 au 30 Juin 2015 à la clinique cardiologique de l’hôpital Aristide Le Dantec de Dakar. Le travail a inclus tous les patients porteurs de CMH vus en consultation (CMH connue) ou en laboratoire d’échocardiographie. Les critères diagnostiques à l’échocardiographie étaient une épaisseur de paroi ≥ 13 mm dans un contexte familial ou ≥ 15 mm en l’absence de contexte familial associée à un rapport septum interventriculaire/paroi postérieure > 1.3 (SIV/PP). Les patients qui présentaient une cause d’hypertrophie ventriculaire gauche (HVG) étaient exclus. Un dépistage familial était proposé et les nouveaux cas étaient inclus. Les patients ont préalablement après consentement éclairé, accepté de répondre au questionnaire et de réaliser les examens paracliniques appropriés. Après examen clinique, tous les patients avaient eu un tracé électrocardiographique, une échocardiographie Doppler, un Holter ECG des 24 heures. L’échocardiographie utilisait une sonde d’imagerie de 3 à 7.0 MHz connecté à un système Vivid 7 Dimension’06 de General ElectricÒ. Afin de minimiser la variabilité entre les examens, tous les enregistrements échocardiographiques étaient effectués par le même médecin. Un test d’effort sur tapis roulant était fait chez tous les patients qui étaient aptes à marcher sur tapis. Les facteurs de risque de survenue de MS ont été évalués et nous avions utilisé le score en ligne de l’ESC pour le calcul.7 Ce score est basé sur un algorithme (validé sur une cohorte de près de 3 000 patients) pour le calcul du risque de survenue d’une MS dans les 5 ans. Il prend en compte l’âge (ans), l’HVG maximale (mm), le pic d’obstruction sous aortique (mmHg) spontané ou au Valsalva, le diamètre antéro-postérieur atrial gauche (mm), l’antécédent de syncope inexpliquée (0/1), l’antécédent familial de mort subite < 40 ans ou à tout âge si rapportée à une CMH (0/1), la présence de tachycardie ventriculaire non soutenue au Holter ECG de 48 heures (0/1). Il permet de prendre une décision par rapport à la prévention primaire de la MS. Concernant les résultats, il y a trois possibilités. Ainsi, lorsque le score < 4% le risque est considéré comme faible ; entre 4–6% il était intermédiaire (et l’implantation d’un DAI peut être discutée); > 6% il était élevé et un DAI est formellement indiqué. Le calcul du risque est possible en ligne sur le web sur le site de l’ESC,7 la formule est la suivante: ProbabilitySCD at 5 years = 1 – 0.998exp(Prognostic index) where prognostic index = [0.15939858 × maximal wall thickness (mm)] – [0.00294271 × maximal wall thickness2 (mm2)] + [0.0259082 × left atrial diameter (mm)] + [0.00446131 × maximal (rest/Valsalva) left ventricular outflow tract gradient (mm Hg)] + [0.4583082 × family history SCD] + [0.82639195 × NSVT] + [0.71650361 × unexplained syncope] – [0.01799934 × age at clinical evaluation (years)]. N.B. In HCM risk-SCD there was a non-linear relationship between the risk of SCD and maximum left ventricular wall thickness. This is accounted for in the risk prediction model by the inclusion of a quadratic term for maximum left ventricular wall thickness.

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Tableau I. Anomalies cliniques retrouvées chez les patients porteurs d’une cardiomyopathie hypertrophique Anomalies cliniques Mort subite familiale Syncope

Nombre de personnes (n = 16) 2 2

Palpitations

Dyspnée d’effort

Souffle systolique d’insuffisance mitrale

Souffle systolique éjectionnel

Résultats Au total, 16 patients étaient inclus. L’âge moyen était de 53.25 ans (27–79 ans). Huit patients avaient un âge compris entre 45 et 64 ans. Il y avait une prédominance masculine (sex ratio de 1.66). En ce qui concerne les facteurs majeurs de MS à l’interrogatoire, une syncope était rapportée chez deux patients. Par ailleurs, deux autres avaient des antécédents familiaux de mort subite à 50 ans et 55 ans. Le tableau I résume les anomalies cliniques. Sur le plan électrocardiographique, un cas de fibrillation atriale était noté. Une HVG était trouvée dans 11 cas. A l’échocardiographie Doppler, l’hypertrophie septale maximale était en moyenne de 20.9 mm (13.8–27 mm). Le rapport SIV/ PP était en moyenne de 2.2 (1.5–4.1) (Fig. 1). La surface de l’oreillette gauche était en moyenne de 21.3 cm2 (16–30 cm2). Le diamètre de l’oreillette gauche était en moyenne de 42.7 mm (36–51 mm). Quatorze patients présentaient une dilatation auriculaire gauche. Sept patients présentaient une obstruction intra-ventriculaire gauche (intra-VG). Cette obstruction était médio-ventriculaire dans quatre cas et intéressait la chambre de chasse dans trois cas. Le gradient maximal intra-ventriculaire gauche (intra-VG) était en moyenne de 31.8 mm Hg (13–54 mm Hg) (Fig. 2). Le Holter ECG des 24 heures révélait des troubles du rythme ventriculaire chez trois patients. Un d’entre eux présentait des épisodes de tachycardie ventriculaire non soutenue après phénomène R/T. Ils étaient classés en hyperexcitabilité ventriculaire degrés I, IVB et V de Lown. Il y avait dans un cas, des troubles de la conduction à type d’alternance de bloc auriculo-ventriculaire (BAV) de 2ème degré Mobitz I et Mobitz II.

Fig. 2. Image d’échographie-Doppler cardiaque coupe apicale 4 cavités d’un patient de 27 ans porteur d’une cardiomyopathie hypertrophique obstructive. On note la présence d’un gradient intra-ventriculaire gauche mesuré à 54.3 mmHg en forme de lame de sabre.

Dix patients avaient pu effectuer le test d’effort qui était maquillé pour huit d’entre eux déjà sous traitement. Les six autres n’ont pu le faire pour des raisons diverses comme l’âge avancé ou des séquelles d’AVC. Un patient avait présenté une mauvaise adaptation des chiffres tensionnels à l’effort avec la différence entre sa pression artérielle systolique (PAS) au maximum de l’effort (palier cinq) et celle au repos < à 20 mmHg. Une patiente avait présenté des nombreuses extrasystoles auriculaires avec apparition d’un PR court. Trois patients avaient présenté un sous-décalage non significatif du segment ST en latéral bas. Nous n’avions pas noté l’apparition de syncope lors du test d’effort. Douze patients (75%) avaient un risque de survenue de mort subite faible (score < 4%), trois (18.75%) avaient un risque intermédiaire (> 4% et < 6%) et un (6.25%) avait un haut risque (> 6%) selon le score en ligne de l’ESC (Fig. 3). Treize patients étaient sous traitement à base de bétabloquant et d’inhibiteur calcique. Une patiente avait eu un DAI avec fonction pace maker. Il s’agit d’une patiente de 51 ans qui avait des antécédents de syncopes, d’accident ischémique transitoire et de mort subite dans la famille. Elle présentait un gradient maximal intra-VG de plus de 40 mm Hg au repos (haut risque

6% Risque faible

19%

Risque intermediaire 75%

Fig. 1. I mage d’échographie cardiaque coupe parasternale petit axe d’un patient de 27 ans porteur de cardiomyopathie hypertrophique. Notez l’hypertrophie septale (26 mm) par rapport à la paroi postérieure (11 mm).

Haut risque

Fig. 3. Répartition des patients en fonction du risque de survenue de mort subite dans les 5 ans

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de mort subite) et des troubles de la conduction au Holter ECG (alternance BAV II type I et type II). Un patient de 27 ans qui avait un gradient maximal intra-VG > 50 mmHg aux efforts minimes et une mauvaise adaptation de la TA à l’effort (risque intermédiaire) a été proposé à la myectomie.

Discussion La MS constitue la hantise au cours de la CMH. Les principaux facteurs de risque de MS reconnus sont:1,8,9 • âge jeune au moment du diagnostic (moins de 30 ans) • histoire familiale de CMH avec mort subite prématurée • syncopes répétées (à l’effort ou inexpliquée) • réponse anormale de la pression artérielle à l’effort (différence pression artérielle au maximum de l’effort et pression artérielle (PA) de repos < 20–25 mmHg, surtout avant 40 ans) • tachycardie ventriculaire (TV) non soutenue (surtout si répétée ou prolongée) • arrêt cardiaque récupéré • TV soutenue • hypertrophie importante (paroi ≥ 30 mm) • mutation maligne (celles du gène troponine T, R403Q du gène MYH7). Dans notre étude, nous avions retrouvé une prédominance masculine avec 68% d’hommes. Niamkey à Abidjan10 retrouvait une prédominance masculine à 66.7% dans une étude ayant porté sur l’identification des facteurs majeurs de MS parmi les patients (au nombre de six) suivis pour CMH. L’âge moyen de nos patients était de 53.2 ans avec des extrêmes de 27 et 79 ans. Niamkey10 retrouvait un âge moyen de 30.5 ans avec des extrêmes de cinq et 45 ans. Maron11 retrouvait un âge moyen de 34 ans dans une étude en 1981. La différence d’âge de notre étude et celles des deux auteurs est due au choix des âges de leurs échantillons. Trois patients présentaient des troubles du rythme ventriculaire au Holter ECG, dont un cas d’hyperexcitabilité ventriculaire degré V de Lown. Une patiente présentait des troubles de la conduction à type d’alternance de BAV de 2ème degré Mobitz I et Mobitz II sur fond de nombreux épisodes de bradycardie. Le plus jeune de nos patients (27 ans) a présenté une mauvaise adaptation des chiffres tensionnels à l’effort. Cette désadaptation tensionnelle à l’effort, les troubles du rythme ventriculaire et de la conduction sont des facteurs qui font la gravité de la maladie. Ils sont à rechercher lors de l’évaluation initiale du patient à la recherche de facteurs pouvant favoriser la survenue de MS. Charron12 retrouvait une hyperexcitabilité supraventriculaire et notait aussi une TV non soutenue chez 25% des patients adultes, les TV soutenues étant rares. Il faisait ressortir la réponse anormale de la PA à l’effort, surtout avant 50 ans comme un facteur de risque de survenue de mort subite. Toutefois, un seul des facteurs de risque majeurs n’a que peu de valeur prédictive positive (environ 15–20%). C’est l’association de plusieurs d’entre eux qui doit être considérée.12,13 Concernant le risque de MS, Niamkey10 retrouvait 33.3% de haut risque de décès et un risque intermédiaire chez les autres patients. Maron et Mckenna14,15 notaient un taux de MS évalué entre 2 à 3% par an chez les adultes et entre 4 à 6% par an chez les enfants. Toutefois, ces travaux présentaient des biais de sélection importants. Cannan, Cecchi et Kofflard16-18 dans des études plus récentes réalisées dans des populations moins sélectionnées ont

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retrouvé des taux de MS bien inférieurs. Ils étaient de l’ordre de 1 à 2% par an, et même moins pour certaines études, indiquant que le pronostic des CMH est bien meilleur que celui communément admis.19 Il est à noter que ces travaux ont évalué l’évolution et le pronostic de la maladie tandis que notre étude a évalué le risque de survenue de MS dans les cinq ans en utilisant le calculateur en ligne de l’ESC. Ce dernier permet de détecter les patients à même d’être proposés à l’implantation d’un DAI. Ce calculateur présente toutefois certaines limites:20 il n’est pas utilisable chez le patient de moins de 16 ans, l’athlète de compétition d’élite, le sujet ayant subi une alcoolisation septale ou une myectomie, de même que lorsque l’hypertrophie septale maximale est ≥ 35 mm. En plus, il n’intègre pas les données concernant le test d’effort. C’est d’ailleurs ce qui explique qu’un de nos patients qui avait une désadaptation tensionnelle à l’effort (facteur de risque majeur) a eu un risque quotté intermédiaire. La prise en charge intégrait, en plus des règles d’hygiène de vie et de proscription de sport de compétition, le traitement médical à base de bétabloquant et d’inhibiteur calcique bradycardisant (chez 13 patients). La patiente à haut risque de survenue de MS et qui présentait le trouble de la conduction avait bénéficié d’un DAI avec fonction pace maker. Elle est en instance de traitement complémentaire à type d’alcoolisation septale voire de myectomie vu la persistance de sa symptomatologie et du gradient intra-VG. La prise en charge de la CMH fait appel à deux grandes catégories de traitement: celui médicamenteux et celui non médicamenteux.21 Le traitement médical est de première intention et fait appel classiquement aux bétabloquants, vérapamil et disopyramide (réservé aux cas résistants aux deux premiers chez les patients avec obstruction).22 Les autres molécules sont administrées en fonction du tableau clinique du patient avec une prudence accrue pour l’utilisation des diurétiques. Le traitement non médicamenteux est réservé aux patients ayant un gradient intra-VG résistant au traitement médical et aux patients restant symptomatiques malgré un traitement optimal. Il s’agit de la myotomie-myectomie de Marrow, de l’alcoolisation septale, de la stimulation double chambre et du DAI avec ou sans fonction pacemaker. Selon les recommandations, la prévention nécessite une évaluation du risque de MS. Ainsi, un DAI devrait être implanté à tout patient à haut risque de MS.23

Conclusion L’évaluation du risque de survenue d’une cardiomyopathie hypertrophique est une étape cruciale permettant d’avoir un traitement adéquat. Notre travail portant sur l’évaluation du risque de mort subite dans la cardiomyopathie hypertrophique à Dakar a trouvé une prédominance de risque faible et intermédiaire de mort subite à cinq ans. Le haut risque n’existait que dans 1 cas. L’évaluation de ce score a par ailleurs, permis de proposer une prise en charge adéquate chez nos patients.

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Maron BJ. Hypertrophic cardiomyopathy: a systematic review. J Am Med Assoc 2002; 287: 1308–1320.

Hagege A. Cardiomyopathie hypertrophique. In: Cohen A, Gueret P (eds). Manuel d’échocardiographie clinique. Paris: Lavoisier Médecine

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Maki S, Ikeda H, Muro A, Yoshida N, Shibata A, Koga Y, et al. Predictors of sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 1998; 82: 774–778.

10. Niamkey T, Anzouan-Kacou JB, Coulibaly I, N’Guetta AR, N’ChoMottoh MP, Gnamba A, et al. Evaluation des facteurs majeurs de mort subite chez les porteurs de CMH primitive. Cardiol Trop 2013; 134: 15–16. 11. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of

1529–1536. 19. Kofflard MJ, Waldstein DJ, Vos J, Ten Cate FJ. Prognosis in hypertrophic cardiomyopathy observed in a large clinic population. Am J Cardiol 1993; 72: 939–943. 20. Dubourg O, Mansencal N, Charron P. Recommendations for the diagnosis and management of hypertrophic cardiomyopathy in 2014. Arch Cardiovasc Dis 2015; 108: 151–155. 21. Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation 2006; 113: 858–862. 22. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of

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Case Report Coronary artery bypass grafting and paraparesis; is there a correlation? Ilias Samiotis, Nikolaos G Baikoussis, Vasileios Patris, Michalis Argiriou, Panagiotis Dedeilias, Christos Charitos hypertension, hyperglycaemia, hyperthermia, hypoxaemia, aortic atheromatosis and peripheral vascular disease.1,2,5

Abstract Adult cardiac surgery is associated with significant perioperative morbidity and mortality rates, mainly in elderly patients with co-morbidities. A series of postoperative complications may arise and delay the recovery of patients undergoing cardiac surgery. Such complications also increase the burden of resource use and may affect late survival rates. Neurological complications appear mainly as stroke of varying degrees, with impairment of mobility and ability of the patient. We describe a rare case of progressive paraparesis after on-pump coronary artery bypass grafting, and review its aetiology, diagnosis and management. Keywords: coronary artery bypass grafting, CABG, stroke, extracorporeal circulation, neurological complications in cardiac surgery, paraparesis, spinal cord ischaemia, transient ischaemic attack Submitted 8/11/16, accepted 26/1/17 Cardiovasc J Afr 2018; 29: e6–e8

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DOI: 10.5830/CVJA-2017-014

Neurological complications after cardiac surgery may occur in the post-operative period. Stroke and transient ischaemic attack are major adverse cardiac events following coronary artery bypass grafting (CABG) and markedly reduce patient shortand long-term survival rates. The causes of these complications are hypoxia, metabolic abnormalities, emboli or haemorrhage. These complications are associated with increased mortality rates, prolonged intensive care unit (ICU) stay and decreased long-term survival rates.1-7 The main risk factors for neurological complications in cardiac surgery are haemodynamic instability, diabetes mellitus, advanced age, complex procedures, prolonged cardiopulmonary bypass time (CPB > two hours), previous stroke,

Cardiovascular and Thoracic Surgery Department, Evangelismos General Hospital of Athens, Athens, Greece Ilias Samiotis, MD, MSc Nikolaos G Baikoussis, MD, PhD, nikolaos.baikoussis@gmail.com Vasileios Patris, MD, MSc Michalis Argiriou, MD, MSc, PhD Panagiotis Dedeilias, MD Christos Charitos, MD, PhD

Case report A 65-year-old man was admitted to our department for a routine CABG due to left main coronary artery disease. The patient’s medical history included smoking, family history of early coronary artery disease, hypertension, diabetes, hyperlipidaemia, percutaneous transluminal coronary angioplasty to the left descending artery (LAD) and to the right coronary artery (RCA) 12 years earlier, and myocardial infarction 11 years earlier due to in-stent stenosis. In his past medical history, there was an unclear history of sensory or motor impairment after coccyx cyst surgery. All laboratory data were within normal limits except for the erythrocyte sedimentation rate (521st, 1 132nd) and a C-reactive protein (CRP) > 2 mg/l. Echocardiographic findings were left ventricular ejection fraction (LVEF) of 45% and mild left ventricular hypertrophy. Coronary artery CT-angiography was performed and stenosis of three coronary arteries was established. The induction of anaesthesia was performed with Dormicum 5 mg, Propofol 150 mg, Esmeron 60 mg and Sevoflurane. The patient underwent triple coronary artery bypass grafting as follows: left internal mammary to left anterior descending artery (LIMA–LAD), a saphenous vein graft to the first obtuse marginalis (SVG–OM1) and another saphenous vein graft to the right coronary artery (SVG–RCA). During surgery his vital signs were stable and the arterial blood gasses (ABGs) were within normal limits. After surgery the patient was moved to the cardiac ICU while intubated and unconscious, with a blood pressure of 110/60 mmHg, heart rate of 77 beats/min and normal sinus rhythm, central venous pressure of 8 cm H2O and peripheral capillary oxygen saturation of 100%. After admission to the ICU, his primary vital signs were normal. The patient was successfully weaned and extubated on the same day. The post-surgery drugs were: enoxaparin 40 mg daily, furosemide 20 mg daily, metoprolol 100 mg twice daily, clopidogrel 75 mg daily, atorvastatin 20 mg daily and acetylsalicylic acid 100 mg daily. On the first postoperative day, laboratory findings in the ICU were: haemoglobin 10 g/dl, haematocrit 30.5%, platelets = 242 000 cells/l, white blood cell count = 9 100 cells/l, prothrombin time = 15.3 sec, activated partial thromboplastin time = 32 sec, INR = 1.47, sodium = 139 mEq/l, potassium = 4.9 mmol/l, blood

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urea nitrogen (BUN) = 17 mg/dl, creatinine = 0.94 mg/dl, creatine phosphokinase (CK) = 847 U/l, CK-MB = 58 U/l. He was moved to the cardiac surgery department. During this first postoperative day, the patient was stable, awake and oriented. No signs of haemodynamic instability or cardiac dysrhythmias were seen. The second day after CABG, the overall condition of the patient was good but he had difficulty moving his lower limbs. Neurological consultation was done and the cranial nerves were found to be intact, cerebellar tests and sensory examinations were normal, muscle strength of the lower limbs was 3/5 and symmetric and plantar reflexes were double flexor. On the third postoperative day, the overall condition of the patient was good but he still had difficulty moving the lower limbs. Progressive paraparesis developed and the muscle strength and deep tendon reflexes (DTRs) began to decrease gradually. Paraparesis progressed and muscle strength decreased from 4/5 to 3/5 and then to 2/5. In the evening, severe weakness of the lower and upper limbs developed, absence of DTRs, no plantar reflexes, and muscle strength was 1/5 on the left and 0/5 on the right side. That night the patient presented with respiratory failure; he was intubated and moved to the ICU. On the fourth day, the patient was haemodynamically stable and he was transferred to the radiology laboratory in order to undergo magnetic resonance imaging (MRI). During the MRI examination, the patient experienced an episode of ventricular fibrillation and cardiac arrest. He was resuscitated after 20 minutes of cardiopulmonary resuscitation and two defibrillations. He was in haemodynamic instability and received high doses of dobutamine, norepinephrine and adrenaline. The laboratory findings were: creatinine = 3.0 mg/dl, urea 111 mg/dl, aspartate transaminase (AST) 1 000 U/l, alanine transaminase (ALT) 6182, LDH 9 119 U/l, CK 3 915 U/l, CK-MB 315 U/l, troponin 10 000 ng/ml. The echocardiogram findings were left atrium 39 mm, telo diastolic volume of the left ventricle 50 mm, the left ventricle showed diffuse hypokinesis and akinesis, with a LVEF of 25%, and pulmonary artery systolic pressure was 40–45 mmHg. The MRI report showed at the level of the fifth and sixth cervical vertebrae that there were posterior osteophytes and circular degeneration of the annulus fibrosis with high-grade stenosis and compressive phenomena in the spinal cord. From the second to the sixth cervical vertebrae, there was a pathological zone and oedema due to myelopathy and ischaemia (Fig. 1). On the sixth day after surgery, the patient was better and was haemodynamically supported with low-dose norepinephrine. However he presented manifestations of post-cardiac arrest brain injury such as coma, seizures and myoclonus. He died 10 days after surgery due to septic shock.

Discussion Neurological complications after cardiac surgery may occur in the post-operative period. Stroke and transient ischaemic attack are major adverse cardiac events following CABG and markedly reduce patient short- and long-term survival rates. The five-year rate of stroke was significantly higher after CABG than after percutaneous coronary intervention in patients with diabetes and multi-vessel coronary artery disease.2 Previous studies comparing surgical outcomes of patients undergoing conventional on-pump CABG with cardiopulmonary bypass versus patients undergoing

Fig. 1. At the level of the fifth and sixth cervical vertebrae, posterior osteophytes and circular degeneration of the annulus fibrosis with high-grade stenosis and compressive phenomena in the spinal cord can be seen. From the second to the sixth cervical level, a pathological zone (white area into the grey zone) and oedema due to myelopathy and ischaemia (arrows) can be seen.

off-pump CABG mostly focused on low-risk patients, for instance, relatively young patients with preserved left ventricular function and without systemic co-morbidity. The causes of these neurological complications are hypoxia, metabolic abnormalities, emboli or haemorrhage. These complications can be divided into two types: type 1 (3%) includes major focal deficit and stupor or coma; type 2 (3%) includes intellectual dysfunction. These complications are associated with increased mortality rates, prolonged ICU stay and decreased long-term survival rates.1-7 Risk factors for neurological complications in cardiac surgery are haemodynamic instability, diabetes mellitus, advanced age, complex procedures, prolonged CPB (> two hours), previous stroke, hypertension, hyperglycaemia, hyperthermia, hypoxaemia, aortic atheromatosis and peripheral vascular disease.1,2,5 Mechanisms and factors causing neurological lesions are embolisation and hypoperfusion, and influencing factors are aortic atheroma plaque, cerebrovascular disease, altered cerebral autoregulation, hypotension, intracardiac debris air, venous obstruction on bypass, CPB circuit surface, cerebral hyperthermia and hypoxia. In our case, the differential diagnoses were cerebrovascular accident or lacunar infarct (internal capsular region) – embolic or haemorrhagic, spinal cord ischaemia and infarct (due to embolic insult or hypoperfusion), acute inflammatory demyelinating polyradiculoneuropathy or critically ill polyneuropathy, peripheral nervous injury, peripheral vascular disease and spinal cord ischaemia. In spinal cord ischaemic stroke, neurological deficits may occur without pain, however, most (> 80%) are painful and this is an interesting difference from cerebral infarction, which is usually not painful. Depending on the level

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of the cord lesion, symptoms may vary from mild to moderate and even from reversible leg weakness to quadriplegia. Fever is a warning to consider infectious origins such as acute meningitis.8-13 Involvement of intrinsic cord vessels has been reported with arteritis such as systemic lupus erythematosus. Anterior spinal artery occlusion has been reported with arteritis, including that associated with syphilis and diabetes mellitus; after trauma; and as a complication of spinal angiography, spinal adhesive arachnoiditis, administration of intrathecal phenol, and spinal anaesthesia. Aortic diseases are blamed for producing spinal infarction in a variety of situations including dissecting aneurysm; aortic surgery, especially with aortic cross-clamping above the renal artery; aortography; atherosclerotic embolisation; and aortic thrombosis. Uncommon causes include complications of abdominal surgery, particularly sympathectomy; circulatory failure as a result of cardiac arrest or prolonged hypotension; and vascular steal in the presence of an arteriovenous malformation, or vascular compression by tumours in the spinal canal, vertebral fracture, or a herniated intervertebral disk.12,13 Suspecting neuropathies, we ordered electromyography and nerve conduction velocity tests, which found peripheral sensory– motor polyneuropathy, mainly of the demyelinating type, with a differential diagnosis of acute inflammatory demyelinating polyneuropathy and critical illness polyneuropathy. A cervical– thoracic MRI showed the pathological osteophytes and circular degeneration of the annulus fibrosis of the fifth and sixth cervical vertebra with a compression in the spinal cord and consequent ischaemia and oedema of the medulla.

References

Conclusion

10. Cheshire WP, Santos CC, Massey EW, Howard JF Jr. Spinal cord infarc-

The complication in our case is a rare condition that has not been discussed in the literature. We considered that this complication was due to a degenerative vertebral condition with compression in the spinal cord, exacerbated by placing a prop under the shoulder to position the body for the sternotomy. Placing a prop to position the body for CABG surgery is unavoidable and one cannot consider possible vertebral pathology in all patients before surgery, especially when the patient does not have any associated symptoms. Therefore in this patient, the diagnosis of paraparesis was made accidentally.

11. Weber P, Vogel T, Bitterling H, Utzschneider S, von Schulze Pellengahr

Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, et al. Adverse cerebral Outcomes after coronary bypass Surgery. Multicenter Study of Perioperative ischemia Research Group and the ischemia Research and Education Foundation investigators. N Engl J Med 1996; 525: 1857.

Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Onnasch JF, et al. Stroke after cardíac surgery: A risk factor analysis Of 16,184 consecutíve adult patients. Ann Thorac Surg 2003; 75: 472

Hogue CW Jr, Barzilai B, Pieper KS, Coombs LP, DeLong ER, Kouchoukos NT, et al. Sex differences in neurologícal outcomes and mortality after cardiac surgery: a Society of Thoracic Surgery National Database report. Circulation 2001; 103: 2133–2137.

Nussmeier NA. A review of risk factors for adverse neurologic Outcome after cardiac Surgery. J Extracorp Technol 2002; 34: 4.

Ridderstolpe L, Ahlgren E, Gill H, Rutberg H. Risk factor analysis Of early and delayed cerebral complications after cardiac surgery. Cardiothorac Vasc Anesth 2002; 16: 278–285.

Wolman RL, Nussmeier NA, Aggarwal A, Kanchuger MS, RoachGW, Newman MF, et al. Cerebral injury after cardiac surgery: identification of a group at extraordinary risk. Multicenter Study of Perioperative lschemia Research Group (MCSPI) and the lschemia Research Education Foundation (lREF) lnvestigators. Stroke 1999; 30: 514–522.

Ahonen J, Salmenpera M. Brain injury after adult cardiac Surgery. Acta Anaesthesiol Scand 2004; 48: 4–19.

Hughes RA, Swan AV, Raphael JC, Annane D, van Koningsveld R, van Doorn PA. Immunotherapy for Guillain-Barre syndrome: a systematic review. Brain 2007; 130: 2245–2245.

Chawla J, Gruener G. Management of critical illness polyneuropathy and myopathy. Neural Clin 2010; 28: 961, 77 tion: etiology and outcome. Neurology 1996; 47: 32130. C, Birkenmaier C. Spinal cord infarction after operative stabilisation of the thoracic spine in a patient with tuberculous spondylodiscitis and sickle cell trait. Spine 2009; 34: E294–297.

12. Hogan EL, Romanul FC. Spinal cord infarction occurring during insertion of aortic graft. Neurology 1966; 16: 67–74. 13. Ross RT. Spinal cord infarction in disease and surgery of the aorta. Can J Neurol Sci 1985; 12: 289–295. 13. Ross RT. Spinal cord infarction in disease and surgery of the aorta. Can J Neurol Sci 1985; 12: 289–295.

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Case Report Acute type A aortic dissection involving the iliac and left renal arteries, misdiagnosed as myocardial infarction Paul Nkemtendong Tolefac, Anastase Dzudie, Sidick Mouliom, Leopold Aminde, Romuald Hentchoya, Martin H Abanda, Charles Mve Mvondo, Vanina D Wanko, Henry N Luma

Abstract Acute aortic dissection is the most frequent and deadly presentation of acute aortic syndromes. Its incidence is estimated at three to four cases per 100 000 persons per year. Its clinical presentation may be misleading, with misdiagnosis ranging between 14.1 and 38% in many series. A late diagnosis or absence of early and appropriate management is associated with mortality rates as high as 50 and 80% by the third day and second week, respectively, especially in proximal lesions. We report on the case of a 53-year-old man who presented with type A aortic dissection, misdiagnosed as acute myocardial infarction, who later died on day 12 of hospitalisation. Although a relatively rare condition, poor awareness in Africa probably accounted for the initial misdiagnosis. Thorough investigation of acute chest pain and initiation of clinical registries are potential avenues to curb related morbidity and mortality. Keywords: aortic dissection, acute chest pain, hypertension, outcome, case report Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon Paul Nkemtendong Tolefac, MD, ptolefac15@gmail.com

Cardiac Intensive Care Unit, Douala General Hospital, Douala Cameroon Anastase Dzudie, MD, PhD, FESC Sidick Mouliom, MD, DSSc Romuald Hentchoya, MD, DSSc

Faculty of Medicine and Biomedical Sciences, University of Queensland, Australia Leopold Aminde, MD

Submitted 3/10/16, accepted 2/10/17 Published online 3/11/17 Cardiovasc J Afr 2018; 29: e9–e13

www.cvja.co.za

DOI: 10.5830/CVJA-2017-042

Cardiovascular diseases are the leading cause of death in the Western world and are on the rise in developing countries.1-3 Acute aortic syndromes include acute aortic dissection (AAD), intramural haematoma, penetrating aortic ulcer and ruptured thoracic aortic aneurysm.3,4 AAD is the most frequent and lethal presentation of acute aortic syndromes, with an incidence of three to four cases per 100 000 persons per year.5 There are several different classification systems of aortic dissection. The two most commonly used formats are the Debakey and Standford classifications, as shown in Table 1. In the absence of treatment, AAD type A has worse outcomes, with an initial mortality rate of 1% per hour, with 50 and 80% of the patients expected to die by the third day and second week, respectively. Progression of the dissection can be either anterograde or retrograde from the initial tear, with resultant malperfusion syndromes, acute coronary syndromes (ACS), cardiac tamponade or aortic valve insufficiency.6 Its clinical presentation may be misleading with misdiagnosis ranging from 14.1 to 38% seen in many series.7-10 The differential diagnosis of AAD may include acute coronary syndromes, pericarditis, pulmonary embolism, acute pancreatitis and peptic ulcer disease. AAD usually mimics ACS.11 Factors favouring misdiagnosis of AAD include clinical similarities with common diseases such as ACS, low regional epidemiology, and limited access to specific diagnostic imaging modalities in some regions. In one study, it was shown that the commonest factors

Cardiavascular Centre, Douala, Cameroon Martin H Abanda, MD

Division of Cardiac Surgery, Shisong Cardiac Centre, Kumbo, Cameroon Charles Mve Mvondo, MD, DSSc

Radiology Unit, Douala General Hospital, Douala, Cameroon Vanina D Wanko, MD, DSSc

Internal Medicine Service, Douala General Hospital, Douala, Cameroon Henry N Luma, MD, DSSc

Table 1. Classification of acute aortic dissection Standford classification

DeBakey classification

Type A

Type B

Type I

Type II

Type III

Dissection involving the proximal aorta (ascending aorta, aortic arch) with or without extension to the descending aorta7,8

Dissection limited to the descending aorta7 (but may be extended to the abdominal segment)

Involving the ascending aorta and a variable amount of descending or thoracoabdominal aorta7

Dissection limited to the ascending aorta8

Dissection of the descending aorta either without (IIIa) or with (IIIb) involvement of the abdominal aorta7

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favouring missed diagnosis of AAD were walk-in patients, anterior chest pain, severe or worst-ever pain and widened mediastinum, with walk-in mode of admission being the single strongest predictor of misdiagnosis.8 Diagnostic imaging studies are pivotal in confirming the diagnosis and classifying the extent of the dissection using either DeBakey (I, II and III) or Standford (A or B) classifications. AAD involving the ascending aorta (Standford type A) is a surgical emergency requiring swift repair of the aortic root or reconstruction of the ascending aorta and arch to improve prognosis, whereas dissections involving the descending aorta (Standford type B) are treated medically with the following surgical indications: propagation of the dissection, intractable pain or poor organ perfusion.3,12

Case report A 53-year-old sub-Saharan African man with poorly controlled hypertension was referred to the cardiac intensive care unit (CICU) by his cardiologist for the management of a sudden-onset, severe and intractable retrosternal chest pain of approximately

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50 hours’ duration. The pain was tearing in character, radiating to the back and lumbar regions, non-positional and associated with shortness of breath and headache. The electrocardiogram (ECG), done three hours after the onset of pain, showed sinus rhythm and non-specific repolarisation changes (flattened or inverted T waves in leads I, aVL and V3–V6). Although ECG changes were suggestive of left ventricular strain, the presence of chest pain and a mildly raised troponin level (0.11 µg/ml) favoured myocardial infarction, and the patient was started on low-molecular weight heparin (LMWH) at a therapeutic dose, aspirin and nitrates. Persistence of the pain after initial therapy prompted referral to our centre. On examination, he was anxious, dyspnoeic (NYHA functional class III with a respiratory rate of 28 breaths/ min) and diaphoretic. His temperature was 36.9°C, heart rate was 79 beats/min, and blood pressure was 187/73 mmHg in the right arm and 145/56 mmHg in the left arm. Physical examination showed a systolic murmur (grade 3/6) in the aortic area, which radiated to the left carotid, but there were no signs of heart failure. The neurological examination was unremarkable. Chest X-ray (Fig. 1A) showed enlargement of the mediastinum

Fig. 1. A nterior–posterior chest X-ray. A: At presentation showing enlargement of the mediastinum. B: On day 11 of hospitalisation showing bilateral interstitial heterogeneous opacities.

Fig. 2. E CG at presentation showing non-specific ST-segment changes consistent with sub-epicardial ischaemia in the inferior and apico-lateral leads.

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Fig. 3. E chocardiography showing dilatation of the ascending aorta.

with cuffing of the aortic knob. The ECG (Fig. 2) at our unit showed a normal sinus rhythm, normal QRS axis with sub-epicardial ischaemia in the inferior and apico-lateral leads. Echocardiography (Fig. 3) showed a dilated left atrium, good left ventricular systolic function (ejection fraction 72%), and severe aortic insufficiency with dilatation of the aortic root and ascending aorta (44 mm). Contrast-enhanced CT (CECT) angiogram of the thorax (Fig. 4) showed dissection of the aorta from the ascending aorta to the iliac arteries, including the coeliac trunk and left renal artery, and causing splenic infarction. Doppler ultrasound of the carotid arteries did not show extension to the carotid arteries. These observations led to a working diagnosis of Standford type A acute aortic dissection. Table 2 shows biological investigations done at presentation and throughout hospitalisation. The patient was placed on high-flow oxygen at 5 l/min, nicardipine in an electric syringe titrated to a maximum of 10 mg/h, bisoprolol 5 mg/12 h, analgesics and compressive stockings. The LMWH was stopped. On day five of hospitalisation, he developed superficial thrombophlebitis on the left forearm (along the peripheral intravenous line). By day six of hospitalisation, blood pressure and heart rate targets (< 120/80 mmHg and < 60 beats/min, respectively) were achieved. On day 10 of hospitalisation, the patient developed a temperature of 39.1°C and sudden dyspnoea at rest. Physical Table 2. Serial biological investigations done at the emergency department and throughout hospitalisation Presentation

Day 1

Day 4

Day 10

Day 11

White cell count, × 106 cells/l

Biological investigation

6.8

9.5

7.3

5.2

17.7

C-reactive protein, mg/l

7.21

30.72

310.43

15.2

13.5

13.2

12.4

10.5

Haemoglobin, g/l Serum creatinine, mg/l

17.2

12.3

13.1

Troponin I

2.26

0.69

0.15

Creatine kinase (CK), IU/l

200

CK-MB, IU/l

24.9

LDH, UI/l

455

D-dimers

24087

117

6,366

NT-pro BNP

LDH = lactate dehydrogenase test; ND = not done.

examination showed a heart rate of 119 beats/min, blood pressure of 124/76 mmHg and oxygen saturation of 98%. Chest examination revealed crepitation in both lung bases, more marked on the right. We decided on a presumptive diagnosis of severe pneumonia. A repeat chest X-ray (Fig. 1B) showed bilateral interstitial heterogeneous opacities. The C-reactive protein (CRP) level was 310.43 mg/l with leucocytosis of 17.7 × 106 cells/l (Table 2). Blood samples were collected for culture, and antibiotics (amoxicillin–clavulanic acid 1 g eight hourly and clarithromycin 1 000 mg 12 hourly) were introduced. Blood culture results (which returned after the patient’s demise) were positive for Klebsiella pneumonia. About three hours later he had persistent dyspnoea and hypoxaemia (SpO2 ≤ 65% and PaO2 ≤ 60 mmHg). He was intubated and during the process sustained a cardiac arrest. The patient later died on day 12 of hospitalisation following cardiopulmonary arrest despite life support.

Discussion AAD is characterised by separation of the layers of the aortic wall, resulting from the entry of extra-luminal blood through an intimal tear, producing a false lumen. Tears are commonly seen at areas of high stress, commonly in the anterior aortic wall just above the aortic valve (66%) and the posterior wall of the proximal descending aorta (33%). When blood enters through an intimal tear it passes longitudinally along the tunica media separating the intima from the adventitia.13 There are several different classification systems of aortic dissection. The two most commonly used formats are the DeBakey and Standford classifications, as described in literature.12,14 The typical presentation of AAD is a sudden, unexpected, intense retrosternal pain radiating to the back and/or abdomen, associated with asymmetrical blood pressure.6 Patients are typically hypertensive, middle aged or elderly and therefore the differential diagnosis would include acute myocardial infarction, acute coronary syndromes, pericarditis, pulmonary embolism, peptic ulcer disease and acute pancreatitis. Due to its possibility of extension to involve the mesenteric, iliac and renal arteries, other presentations may include intestinal ischaemia, stroke and

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Fig. 4. C ontrast-enhanced CT angiogram of the thorax showing aortic dissection extending to the left renal (green arrow), iliac (yellow arrow) and superior mesenteric (red arrow) arteries and causing splenic infarction (blue arrow).

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renal failure.5 A misdiagnosis at presentation may occur in up to 38% of AADs, as well as being discovered during post mortem in 28% of cases without any prior identification or suspicion.15 Our patient presented with typical features of AAD, which was initially diagnosed as myocardial infarction (MI), probably due to the relative rarity of the condition compared to MI in our setting. However, a thorough clinical assessment and high index of suspicion may have picked up suggestive clinical features. Furthermore, a chest X-ray, which usually shows enlargement of the mediastinum with knobbing of the aorta in about 60% of the cases was not done.16 This further emphasises the importance of a chest X-ray among first-line investigations in the management of acute chest pain. According to the American Heart Association 2010 guidelines for the management of acute thoracic disease, possible ECG findings in the evaluation of AAD include: 30% normal ECG, 40% non-specific ST-segment changes, 26% left ventricular hypertrophy and 15% signs of ischaemia.15 Our patient had non-specific ST-segment changes consistent with myocardial ischaemia. CECT angiogram of the thorax was used to confirm the diagnosis of Standford type A AAD in the indexed case, with the dissection extending to the iliac, mesenteric and left renal arteries. Although the diagnosis of AAD type A was made relatively late in our patient, he was not operated on because of lack of local cardiosurgical centres, financial constraints and his refusal of evacuation to another country. The target blood pressure and heart rate, as described in the literature,3 were achieved after six days of hospitalisation. Potential contributing factors to the fatality included late referral and diagnosis, initial treatment with LMWH at therapeutic dose and aspirin, lack of local cardiosurgical centres for emergency surgery, and severe sepsis.

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References 1.

Bergmark BA, Sobieszczyk P, Gravereaux EC, Bonaca M, Giugliano RP. Acute dissection of the descending aorta: a case report and review of the literature. Cardiol Ther 2013; 2(2): 199–213.

Ince H, Nienaber CA. Diagnosis and management of patients with aortic dissection. Heart 2007; 93(2): 266–270.

Carpenter SW, Kodolitsch YV, Debus ES, Wipper S, Tsilimparis N, Larena-Avellaneda A, et al. Acute aortic syndromes: definition, prognosis and treatment options. J Cardiovasc Surg (Torino) 2014; 55(2 Suppl 1): 133–144.

LeMaire SA, Russell L. Epidemiology of thoracic aortic dissection. Nat Rev Cardiol 2011; 8(2): 103–113.

Mészáros I, Mórocz J, Szlávi J, Schmidt J, Tornóci L, Nagy L, et al. Epidemiology and clinicopathology of aortic dissection: a populationbased longitudinal study over 27 years. Chest 2000; 117(5): 1271–1278.

Zhan S, Hong S, Shan-shan L, Chen-ling Y, Lai W, Dong-wei S, et al. Misdiagnosis of aortic dissection: experience of 361 patients. J Clin Hypertens 2012; 14(4): 256–260.

Kurabayashi M, Miwa N, Ueshima D, Sugiyama K, Yoshimura K, Shimura T, et al. Factors leading to failure to diagnose acute aortic dissection in the emergency room. J Cardiol 2011; 58(3): 287–293.

Ansari-Ramandi MM. Acute type a aortic dissection missed as acute coronary syndrome. J Clin Diagn Res 2016 [cited 2016 Sep 24]; Available from: http://jcdr.net/article_fulltext.asp?issn=0973-709x&year=2016&v olume=10&issue=5&page=OD33&issn=0973-709x&id=7854.

10. Jackson E, Stewart M. Thoracic aortic dissection presenting as acute coronary syndrome. Case Reports 2013; 2013(dec20 1):bcr2013201904– bcr2013201904. 11. Hawatmeh A, Abu Arqoub A, Isbitan A, Shamoon F. A case of ascending aortic dissection mimicking acute myocardial infarction and

Conclusion Despite the relative rarity of AAD in sub-Saharan African settings, this case highlights the importance of thorough early clinical assessment and investigation in the emergency room of patients with acute chest pain. Furthermore, limited resources common in low-income settings contribute to this health burden. The initiation of clinical registries is a potential avenue to increase awareness around these fatal conditions and thereby contribute to reduction of cardiovascular-related morbidity and mortality.

complicated with pericardial tamponade. Cardiovasc Diagn Ther 2016; 6(2): 166–171. 12. Guilmet D, Bachet J, Goudot B, Dreyfus G, Martinelli GL. Aortic dissection: anatomic types and surgical approaches. J Cardiovasc Surg (Torino) 1993; 34(1): 23–32. 13. Morris-Stiff G, Coxon M, Ball E, Lewis MH. Post-coital aortic dissection: a case report. J Med Case Reports 2008; 2: 6. 14. Cohen R, Mena D, Carbajal-Mendoza R, Arole O, Mejia JO. A case report on asymptomatic ascending aortic dissection. Int J Angiol Off Publ Int Coll Angiol Inc 2008; 17(3): 155–161. 15. Hagan PG, Nienaber CA, Isselbacher EM, et al. The international registry of acute aortic dissection (irad): New insights into an old disease. J

We express our sincere gratitude to all doctors, nurses and medical students

Am Med Assoc 2000; 283(7): 897–903.

who took part in the management of the patient. Written, signed, informed

16. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE,

consent was obtained from the patient’s next of kin for the publication of this

et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM

case and accompanying images. The patient’s confidentiality was maintained

guidelines for the diagnosis and management of patients with thoracic

throughout.

aortic disease. J Am Coll Cardiol 2010; 55(14): e27–e129.

ECG rhythms CPD CPD developed by Prof Rob Scott Millar, Cardiac Clinic, UCT/Groote Schuur Hospital CPD overview: Following the introductory “Approach to Rhythms”, this online educational CPD quiz will consist of a series of ECGs with a variety of important cardiac rhythms. Each will be accompanied by a series of questions, followed by a detailed analysis and explanation. Target audience: Cardiologists, physicians, emergency unit doctors and anaesthetists. Including those studying for FCP and certificate in cardiology. Total time commitment: ± 30 to 60 minutes. Assessment information: A pass mark of 70% is required. A candidate has 60 days to complete the CPD after registration. CPD certificate: A PDF certificate of completion will be issued on successful completion the CPD. CPD enrollment fee: Free / no charge. Important notice: The CPD was made possible by an unrestricted educational sponsorship from Bayer Pharmaceuticals South Africa, which had no control over the content. Publisher information: This CPD is endorsed by the Cardiovascular Journal of Africa published by Clinics Cardive Publishing.

For more information please visit www.cvja.co.za

Cardiovascular Journal of Africa

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ypertens i i-h

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JANUARY/FEBRUARY 2018 VOL 29 NO 1

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CardioVascular Journal of Africa (official journal for PASCAR)

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- has a positive effect on metabolic parameters.1

6,25 mg 12,5 mg

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Cardiovascular Journal of Africa . Vol 29, No 1, January/February 2018

CARVEDILOL

Published online: • Acute type A aortic dissection of iliac and left renal arteries misdiagnosed as myocardial infarction