The 2014 Asia Pacific Cardiology Symposium up close

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Cardiometabolic News

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A report from the 2014 Asia Pacific Cardiology Symposium Managing cardiovascular risk factors to prevent the fatal end of the cardiovascular continuum


Welcome zz address the recognized need to promote clinical management of hypertension that is derived from evidence-based medicine and scientific guidelines zz ensure that scientific knowledge is transferred into clinical practice.

Professor Brian Tomlinson

Professor Lin Shuguang

Welcome to this launch issue of the EXCEMED ‘Cardiometabolic News’ which features a report and presentation summaries from the 2014 Asia Pacific Cardiology Symposium - Managing cardiovascular risk factors to prevent the fatal end of the cardiovascular continuum. Delegates at the meeting, held in Guangzhou (China) on 1st and 2nd March 2014 participated in two days of lectures, debate and review of clinical cases. The delegates were primarily from China but also from India, Philippines, Malaysia and Vietnam. The Scientific Organisers, Prof Brian Tomlinson1 and Prof Lin Shuguang2 introduced the aims of the symposium and the work of EXCEMED to: 1 2

The faculty covered recent evidence in the treatment of hypertension with a specific focus on tried and tested approaches, such as beta-blockers and the ‘new’ therapeutic approaches, such as renal denervation. Sessions were also devoted to discussing emerging health problems in the Asia-Pacific (APAC) area and considering possible solutions for the management of patients with hypertension complicated by other risk factors or related diseases. All the summaries presented here link to the conference website, www.cardiometabolic.excemed.org where copies of the presentation slides are also available. A selection of videos recorded at the event may also be viewed online at the conference website by clickingthrough using the links in the document. We hope you enjoy reading about and viewing the presentations. Please contact us via the EXCEMED website or by emailing info@excemed.org with any comments or requests for content in future issues. All references and links were accessed in August 2014 and were correct at the time of publication.

Prof Brian Tomlinson (Dept Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China) Lin Shuguang (Guangdong General Hospital, Guangdong, China)

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Contents Keynote presentation Novelties from recent guidelines in hypertension.....4 Session I - Specific issues in the pharmacological treatment of hypertension Does a first-choice treatment exist?..........................7 Debate on beta-blockers.............................................9 Clinical case..............................................................13 Session II - Specific problems in APAC Burden of cardiometabolic diseases........................15 Factors determining differences in responsiveness to hypertensive drugs...............................................17 Effect of pollution......................................................20 Session III - Hypertension in special populations Clinical case: diabetes..............................................22 Clinical case: acute myocardial infarction in a young person.......................................................................25 Session IV - Beta-blockers in the management of cardiovascular diseases: are all beta-blockers the same? Beta-blockers in Asian patients: pharmacodynamics, pharmacokinetics, pharmacogenetics.....................27

Comparing two beta-blockers in patients with hypertension.............................................................29 Comparison of the effects of two beta-blockers on sympathetic nervous activity and central aortic pressure in hypertensive patients............................30 Panel discussion: which are the key criteria for the selection of a beta-blocker?.....................................32 Session V - Control of heart rate: a new therapeutic approach in hypertension Sympathetic nervous system and hypertension: an overview.....................................................................35 Debate: is heart rate a target in the treatment of hypertension?............................................................37 Session VI - Hypertension and related diseases Hypertension and atrial fibrillation..........................39 Coronary artery disease............................................41 Heart failure..............................................................43 Faculty members..........................................................46 About EXCEMED...........................................................47

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Keynote presentation Novelties from recent guidelines in hypertension Prof Marlon T. Co It is important to take the advice offered, ‘with a pinch of salt’. We need guidelines since physicians are continuously flooded with study data and advice. Robust guidelines help to chart the right course through this sea of information. But to be of value, guidelines need to be updated regularly so that their recommendations are based on the latest available evidence.

Guidelines, Prof Co3 told delegates, are like the satellite navigation systems in vehicles (SatNav), a modern and useful tool for navigating the route to a successful outcome. However, like a SatNav, guidelines alone are not guaranteed to provide the correct route in every situation.

They should be simple, easy to comprehend and comprehensive. To be trusted, guidelines should be free from bias, whether personal or commercial. Finally, guidelines should not be confusing. Gupta et al (2010)4 reported that one of the key reasons for inadequate control of blood pressure is guideline confusion.

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Prof Marlon T Co (Chong Hua Hospital, Cebu City, Philippines)

Gupta AK et al. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents. Hypertension 2010;55:399-407

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Prof Co asked delegates which hypertension guidelines they actually followed. The most used guidelines (30% of delegates) were those issued by the European Societies of Hypertension and Cardiology (ESCESH)5, followed by the USA guidelines (23%) issued by the Joint National Committee (JNC) on Prevention, Detection, Evaluation and Treatment of high blood pressure6. A small number favoured the British guidelines (1%) issued by the National Institute for Health and Care Excellence (NICE)7 and no delegates used the Canadian Hypertension ducation Programme (CHEP)8 guidelines.

and daytime average or home blood pressure monitoring (HBPM) zz global/total cardiovascular risk assessment and cardiovascular protection zz use of combination therapy zz the importance of lifestyle modification. There were, however, still some key differences between the various guidelines: zz definitions of ‘normal’ blood pressure zz definitions of 'elderly' and recommendations for this patient group

The majority of delegates (44%) revealed that they did not follow a single guideline but referred to them all, taking the best and most relevant information from each. Prof Co was pleased to see that only 1% admitted to not following guidelines at all. The professor welcomed the continuing trend towards consensus between the different guidelines commenting that across the world the bodies responsible for them were working to ensure they were more straightforward and were based on appropriate evidence. He said that in general, there is now a greater common emphasis on: zz out of office blood pressure monitoring; both ambulatory blood pressure monitoring (ABPM) 5 6

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2013 ESH/ESC Guidelines for the management of arterial hypertension. www.esh2013.org James MD et al. 2014 evidence-based guidelines for the management of high blood pressure in adults. Report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA 2014;311(5):507-520 CG127 Hypertension: Clinical management of primary hypertension in adults. NICE. www.nice.org.uk Canadian Hypertension Education Program (CHEP) 2014 Recommendations. www.hypertension.ca/en/chep

zz target blood pressure recommendations zz recommended combination treatments and the use of beta-blockers as first-line therapy. The recommendations on treatment for different ages illustrate two problems with guidelines. Firstly, there is disagreement between them on how to define old age and which treatments should be preferred. Secondly, there is the issue that the patient’s chronological age and their biological or, rather, vascular age might not match. As long ago as 1898 the physician Sir William Osler9 said ‘Longevity is a vascular question, which has been well expressed in the axiom that man is only as old as his arteries.’ For some patients, with early vascular aging, early detection and appropriate treatment can make a significant difference to the outcome, as highlighted 9

Sir William Osler, 1st Baronet (July 12th, 1849 – December 29th, 1919) was a Canadian physician and one of the four founding professors of the Johns Hopkins Hospital in Baltimore, Maryland (USA).

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It is important to understand the whole picture: zz pathophysiology and pharmacology of hypertension zz indications of the various therapeutic agents available zz patients' clinical characteristics, risk profile and target organ damage of the patient zz data from clinical trials zz recommendations from guidelines.

by Nilsson et al (2009)10. The need to inform patients of their global risk using analogies such as ‘cardiovascular age’, ‘vascular age’ or ‘heart age’ is particularly recommended in the CHEP guidelines. The most recent guidelines have all been strongly influenced by meta-analyses such as Lindholm et al (2005)11 which have shown poorer outcomes for patients receiving beta-blockers compared with other classes of drugs. Here we see a problem when guidelines rely overly on such meta-analyses, as much of the data is drawn from trials where the beta-blocker in use was atenolol.

Like the SatNav in your car, if the guidelines appear to be sending you the wrong way, stop, look at what is in front of you and reconsider.

Prof Co's lecture and a selection of other presentations from the Guangzhou symposium are available online as video lectures with slides. Visit: http://bit.ly/cardiometapac2014

This is an older, less selective beta-blocker than those now at our disposal and the results are not entirely applicable today. Guidelines, concluded Prof Co, are a vital tool, but no substitute for the sound judgement of the knowledgeable physician. 10 11

Nilsson P et al. Vascular aging. A tale of EVA and ADAM in Cardiovascular risk assessment and prevention. Hypertension 2009;54:3-10 Lindholm LH et al. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545-53

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Session I - Specific issues in the pharmacological treatment of hypertension Does a first-choice treatment exist? Prof Stefano Taddei This perhaps explains why we see that monotherapy can normalize BP values in no more than 30% of hypertensive patients and therefore in most cases it is necessary to use a drug combination. Guidelines provide a good ‘textbook’ on hypertension but there is a limit to their applicability in day-today practice; they cannot provide instructions for the management of individual patients. It is perhaps not surprising that we see a great deal of difference between guidelines with regard to first-choice treatment. The selection of a first-choice therapy needs to be based on many factors that are patient specific: age, comorbidities, likelihood of adherence, relationship with the physician, etc. Prof Taddei12 told delegates. In the Brisighella and Framingham studies the number of patients who had hypertension without comorbidities was less than 20%, Borghi et al (2004)13 and Kannel (2000)14. 12 13 14

Different recommendations are made by some guidelines based on a range of demographic and risk factors. There is, however, general agreement that the main benefits of antihypertensive treatment are due to the lowering of blood pressure per se and are largely independent of which drugs are employed. We should, however, be cautious of treating blood pressure reduction as a primary outcome, warned Prof Taddei.

Prof Stefano Taddei (Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy) Borghi C et al. Trends in blood pressure control and antihypertensive treatment in clinical practice: the Brisighella Heart Study. J Hypertens 2004;22:1707-16 Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens 2000;13:3S-10S

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There is clear evidence that: zz lowering blood pressure reduces the risk of major clinical cardiovascular outcomes (fatal and non-fatal stroke, myocardial infarction, heart failure) and other cardiovascular deaths in hypertensive patients zz regression of organ damage, such as left ventricular hypertrophy and urinary protein excretion after blood pressure reduction may be accompanied by a reduction of adverse outcomes. However, blood pressure per se is not the end of the story, as there appear to be other mechanisms at work. In the Gรถteborg study, a comparison between treatedhypertensive and normotensive patients the mortality in the treated-hypertensive group is still higher, whether we look at chronic heart disease, stroke or all-cause mortality. There were over 6,810 patients in this study and follow-up was over more than 20 years, Andersson (1998)15. We should stop to consider the nature of the studies on which the guidelines are based. Randomized trials based on hard clinical cardiovascular outcomes have limitations caused by the practical challenges of conducting them: there is a limit to the number of patients enrolled to the trial, trials commonly enrol high-risk patients (old age, concomitant illnesses or previous disease) and the duration of controlled trials is necessarily short (from 3 to 6 years). Yet on the basis of these trials, recommendations are made for life-long intervention. This means that there is considerable

extrapolation from data collected over periods much shorter than the life expectancy of most patients. Prof Taddei observed that the guidelines themselves are not entirely free of bias from the personal opinions of the expert members of the panels that author them. The choice to include some meta-analyses while ignoring others should be questioned when the results of these studies could be contradictory. As an example, take van Vark et al (2012)16 who conclude, from a meta-analysis of nearly 160,000 patients that angiotensin-converting-enzyme inhibitors (ACEi) reduce total mortality while angiotensin receptor blockers (ARB) do not and then look at Savarese et al (2013)17 who reach the opposite conclusion from a meta-analysis involving 110,000 patients. Prof Taddei concluded by reiterating that a list of suitable first-choice antihypertensive drugs should include diuretics (thiazides, chlorthalidone and indapamide), beta-blockers, calcium channel blockers (CCBs), ACEi and ARBs; either as monotherapy or in combination, as these are all suitable for the initiation and maintenance of antihypertensive treatment. In clinical practice, choice of antihypertensive drugs should be informed by a careful evaluation of the clinical characteristics of each individual patient balanced with knowledge of the different pharmacological and therapeutic characteristics of the available drugs.

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Andersson O. Survival in treated hypertension: follow up study after two decades. BMJ 1998;317:167-171

van Vark LC et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012;33:2088-97 Savarese G et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure. J Am Coll Cardiol 2013;61:131-42

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Debate on beta-blockers The motion under consideration was, ‘Beta-blockers are a suitable first-choice for the treatment of hypertension.’ The proposer, Prof Soetanto Arieska Soenarta spoke first and in response, Dr Jamshed J. Dalal spoke against the motion.

Prof Soetanto Arieska Soenarta

However: zz of seven large trials that compared beta-blockers (often combined with diuretics) with other antihypertensive agents19, only two (the LIFE20 and ASCOT21 studies) concluded that beta-blockers lead to inferior cardiovascular outcomes when compared to other antihypertensive agents zz a thorough meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC)22 that looked at the effects of different blood pressure-lowering regimens on cardiovascular events in 31 trials involving data from 190,606 patients found that there was no significant difference in outcomes between the different classes of drugs

Prof Soenarta18 reminded delegates that beta-blockers have been in use as anti-ischemic agents for 45 years, as antihypertensive agents for 40 years and as anti-heart failure agents for 30 years. They can intervene at many points in the cardiovascular continuum and have proven useful in both primary and secondary prevention. Their use as anti-ischemic and anti-heart failure drugs remains unchallenged but some controversy has emerged over their use as antihypertensives.

zz the various guidelines are more or less in agreement that the main benefits of antihypertensive treatment are due to lowering blood pressure and are largely independent of which drugs are employed. Selecting the right drug, whether a diuretic, ACEi, CCB, ARB or beta-blocker should depend on the comorbidities of the patient and be the choice of the physician. 19 20

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Prof Soetanto Arieska Soenarta (National Heart Center Harapan Kita, Jakarta, Indonesia)

STOP2, CAPPP, LIFE, CONVINCE, NORDIL, INVEST, ASCOT Dahlöf B et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003 Dahlöf B et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906 Turnbull F et al. Effects of different blood pressure–lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus. Arch Intern Med 2005;165:1410-9

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The guidelines note (to varying degrees) that beta-blockers are not preferred in hypertensive patients with multiple metabolic risk factors. Specifically, they are not recommended when there is metabolic syndrome or a high risk of incident diabetes. However, we should pause to reflect on the evidence on which the guidelines are based. The beta-blocker used in the majority of the studies, and subsequent meta-analyses using the study data, was atenolol. This has a bearing on the applicability of the conclusions drawn because the beta-blockers are a heterogeneous drug class with a wide range of pharmacological effects. We can divide the beta-blocker class into selective and non-selective groups. The selective beta-blockers have greater binding to the beta1-receptor than the beta2-receptor. There are more beta1-receptors in the myocardium, so beta1-stimulation results in increased heart contraction and rate. In the pancreas, beta2-receptors predominate and so stimulation of these receptors will cause insulin release. Beta2-stimulation also results in a good cholesterol profile; low triglycerides (TG) and high levels of high-density lipoproteins (HDL). Selective beta-blockers have the advantage over the non-selective because of their ability to target the heart without undesirable effects on glucose and lipid metabolism.

We can also classify beta-blockers with regard to their levels of intrinsic sympathomimetic activity (ISA). Drugs in this category still cause a degree of sympathetic adrenergic stimulation once bound to the receptor. So, generally, we should look for a beta-blocker with high selectivity and low ISA. In 1987, Wellstein23 looked at this and showed that bisoprolol had the highest beta1-/beta2- ratio. This was some time ago and we now have newer beta-blockers, such as nebivolol, that perform similarly well. Now consider atenolol. This has low beta1-selectivity and therefore has dismetabolic effects associated with blocking beta2-receptors. It also has a plasma half-life of 6-7 hours, which means that a single daily dose is not enough to lower blood pressure adequately for an entire day. The trough/peak (T/P) ration of only 31% is also an issue; normally a T/P ratio of more than 50% is preferred. There are advantages and disadvantages with using beta-blockers as hypertensive agents, but this is also true of the other antihypertensive agents. Overall, they should be considered as suitable first-line treatments.

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Wellstein A et al. Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur Heart J 1987;8(Suppl M):3-8

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Dr Jamshed J. Dalal

There is also some evidence of efficacy in acute coronary syndrome, stable angina without MI, perioperative (non-cardiac surgery) and hypertrophic obstructive cardiomyopathy. However, beta-blockers do not provide the vascular protection achieved by newer drugs, particularly ACEi and that there is no evidence to support their use over other drugs when faced with uncomplicated hypertension. There are several mechanisms underlying the lower levels of vascular protection afforded by beta-blockers when compared with other agents:

Speaking in response, Dr Dalal24 told delegates that the primary aim of hypertension treatment should not be, solely, the lowering of blood pressure but should be the prevention of vascular degeneration. It is important to use drugs that will actually achieve: organ protection, a reduction in cardiovascular events and reduced mortality. Currently, there is no evidence that beta-blockers prevent first episodes of cardiovascular events in patients with hypertension and in some trials, outcomes were worse with beta-blockers than with other classes of drugs. Dr Dalal reminded the audience that there is strong evidence in favor of using beta-blockers in heart failure and after myocardial infarction (MI).

zz beta-blockers lower brachial blood pressure but fail to lower the central aortic pressure (CAP) which is responsible for organ damage. Reduction in CAP is needed to protect the brain, the heart and the kidneys. Amlodipine reduces central aortic blood pressure more than atenolol25. This is why beta-blockers are less effective at reducing risk of stroke. The risks of augmented central systolic pressures are also highlighted by Safar (2009)26. Various studies have shown the benefits of reducing heart rate but this must be associated with a reduction in CAP27 zz there are numerous adverse effects with beta-blockers which reduce compliance

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Dr Jamshed J. Dalal (Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital and Medical Reseatch Institute, Mumbai, India)

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Williams B et al. Differential impact of blood-pressure –lowering drugs on aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFÉ) study. Circulation 2006; 113:1213-25 Safar M et al. Statins, central blood pressure, and blood pressure amplification. Circulation 2009;119:9-12 Bangalore S et al. Relation of beta-blocker–induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008;52:1482-9

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zz there are unfavorable metabolic effects involving the vascular and endothelial integrity regression of left ventricular hypertrophy (LVH) is lower with beta-blockers than with ACEi; cardiovascular morbidity and morbidity are directly related to the level of LVH. There are also metabolic concerns with beta-blockers which include: zz negative effects on lipid metabolism, glucose metabolism, renal blood flow. Gress et al (2000)28 reported a 25% increase in the chance of early onset diabetes with beta-blockers compared with ACEi or CCBs. Messerli et al (2008)29 conducted a meta-analysis concluded that beta-blockers and diuretics could account for more than 100,000 cases of new-onset diabetes in the USA every year zz masked hyperglycemia.

Dr Dalal acknowledged that most of the trials that compared beta-blockers with other classes of drugs used atenolol, which is not an ideal representative of the class. He also noted that younger patients have hemodynamic characteristics that would seem to be amenable to beta-blocker therapy. However, most trials did not stratify patients by age. Dr Dalal questioned whether the newer beta-blockers with vasodilatory properties and a more favorable hemodynamic and metabolic profile, such as: bisoprolol, nebivolol and carvedilol will be more efficacious in reducing morbidity and mortality. This remains to be determined because, to date, there are no convincing data that show better efficacy with these new beta-blockers versus ACEi, ARB or CCB. Until such data are available we cannot recommend that beta-blockers should be a first-line choice for patients.

Beta-blockers also raise tolerability concerns: zz fatigue zz impotence zz weight increase zz peripheral vasoconstriction zz depression zz bronchospasm.

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Gress TW et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. NEJM 2000;342:905-12

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Clinical case Prof Soetanto Arieska Soenarta Managing hypertension with cardiovascular risk factors. Physical examination: zz Looks stressed zz Blood pressure is 165/100 mmHg zz Resting pulse rate is 84-94 bpm zz electrocardiogram (ECG) shows ST ischemic changes zz Chest X-ray normal zz BMI 29 kg/m2 and waist circumference 89 cm

Prof Soenarta30 presented the case of a male patient, aged 55-years, who had recently (48 hours) been discharged following MI but still had angina pectoris. He had a stressful job and hypertension for which he had been taking amlodipine 10 mg daily. He reported palpitations. There was a family history of coronary artery disease (CAD), hypertension and stroke.

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zz laboratory findings: fasting blood sugar (FBS): 135 mg/dl, HbA1c: 7, creatinine normal, urea normal, low-density lipoprotein 100 mg/dl, HDL 30 mg/dl , TG 125 mg/dl, total cholesterol 200 mg/dl. This is a high-risk hyperkinetic hypertensive patient, prone to develop cardiovascular disease. Despite the amlodipine his blood pressure is still high. So, Prof Soenarta asked, should the CCB be changed to a beta-blocker as the antihypertension agent?

Prof Soetanto Arieska Soenarta (National Heart Center Harapan Kita, Jakarta, Indonesia)

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With angina pectoris present and no metabolic syndrome a beta-blocker would appear to be the best choice. This is supported by the European 2013 ESH/ ESC guidelines which only specifically warn against their use with metabolic syndrome or where there is a high risk of developing diabetes, in which case renin-angiotensin system (RAS) inhibitors are favored. Prof Soenarta raised the question: if we use a beta-blocker, will it lower blood pressure as effectively as other agents? Hiltunen et al (2007)31 showed that bisoprolol lowered blood pressure more than losartan, amlodipine or hydrochlorothiazide. But all beta-blockers are not the same. In choosing, we need to be aware of:

zz ISA - results of the post-MI survival trials, where beta-blockers without ISA reduced morbidity and mortality34. But, where pulse rate is <60 bpm, the use of a beta-blocker with ISA might be indicated. But is the elevated fasting blood sugar a concern? Should we still consider beta-blockers for this patient? The answer is yes. The LIFE35 and ASCOT36 studies show clearly that atenolol is inferior to losartan and amlodipine. However, Janka et al (1986)37 show that bisoprolol does not have an effect on glucose metabolism in Type II diabetic patients. Treatment with beta-blockade, after MI results in general mortality reduction of 23%38.

zz selectivity - the relative selectivity in blocking beta1- versus beta2-receptors, lipid solubility and the degree of ISA. Bisoprolol performs better here than atenolol32,33 zz lipid solubility - metoprolol and propranolol for example are lipid soluble, cross the blood-brainbarrier and have greater CNS effects. They are metabolized more rapidly in the liver and have a shorter half-life than the water-soluble beta-blockers. 34 35

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Hiltunen TP et al. Predictors of antihypertensive drug responses: initial data from a placebocontrolled, randomized, cross-over study with four anti-hypertensive drugs (The GENRES Study). Am J Hypertens 2007;20:311-8 Wellstein A et al. Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur Heart J 1987;8 (Suppl M): 3-8 Smith C, Teitler M. Beta-blocker selectivity at clones human beta 1- and beta 2-adrenergic receptors. Cardiovasc Drugs Ther 1999;13:123-126

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Yusuf S et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Progress Cardiovasc Dis 1985;5:335-371 Dahlöf B et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003 Dahlöf B et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906 Janka HU et al. Influence of bisoprolol on blood glucose, glucosuria, and haemoglobin A1 in noninsulin-dependent diabetics. J Cardiovasc Pharmacol 1986;8(Suppl. 11):96–99 Rydén L et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88-136

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Session II - Specific problems in APAC Burden of cardiometabolic diseases Dr Piyamitr Sritara The cardiometabolic risk factors associated with abdominal obesity are: low levels of high-density lipoproteins (HDL), high triglycerides (TG), high fasting blood glucose and high blood pressure. Intra-abdominal adiposity also promotes insulin resistance. So what, asked Dr Sritara, can be done?

Metabolic syndrome and diabetes are both increasing rapidly among the Asian population, Dr Sritara39 told delegates. Women with low socioeconomic status are particularly at risk. Studies by Wenying et al (2010)40 and Aekplakorn et al (2011)41 show that the abandonment of traditional lifestyles and foods in favour of unhealthier ‘urban’ lifestyles and ‘fast foods’ are playing a big part in this. 39 40 41

Dr Piyamitr Sritara (Dept of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand) Wenying Y et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090-101 Aekplakorn W et al. Urban and rural variation in clustering of metabolic syndrome components in the Thai population: results from the fourth National Health Examination Survey 2009. BMC Public Health 2011;11:854

The INTERHEART study group, Rosengren et al (2004)42 looked at the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (15,152 cases and 14,820 controls.) Abdominal obesity was shown to be a greater predictor of cardiovascular disease than BMI. We have found in Thailand that central or abdominal obesity is a good predictor of cardiovascular risk. We use a weight to height ratio and as a guide when assessing the ‘heart score’ rather than BMI.

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Rosengren A et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the Interheart Study): casecontrol study. Lancet 2004;364;953-62

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We now recommend that waist circumference should be less than half the height. So a patient of 180 cm height should have a waist circumference below 90 cm. We have found that the population that has central obesity have 2.3 times the likelihood of cardiovascular disease. These figures agree with published data43. We encourage lifestyle modification because we have seen that the first 10% reduction in weight reduces the visceral fat by 30-40%. This has major benefits for patient outcome.

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Mottillo S et al. The metabolic syndrome and cardiovascular risk - a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113-32

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Factors determining differences in responsiveness to hypertensive drugs Prof Brian Tomlinson Guidelines suggest that the factors affecting responsiveness to antihypertensive drugs include age and ethnicity, but the evidence supporting this is limited. Age has in the past been considered an important factor. This would appear to have merit if one stops to consider the evolution of hypertension with age. In younger, pre-hypertensive, patients we see activation of the RAS and sympathetic nervous system (SNS) along with vasoconstriction, increased peripheral resistance and vascular remodelling. To achieve the goal of personalized medicine we have to identify the factors that affect drug responsiveness, said Prof Tomlinson44. But what criteria are useful in identifying sub-populations of hypertensive patients who will respond similarly? We could use: zz demographics - age, gender and ethnicity zz physiological phenotype - renin profiling and salt sensitivity zz pharmacogenetics - pharmacokinetics and pharmacodynamics [Prof Tomlinson discusses this in 'Beta-blockers in Asian patients: pharmacodynamics, pharmacokinetics, pharmacogenetics'] 44

Prof Brian Tomlinson (Dept Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China)

As patients become older they become hypertensive and damage starts to build so that in older patients we see declining glomerular filtration rate (GFR), sodium retention, increased cardiac output and stiffening of the blood vessels. Plasma renin also decreases with age. Dickerson et al (1999)45 compared the efficacy of a range of antihypertensives in 56 patients aged 22 to 51 years. Another study, Deary et al (2002)46, is based on 34 patients aged 28-55. These studies both demonstrate that the most effective treatments were beta-blockers and ACEi.

45 46

Dickerson JE et al. Optimisation of antihypertensive treatment by cross-over rotation of four major classes. Lancet 1999;353:2008-13 Deary AJ et al. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens 2002;20:771-7

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A more recent meta-analysis by Turnbull et al (2008)47 compared a range of treatments in older and younger patients. Blood pressure reduction produces similar proportional reductions in the risks of vascular events in younger (<65 years) and older (≼65 years) adults. Can we use ethnicity as a predictor? Mean reductions in blood pressure with diuretics and CCBs are greater in black (African/Caribbean origin) patients. Both ACEi and beta-blockers reduce mean blood pressure more in white patients. However, there is a huge degree of overlap, greater than 80%, so that individual patients of either ethnic group may respond better with either drug. Physiological phenotype may be more useful to predict drug responsiveness but whether this will influence cardiovascular outcomes remains uncertain. But is renin profiling a possibility? Brown (2011)48 examined this question, looking at patients who are not responding to treatment and are already taking an ACEi, a CCB and a diuretic. Brown suggests measuring plasma renin. If the level is high (>100 mU/L) then a beta-blocker or a second ACEi should be added; if normal, add an alpha-blocker and if low (<20 mU/L), change the diuretic or dosage.

In the ASCOT49 study plasma renin was measured at the beginning. These analyses suggest an association between elevated baseline plasma renin activity (PRA) and the subsequent development of renal impairment but do not support its use to predict future cardiovascular events or all-cause mortality in treated hypertensive patients. Many hospitals lack the facilities to measure renin so this is not a method that can be used widely. Salt-sensitive hypertension can be addressed because salt-sensitive patients can be identified, as shown by Sanada (2006)50. Such patients would respond well to a diuretic, a CCB or some of the newer agents such as the neprilysin inhibitors. Salt-sensitivity may in itself be an important predictive factor. Pharmacogenetic influences may become more important but currently these do not assist treatment choice. A video of Prof Tomlinson's lecture is online at http://bit.ly/ cardiometapac2014.

49

47 48

Turnbull F et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ 2008;336:1121-3 Brown MJ. Personalised medicine for hypertension. BMJ 2011;343:d4697

50

DahlĂśf B et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906 Sanada H et al. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin Chem 2006;52:352-60

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European guidelines recommend combinations of treatments. Additive and synergistic effects are seen. Perhaps with the move to combination treatments the choice of first-line will become less crucial. This is illustrated in figure 1 (below) where we see three patients with very different profiles.

Patient 1

For further information, Prof Tomlinson recommends: NICE Hypertension update51, Mangia et al (2013)52, Chan et al (2012)53, Johnson et al (2003)54, Pacanowski et al (2008)55.

Patient 2

Na+

Patient 3 RAS

RAS

RAS ACEI or ARB CCB Diuretic

Patient 1 (perhaps younger) with higher activation of RAS; patient 3 is salt-sensitive. They will respond differently to medicines but a suitable combination may be of benefit to all of them.

+++ ++ +

ACEI or ARB + CCB ++++ ACEI or ARB + Diuretic ++++

Na+

Na+

ACEI or ARB CCB Diuretic

++ ++ ++

ACEI or ARB CCB Diuretic

ACEI or ARB + CCB ++++ ACEI or ARB + Diuretic ++++

+ +++ +++

ACEI or ARB + CCB ++++ ACEI or ARB + Diuretic ++++

51 52

53 54 55

Figure 1. Combination therapy reduces heterogeneity in response to treatment as initial therapy. Three patients with different levels of RAS activation and salt sensitivity (Na+). The relative areas of the shapes in the pictogram represent the degree of activation/sensitivity.

National Institute of Health and Clinical Excellence (NICE). Hypertension (update): full guidance. www.nice.org.uk Mangia G et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159-219 Chan SW et al. The pharmacogenetics of β-adrenergic receptor antagonists in the treatment of hypertension and heart failure. Expert Opin Drug Metab Toxicol 2012;8:767-90 Johnson JA et al. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003;74:44-52 Pacanowski MA et al. Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther 2008;84:715-21

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Effect of pollution Prof Stefano Taddei The main sources of high pollution are: traffic (60%), industry (16%) and indoor heating (7%.) Airborne microparticles of soot, organic material, crustal material, sulfates, nitrates, other inorganic salts, metals, and biological materials are responsible for most of the harmful effects (see table below). These can be inhaled and the smallest particulate pollution can reach the bloodstream.

Pollution is a dramatic and emerging problem throughout the world, said Prof Taddei56. There is a strong association between increase in population and increase in pollution. Looking at the Global Burden Disease Study 201057 household air pollution is the fourth biggest risk factor, ambient pollution is at number nine. There are some chilling statistics: zz total number of deaths due to pollution worldwide in 2010: 52.8 million (760,000 in China)

Components

Principal source

Particulate matter (PM10, PM2.5, PM<0.1)

Combustion & road traffic

Nitrogen oxides (NOx)

Road traffic

Sulphur dioxide (SO2)

Factories burning coal & oils

Carbon monoxide (CO)

Incomplete combustion

Ozone (O3)

A product of the reaction of NOx with heat & sunlight

Air pollution is associated with many diseases, including cardiovascular disease. The Pope and Dockery (1999)58 meta-analysis shows that an acute increase (10 mg/m3) in PM10 (less than 10 Âľm diameter) particulate pollution caused increase in hospitalization, cardiovascular events and mortality.

zz outdoor ambient pollution accounted for 3.3 million deaths (350,000-400,000 in China) zz indoor household pollution accounted for 3.6 million deaths (300,000 in China). 56 57

Prof Stefano Taddei (Dept Clinical and Experimental Medicine, University of Pisa, Pisa, Italy) Lim SS et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions. 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224-2260

58

Pope, CA, Dockery, DW. Epidemiology of particle effects. In: Air Pollution and Health. Eds Holgate ST, Samet JM, Koren HS, Maynard RL. Academic Press, San Diego, 1999 p.841

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Women are particularly susceptible to pollution, as shown by Miller et al (2007)59. Aphekom60 reports that a significant fraction of non-communicable disease is attributable to exposure to traffic-related pollution. We see a range of evidence in the literature that shows pollution is linked to increased rates of heart failure, arrhythmia, cardiac arrest, ischemic stroke and venous thromboembolism. With cardiovascular events we see that short-term exposure is as serious as long-term exposure. Furthermore, there is a strong association between pollution and cardiovascular hospitalization and mortality, and also with MI. The principal mechanisms of heart rate alteration, hypertension and endothelial dysfunction/ inflammation are likely to be key to this.

Mannucci (2013)62 writes, in an editorial for the European Heart Journal, that practical steps to reduce exposure to airborne pollutants should be taken. These include: zz avoiding walking and cycling in streets with high traffic intensity zz refraining from exercising by busy roads on sunny days zz keeping infants indoors when pollution levels are high zz carrying infants in slings and pouches is preferrable to using pushchairs as pollution is greater close to the ground.

Improvements in air quality have positive effects. Pope et al (2009)61 studied 51 metropolitan areas of the USA and reported that a decrease of 10 Âľg/m3 in the concentration of PM2.5 is associated with an increase in mean life expectancy of 0.77 year. This has led to the American Heart Association statement that PM2.5 exposure is a modifiable factor that contributes to cardiovascular morbidity and mortality.

59 60 61

Miller KA et al. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med 2007;356:447-58 Aphekom: Improving Knowledge and Communication for Decision Making on Air Pollution and Health in Europe. www.aphekom.org Pope CA et al. Fine-particulate air pollution and life expectancy in the United States. N Engl J Med 2009;360:376-86

62

Mannucci PM. Airborne pollution and cardiovascular disease: burden and causes of an epidemic. Eur Heart J 2013;34:1251-3

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Session III - Hypertension in special populations Clinical case: diabetes Dr Hung-Fat Tse High blood glucose and raised blood pressure are ranked third and first in the ranking of risk factors of cause of death, WHO (2011)64. According to Meigs (2010)65, the two together is clearly very bad; stroke risk is increased two-fold, chronic heart failure is increased three-fold, left ventricular hypertrophy two-fold and chronic kidney disease (CKD) six-fold. The patient is male, 78 years of age and has been treated for Type II diabetes mellitus for four years. He is taking metformin. On examination, his clinic BP is 135-140/70 mmHg; latest HbA1c is 8.6%. Dr Tse63 looked at the treatment needs of a patient with diabetes and hypertension. How should the physician set therapeutic targets (blood pressure and plasma glucose levels)?

Patient reports episodes of dizziness and has had elevated blood pressure to 165/75 mmHg. Cardiovascular examination was unremarkable and he was found to have a left carotid bruit.

Which drugs should and, importantly, should not be used? We know, said Dr Tse, that there is a prevalence of hypertension in the diabetic population of 60%-80% (2-fold greater than the non-diabetic population, with a particularly strong correlation in males).

64 65

63

Dr Hung-Fat Tse (Cardiology Division, The University of Hong Kong, Hong Kong SAR, China)

Global Health Risks: Mortality and burden of disease attributable to selected major risks. WHO (2009) www.who.int Meigs JB. Epidemiology of type 2 diabetes and cardiovascular disease: translation from population to prevention. Diabetes Care 2010;33:1865-1871

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We decided to look at ambulatory blood pressure because evidence from Parati et al (2009)66 and Hata et al (2013)67 suggests that this is a good tool for predicting cardiovascular risk. ECG shows sinus rhythm and LVH, magnetic resonance imaging (MRI) reveals multiple small lacunar infarcts (quite common in the Asian population) and 40% left carotid artery stenosis. Blood test results are as follows: creatinine 180 mmol/L (eGRF=35ml/min); LDL 3.4 mmol/L, TG 2.1 mmol/L. Urine albumin 2+ (≼100 mg/dL). ABPM reveals a daytime average of 158/76 mmHg and a night-time average of 148/73 mmHg. It was clear that we needed to look at both blood pressure and glycemic control for this patient. There has been some debate over blood pressure targets for this group in recent years. Bangalore et al (2011)68 showed that there is no significant difference between all-cause mortality between 135 and 130 mmHg as targets. This suggests that aggressively lowering blood pressure does not benefit diabetes patients. However, authors such as Zancetti et al (2009)69 and Mancia et al (2009)70 have found differences in the incidence of specific types of damage.

66 67

68

69 70

Parati G et al. Should 24-hour ambulatory blood pressure monitoring be done in every patient with diabetes? Diabetes Care 2009;32:S298-304 Hata J et al. Effects of visit-to-visit variability in systolic blood pressure on macrovascular and microvascular complications in patients with type 2 diabetes mellitus: the ADVANCE trial. Circulation 2013;128:1325-1334 Bangalore S et al. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation 2011;123:2799-2810 Zanchetti A et al. When should antihypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical reappraisal. J Hypertens 2009;27:923-34 Mancia G et al. Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension. J Hypertens 2009;27:1672-8

As James et al (2014)71 pointed out, it should be noted that aggressively lowering blood pressure below 130 mmHg in some patients, the elderly for example, may increase adverse events. Given this debate, the latest treatment guidelines have revised their criteria and advise less aggressive control. How aggressive should glyemic control be? There is a potential for hyperglycemia to cause damage and contribute to a worse outcome. Generally, we now look to reduce HbA1c to around 7% (<6.5% in young patients). However, with a patient such as this, age and comorbidities may dictate that we titrate or individualize the glycemic control and blood pressure. Statins may be an option for this patient. Stone et al (2014)72 identify four groups of patients that benefit from statins. These include patients with clinical atherosclerotic cardiovascular disease (ASCVD) and patients with diabetes aged 40 to 75 years with LDL 70 to 189 mg/dL and without clinical ASCVD. We may need to consider quite potent/high intensity statins for our patient. Our drug choice includes: diuretic, beta-blocker, CCB, ACEi/ARB but what should we choose? Diuretics, especially if combined with a beta-blocker increase the risk of worsening glycemic control. CCB or ACEi has a neutral effect on the glycemic control.

71 72

James P et al. Let’s prioritize the right care for the right patients with hypertension. JAMA Intern Med. 2014;174:1261-1262 Stone NJ et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines. J Am Coll Cardiol 2014;63:2889-934

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For this patient we recommended life-style modification and added: DDP4 inhibitor for control of diabetes mellitus to achieve HbA1c <7.5, aspirin 100 mg and atorvastatin 20 mg daily. We also introduced ramipril 5 mg daily (because ARB or ACEi is recommended). Clinic blood pressure was 158/78 mmHg. The patient reported occasional chest discomfort on exertion. Our patient developed a cough with ramipril so this was switched to candesartan (16 mg daily). His clinic blood pressure was 152/80 mmHg. The patient still reported occasional chest discomfort; a cough is quite common with ACEi, particularly in the Asian population. So what next? Our options were: increase the dose, add a second drug or switch to a new drug combination.

With this patient we actually achieved a reasonable dose of ARB so the other option to consider was adding on another drug. But what other drug would we add in with this patient with kidney dysfunction, CAD and possibly carotid artery disease? Beta-blockers, particularly in combination with a diuretic can have an effect on glycemic control as we know, but with this patient, blood pressure is the main issue. If care is taken with the choice of a selective beta-blocker this would be the ideal. So we added bisoprolol 2.5 mg daily. The latest followup blood pressure measure was 138/76 mmHg without chest pain.

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Clinical Case: acute myocardial infarction in a young person Dr Bambang Budi Siswanto Use of beta-blockade is appropriate for this patient because of the MI. Effective beta1-blockade will inhibit the cardiovascular-toxic effects of chronically increased sympathetic nerve activation. An ECG was recorded two hours after the first onset of pain (see figure 2, page 26) with the following findings: sinus rhythm 81 bpm, normal P wave, PR interval 160 ms, QRS duration 110 ms, ST elevation (I, aVL, V2-V6), ST depression (II, III, aVF), T inverted (III, aVF, V1).

Dr Siswanto73 presented the case of a male, 22-yearsold, referred from a private hospital with chest pain typical of acute MI. His body weight was 74 kg, height was 168 cm and his BMI was 26.1. His heart rate was 113 bpm and regular. His blood pressure was 141/81 mmHg. Risk components were identified as hypertension, dyslipidemia and dysglycemia.

For this patient, aspirin and clopidogrel with statin, low molecular-weight heparin and a beta-blocker were prescribed. However, it is vital that we achieve an alteration in the body fat distribution for this patient. Lifestyle change is essential. In addition, weight loss drugs could also be an option.

It is important, Dr Siswanto said, to pay attention to the waist circumference measurement in line with evidence from authors, such as Matsuzawa (2006)74, Gelfand et al (2006)75 and Vsudevan et al (2005)76, that this is an acute predictor of cardiovascular complications. 73 74 75 76

Dr Bambang Budi Siswanto (National Heart Center, Harapan Kita, Jacarta Barat, Indonesia) Matsuzawa Y. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006;3:35-42 Gelfand EV et al. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 2006;47:1919-26 Vasudevan AR et al. Cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus. Clin Cornerstone 2005;7:7-16

25


In summary: zz the combined measure of waist circumference and BMI is superior to the separate indices in identifying cardiometabolic syndrome and cardiovascular risk; as highlighted by Dagenais et al (2005)77, and Tchernof and Despres (2013)78 zz overweight or obese adults who were obese as children had increased risk of developing Type II diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis

zz when treating hypertension in the obese individual, addressing the obesity is an essential part of the therapeutic plan; lifestyle management is required in every case, with a focus on weight loss and risk reduction zz the end objectives of treatment are substantially to reduce the risk of cardiovascular and obesityrelated metabolic disease, to minimize the need for medications, and to render the required pharmacologic therapy more effective.

zz hypertension (of all ages) with ischemia is well suited to beta-blockade as the prevalence of obesity increases, the prevalence of hypertension with its associated cardiovascular risk will also increase

Figure 2. An ECG was recorded two hours after the first onset of pain.

77 78

Dagenais GR et al. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. Am Heart J 2005;149:54-60 Tchernof A, DesprÊs J-P. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013;93:359–404

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Session IV - Beta-blockers in the management of cardiovascular diseases: are all beta-blockers the same? Beta-blockers in Asian patients: pharmacodynamics, pharmacokinetics, pharmacogenetics Prof Brian Tomlinson

The use of beta-blockers to slow heart rate is of interest potentially in the treatment of hypertension, said Prof Brian Tomlinson79. But, which is the right one to use and what is the right dose? Early studies on the efficacy of propranolol revealed that black (African heritage) patients responded less well to beta-blockers. Empirical observations suggest that Chinese patients are more sensitive to propranolol than white Caucasian.

79

As a consequence, lower starting doses are used with Chinese patients (Chinese in Hong Kong 10 mg, 3 times a day / Europe 40 mg, 3 times a day.) Are there genetic factors influencing responsiveness? One potential factor is genotypic variation that results in alternate forms of cytochrome P450 2D6 (CYP2D6), a key enzyme that metabolizes propranolol and metoprolol. A common polymorphism, CYP2D6*10 is common in East Asian populations. Patients with one or two copies of the variant (1/3 are homozygous for the variant) will have higher levels of propranolol because they don’t metabolize it so rapidly. Studies with metoprolol have had conflicting results. But although the effects of CYP2D6 genotypes on beta-blocker responses have been inconsistent, there may be a role for CYP2D6 genotyping in certain populations to achieve the optimal dose of metoprolol more rapidly.

Prof Brian Tomlinson (Dept Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China)

27


The common polymorphisms producing changes in the beta1-adrenergic receptors and their signalling pathways have been associated with clinical outcomes in several studies in hypertension and heart failure. There are two common polymorphisms of the beta1-receptor: Ser49Gly and Arg398Gly. These are more common in patients of African origin and may be one of the reasons why this population often responds less well to beta-blockers. The difference in frequency of these polymorphisms between Asian and white Caucasian populations is not so great. This mechanism doesn’t therefore explain the observed difference in responsiveness to propranolol. However, treatment with beta-blockers, especially with higher doses, appears to have greater benefits in patients with the more responsive genetic forms of the beta1-adrenergic receptor.

Being able to predict the effects of a beta-blocker in advance of prescribing it would certainly be a great advantage but current data are not sufficiently consistent to support genotyping for these polymorphisms before selecting or initiating beta-blocker treatment and further study results are needed to clarify the situation. For further information, Prof Tomlinson recommends: Zhou et al (1989)80, Lai et al (1995)81, Johnson et al (2003)82 and Pacanowski et al (2008)83.

A video of Prof Tomlinson's lecture is online at http://bit.ly/cardiometapac2014

80 81 82 83

Zhou HH et al. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med 1989;320:565-70 Lai ML et al. Propranolol disposition in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1995;58:264-8 Johnson JA et al. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003;74:44-52 Pacanowski MA et al. Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther 2008;84:715-21

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Comparing two beta-blockers in patients with hypertension Dr Aniruddha Dharmadhikari Bisoprolol is suitable as a first-line treatment for Stage-I hypertension, Dr Aniruddha Dharmadhikari84 told delegates. Reporting on the recent ABPM study85, bisoprolol produced similar results when compared to metoprolol sustained release (SR) in terms of: responder rates, fall in both blood pressure and heart rate, fall in 24-hour blood pressure and heart rate parameters, global efficacy, tolerability and safety. Bisoprolol and metoprolol are two beta-blockers commonly used for prophylaxis and treatment of cardiovascular disease, including hypertension and ischemic heart disease. However, bisoprolol is more selective than metoprolol and is likely to have a theoretical advantage over metoprolol in terms of adverse events and sustained blood pressure control due to its longer period of activity. In this study, metoprolol succinate was used rather than metoprolol tartrate, used in past studies by Haasis & Bethge (1987)86 and Montoya et al (2000)87. Metoprolol succinate is a longer-acting formulation that can, like bisoprolol, be taken once-a-day. The ABPM study was a 12-week multicenter, parallel group, open label, randomized, non-inferiority trial conducted at six cardiology centres in India. 84 85 86

87

Dr Aniruddha Dharmadhikari (Shree Saibaba Heart Institute and Research Center, Near Kalidaskala Mandir, Shalimar, Nasik, India) Comparison of Bisoprolol With Metoprolol Succinate Sustained-release on Heart Rate and Blood Pressure in Hypertensive Patients (CREATIVE). clinicaltrials.gov/show/NCT01508325 Haasis R, Bethge H. Exercise blood pressure and heart rate reduction 24 and 3 hours after drug intake in hypertensive patients following 4 weeks of treatment with bisoprolol and metoprolol: a randomized multicentre double-blind study (BISOMET). Eur Heart J 1987;8 (Suppl M):103-13 Montoya A et al. Comparative study between bisoprolol and metoprolol, combined with hydrochlorothiazide, as antihypertensive therapy. Arch Inst Cardiol Mex 2000;70:589-95 [Article in Spanish]

200 patients between the ages of 18 and 65 years with Stage-1 hypertension were randomly assigned to receive either bisoprolol or metoprolol. After screening, patients were assigned to one of two groups to receive either bisoprolol (5 mg, once a day in the morning) or metoprolol succinate (50 mg tablet, once a day in the morning). At study visits, dosage of either drug could be increased in order to achieve better control. Other antihypertensives were not allowed with the exception of amlodipine. The primary end point was the responder rate (%) at 12 weeks (blood pressure <140/90 mmHg throughout 24 hours) carried out by monitoring the systolic blood pressure (SBP) and diastolic blood pressure (DBP) using ABPM. The baseline demographics of both groups were more or less the same. Sex ratio, age, weight, height, etc. were comparable. The responder rate (24 hour blood pressure control) at 12 weeks was higher for bisoprolol (68%) than metoprolol (63%) but this was not significant. Bisoprolol and metoprolol had similar efficacy. Only a few patients required the addition of amlodipine. The night-time blood pressure, a significant risk factor in CAD, was well controlled with both bisoprolol and metoprolol. SBP and DBP were equivalently controlled. The global efficacy and tolerability scores were equivalent.

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Comparison of the effects of two beta-blockers on sympathetic nervous activity and central aortic pressure in hypertensive patients Dr Pinjin Gao All patients were treatment-na誰ve and aged between 25 and 65 years old with SBP of 140-160 mmHg and/ or DBP of 90-100 mmHg, normal sinus rhythm and resting heart rate (RHR) > 70 bpm. There were 109 patients recruited from the hypertension clinic at Ruijin Hospital (Shanghai, China.) Patients were assigned to one of two groups to receive either bisoprolol or atenolol. The two groups were well matched with regard to age, sex, BMI, serum glucose, TG, total cholesterol, HDL cholesterol and LDL cholesterol.

Dr Pinjin Gao88 presented a phase IV randomized controlled study of the effects of bisoprolol and atenolol on sympathetic nervous activity and CAP in patients with essential hypertension89. Beta-blockers have dissimilar effects on arterial distensibility and compliance in hypertensive subjects. Compared with atenolol, bisoprolol may have a better effect on CAP. The results from this small sample, single-center study justify an extension of the work to cover multiple centers, said Dr Gao. 88 89

Dr Pinjin Gao (Dept of Hypertension, Ruijin Hospital, Shanghai, Jiao Tong University School of Medicine, Shanghai, China) Zhou WJ et al. A randomized controlled study on the effects of bisoprolol and atenolol on sympathetic nervous activity and central aortic pressure in patients with essential hypertension. PLoS One 2013;8: e72102

Measurements of sympathetic nervous activity were performed after a 30-minute rest in the sitting position. Patients were monitored noninvasively with a Finometer in both the supine and the standing positions. Baroflex sensitivity (BRS) was defined by the slope of the linear regression curve obtained by plotting the changes of SBP against the pulse interval. The mean value of the various slopes was calculated and used as the definitive BRS value for each subject. Heart rate variability (HRV) was calculated from the time-sequential analysis and was expressed as: low frequency (LF), high frequency (HF), and LF/HF ratio. CAP analysis was performed by pressure tonometry using the integral software (SphygmoCor) at the radial pulse.

30


Both brachial blood pressure (BBP) and CAP levels were similar between the two groups before treatment. BBP in the two groups was significantly reduced to a similar extent after treatment. However, the decrease in aortic-SBP and BBP was significantly greater with bisoprolol than with atenolol. The change in BRS in the bisoprolol group (3.99Âą4.19 ms/mmHg) was higher than that in the atenolol group (2.66Âą3.78 ms/mmHg) at the final visit; however, the difference was not statistically significant (P=0.107). Dr Gao noted that there was no difference in BRS between the final visit and the visit during which the target heart rate was achieved.

There was little difference in HRV between the two groups (although an improved LF component was seen in the last visit for the bisoprolol group). Regarding the resting heart rate, there was no difference between the two groups at baseline, at two weeks or at the last visit. Resting heart rate decreased significantly from the baseline in each treatment group and almost identically with the two drugs.

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Panel discussion: which are the key criteria for the selection of a beta-blocker? Panel discussion Prof Brian Tomlinson90 and Dr Aniruddha Dharmadhikari answered questions from delegates. 91

All the current guidelines now recommend less use of beta-blockers but this is based on work with older beta-blockers such as atenolol. With the availability of newer, more selective, beta-blockers will we see a return to greater use?

What are your views on non-pharmacological therapies for hypertension that target the sympathetic nervous system? BT – Renal sympathetic denervation has become popular, although its effectiveness is perhaps a little disputed after the failure of the Symplicity HTN-3 study to meet its primary efficacy endpoint [discussed in Persu A et al. (2014)92, Ed.] I have a concern that many of the patients that are subjected to the treatment may not have had the ideal degree of blockade in the first instance in some of these studies. Maybe they weren’t titrated to the top dose of ACEi and beta-blocker and as a result didn’t have full blockade of the SNS and RAS. If the drugs had been titrated a bit more they might not have needed the renal denervation.

BT – I think there is still an important role for beta-blockers, as we’ve seen from some of the data presented at this meeting. I don’t think we should necessarily advocate beta-blockers for all patients but I think we can select out patients who are likely to do well. Perhaps one of the criteria might be patients with a high resting heart rate as these patients, particularly the younger ones, may respond well. In elderly patients, reducing the heart rate too much may actually have a negative effect on the central aortic pressure.

AD – I think sympathetic overdrive is a very important precipitating factor for hypertension. Beta-blockers help in treating this sympathetic overdrive. The newer drugs, which are now being utilized for sympathetic overdrive, are also efficacious in the treatment of hypertension but, as I said, the subjective feeling of the patients on beta-blockers is that they are calmer and less anxious than they are with other antihypertensive drugs. This is precisely because beta-blockers subdue the sympathetic overdrive.

AD – I agree. We are still not sure quite how beta-blockers are helpful in reducing blood pressure, but one key mechanism is the reduction in cardiac output. This however affects the patient’s overall work efficiency, he feels more tired at the end of the day. But the patient’s perception of fatigue has been found to be much less with selective beta-blockers such as bisoprolol and nebivolol though they caused significant reduction in heart rate. 90 91

Prof Brian Tomlinson (Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China) Dr Aniruddha Dharmadhikari (Shree Saibaba Heart Institute and Research Center, Near Kalidaskala Mandir, Shalimar, Nasik, India)

92

Persu A et al. Renal denervation after symplicity htn-3: an update. Curr Hypertens Rep 2014;16:460

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Do you think controlling blood pressure variability is a factor in reducing cardiovascular events? BT – Some of the studies certainly suggest that there is a benefit from reducing blood pressure variability, but this has mainly been measured from visit to visit. We have data suggesting that a long-acting CCB has an advantage in this regard. It’s difficult to say what the effect of beta-blockers on variability is because we don’t have the data. But, I think it’s important to have a beta-blocker that has a consistent effect over 24 hours. Once-daily bisoprolol and slow-release metoprolol succinate can do this, as we have seen. AD – Heart rate variability has always been mentioned as a significant risk factor for CAD and longer acting formulations of beta-blockers such as metoprolol succinate, bisoprolol and nebivolol have been very effective in controlling heart rate variability. Amlodipine and other classes of hypertensive drugs do not reduce the heart rate variability like the beta-blockers, especially the newer beta-blockers and the longer acting formulations. The older generation of beta-blockers, like propranolol and atenolol, were shorter acting and the night-time blood pressure and heart rate variability were not very well controlled unless taken twice or three-times a day. The newer beta-blockers control the night-time surge, early-morning surge and heart rate variability thus reducing the coronary risk factors.

Do you think the timing of doses can play a role in reducing the cardiovascular risk? BT – If one sees a patient who doesn’t have dipping during the night-time, identified by ABPM, there would certainly seem to be an advantage in giving a drug to help improve this. Night-time blood pressure seems to be taking on more and more importance nowadays. We don’t yet know whether giving a beta-blocker at night rather than in the morning would improve this or not. I think it would be an interesting study to do. Is there any limit to how much blockade should be applied? Surely we need to have adrenergic activity? Has any study been done? BT – Actually, I was involved in such a study myself many years ago when I worked with Brian Pritchard in London. We did a dose-response study to see if we could get a full blockade of beta-receptors. We looked at the exercise heart rate and we went up with single doses starting with atenolol 50 mg. We ended up with atenolol at 1600 mg and even that didn’t fully block the beta1-receptor although the participants could hardly stand up after that dose.

33


Because of the inconclusive evidence that different CYP2D6 have an effect on the dose of metoprolol should we start with low doses and slowly increase the titration as a matter of course? BT - In a lot of the studies they did do a careful dose titration, particularly in heart failure. They started with a very small dose and increased gradually. In this situation you don’t really see an effect from CYP2D6 variants because you have overcome this through the titration. However, if you just want to put a patient on a fixed dose of metoprolol and expect that to work I think this is where you see a problem. This has occurred in certain situations such as the study in patients with non-cardiac surgery where they put them on a fixed dose of propranolol and metoprolol in advance and the outcome was bad. Some of the patients will be harmed because their dose has not been titrated properly. In the end, of course, this then affects the meta-analysis of that type of study, and I think that gives us the wrong message.

AD – Ethnicity and genetics also play an important role in the tolerability of beta-blockers. The white Caucasian population tolerates beta-blockers more than the Asian and the Indian population. Take propranolol for example, an initial dose for an Asian of 10 mg, three times a day can bring the heart rate down to 50 bpm. A white Caucasian typically requires a dose of 40 mg, three times a day, to do this.

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Session V - Control of heart rate: a new therapeutic approach in hypertension Sympathetic nervous system and hypertension: an overview Prof Guido Grassi 1 Assess plasma norepinephrine in venous blood – this is an indirect approach 2 Power spectral analysis of blood pressure and heart rate signals 3 Clinical microneurography, a technique which allows us to record postganglionic sympathetic nerve traffic 4 Plasma norepinephrine spillover, which gives us a clear picture of the norepinephrine increase coming from the central SNS.

There is, said Prof Grassi93, evidence dating back to the 18th Century that the SNS is both a direct and indirect promoter of hypertension. It has a direct effect via systemic vasoconstriction and blood pressure increase. It has an indirect effect through stress-induced hypertension and hemodynamic alterations associated with hypertension. New approaches have been developed over the last few years to measure sympathetic activity. We now have four principal methods: 93

Prof Grassi presented evidence from studies showing how knowledge of the role that sympathetic activation plays in the cardiovascular continuum has grown over the last 300 years. We have, he told delegates, a lot of evidence of sympathetic overdrive in hypertension but we have problems explaining the adrenergic overdrive. There are many potential factors involved. The ideal antihypertensive agent is a drug that can lower blood pressure, control 24-hour blood pressure and also possesses ancillary properties for example the ability to favor regression of target organ damage or reduce sympathetic activation.

Prof Guido Grassi (Medical Clinic San Gerardo dei Tintori Hospital, Monza, Italy and MilanoBirocca University, Milan, Italy)

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Central sympatholytic agents such as clonidine are capable of reducing central and peripheral sympathetic overdrive.

Looking to the future, there are number of priorities for SNS research in hypertension. 1 Implementation of new techniques (e.g. microdialysis, imaging)

A short-acting CCB may increase sympathetic activity centrally and peripherally as, to an extent, a thiazide diuretic will. In contrast, beta-blockers and drugs which act on the RAS reduce cardiac and central sympathetic overdrive.

2 Dynamic assessment of SNS during sleep 3 Evaluation of genetic/SNS interactions 4 Assessment of the link between SNS activation and hypertension prognosis

If you have a drug that increases sympathetic activity you may have unfavorable effects that result in:

5 Greater focus on combination-drug treatments 6 Deeper assessment of new therapeutic procedures (catheter-based renal sympathetic denervation, implantable carotid sinus baroreflex activating system)

zz increase in heart rate and myocardial oxygen demand increase in blood pressure variability zz increase in insulin resistance zz reduction in the trough to peak ratio and possibly the smoothness index

For further reading Prof Grassi recommended: Grassi (2010)94, Grassi et al (2012)95, Grassi et al (1998)96 and Mancia et al (1998)97.

zz a lack of organ protection and organ damage regression.

94 95

96

97

Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens 2010;23:1052-60 Grassi G et al. Total cardiovascular risk, blood pressure variability and adrenergic overdrive in hypertension: evidence, mechanisms and clinical implications. Curr Hypertens Rep 2012;14:333-8 Grassi G et al. Effect of chronic angiotensin converting enzyme inhibition on sympathetic nerve traffic and baroreflex control of the circulation in essential hypertension. J Hypertens 1998;16:1789-96 Mancia G et al. Early and late sympathetic activation in hypertension. Scand Cardiovasc J Suppl 1998;47:9-14

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Debate: is heart rate a target in the treatment of hypertension? Prof Guido Grassi proposed the motion that ‘Heart rate is both an independent indicator of cardiovascular risk and a suitable target for treatment.’ The motion was opposed by Dr Arintaya Phrommintikul.

Prof Guido Grassi There are a number of drugs that can be used to moderate sympathetic activity, principally betablockers. Some debate remains about the best way to define an increase in heart rate. How should we measure it, a clinic or ambulatory measure? What is a ‘normal’ heart rate? At present, ‘normal’ is defined as a range from 60 to 80 bpm. Progress is however being made and, said Prof Grassi, when we have a better definition of normality, the value of reducing heart rate in order to reduce cardiovascular risk will be demonstrated. Heart rate, said Prof Grassi98, is a ‘principal actor’ in the cardiovascular risk profile and not a ‘bit player’. Heart rate is a predictor and precursor of: hypertension, obesity, metabolic alteration and diabetes. It is a determinant of target organ damage, but also of cardiovascular complications. It may also be a factor of cardiovascular risk in the general population.

A video of Prof Grassi's lecture is online at http://bit.ly/cardiometapac2014

There is a broad evidence base collected in different clinical conditions showing that where you have an increase in plasma epinephrine, cardiac norepinephrine spillover or sympathetic nerve traffic, then the prognosis will be worse. 98

Prof Guido Grassi (Medical Clinic San Gerardo dei Tintori Hospital, Monza, Italy and MilanoBirocca University, Milan, Italy)

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Dr Arintaya Phrommintikul Furthermore, the mechanism of heart rate reduction is such that we cannot be sure whether any effects of treatment are the result of alteration of the augmentation index or due to beta-blockers. The picture we have of the role of beta-blockers from meta-analyses does not reflect the differences in the class. Going back to the core question. Should heart rate be a target in hypertension treatment? I would say no. Not for now! For further reading, Dr Phrommintikul recommended: Salles et al (2013)100, Wilkinson (2000)101 and Flannery et al (2008)102

In response, Dr Phrommintikul99 agreed with Prof Grassi that heart rate is an important risk factor and a risk marker in hypertension. However, she highlighted the conflicting data on the prognostic value of heart rate on cardiovascular events.

A video of Dr Phrommintikul's lecture is online at http://bit.ly/cardiometapac2014

1 We have no clear indication on how to measure heart rate: baseline or in-treatment, in-clinic or ambulatory 2 We have no agreement on what a normal heart rate should be 3 We have no evidence that there is clinical benefit from pharmacological reduction in heart rate; will such intervention reduce the likelihood of cardiovascular events?

99

Dr Arintaya Phrommintikul (Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand)

100 Salles GF et al. Prognostic significance of baseline heart rate and its interaction with betablocker use in resistant hypertension: a cohort study. Am J Hypertens 2013;26:218-26 101 Wilkinson IB et al. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 2000;525:263–270 102 Flannery G et al. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving betablockers. Am J Cardiol. 2008;101:865-9

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Session VI - Hypertension and related diseases Hypertension and atrial fibrillation Dr Claudio Borghi Chugh et al (2014)105 demonstrated that the incidence of the disease has increased significantly over the last 20 years in both men and women. This large prevalence of atrial fibrillation in the general population is associated with a progressive increase in the mortality from many different cardiovascular causes in the developed and developing countries. The incidence in men and women is similar in developed countries but in the developing countries the increase in mortality seems to be larger in women.

Beyond its ability to increase the rate of coronary heart disease and stroke, said Dr Borghi103, hypertension is associated with an extensive incidence of target organ damage that involves organs including the heart where it manifests as LVH, fibrosis, atrial remodelling and apoptosis. These in turn, are responsible for the onset of additional cardiovascular disease, as shown by Kannel (1998)104. Atrial fibrillation is probably the most common arrhythmia in the general population and more particularly in the hypertensive population. 103 Dr Claudio Borghi (Dept of Medicine and Surgical Sciences, University of Bologna, Bologna, Italy) 104 Kannel WB. Risk stratification in hypertension: new insights from the Framingham Study. Am J Hypertens 2000;13:3S-1

In addition, Manolis et al (2012)106 have shown that between 49% and 90% of the population with atrial fibrillation also have hypertension. There are three possible mechanisms responsible for the strong interaction between hypertension and atrial fibrillation: 1 blood pressure increase 2 extent of activation of the neurohumoral RAS 3 cardiac organ damage, including left ventricular structure. 105 Chugh SS et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129:837-847 106 Manolis AJ et al, Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group ‘Hypertension Arrhythmias and Thrombosis’ of the European Society of Hypertension. J Hypertens 2012;30:239-52

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All these acting together (or sometimes individually) can lead to atrial remodelling (functional, structural and electrical) which is the main mechanism for atrial fibrillation. An increase in the relative risk of atrial fibrillation has been described in patients with high normal blood pressure, whose blood pressure values were only mildly or moderately elevated. This again supports the theory that hemodynamic overload has a role in the onset of atrial fibrillation but also points to the possibility that there is a common mechanism that involves the blood pressure increase and the structural abnormalities of the ventricle/atria which both then lead to atrial fibrillation.

Hypertension is likely to be a reversible risk factor for atrial fibrillation. Hennersdorf et al (2007)107 showed that if you effectively reduce blood pressure, by doing so you can achieve regression of LVH and you can also see a significant decrease in the development of atrial fibrillation. The possibility may exist for a treatment path that could prevent the development of atrial fibrillation in hypertension. This would need to be based on systemic blood pressure control, central (aortic) blood pressure control, persistent heart rate control, improved arterial stiffness, protection against target organ damage and effective regression of LVH, effective blockade of RAS and SNS, new oral anticoagulants and possibly antioxidant treatment.

107 Hennersdorf MG et al. Prevalence of paroxysmal atrial fibrillation depending on the regression of left ventricular hypertrophy in arterial hypertension. Hypertens Res 2007;30:535-540

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Coronary artery disease Prof Roberto Ferrari They are good for the coronary artery because they improve the life and death cycle of the endothelium. Endothelial cells undergo apoptosis (cell death) after approximately three months. Normally, the endothelium regenerates in synchrony but when a mismatch occurs between regeneration and apoptosis the endothelium loses its continuity. This causes: atherosclerosis, angina and plaque rupture and acute coronary syndrome. It is important to measure the rate of endothelial apoptosis but this is very difficult to do.

The cardiovascular continuum starts with several possible risk factors: hypertension, dyslipidemia, insulin resistance, smoking and abnormal heart rate. Before going directly to atherosclerosis there is a step; endothelial dysfunction. So the question, posed by Prof Ferrari108 was, ‘CAD: A disease of the myocyte or of the endothelium, or both?’

Valgimigli et al (2003)109 investigated this in the laboratory by isolating human endothelium and incubating it for 72 hours with serum from both healthy subjects and patients with coronary artery disease. Following incubation we measured two classical indices of endothelial function: nitric oxide synthase and the rate of apoptosis. In hypertensive patients with CAD there is a clear reduction of the expression and activity of nitric oxide synthase and even more if the patient has acute coronary syndrome, .

Might CAD be a disease of the endothelium of the coronary arteries that then, only as a consequence becomes a disease of the myocyte?

The rate of endothelial apoptosis in the healthy volunteers was about 3% but in hypertensive patients with angina it rose to 10% and nearly 20% in patients with acute coronary syndrome.

Clinically, statins and ACEi are able to reduce atherosclerosis. These drugs act beyond cholesterol and blood pressure reduction.

This suggests that the combination of hypertension and coronary artery disease is incredibly dangerous for the endothelium and causes more apoptosis to occur.

108 Prof Roberto Ferrari (Department of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, Italy and the Maria Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation, Cotignola, Italy)

109 Valgimigli N et al. Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells: a possible link to pan-coronary syndromes. Circulation 2003;107:264-70

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If you have an excess of apoptosis you will have a loss of endothelial continuity that will cause atherosclerosis. If the endothelium is already covering a plaque, this is where the thrombosis will form. Ceconi et al (2006) showed that perindopril reduces endothelium apoptosis by reducing angiotensin II and tumour necrosis factor TNF-β (pro-apoptotic agents) and by enhancing bradykinin (an anti-apoptotic agent). 110

Bone marrow produces endothelial progenitor cells (EPC) to be incorporated into blood vessels. There is a marked increase in the production of EPC cells in stable angina patients (relative to control) when given perindopril. This suggests that ACEi not only reduce apoptosis but they improve the function of the endothelium. Statins also have a marked effect, reducing apoptosis by inhibition of pro-caspase 9 (pro-apoptotic) enzymes at the mitochondrial level, inhibition of BAD-BCL2 (pro-apoptotic) and activation of AKT (anti-apoptotic). This is a different mechanism from ACEi and is the reason why ACEi and statin combinations are effective at reducing cardiovascular disease and death. What about ARBs? Do ARBs afford the same cardiovascular effect as ACEi? Asked Prof Ferrari. Various studies (including KYOTO111, NAVIGATOR112 and ROADMAP113) have shown no effects or increased cardiovascular mortality with ARBs. This is because 110 Ceconi C, et al. ACE inhibition with perindopril and endothelial function. Results of a sub-study of the EUROPA study: PERTINENT. Cardiovasc Res 2007;73:237-46 111 Sawada T et al. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461-2469 112 Califf RM et al. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: Rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. American Heart Journal 2008;156:623–632 113 Hermann H et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-917

ARBs have little or no effect on bradykinin, do not reduce endothelial apoptosis and do not improve endothelial regeneration. The reason for this is that ARBs act on various different angiotensin receptors that have simultaneous positive and negative effects: the use of an ARB does not reduce the level of angiotensin II. Because angiotensin I receptors are blocked, all the angiotensin II binds to angiotensin II receptors. This causes vasodilation, which is good; it reduces blood pressure, which is excellent; but it also increases anti-proliferation and pro-apoptosis, which is dangerous for the epithelium. When perindopril is compared to valsartan in post-acute MI patients there is a very clear reduction of apoptosis and improvement in EPC production. Looking at the guidelines in patients with hypertension and CAD, aspirin, statins and ACEi are recommended as preventive agents. For reducing symptoms, beta-blockers or CCBs are recommended in first-line and a broader range for second line. Why use beta-blockers? Because sympathetic activation is dangerous in CAD, said Prof Ferrari. The benefit of beta-blockers is related to the extent of heart rate reduction. Better reduction means better survivability. Beta-blocker therapy is important because betablockers are working on two risk factors, blood pressure and heart rate. This has a good effect on atherosclerosis and specific effects on patients with CAD, MI and heart failure.

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Heart failure Prof Roberto Ferrari Guidelines clearly advise using ACEi and beta-blockers as soon as possible to achieve better action on remodelling and greater reduction in sudden death. There are many studies that validate the use of beta-blockers. This class of drugs remains a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF) because they reduce heart rate (and therefore oxygen consumption), the negative effects of increased catecholamine levels on the myocardium, cardiac remodelling and sudden death.

We have seen huge changes over the last fifty years in the diagnosis and treatment of heart failure, Prof Ferrari114 told delegates. Most notably: zz the recognition that it should be considered a neuroendocrine disease zz the adoption of evidence-based approaches that focused on the prognosis rather than the symptoms. Therapeutic approaches have evolved. In the past, rest was advised whereas today doctors prescribe exercise. Vasodilators have been replaced by ACEi and positive inotropes by beta-blockers.

114 Prof Roberto Ferrari (Department of Cardiology and LTTA Centre University Hospital of Ferrara, Ferrara, Italy and the Maria Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation, Cotignola, Italy)

Beta-blockers are the 'ideal' inotropes as they reduce heart rate and improve ejection fraction without increasing oxygen consumption. The relationship between frequency and force of contraction in heart failure is different to the normal case. Increased heart rate normally corresponds to an increase in the force of contractions. This is not the case in heart failure where increasing heart rate causes reduced force of contraction. Although there is no question that beta-blockers are useful in HFrEF, Prof Ferrari questioned whether they are being used correctly. According to Maggioni et al (2013)115 in the European population 92% are receiving the target dose of beta-blockers. It is however, more important to monitor the target effect rather than the target dose. 115 Maggioni AP et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173-84

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It is important to use a dose sufficient to reduce heart rate to 70 bpm. But what happens when the ejection fraction is preserved (HFpEF)? This is a much more difficult issue, said Prof Ferrari. When Gandhi et al (2001)116 looked at all the clinical trials conducted in heart failure with preserved left ventricular function there were no conclusive results. This means that we do not have, Prof Ferrari noted, guidance on how to treat HFpEF patients, thought this condition affects about half of the heart failure population. The Euro Heart Failure Survey117 included over 10,000 patients: 6,800 had measurements of left ventricular function. Equal numbers had left ventricular systolic dysfunction and 46% had preserved systolic function (ejection fraction ≥ 40%.) Shah (2013)118 defined three difference HFpEF clinical profiles: 1 exercise-induced diastolic dysfunction: ambulatory patients with New York Heart Association (NYHA) class II-III symptoms, impaired LV relaxation (grade I) and near normal brain natriuretic peptide (BNP) levels 2 chronic volume overload: patients with NYHA class II-IV and a history of hypertension and of heart failure hospitalization, elevated BNP, and/or left atrial enlargement

patients with NYHA class III-IV symptoms with evidence of pulmonary vascular disease and/or right ventricular dysfunction. Heart failure with reduced or preserved ejection fraction comprises two distinct entities: 1 HFpEF is a systemic syndrome, driven by accumulated risk factors/comorbidities in vulnerable subjects (although we have yet to define ‘vulnerable’) with an important cardiovascular component (loss of compliance and adaptability) 2 HFrEF is a disease of the heart that then causes a systemic syndrome. In HFpEF there are often several risk factors such as: being overweight or obese, hypertension, diabetes mellitus, chronic obstructive pulminary disease (COPD) and iron deficiency. These cause damage at the level of the endothelium which then causes damage to the myocardium. Diagnosing HFpEF remains difficult. Predictors are neither specific nor sensitive. In HFrEF the risk factors are: ischemia, infection and toxicity. These cause death of the myocyte which then causes the condition. The results of studies regarding prognosis conflict. Some conclude that there is no difference in prognosis and others that there is lower mortality with HFpEF.

3 right heart failure / pulmonary hypertension: 116 Gandhi SK et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344,17-22 117 Lenzen MJ et al. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 2004;25:1214-20 118 Shah S. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction. J Am Coll Cardiol 2013;62:1339-1342

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No treatment has yet been shown, convincingly, to reduce morbidity and mortality in HFpEF patients. Diuretics are used to control sodium and water retention and relieve breathlessness and edema. Adequate treatment of hypertension and myocardial ischemia with beta-blockers is important, as is control of heart rate if there is atrial fibrillation. The drugs that should be avoided in HFrEF should also be avoided in HFpEF, with the exception of CCBs. To date, negative results have been reported with RAS modulators (ACEi, ARB and mineralocorticoid receptor antagonists), beta-blockers (carvedilol and nebivolol), ranolazine, sildenafil and nitroprusside. There have been positive results from exercise.

In conclusion, Prof Ferrari summarized the unmet needs with respect of HFpEF: 1 understanding (research) but this is not easy there are no easy animal models and the condition is difficult to diagnose 2 prevention (control of risk factors and comorbidities) 3 therapy (no specific therapy available). For further reading, Prof Ferrari recommended: Palatini et al (2006)119, Gillman et al (1993)120, Palatini & Julius (1997)121.

119 Palatini P et al. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens 2006;24:603-10 120 Gillman MW et al. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993;125:1148-54 121 Palatini P, Julius S. Heart rate and the cardiovascular risk. J Hypertens 1997;15:3-17

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Faculty members Claudio Borghi Department of Medical and Surgical Sciences University of Bologna, Bologna, Italy Marlon T. Co Chong Hua Hospital Cebu City, Philippines Jamshed J. Dalal Cardiac Sciences Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, India Aniruddha Dharmadhikari Shree Saibaba Heart Institute and Research Center Near Kalidaskala Mandir Shalimar, Nasik, India Roberto Ferrari Department of Cardiology and LTTA Centre, University Hospital of Ferrara Ferrara, Italy and Maria Cecilia Hospital GVM Care & Research, E.S: Health Science Foundation Cotignola, Italy

Pinjin Gao Department of Hypertension Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai, China Guido Grassi Medical Clinic San Gerardo dei Tintori Hospital Monza, Italy and Milano-Bicocca University Milan, Italy Arintaya Phrommintikul Department of Internal Medicine Faculty of Medicine Chiang Mai University Chiang Mai, Thailand Lin Shuguang (Scientific organiser) Guangdong General Hospital Guangdong, China Bambang Budi Siswanto National Heart Center Harapan Kita Jakarta Barat, Indonesia

Soetanto Arieska Soenarta National Heart Center Harapan Kita Jakarta, Indonesia Piyamitr Sritara Department of Medicine Ramathibodi Hospital Mahidol University Bangkok, Thailand Stefano Taddei Department of Clinical and Experimental Medicine University of Pisa Pisa, Italy Brian Tomlinson (Scientific organiser) Department of Medicine and Therapeutics The Chinese University of Hong Kong Hong Kong SAR, China Hung-Fat Tse Cardiology Division Department of Medicine The University of Hong Kong Hong Kong SAR, China

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About EXCEMED EXCEMED – Excellence in Medical Education has been providing world-class education to thousands of healthcare professionals over the past four decades, during this time organizing over 1500 international scientific congresses with more than 500 proceedings appearing in leading international publications. EXCEMED has also pioneered online CME courses since 2000 and oversees an expanding portfolio of e-learning activities including video lectures, CMEaccredited online courses and symposia. EXCEMED provides a series of activities in cardiometabolic medicine, such as CME accredited live events and online courses that are focused on hypertension, diabetes, arrythmias, and cardiac, cerebral and peripheral limb ischemic diseases.

The new name symbolizes an enduring mission to support the best possible outcomes for patients through excellent medical education. EXCEMED is headquartered in Geneva, Switzerland and has a Representative Office in Rome, Italy. Representative office Salita di San Nicola da Tolentino 1/B, 00187 Rome, Italy T +39.06.420.413.206 F+39.06.420.413.677 Headquarters 14 Rue du Rhone, 1204 Geneva, Switzerland

EXCEMED Excellence in medical education We welcome your feedback or requests for topics in future issues. Please contact us: www.excemed.org info@excemed.org Cardiometabolic News: Scientific Advisor Prof Brian Tomlinson Editor Howie Watkins

Our activities are designed for healthcare professionals who are seeking to improve their knowledge, competence and performance in order to provide the best diagnostic and therapeutic solutions to their patients.

Contributors Alison Eden, Howie Watkins Copyright © EXCEMED, 2014. All rights reserved

The organisation changed its name from Serono Symposia International Foundation (SSIF) on 28 April 2014. The name change marked an exciting point in the evolution of the organisation – a time of strong developments in its scientific and geographical presence. Follow EXCEMED Cardiometabolic on Twitter: @EXCEMED_Cardio

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