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SPECIAL REPORT

Improving the Diagnosis and Treatment of Hypertension Sponsored by

Improving the Diagnosis and Treatment of Hypertension Dealing with the Problem by Understanding the Physiology and Structure Involved Secondary Causes of Hypertension Salt, Culture and Hypertension The Pro-Active General Practitioner – Detecting, Managing and Treating Hypertension in the Community with Multi-Disciplinary Help

Published by Global Business Media


DiaSorin Direct Renin and Aldosterone testing the lIAIson® direct renin 7,8,9 is: 1

RELIABLE

standardized to WHO IRP 68/356; provides accurate results to assist clinicians in the management of hypertensive patients

2

EFFICIENT

simpler, faster, reproducible good alternative to Plasma Renin Activity (PRA) assays

3

FLEXIBLE

highly suitable to improve laboratory workflow

the lIAIson® Aldosterone 10,11 is: 1

RELIABLE

quantitative determination of aldosterone in human serum, plasma and urine specimens

2

EFFICIENT

easier than mass spectrometry, faster and reliable with reduced intra laboratory variability and results

3

FLEXIBLE

highly suitable to improve laboratory workflow

LIAISON ® Direct Renin & Aldosterone tests to obtain 1 Aldosterone/Renin Ratio to early diagnose PA

aVaILaBLe on LIaISon® SYSteMS references 1. 2. 3. 4.

G. Mancia at al, Journal of Hypertension 2013, 31:1281–1357 N. Kaplan, Lancet vol 367 January 14 2006 E. Pimenta and D.A. Calhoun, Circulation 2012;125:1594-1596 M.A. Acelajado and D.A. Calhoun, Journal of Hypertension vol 2011, article ID 837812, 7 pages 5. John W. Funder et al, “Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: an Endocrine Society Clinical Practice Guideline” Journal of Clinical Endocrinology & Metabolism, September 2008, 93 (9): 3266–3281

6. F.H. Perschel, Clinical Chemistry 2004 50:9 1650-1655 7. A. Morganti et al, Journal of Hypertension 2010, Vol 28 No 6 8. A. Morganti et al, Journal of Hypertension 2014 Vol 32 No 1 9. D. Gruson et al, Biomarkers, 2011; 16(7): 605–609 10. A. Fortunato et al, Clin Chem Lab Med 2013 11. D. Gruson et al, Biomarkers Dec 2013


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

SPECIAL REPORT

Improving the Diagnosis and Treatment of Hypertension Sponsored by

Improving the Diagnosis and Treatment of Hypertension Dealing with the Problem by Understanding the Physiology and Structure Involved

Contents

Secondary Causes of Hypertension Salt, Culture and Hypertension The Pro-Active General Practitioner – Detecting, Managing and Treating Hypertension in the Community with Multi-Disciplinary Help

Foreword

2

Dr Charles Easmon, Editor

Improving the Diagnosis 3 and Treatment of Hypertension Miriam T. Brady BSc. PhD., DiaSorin Ltd. Dartford, Kent, UK.

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org

Introduction Screening – Who and When? Evaluation of the ARR Renin and Choice of Therapy Conclusions

Dealing with the Problem by Understanding the Physiology and Structure Involved

Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

Publisher Kevin Bell

The Renin-Angiotensin-Aldosterone System The Nervous System Renal Nerves The Entero-Salivary Circuit Summary

Business Development Director Marie-Anne Brooks

Secondary Causes of Hypertension

Editor Dr Charles Easmon Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org

The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles. © 2016. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

7

9

Sophie Levingworth, Medical Correspondent

Kidney Related Causes of Hypertension Neurological and Respiratory Causes of Hypertension Medication, Gestational Hypertension Pre-eclampsia and Diet Causes of Hypertension Summary

Salt, Culture and Hypertension

11

Sophie Levingworth, Medical Correspondent

Dietary Types and Culture Why do Some Cultures Have Higher Levels of Hypertension? Summary

The Pro-Active General Practitioner – Detecting, 13 Managing and Treating Hypertension in the Community with Multi-Disciplinary Help Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

Real or ‘White Coat Hypertension’? Sugar and Salt Regular Testing Professor Graham MacGregor’s Initiatives Other Help is at Hand The Role of the GP


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Foreword H

YPERTENSION IS the invisible enemy that

from a single EDTA tube, thus also simplifying lab

causes disability and early death amongst a

processes and workflow.

significant portion of your GP practice. We now

The scale of the hypertension problem is very

laugh at the prevalence with which blood-letting

significant. Hypertension affects more than 25% of

and leeches were used as medical therapies for

adults in England, and is the second biggest risk factor

hundreds of years, but perhaps they did relieve

for premature death and disability. People from the

some cases of hypertension. In another hundred

most deprived areas are 30% more likely than the

years, perhaps the next generations will wonder

least deprived to have high blood pressure, and the

why we didn’t know the cause of more than 90%

condition disproportionately affects some ethnic

of cases of hypertension. In today’s day and age

groups including black Africans and Caribbeans1.

we can identify causes in only 5-10% of those

If we managed and detected hypertension better,

with hypertension and often these causes are to

it has been estimated that at least 45,000 years of

do with disturbances of the renin-angiotension-

life could be saved and £850m not spent on related

aldosterone system. Faster and more reliable

health and social care. Key approaches are at

testing of renin and aldosterone would be a

individual, societal and policy levels. Individuals

great boon to hypertension diagnosis and

need to be aware of salt and reduce intake as well

management. Fortunately such testing exists and

as exercising more, moderating alcohol and avoiding

is commercially available.

obesity, as well as smoking. Societies can ensure

The opening article in this Special Report looks

community initiatives for regular blood pressure

at the impact of hypertension, one of the most

checks and follow-ups. Policy makers can legislate

preventable causes of premature morbidity and

for salt and sugar reduction in dietary products.

mortality throughout the UK and worldwide. Miriam

The General Practitioner should never become

Brady of DiaSorin Ltd. examines the causes of the

blasé about hypertension and should focus on

condition and describes automated assays developed

relentless measurement and management to save

by DiaSorin, allowing meaningful Aldosterone-to-Renin

life and disability. The use of the new tools for

Ratio (ARR) evaluation and primary aldosteronism

measuring renin and aldosterone has the potential

(PA) diagnosis with comparable specificity and

to transform practice.

sensitivity to existing methods. The assays are based on CLIA technology and can give a complete ARR assessment in as little as just over half an hour, measuring direct concentrations of both analytes

Dr Charles Easmon Editor

Dr Charles Easmon is a medical doctor with 30 years’ experience in the public and private sectors. After qualifying as a physician, he developed his interests in occupational medicine, public health and travel diseases. 1

https://www.gov.uk/government/publications/high-blood-pressure-action-plan Accessed 17/2/16

2 | WWW.PRIMARYCAREREPORTS.CO.UK


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Improving the Diagnosis and Treatment of Hypertension Miriam T. Brady BSc. PhD., DiaSorin Ltd. Dartford, Kent, UK. The right test, at the right time for the right people – early diagnosis and assessment are paramount in hypertension management

Complete and fully automated solution for reliable and accurate assesment of hypertension

Introduction

Screening – Who and When?

Despite important advances in our understanding of its pathophysiology, and the availability of effective treatment strategies, hypertension remains one of the most important preventable causes of premature morbidity and mortality throughout the UK and worldwide (1). It remains a major modifiable risk factor for cardiovascular disease, chronic kidney disease, cognitive decline and premature death. Overall, the prevalence of hypertension appears to be around 30-45% of the general population, which increases markedly with age. Left untreated it is usually associated with a progressive rise in blood pressure (BP), which may culminate in a treatment-resistant state due to vascular and renal damage. Given the substantial evidence, it is clear that timely and adequate control of blood pressure is of enormous public health importance.

Of the different forms of hypertension, essential, or primary hypertension, accounts for the vast majority of presentations (2). Within the less prevalent secondary hypertension, primary aldosteronism (PA) is the most common form, with prevalence estimates as high at 18% (3). This is a specific and potentially reversible cause of BP elevation, in a relatively small proportion of patients, characterised by inappropriately high aldosterone production that is relatively autonomous from normal regulation mechanisms and not suppressed by sodium loading (4). However, because of the overall high prevalence of hypertension, secondary forms can affect millions of patients worldwide. In addition, PA patients have higher cardiovascular morbidity and mortality than age- and sex-matched essential hypertension patients with the same WWW.PRIMARYCAREREPORTS.CO.UK | 3


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“Fast, sensitive and standardised methodology, is therefore of significant importance for effective and efficient assessment of the large numbers of patients with hypertension, particularly high-risk groups”

”Aldosterone and Renin are the two main hormones involved in the renin-angiotensin-aldosterone system (RAAS), the main regulator of blood pressure and sodium-water homeostasis” level of BP (4,5). This excess of cardiovascular risk is in part due to aldosterone exhibiting several non-epithelial effects such as the induction of inflammation, fibrosis and necrosis in various organs, somewhat independent from the effects on BP (6). PA is particularly common in patients with resistant hypertension (RHTN), defined as BP that remains above goal in spite of use of at least 3 antihypertensive medications, ideally prescribed at optimal doses and one of which is a diuretic (7). Many studies have shown that PA prevalence is higher in patients with moderate to severe hypertension on multiple antihypertensive medications, compared to the general hypertensive population (8). Early detection of hypertension can identify those individuals at high risk, enabling clinicians to rapidly initiate appropriate treatment, and so has the possibility of preventing potential target organ damage and cardiovascular complications, improving quality of life, prognosis of patients and healthcare costs. Given the evidence, ideally all hypertensive patients should be screened for PA, but as this tends not always to be practical or possible, higher prevalence groups should at least be fully considered. Indeed the Endocrine Society guidelines recommend screening of 4 | WWW.PRIMARYCAREREPORTS.CO.UK

these high-prevalence groups (4). In reality, a small percentage of patients are screened for PA, delaying administration of effective treatments, and potentially exacerbating deleterious patient outcomes. The Endocrine Society guidelines emphasise the importance of detecting the presence of PA because of the associated adverse cardiovascular risks and the availability of specific treatments. Categories suggested for screening are those with high prevalence (4), including hypertensive patients at stage 2 and 3, drug-resistant hypertensive patients (where PA prevalence can be as high as 20%), hypertensive patients with spontaneous or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, or hypertensive patients with suspected familial hyperaldosteronism (4). The most reliable screening test for PA in hypertensive patients, and one recommended by the same guidelines (4), is the Aldosterone-to-Renin Ratio, or ARR, first described by Hiramatsu et al. (9), and characterised by an elevated ARR. Aldosterone and renin are the two main hormones involved in the renin-angiotensin-aldosterone system (RAAS), the main regulator of blood pressure and sodiumwater homeostasis. The evaluation of the RAAS,


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

by measurement of aldosterone and renin, is pathophysiologically relevant in the assessment of hypertensive patients, both through diagnosing PA, and also through guiding clinicians in the management of essential hypertensive patients.

Evaluation of the ARR Evaluation of the ARR has led to a marked increase in the detection rate of PA (10,11), but is dependent on the reliability and sensitivity of the aldosterone and renin measurements (12). Plasma renin has traditionally been estimated using plasma renin activity (PRA) assays, which have long incubation times and consequently long turnaround times. Because of the manual nature of the assay, which is technically demanding and therefore inherently variable, interlaboratory comparability is very poor. Results are also affected by the endogenous substrate (angiotensinogen) concentration that may be elevated in certain conditions, for example, pregnancy, and the use of various antihypertensive medications, which requires specialist knowledge when interpreting results. Furthermore the PRA cannot be automated as it involves substrate generation followed by radioimmunoassay (RIA). Similarly, aldosterone testing has been mainly achieved by RIA, which requires a dedicated facility to run, trained staff, and specific waste disposal procedures. Fast, sensitive and standardised methodology, is therefore of significant importance for effective and efficient assessment of the large numbers of patients with hypertension, particularly high-risk groups. DiaSorin have developed a combination of LIAISON® Direct Renin and Aldosterone automated assays allowing meaningful ARR evaluation and PA diagnosis, with comparable specificity and sensitivity to existing methods. The assays are based on CLIA technology and can give a complete ARR assessment in just over half an hour, measuring direct concentrations of both analytes from a single EDTA tube, thereby also simplifying lab processes and workflow. In terms of performance, numerous studies have shown a highly significant correlation between plasma renin activity assays (PRA) and the DiaSorin Liaison® direct renin assay, identifying the same group of patients as the PRA, but with the added advantages of high throughput and economy (13,14,15,16). Given that the ARR is mathematically dependent on the renin measurement, sensitivity is an important consideration. The DiaSorin Liaison® assay meets the guideline recommendation (4) that the assay sensitivity should be as low as 2μIU/mL for direct measurement of renin concentration. Evaluation of the DiaSorin Liaison® aldosterone assay in a clinical setting also displays the analytical validity of an automated immunoassay which can

facilitate the screening of PA and risk stratification of cardiovascular diseases (17). The advantages of these assays are based not only on their ability to improve the accessibility of aldosterone and renin testing, but also to reduce and stabilise the turnaround time of analysis, and therefore improve the delivery of results to physicians, and ultimately patient care. After screening or evaluation of the ARR, it is recommended that all patients with an increased ARR should undergo one of four confirmatory tests, for final confirmation of the non-suppressibility of aldosterone secretion and therefore PA diagnosis (4). These tests include the oral sodium loading test, saline infusion test, fludrocortisone suppression test and the captopril challenge test. Confirmatory tests are not without their limitations. There is no consensus as to which tests should be used to confirm PA (18), and it is generally acknowledged that there may be differences in sensitivity, specificity and reliability.

Renin and Choice of Therapy A large-scale potential of automated renin assays is in the rationalisation of drug treatment for hypertension (19). Most essential hypertensive patients are treated with one or more antihypertensive drugs and display a marked heterogeneity of blood pressure response to different therapies. Given the diversity in the pathophysiological mechanisms involved in essential hypertension, and the choice of more than 10 classes of antihypertensive drugs, how can the appropriate treatment be chosen? The guidelines from the European Society of Hypertension / European Society of Cardiology do not specify use of a single class of drugs but rather leave the decision to the clinician from a group of preferred drug type (CCB’s, ARB’s, ACEI’s, diuretics and β-blockers, BB) (1). One method proposed to guide healthcare professionals in the clinical decision-making process, is RAAS profiling, a method of clarifying the main pathophysiological alterations in a single patient and providing guidance in the choice of the most appropriate treatment (20). The hypothesis is based on the classical formula regulating blood pressure, which is determined by peripheral vascular resistances and blood volume. Based on their levels of renin, patients are divided into two categories: low renin hypertensives (LRH) and normal high renin hypertensives (NHRH). According to this hypothesis LRHs are relatively more expanded in volume and therefore respond more the therapy with diuretics or CCBs, whereas NHRH’s will probably respond better to ACE-I’s or BB (20). If after monotherapy, blood pressure is still not controlled, renin can be measured again and CCB / diuretic, or ACE-I / ARB added

Complete and fully automated solution for reliable and accurate assesment of hypertension

WWW.PRIMARYCAREREPORTS.CO.UK | 5


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“The advantages of these assays are based not only on their ability to improve the accessibility of aldosterone and renin testing, but also to reduce and stabilise the turnaround time of analysis, and therefore improve the delivery of results to physicians, and ultimately patient care”

to therapy, if renin is low or high, respectively. In another study, renin-guided therapeutic choice was also shown to be a feasible approach for treating hypertensive patients (21), and may be associated with higher control rates than alternative strategies recommended in current guidelines. In terms of benefits, patients would be taking fewer medications, reducing side-effects and potentially harmful interactions. In addition, the administration of multiple drugs to control BP is far more costly than renin measurement (20).

Conclusions Hypertension is a global health problem, representing a significant cause of morbidity and mortality worldwide. The definition, etiology and treatment of hypertensive conditions is therefore of paramount importance, and can aid the clinician in identifying those individuals at high risk, allow the initiation of the appropriate treatment and prevent adverse cardiovascular events. PA in particular is associated with major adverse cardiovascular outcomes, and early diagnosis can identify the appropriate treatment and improve patient prognosis. A simple but effective screening method for PA is an investigation of

the RAAS system, through the measurement of renin and aldosterone. Rapid and accurate assessment of the renin-angiotensin-aldosterone axis with automated CLIA assays, can not only significantly improve lab work flow and processes due to fast turnaround times, but also makes screening of groups with high-prevalence of PA much more accessible and facilitates the management of hypertensive patients. The renin assay is very useful for the clinician in choosing the class of drug to treat essential hypertension, which can potentially reduce the number of drugs administered, and hence the cost, while concomitantly improving blood pressure control.

Contact Details: DiaSorin Limited Central Road Dartford Kent UK DA1 5LR Office: +44 (0) 1322 317949 Fax: +44 (0) 1322 317909 www.diasorin.com

References: 1.

2013 practice guidelines for the management of arterial hypertension. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). J. Hypertens. 2013; 31: 1925-1938.

2. Carretero, O.A., Oparil, S. Essential Hypertension Part I: Definition and Etiology. Circulation. 2000; 101: 329-335. 3. Hannemann, A., Wallaschofski, H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies – a review of the current literature. Horm. Metab. Res. 2012; 44: 157-162. 4. Funder, J. W., Carey, R. M., Fardella, C. et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J. Clin. Endocrin. Metab. 2008; 93: 3266-3281. 5. Mulatero, P., Monticone, S., Bertello, C., et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J. Clin. Endocrinol. Metab. 2013; 98: 4826-4833. 6. Mulatero, P., Milan, A., Williams, T. A., and Veglio, F. Mineralocorticoid Receptor Blockade in the Protection of Target Organ Damage. Cardiovacs. Hematol. Agents Med. Chem. 2006; 4: 75-91. 7. Calhoun. D. A., Jones. S., Textor, S. et al. “Resistant hypertension: Diagnosis, evaluation, and treatment. A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403-1419. 8. Acelajado. M. C. and Calhoun, D. A. Aldosteronism and resistant hypertension. Int. J. Hypertens. 2011; 2011: 837817. 9. Hiramatsu, K., Yamada. T., Yukimara, Y. A screening test to identify aldosterone producing adenoma by measuring plasma renin activity: results in hypertensive patients. Arch. Intern. Med. 1981; 141: 1589-1593. 10. Mulatero, P., Stowasser, M., Loh, K. C. et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004; 89: 1045-1050. 11. Olivieri, O., Ciacciarelli, A., Signorelli, D. et al. Aldosterone to Renin ratio in a primary care setting: the Bussolengo study. J Clin Endocrinol Metab. 2004; 89: 4221-4226. 12. Campbell, D. J., Nussberger, J., Stowasser, M. et al. Activity assays and immunoassays for plasma Renin and prorenin: information provided and precautions necessary for accurate measurement. Clin Chem. 2009;55: 867-877. 13. Morganti, A. A comparative study on inter and intralaboratory reproducibility of renin measurement with a conventional enzymatic method and a new chemiluminescent assay of immunoreactive renin. J. Hypertens. 2010; 28: 1307-1312. 14. Dorrian, C. A., Toole, B. J., Alvarez-Madrazo, S. et al. A screening procedure for primary aldosteronism based on the Diasorin Liaison automated chemiluminescent immunoassay for direct renin. Ann. Clin. Biochem. 2010; 47: 195-199. 15. Wedatilake, Y. N., Scanlon, M. J., Barnes, S. C. The clinical utility of two renin mass methods to detect primary hyperaldosteronism compared with renin activity. Ann. Clin. Biochem. 2011; 48: 256-262. 16. Manolopoulou, J., Fischer, E., Dietz. A. et al. Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays. J. Hypertens. 2015 Sep 12. [Epub ahead of print] 17. Derlet, F., Lepoutre, T., Gruson, D. Aldosterone testing: evaluation of a novel automated immunoassay. Biomarkers. 2014; 19: 86-91. 18. Nanba, K., Tamanaha, T., Nakao, K., et al. Confirmatory testing in primary aldosteronism. J. Clin. Endocrinol. Metab. 2012; 97: 1688-1694. 19. Brown, M. J. Renin: friend or foe? Heart. 2007; 93: 1026-1033. 20. Laragh, J. H., Sealey, J. E. The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin (R) vasoconstriction to long-term blood pressure. Am. J. Hypertens. 2011; 24: 1164-1180. 21. Schwartz, G. L., Bailey, K., Chapman, A. B., et al. The role of plasma renin activity, age, and race in selecting effective initial drug therapy for hypertension. Am. J. Hypertens. 2013; 26: 957-964.

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IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Dealing with the Problem by Understanding the Physiology and Structure Involved Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

Pressure pushing down on me Pressing down on you1 The late greats: David Bowie & Freddie Mercury

T

HE EFFECT of pressure in a limited space is tension. Blood vessels are an expandable but limited space. Clearly, if tension is too high for too long it will have an effect on the vessels themselves and the organs that the vessels supply. So, in blood pressure, the effect on target organs can be heart failure, kidney failure, liver disease, papilloedoema, strokes and dementia amongst many other issues. One simple way to explain blood pressure to your patients is by comparing it to a thermostat or pressure valve with the wrong setting. In many cases, people do not know that their blood pressure is high but the general practitioner should investigate in case there is a treatable cause and also to monitor any early evidence of target organ damage. Understanding the physiology and structures can lead to a more logical approach to diagnosis, treatment and management.

The Renin-AngiotensinAldosterone System2,3 The kidney can be thought of as a brilliant machine designed do look after itself by ensuring a decent flow of blood so that it can work efficiently, but its core mechanism to do this can go wrong and lead to hypertension. Low flow, low sodium or sympathetic nerve activity (acting through β1-adrenoceptors) triggers a mechanism to reverse low sodium and ensure better flow. This mechanism starts with the release of renin from the juxtaglomerular cells. Renin leads to the release of angiotensin I, which, as its name implies, is an agent to increase the tension in blood vessels. An enzyme then cleaves 2 polypeptides from the 10 of

Complete and fully automated solution for reliable and accurate assesment of hypertension

FEMALE CIRCULATORY SYSTEM

angiotensin I to create the more active angiotensin II. The enzyme that does this is conveniently (if not unimaginatively called) – angiotensin converting enzyme (ACE). The angiotensin II then stimulates the adrenal glands to release aldosterone, which has the actions on the kidney of increasing sodium and fluid retention. Aldosterone also has extrarenal activity of constricting small arteries. Angiotensin II also constricts blood vessels by preventing the nerve reuptake of the hormone norepinephrine as well as facilitating its release from sympathetic nerve endings. Its other actions are to increase systemic vascular resistance and arterial pressure by resistance vessel constriction. It stimulates sodium reabsorption at several renal tubular sites, stimulates thirst centres in the brain and stimulates both cardiac and WWW.PRIMARYCAREREPORTS.CO.UK | 7


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“Once the mechanisms of the Renin-angiotensinaldosterone system were elucidated, answers as to how to deal with hypertension became self-evident”

vascular hypertrophy. It stimulates the release of vasopression (antidiuretic hormone, ADH) from the posterior pituitary, which increase fluid retention by the kidneys. The cause of the low flow or low sodium that triggers this mechanism may be diarrhea, vomiting, excess perspiration, or narrowing of a renal artery. The renin-angiotensin-aldosterone system controls both blood volume and systemic vascular resistance and in this way influences both cardiac output and arterial pressure. Non-renal triggers of the renin-angiotensinaldosterone include the natriuretic peptides released by the heart (ANP and BNP). The natriuretic peptides, ANP and BNP, act as an important counter-regulatory system. Drugs that block the binding of angiotensin II to its receptor can also be used. In parasitology they say that, once you know the life-cycle, you know where to target your intervention. Similarly, once the mechanisms of the rRenin-angiotensin-aldosterone system were elucidated, answers as to how to deal with hypertension became self-evident. One of our biggest successes has been the angiotension converting enzyme inhibitors which, as predicted, reduce blood pressure. Other attack points to reduce blood pressure include:

The Nervous System Renal Nerves The word Guru in Sankrit means the destroyer of darkness and hence the bringer of light. The word Yogi has the same derivation as the English word ‘yoke’ and has the meaning of someone attached or committed to a search for truth. Indian Yogis for many years have challenged Western science with their abilities to control their pulse, breathing and blood pressure but we now know that the nerves to the renal system have a role in controlling blood pressure and that methods of breathing can affect these nerves. Modern science can now use radio-frequency waves delivered by a catheter similar to angiography to control the renal nerves and in this process a treatment for intractable hypertension is now possible. The process is called renal denervation.

In the United States, the Federal Drug Authority (FDA) has approved a device by an Israeli Doctor/ Inventor that, by regulating breathing, has been shown to reduce blood pressure. This appears to be a classic bio-feedback mechanism in which bodily symptoms or signs are controlled by sentient or non-sentient processes4. Research on control of heart rate variability has found that controlling this also has a positive effect on blood pressure5.

The Entero-Salivary Circuit Nitrates in swallowed saliva can lower blood pressure. The saliva can contain highly concentrated levels of bio available nitrate. The exact mechanism for each stage of this phenomenon is still being researched but the implications have significant uses and effects if this circuit is disrupted. Nitrate in food is ingested across the gut wall and whilst most of it (75%) is excreted within 48 hours the remainder gets concentrated in the salivary glands, which then gets reabsorbed, when the saliva is swallowed. Antibiotics can interrupt this process, which requires facultative bacteria to help the transport of nitrate into the salivary glands. This part of the blood pressure mechanism is the probable explanation as to why beetroot juice, fruit and vegetables are beneficial in controlling and managing blood pressure.

Summary Our treatments for blood pressure rely on us understanding the mechanisms for its control or aberrant activity. It is fascinating that some of the non-medication treatments were known thousands of years ago by Ancient Eastern civilisations. These mechanisms rely on the control of breathing and the nervous system. Our drug treatments rely on controlling renin, angiotension I or II, aldosterone, β-Blockers or diuretics. Our surgical treatments require removal of aldosterone or pituitary tumours or dernervating the renal nerves. Our dietary treatments involve increasing bio-available nitrates. Understanding the pathology and physiology of hypertension should make it easier to explain to our patients the problem, the tests, the solutions and the requirement for on-going management.

References: 1. 2. 3.

8 | WWW.PRIMARYCAREREPORTS.CO.UK

http://www.metrolyrics.com/under-pressure-lyrics-queen.html Accessed 7/2/16 http://www.britannica.com/science/renin-angiotensin-system Accessed 9/2/16 http://www.cvphysiology.com/Blood%20Pressure/BP015.htm Accessed 9/2/16

4.

http://www.ncbi.nlm.nih.gov/pubmed/9178345 Accessed 9/2/16

5.

https://www.heartmath.org/assets/uploads/2015/01/hrv-biofeedback.pdf Accessed 9/2/16


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Secondary Causes of Hypertension Sophie Levingworth, Medical Correspondent

S

ADLY, IN most cases, we do not know the reason for a person’s hypertension, but this does not stop us searching for a known or treatable cause. If the problem is structural, such as co-arctation of the aorta1 or mid-aortic syndrome2 the clues usually appear early because of associated valve issues or heart wall defects. Endocrine causes must be excluded. High aldosterone levels may be because of a primary or secondary cause. In primary hyperaldosteronism3 also known as Conn’s Syndrome4, a tumour or bilateral hyperplasia in the adrenal gland(s) secretes excess amounts. These cases may represent up to 5% of all causes of hypertension and even higher levels in those with resistant hypertension. New tests for renin and aldosterone will allow faster diagnoses in this area. If the problem is an adrenal tumour, this requires surgical removal, but if the problem is adrenal hyperplasia, then medical treatment is required. Very rarely aldosterone can be produced by an ectopic source such as tumours of the kidney or ovaries. Secondary causes of raised aldosterone are those that are non-pituitary and are outside of the adrenal gland. Amongst these are causes of renal artery stenosis and hypovolaemia. The hypersecretion of aldosterone is caused by reduced renal blood flow, which can occur with atheroma, stenosis, renal vasoconstriction (as occurs in accelerated hypertension), and oedematous disorders (e.g., heart failure, cirrhosis with ascites, nephrotic syndrome). Pheochromocytoma5 as a tumour, which may be benign or malignant (10%), leads to intermittent excess catecholamine release and will, in at least 50% of cases, feature severe hypertension. Clinical history and testing will lead to the diagnosis and subsequent surgical removal. Growth hormone excess from the pituitary gland in adulthood leads to acromegaly6 and hypertension may be a presenting feature if the practitioner does not note the facial coarseness and enlarged shoe or hand size.

Cushing’s syndrome7 is an obvious endocrine cause as are both hyperthyroidism and hyperparathyroidism.

Kidney Related Causes of Hypertension It is always important to work out via the history and family history whether your patient may have renovascular disease, polycystic kidneys, glomerulonephritis, a renin secreting tumour or a specific syndrome such as Liddle’s8 (a genetic and structural defect of the epithelial sodium channels) or Gordon’s9.

Complete and fully automated solution for reliable and accurate assesment of hypertension

Neurological and Respiratory Causes of Hypertension Hypertension can cause strokes but interestingly strokes (whether haemorrhagic or ischaemic) can cause hypertension as can intracranial masses, traumatic brain injury and brainstem neurovascular compression.

CT SCAN OF BRAIN SHOWS ISCHEMIC STROKE OR HEMORRHAGIC STROKE

The main respiratory cause is obstructive sleep apnea.

Medication, Gestational Hypertension Pre-eclampsia and Diet Causes of Hypertension The role of glucocorticoids in hypertension is well known as is that of some oral contraceptive pills. However, caution is also required with drugs, Nonsteroidal anti-inflammatory drugs, WWW.PRIMARYCAREREPORTS.CO.UK | 9


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“Very rarely aldosterone can be produced by an ectopic source such as tumours of the kidney or ovarie”

COX-2 inhibitors10, calcineurin inhibitors 11, antidepressants (MAOIs, venlafaxine), VEGF inhibitors 12, sympathomimetics (including recreational drugs like cocaine and amphetamines) and alcohol. Excess salt consumption is a well-known and well-established cause but many may not know that excess liquorice consumption can have the same effect. Pregnancy related hypertension will be selfevident by regular measurement and observation.

Summary The GP should always keep in mind that, although the majority of hypertension patients have no current known reason, there are causes and these should be looked for. Ideally renin and aldosterone should both be measured. A questionnaire for your patient could include: Are there any family related causes of hypertension? Has any family member, friend or colleague complained about your snoring at night and do you think you get a normal night’s sleep? (obstructive sleep apnea) Have you or your family members had any kidney related diseases? Do you get flushing attacks, facial redness or feelings of impending doom? (pheochromocytoma) Have you noticed any centralised obesity, unexpected stretchmarks? (Cushing’s Disease or steroids) In your diet are you aware of your salt intake? Do you have any recreational drug activity that you would like to disclose?

Let’s calculate your weekly alcohol consumption. Have you noticed any coarsening of your facial features or a need for bigger sized gloves or shoes in adulthood? (growth hormone/ acromegaly) As a woman, do any of your symptoms fit with polycystic ovary disease or pregnancy? When we review your medication, I am particularly interested in the following (steroids, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, calcineurin inhibitors, antidepressants (MAOIs, venlafaxine), VEGF inhibitors, sympathomimetics (including recreational drugs) and alcohol), any of which could cause or aggravate hypertension In my tests I will look at your blood, urine and the current state of your heart by an electrocardiogram (ECG). The latter will tell me if your heart has enlarged, if you have any evidence of ischemia or an abnormal heart rhythm. The urine test will tell me if there are any obvious signs of kidney disease as indicated by excess protein or glucose. The blood test will tell me if your sodium, potassium and creatinine levels are normal but, most importantly, in combination with your urine I can measure the proficiency of your kidney function (eGFR). With more advanced tests my laboratory can look at your renin and aldosterone balance. Once you are on treatment we can look at the renin level to check that you are on the right medication. With the above questions, examination and resources tool kit of The National Institute for Health and Care Excellence (NICE) guidance and relevant websites (www.bloodpressureuk. org, Change4Life13, www.actiononsalt.org.uk, www.actiononsugar.org) the GP is well armed to help their patient identify and manage secondary causes of hypertension.

References: 1.

http://emedicine.medscape.com/article/895502-overview#a3 Accessed 13/2/16

2.

http://www.ncbi.nlm.nih.gov/pubmed/16273154 Accessed 13/2/16

3.

http://emedicine.medscape.com/article/127080-overview Accessed 13/2/16

4.

http://rarediseases.org/rare-diseases/conn-syndrome/ Accessed 13/2/16

5.

http://emedicine.medscape.com/article/124059-overview Accessed 13/2/16

6.

http://www.niddk.nih.gov/health-information/health-topics/endocrine/acromegaly/Pages/fact-sheet.aspx Accessed 13/2/16

7.

https://www.nlm.nih.gov/medlineplus/ency/article/000410.htm Accessed 13/2/16

8.

http://ghr.nlm.nih.gov/condition/liddle-syndrome Accessed 16/2/16

9.

http://rarediseases.org/rare-diseases/gordon-syndrome/ Accessed 16/2/16

10.

http://www.drugs.com/drug-class/calcineurin-inhibitors.html Accessed 17/2/16

12.

http://www.drugs.com/drug-class/vegf-vegfr-inhibitors.html Accessed 17/2/16

13.

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http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm429364.htm Accessed 17/2/16

11.

https://www.nhs.uk/change4life-beta/campaigns/sugar-smart/home?gclid=CMWZtezO_soCFRYTGwodB-cCeQ&gclsrc=aw.ds Accessed 17/2/16


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Salt, Culture and Hypertension Sophie Levingworth, Medical Correspondent

I

F DISEASES had villains, salt would be one of the villains in the hypertension story and societal prejudice might be another. The excellent journalist and author, Mark Kurlansky, wrote an enlightening book on the history of ‘Salt’1. He tells us that salt was so important to the Roman legions that that is where we get the word ‘salary’ from because they were ‘paid’ partly in salt. Humans need salt but not too much of it and sadly we take excess amounts sometimes without being aware of doing so. Those who are unaware will be surprised about the salt content of many foods, some of which are misleadingly labelled as healthy. The scale of this problem prompted Queen Mary’s University Professor Graham MacGregor, to set up a public information website and campaign2. This incredibly useful resource informs us that we only need 6g salt per day (equivalent to a teaspoon) but we average more than 8g3. It explains that the salt content may be high in food items that we think of as sweet such as pastry, cakes, cheesecake, and ice cream. Interestingly, physiologically we have different salt requirements and there can be an 8-fold variation in sodium output after heavy exercise.

Adults should eat no more than 6g of salt a day, and children even less. Reducing the UK’s average daily salt intake for adults to 6g could prevent about 17,500 deaths from heart attacks and strokes a year4. This matters because if too little sodium is replaced it leads to cramps, fatigue and decreased sporting performance.

Dietary Types and Culture

Complete and fully automated solution for reliable and accurate assesment of hypertension

The Chinese are famous for their salty ‘Soy Sauce’ and the African-Caribbean’s have many salt based dishes. Culturally specific healthy nutrition advice is a challenge worth pursuing5.

Why do Some Cultures Have Higher Levels of Hypertension? The fact is that African-Caribbeans in the same environment as non-African-Caribbeans have higher rates of hypertension. One theory for this is ‘The slavery hypothesis’, which essentially postulates a form of genetic selection amongst those who survived the awful and inhuman conditions of the Middle Passage.

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IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“We need to help people understand the harms caused by excess salt intake and help them reduce their daily amounts”

Those genetically better able to preserve salt and water were more likely to survive and these genetic traits then got passed on in subsequent generations over the last 300 years or so. It is the sort of theory that may never be proved or disproved. Other considerations as to whether genes play a role in African-Caribbeans’ hypertension hit several walls that throw significant doubt on the plausibility of such factors. The first is raised by what is ‘race’ and the second by the nature of genes themselves. Race is not genetics and, as the American Anthropological Association6 states: “...human biological variations should not be reduced to race. It is too complex and does not fit this outdated idea. Race is real. Rather than being based on biology, it is a social and political process that provides insights into how we read deeper meaning into phenotypes. Racialization and racism come about because, in a racialized culture, we read meaning into skin color and other phenotypic variants. Rather than biology affecting behavior, ideology and behavior affect individuals ‘under the skin.’ In the gene debate, the rising science of epigenetics7 has helped us realise that genes themselves are not as important as which ones are switched on and which ones are switched off. The factors that affects these switches are situational and environmental. It is fair now to say

that we should not talk of nature or nurture but of nature and nurture or as author Matt Ridley puts it nature via nurture8. ‘We talk about DNA as if it’s a template, like a mould for a car part in a factory… But DNA isn’t really like that. It’s more like a script. …Identical starting points, different outcomes.’ Author Nessa Carey in The Epigenetics Revolution9 So we have the interesting possibility that skin colour, which is not genetics, may correlate with increased blood pressure, not because of any significant genetic differences but because of how people are treated or how they feel they are treated by others and the system around them – the tension may be a societal one, which as might be expected, could lead to rises in blood pressure amongst a marginalised and discriminated group of people.

Summary We need to help people understand the harms caused by excess salt intake and help them reduce their daily amounts. Also, at a societal level, we need to help people feel less ‘tension’ and have ways of successfully managing life stress. Meditation clearly has benefits for some and Apps like ‘Headspace’ have had some noteworthy organisational endorsements as well as anecdotal reports of benefit.

References: 1.

http://www.actiononsalt.org.uk/salthealth/index.html Accessed 16/2/16

3.

12 | WWW.PRIMARYCAREREPORTS.CO.UK

http://www.amazon.co.uk/Salt-World-History-Mark-Kurlansky/dp/0099281996 Accessed 11/2/16 http://www.actiononsalt.org.uk/resources/ordering/125232.pdf Accessed 11/2/16

2.

4.

http://www.maturetimes.co.uk/week-salt-awareness-week/

5.

http://www.healthywestafrican.com/index-1.html Accessed 16/2/16

6.

http://www.americananthro.org/ Accessed 11/2/16

7.

http://www.whatisepigenetics.com/fundamentals/ Accessed 16/2/16

8.

http://tiny.cc/28dd9x Accessed 16/2/16

9.

http://www.amazon.com/The-Epigenetics-Revolution-Understanding-Inheritance/dp/0231161174 Accessed 16/2/16


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

The Pro-Active General Practitioner – Detecting, Managing and Treating Hypertension in the Community with MultiDisciplinary Help Dr Charles Easmon MBBS MRCP MSc Public Health DTM&H DOccMed, Editor

A

MONGST YOUR adult patients at least a quarter will have hypertension1 – overall it is the second biggest risk factor for death and disability amongst all your patients. Unfortunately, only 40% of your patients with hypertension are aware of it and are receiving adequate treatment (a problem that therefore affects 1 in 10 of your total adult population). Sadly, these problems disproportionately affect those from deprived social backgrounds and your African and Caribbean communities. Prevention could save life, disability and money. To some extent, hypertension is the invisible enemy in your adult patient population. It makes sense to use every visit as an opportunity to detect and manage it. However, for those amongst your community who do not visit the practice, other strategies are required, especially since the National Health Service (NHS) is not designed around the working person in terms of hours and accessibility. Many men boast of not having seen their doctor for years.

patient to buy or borrow their own reliable blood pressure measuring device3. A stroke or heart attack victim aged in their 50s and their family is in no way consoled by the fact that many years before, everyone thought that they just had ‘white coat hypertension’.

Complete and fully automated solution for reliable and accurate assesment of hypertension

Sugar and Salt Obesity is known to increase the risk of hypertension by three times in men and four times in women. Doctors and practice staff ideally would set an example in terms of their own lifestyle and well-being but, sadly, this is often not the case and it is hard for an obese nurse to advise an obese patient with any degree of credibility. However, the key message of obesity reduction and prevention should be readily available and promoted to all of your patients. Additional advice on sugar avoidance and reduction is available via websites such as Action on Sugar 4.

Real or ‘White Coat Hypertension’? A common problem amongst those who visit the practice is the phenomenon we know as ‘white coat hypertension’2, which raises the question ‘is the hypertension real or just an anxious state bought about by a visit to the doctor?’ If this is real hypertension, the problems many years later are self-evident and are a preventable tragedy. Every GP should be very cautious with these cases and ensure that there is some objective measure of normal blood pressure, even if this requires the

Excess salt intake is well known to increase the risk of blood pressure. Advice to your patients is available through websites such as Consensus Action on Salt and Health5. WWW.PRIMARYCAREREPORTS.CO.UK | 13


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

“A stroke or heart attack victim aged in their 50s and their family is in no way consoled by the fact that many years before, everyone thought that they just had ‘white coat hypertension’”

Regular Testing Constructive strategies to address hypertension amongst your GP population include: Encouraging everybody to get their blood pressure checked at least every 5 years as with Quality and Outcomes Framework (QOF) guidelines6. In addition, the charity BloodPressureUK have a successful ‘Know your Numbers’ 7 campaign which helps push testing out to where the people are i.e. pharmacies and even pubs! Companies could also be pro-active in encouraging their staff to have their blood pressure checked8 and as a GP you may be able to give a talk or presentation to a business group or network to encourage this. In 1971 Julian Tudor Hart first explained his concept of the ‘Inverse care law”9,10 in which those with the least need get the best out of their GP practice. Targeting those from the deprived social groups and any African-Caribbeans in your community is a duty and an opportunity that could be delegated to the practice staff under your supervision.

Professor Graham MacGregor’s Initiatives Resources that can help in these areas include Change4Life11 and the already mentioned Action on Sugar and Action on Salt12. These last two are the initiative of Professor Graham MacGregor, a Professor of Cardiovascular Medicine at the Wolfson Institute of Preventive Medicine, Queen Mary, University of London and Honorary Consultant Physician at Barts and The London Hospital. He is also a visiting Professor at St George’s Hospital Medical School, London. This inspiring clinician trained as a nephrologist but became interested in blood pressure control mechanisms, particularly related to the renin-angiotensin system, the mechanisms whereby salt puts up blood pressure. He has published more than 400 scientific articles on various aspects of blood pressure and cardiovascular medicine. In 1996 he set up an action group on salt, Consensus Action on Salt and Health, to try and get the food industry to add less salt to food and thereby get a reduction in salt intake. This was very successful and resulted in the Food Standards Agency taking on the task of salt reduction. The UK is now leading the world in salt reduction. He later set up World Action on Salt and Health, Blood Pressure UK, and most recently, Action on Sugar, an

14 | WWW.PRIMARYCAREREPORTS.CO.UK

action group which aims to reduce added sugar in foods and soft drinks in the same way as has been done with salt.

Other Help is at Hand The General Practitioner cannot and does not need to do it all for hypertension. Community groups can and should be encouraged to arrange blood pressure tests using all available resources. These should be supplemented by access to reliable laboratories that can test for both renin and aldosterone and thus detect those cases of primary aldosteronism. Communities and work places can be encouraged to deal with lifestyle factors like weight loss, smoking, excess alcohol consumption and the relief of stress. Specific communities such as African-Caribbeans can be especially encouraged in all these areas.

The Role of the GP Once a case of hypertension is identified, the GP’s role includes monitoring for complications to target organs13. The urine test for kidney damage is relatively simple as is the test for damage to the retina. For both of these, near patient testing solutions may make life even easier (i.e. PEEK for eyes). The GP should also advise on drug and non-drug management of hypertension. For those vehemently against drugs, options that involve bio-feedback such as the Resperate14 device can be considered as long as the Blood Pressure is monitored and maintained below 140/90 in those under 80 and 150/90 in those aged 80 and above. Such devices use controlled breathing to manage the autonomic nervous system15. Some of your patients may benefit from daily beetroot juice16. Those who need and accept medication will be guided by the National Institute for Clinical and Care Excellence (NICE) guidelines. The three key agents of ACE inhibitors, β-blockers and diuretics may be needed in combination in those with resistant hypertension. For some, the surgical solution of renal denervation17 may be the answer to their resistant hypertension. In summary, The GP and the community can work together to deal with the otherwise invisible threat of adult hypertension. The task is to be a better detective than the fictional Sherlock Holmes created by our medical colleague Sir Arthur Conan Doyle.


IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

References: 1.

https://www.gov.uk/government/publications/high-blood-pressure-action-plan Accessed 16/2/16

2.

http://pathways.nice.org.uk/pathways/hypertension/management-of-hypertension#content=view-node:nodes-blood-pressure-targets Accessed 16/2/16

http://www.bloodpressureuk.org/BloodPressureandyou/Homemonitoring/Choosingyourmonitor Accessed 16/2/16

3.

4.

http://www.bma.org.uk/qofguidance Accessed 16/2/16

6.

7.

http://www.actiononsugar.org/ Accessed 16/2/16

http://www.actiononsalt.org.uk/?gclid=CPiq0YXw-8oCFVIW0wodXmwIJQ Accessed 16/2/16

5.

8.

9.

http://www.bloodpressureuk.org/microsites/kyn/Home Accessed 16/2/16

http://circ.ahajournals.org/content/130/8/719/T3.expansion.html Accessed 16/2/16 http://www.sochealth.co.uk/national-health-service/public-health-and-wellbeing/poverty-and-inequality/the-inverse-care-law/ Accessed 16/2/16

10.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(71)92410-X/abstract Accessed 16/2/16

11.

https://www.nhs.uk/change4life-beta/campaigns/sugar-smart/home?gclid=CL_gspj8-8oCFVG6Gwod_tsMsQ&gclsrc=aw.ds Accessed 16/2/16

12.

13.

14.

http://www.actiononsalt.org.uk/resources/ordering/125232.pdf Accessed 16/2/16 http://pathways.nice.org.uk/pathways/hypertension#content=view-quality-statement%3Aquality-statements-investigations-for-target-organ-damage Accessed 16/2/16 http://bhsoc.org/pdfs/Statement%20on%20RESPeRATE%20April%2012.pdf Accessed 16/2/16

15.

http://www.resperate.com/who-we-are Accessed 16/2/16

16.

http://www.qmul.ac.uk/media/news/items/smd/146262.html Accessed 16/2/16

17.

http://www.dailymail.co.uk/health/article-2187913/Nerve-tingler-operation-cuts-blood-pressure-available-NHS.html Accessed 16/2/16

Complete and fully automated solution for reliable and accurate assesment of hypertension

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IMPROVING THE DIAGNOSIS AND TREATMENT OF HYPERTENSION

Notes:

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Primary Care Reports – improving the Diagnosis & Treatment of Hypertension – Diasorin Limited  

Improving the Diagnosis and Treatment of Hypertension

Primary Care Reports – improving the Diagnosis & Treatment of Hypertension – Diasorin Limited  

Improving the Diagnosis and Treatment of Hypertension