Journal of Human Hypertension (2015) 29, 7–8 & 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15 www.nature.com/jhh
COMMENTARY
High normal blood pressure: to treat or not to treat? A Ahmed1 and R Senior1,2 Journal of Human Hypertension (2015) 29, 7–8; doi:10.1038/ jhh.2014.24; published online 17 April 2014
High blood pressure (BP) remains the most common, readily identifiable and reversible risk factor for cardiovascular disease, stroke and death. Considering the enormous costs involved, it remains imperative to identify and implement effective approaches to achieve optimal control of this condition. However, any BP level used to define normal or high BP is arbitrary indeed. The view that BP is a continuous variable with no specific separation between normal and abnormal values was not always accepted, until a long and famous debate between Sir George Pickering and Lord Robert Platt in 1950s.1 The general consensus was that Pickering won and the unimodal rather than bimodal distribution holds sway. In clinical practice, however, cut-off BP values are universally accepted to simplify management even though epidemiologic data shows continuous, graded and etiologically significant positive relationship with cardiovascular outcome, even with BP values as low as 115/75 mm Hg.2 Thus, this artificial dichotomy between hypertension and normotension could prove detrimental and cause delay in medical treatment, irreversibly compromising vascular health by BP values considered to be normal. The recent 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for hypertension have proposed seven categories of BP levels.3 High normal BP (defined as systolic BP of 130–139 mm Hg and/or diastolic BP 85–89 mm Hg) has been shown to be associated not only with increased risk of developing hypertension4,5 but also with risk of cardiovascular disease6 including atrial fibrillation.7 Prospective data from the Women’s Health Study8 also suggest that BP in the high normal range confers substantially higher risk of major cardiovascular events and incident hypertension than normal BP. In this issue of the JHH, Ueda et al. present interesting and methodological data from a prospective cohort elucidating the possible relation between high normal BP and evidence of organ damage represented by new-onset left ventricular hypertrophy (LVH) on electrocardiography (ECG). The authors, having examined 44000 subjects 3 years apart, conclude that high normal BP was related to new-onset LVH, a 42-fold higher risk compared with optimal BP, a finding that remained independent in multivariate analyses. This is thought provoking and at the same time complementing the results from previous studies that high normal BP is not entirely benign. The results as well suggest that the occurrence of target organ damage (LVH) with BP currently considered to be below the threshold for treatment could represent an early marker of future cardiovascular risk, and identifying these patients could help direct preventive strategies. The authors have used office BP to classify subjects into four different categories: optimal BP, normal BP, high normal BP and hypertension. Categorizing subjects on the basis of single office BP reading has its limitations. Out-of-office BP monitoring, using
home or ambulatory BP monitor, is a more reliable assessment of actual BP and closely related to hypertension-induced organ damage. It is possible that subjects with high normal office BP could have BP in the optimal or normal range—that is, ‘true normotensives’. At the same time, we do not know how many of the normal and high normal subjects are having masked hypertension, the prevalence of which ranges from 10% to 17% in population-based studies.9 Moreover, the prevalence of masked hypertension is higher when office BP is in the high normal range.10 The fact that masked hypertension is largely undetected and untreated may have contributed to the findings in the present study. One of the strengths of this study is the use of a basic investigational tool available to all physicians, including those in the primary care. Undoubtedly, ECG remains the cheapest, most readily available and forms part of routine assessment especially in population at increased cardiovascular risk. Ueda et al. have remarkably used ECG to mark their observation; however, at the same time it remains the weakest link in the chain of evidence put forward. As the master investigator, Sherlock Holmes once said to his friend ‘Watson! No chain is stronger than its weakest link’; the ECG remains too insensitive to be used alone to screen for LVH,11 although it may be still valuable in patients over 55 years of age where the prevalence of heart disease is higher. Over the years, many different criteria have been proposed for electrocardiographic LVH; most well known are the Cornell voltage, the Sokolow–Lyon index and the Romhilt–Estes point score system. Most of these criteria have been developed for populations with a high prevalence of heart disease. The Bayes theorem predicts that these criteria would result in a high incidence of false-positive ECG interpretation in populations with a low prevalence of heart disease. Whereas the specificity is acceptable for all, the sensitivity is too low to be used alone for screening; the median sensitivity being 19.5, 21 and 17%.11 Despite its limitations, ECG still has a role in the management of hypertension. Several studies have shown that regression of electrocardiographic LVH is associated with the reduction in cardiovascular risk12,13 as well as with the decrease in the incidence of new-onset diabetes mellitus,14 atrial fibrillation15 and hospitalization for heart failure.16 These results suggest that ECG may be useful to monitor antihypertensive therapy akin to use of HaA1c in diabetic patients. The study by Ueda et al. goes further to suggest that ECG screening could potentially be used to assess target organ damage in individuals with BP in the range not currently considered for pharmacologic therapy. As the current evidence is at best scanty, the 2013 ESH/ESC3 guidelines do not recommend antihypertensive treatment with BP in the high normal range (130–139/85–89 mm Hg), even in patients with high risk due to diabetes, concomitant cardiovascular or renal disease. It can, however, be recommended that subclinical organ damage either in the form of microalbuminuria or LVH could support initiation of pharmacologic therapy in these patients. At the same time, it remains to be proven whether early intervention can delay
1 Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK and 2Department of Cardiology and Echocardiography Laboratory, Royal Brompton Hospital, Biomedical Research Unit, National Heart and Lung Institute, Imperial College, London, UK. Correspondence: Professor R Senior, Department of Cardiology and Echocardiography Laboratory, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: [email protected]
Commentary
8 events and be cost-effective as the current evidence is limited to couple of studies only.17,18 Further trials need to be completed before firm recommendations can be given. Finally, it would be interesting to see whether echocardiographic evidence of increased left ventricular mass index is also demonstrated in patients with new-onset electrocardiographic LVH. We would suggest the authors to follow-up the patients with echocardiographic data to complement their results. As the authors rightly conclude that BP even below the hypertension range does not guarantee freedom from the organ damage, doors remain open for further research to precisely estimate the prevalence of LVH at varying levels of BP and also define the optimal test that will not only be sensitive but also cost-effective for general screening. Needless to say, for all persons with or without hypertension, the benefit of healthy diet, weight control and regular exercise cannot be overemphasized. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Swales JD. Platt versus Pickering. An Episode in Recent Medical History, Vol. 8. Keynes Press (British Medical Association), London; 1985, pp. vii, 155. 2 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913. 3 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M 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 the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281–1357. 4 Leitschuh M, Cupples LA, Kannel W, Gagnon D, Chobanian A. High-normal blood pressure progression to hypertension in the Framingham Heart Study. Hypertension 1991; 17(1): 22–27. 5 Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001; 358: 1682–1686. 6 Vasan R, Larsen MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB et al. Impact of high normal blood pressure on the risk of cardiovascular disease. New Engl J Med 2001; 345: 1291–1297.
Journal of Human Hypertension (2015) 7 – 8
7 Grundvold I, Skretteberg PT, Liestol K, Erikssen G, Kjeldsen SE, Arnesen H et al. Upper normal blood pressure predict incident atrial fibrillation in healthy middle aged men: a 35-year follow-up study. Hypertension 2012; 59: 198–204. 8 Conen D, Ridker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. BMJ 2007; 335: 432. 9 Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: meta analysis. J Hypertens 2007; 25: 2193–2198. 10 Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008; 26: 1715–1725. 11 Pewsner D, Juni P, Egger M, Battaglia M, Sundstorm J, Bachmann LM. Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review. BMJ 2007; 335: 711. 12 Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q et al. Heart Outcomes Prevention Evaluation (HOPE) investigators. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001; 104: 1615–1621. 13 Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004; 292: 2350–2356. 14 Okin PM, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Lindholm LH et al. In-treatment resolution or absence of electrocardiographic left ventricular hypertrophy is associated with decreased incidence of new-onset diabetes mellitus in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Hypertension 2007; 50: 984–990. 15 Okin PM, Wachtell K, Devereux RB, Harris KE, Jern S, Kjeldsen SE et al. Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation in patients with hypertension. JAMA 2006; 296: 1242–1248. 16 OKin PM, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Julius S et al. Regression of electrocardiographic left ventricular hypertrophy is associated with less hospitalization for heart failure in hypertensive patients. Ann Intern Med 2007; 147: 311–319. 17 Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Karioti N et al. Feasibility of treating prehypertension with an angiotensin receptor blocker. New Engl J Med 2006; 354: 1685–1697. 18 Luders S, Schrader J, Berger J, Unger T, Zidek W, Bohn M et al. The PHARAOStudy: prevention of hypertension with the angiotensin converting enzyme inhibitor ramipril in patients with high normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens 2008; 26: 1487–1496.
& 2015 Macmillan Publishers Limited
Copyright of Journal of Human Hypertension is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
COMMENTARY
High normal blood pressure: to treat or not to treat? A Ahmed1 and R Senior1,2 Journal of Human Hypertension (2015) 29, 7–8; doi:10.1038/ jhh.2014.24; published online 17 April 2014
High blood pressure (BP) remains the most common, readily identifiable and reversible risk factor for cardiovascular disease, stroke and death. Considering the enormous costs involved, it remains imperative to identify and implement effective approaches to achieve optimal control of this condition. However, any BP level used to define normal or high BP is arbitrary indeed. The view that BP is a continuous variable with no specific separation between normal and abnormal values was not always accepted, until a long and famous debate between Sir George Pickering and Lord Robert Platt in 1950s.1 The general consensus was that Pickering won and the unimodal rather than bimodal distribution holds sway. In clinical practice, however, cut-off BP values are universally accepted to simplify management even though epidemiologic data shows continuous, graded and etiologically significant positive relationship with cardiovascular outcome, even with BP values as low as 115/75 mm Hg.2 Thus, this artificial dichotomy between hypertension and normotension could prove detrimental and cause delay in medical treatment, irreversibly compromising vascular health by BP values considered to be normal. The recent 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for hypertension have proposed seven categories of BP levels.3 High normal BP (defined as systolic BP of 130–139 mm Hg and/or diastolic BP 85–89 mm Hg) has been shown to be associated not only with increased risk of developing hypertension4,5 but also with risk of cardiovascular disease6 including atrial fibrillation.7 Prospective data from the Women’s Health Study8 also suggest that BP in the high normal range confers substantially higher risk of major cardiovascular events and incident hypertension than normal BP. In this issue of the JHH, Ueda et al. present interesting and methodological data from a prospective cohort elucidating the possible relation between high normal BP and evidence of organ damage represented by new-onset left ventricular hypertrophy (LVH) on electrocardiography (ECG). The authors, having examined 44000 subjects 3 years apart, conclude that high normal BP was related to new-onset LVH, a 42-fold higher risk compared with optimal BP, a finding that remained independent in multivariate analyses. This is thought provoking and at the same time complementing the results from previous studies that high normal BP is not entirely benign. The results as well suggest that the occurrence of target organ damage (LVH) with BP currently considered to be below the threshold for treatment could represent an early marker of future cardiovascular risk, and identifying these patients could help direct preventive strategies. The authors have used office BP to classify subjects into four different categories: optimal BP, normal BP, high normal BP and hypertension. Categorizing subjects on the basis of single office BP reading has its limitations. Out-of-office BP monitoring, using
home or ambulatory BP monitor, is a more reliable assessment of actual BP and closely related to hypertension-induced organ damage. It is possible that subjects with high normal office BP could have BP in the optimal or normal range—that is, ‘true normotensives’. At the same time, we do not know how many of the normal and high normal subjects are having masked hypertension, the prevalence of which ranges from 10% to 17% in population-based studies.9 Moreover, the prevalence of masked hypertension is higher when office BP is in the high normal range.10 The fact that masked hypertension is largely undetected and untreated may have contributed to the findings in the present study. One of the strengths of this study is the use of a basic investigational tool available to all physicians, including those in the primary care. Undoubtedly, ECG remains the cheapest, most readily available and forms part of routine assessment especially in population at increased cardiovascular risk. Ueda et al. have remarkably used ECG to mark their observation; however, at the same time it remains the weakest link in the chain of evidence put forward. As the master investigator, Sherlock Holmes once said to his friend ‘Watson! No chain is stronger than its weakest link’; the ECG remains too insensitive to be used alone to screen for LVH,11 although it may be still valuable in patients over 55 years of age where the prevalence of heart disease is higher. Over the years, many different criteria have been proposed for electrocardiographic LVH; most well known are the Cornell voltage, the Sokolow–Lyon index and the Romhilt–Estes point score system. Most of these criteria have been developed for populations with a high prevalence of heart disease. The Bayes theorem predicts that these criteria would result in a high incidence of false-positive ECG interpretation in populations with a low prevalence of heart disease. Whereas the specificity is acceptable for all, the sensitivity is too low to be used alone for screening; the median sensitivity being 19.5, 21 and 17%.11 Despite its limitations, ECG still has a role in the management of hypertension. Several studies have shown that regression of electrocardiographic LVH is associated with the reduction in cardiovascular risk12,13 as well as with the decrease in the incidence of new-onset diabetes mellitus,14 atrial fibrillation15 and hospitalization for heart failure.16 These results suggest that ECG may be useful to monitor antihypertensive therapy akin to use of HaA1c in diabetic patients. The study by Ueda et al. goes further to suggest that ECG screening could potentially be used to assess target organ damage in individuals with BP in the range not currently considered for pharmacologic therapy. As the current evidence is at best scanty, the 2013 ESH/ESC3 guidelines do not recommend antihypertensive treatment with BP in the high normal range (130–139/85–89 mm Hg), even in patients with high risk due to diabetes, concomitant cardiovascular or renal disease. It can, however, be recommended that subclinical organ damage either in the form of microalbuminuria or LVH could support initiation of pharmacologic therapy in these patients. At the same time, it remains to be proven whether early intervention can delay
1 Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, UK and 2Department of Cardiology and Echocardiography Laboratory, Royal Brompton Hospital, Biomedical Research Unit, National Heart and Lung Institute, Imperial College, London, UK. Correspondence: Professor R Senior, Department of Cardiology and Echocardiography Laboratory, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: [email protected]
Commentary
8 events and be cost-effective as the current evidence is limited to couple of studies only.17,18 Further trials need to be completed before firm recommendations can be given. Finally, it would be interesting to see whether echocardiographic evidence of increased left ventricular mass index is also demonstrated in patients with new-onset electrocardiographic LVH. We would suggest the authors to follow-up the patients with echocardiographic data to complement their results. As the authors rightly conclude that BP even below the hypertension range does not guarantee freedom from the organ damage, doors remain open for further research to precisely estimate the prevalence of LVH at varying levels of BP and also define the optimal test that will not only be sensitive but also cost-effective for general screening. Needless to say, for all persons with or without hypertension, the benefit of healthy diet, weight control and regular exercise cannot be overemphasized. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Swales JD. Platt versus Pickering. An Episode in Recent Medical History, Vol. 8. Keynes Press (British Medical Association), London; 1985, pp. vii, 155. 2 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913. 3 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M 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 the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281–1357. 4 Leitschuh M, Cupples LA, Kannel W, Gagnon D, Chobanian A. High-normal blood pressure progression to hypertension in the Framingham Heart Study. Hypertension 1991; 17(1): 22–27. 5 Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001; 358: 1682–1686. 6 Vasan R, Larsen MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB et al. Impact of high normal blood pressure on the risk of cardiovascular disease. New Engl J Med 2001; 345: 1291–1297.
Journal of Human Hypertension (2015) 7 – 8
7 Grundvold I, Skretteberg PT, Liestol K, Erikssen G, Kjeldsen SE, Arnesen H et al. Upper normal blood pressure predict incident atrial fibrillation in healthy middle aged men: a 35-year follow-up study. Hypertension 2012; 59: 198–204. 8 Conen D, Ridker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. BMJ 2007; 335: 432. 9 Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: meta analysis. J Hypertens 2007; 25: 2193–2198. 10 Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008; 26: 1715–1725. 11 Pewsner D, Juni P, Egger M, Battaglia M, Sundstorm J, Bachmann LM. Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review. BMJ 2007; 335: 711. 12 Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q et al. Heart Outcomes Prevention Evaluation (HOPE) investigators. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 2001; 104: 1615–1621. 13 Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004; 292: 2350–2356. 14 Okin PM, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Lindholm LH et al. In-treatment resolution or absence of electrocardiographic left ventricular hypertrophy is associated with decreased incidence of new-onset diabetes mellitus in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Hypertension 2007; 50: 984–990. 15 Okin PM, Wachtell K, Devereux RB, Harris KE, Jern S, Kjeldsen SE et al. Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation in patients with hypertension. JAMA 2006; 296: 1242–1248. 16 OKin PM, Devereux RB, Harris KE, Jern S, Kjeldsen SE, Julius S et al. Regression of electrocardiographic left ventricular hypertrophy is associated with less hospitalization for heart failure in hypertensive patients. Ann Intern Med 2007; 147: 311–319. 17 Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Karioti N et al. Feasibility of treating prehypertension with an angiotensin receptor blocker. New Engl J Med 2006; 354: 1685–1697. 18 Luders S, Schrader J, Berger J, Unger T, Zidek W, Bohn M et al. The PHARAOStudy: prevention of hypertension with the angiotensin converting enzyme inhibitor ramipril in patients with high normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens 2008; 26: 1487–1496.
& 2015 Macmillan Publishers Limited
Copyright of Journal of Human Hypertension is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
