blood pressure components in clinical hypertension

VOL. 8 NO. 9 SEPTEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION 659

This review offers a critical evaluation of the remarkable progress in antihypertensive therapy since its inception. Despite the introduction of newer, more sophisticated drugs, treatment results have remained stable. Problems impeding further improvement include limited patient compliance, clinical inertia, incomplete adherence to guide-lines, and dependence on brachial artery cuff pres-sures for diagnosis, risk assessment, and treatment response. Brachial artery systolic and pulse pres-sures do not reliably represent aortic or carotid artery pressures, which are better risk predictors for the heart and brain. Mean pressure, which is the same throughout the arterial tree, is directly measurable by cuff oscillometry, and might become the best single risk predictor. Available drugs have limited ability to decrease the aortic stiffness that is responsible for the elevated systol-ic blood pressure of aging. Therefore, to improve risk assessment and therapeutic benefit, we might include mean blood pressure and pulse pressure into blood pressure measurements, pursue efforts to measure central blood pressure, and search for new drugs to reduce arterial stiffness. (J Clin Hypertens. 2006;8:659–666) ©2006 Le Jacq

During the 30-year evolution of therapeutic trials and meta-analyses,1–9 it is evident that: (1) the

clinical face of hypertension has evolved from severe and malignant hypertension to milder forms, includ-ing systolic hypertension in the aged, (2) the num-ber of classes of antihypertensive agents has also increased, as a function of the discovery and com-mercialization of new agents, (3) the concomitant use of nonantihypertensive agents, such as statins, has also increased, and (4) no consistent difference has been observed in the strategy of drug treatment between men and women despite the well known lower cardiovascular (CV) risk in women.10,11

During these remarkable changes over time, the effects of drug treatment on CV risk have remained relatively stable. Based on initial epidemiologic studies,1–9 the major results over the years have been the impressive reduction of stroke and conges-tive heart failure. Another salutary result has been the stabilization or even the improvement of renal function, although there have been relatively few large therapeutic trials on this subject.12 Finally, prevention of coronary heart disease has also been markedly improved but remains somewhat lower than expected from the initial epidemiologic pre-dictions. In summary, available population data indicate major effectiveness of antihypertensive drug therapy in the prevention of CV disease but, despite newer, more sophisticated drugs, the ben-efits of therapy have not increased.

There are many possible explanations for the absence of further improvement in antihyperten-sive drug therapy. These include lack of patients’ compliance with medications, clinical inertia, and/or incomplete adherence to guidelines. These fac-tors have been described in detail elsewhere.13,14 The principal goal of this review is to illustrate the difficulty in interpreting the results of thera-peutic trials based on conventional brachial blood

R e v i e w P a p e r

Blood Pressure Components in Clinical Hypertension

Michel E. Safar, MD;1 Harold Smulyan, MD2

From Hôpital Hotel Dieu, Paris, France;1 and State University of New York Upstate Medical University, Syracuse, NY2

Address for correspondence: Harold Smulyan, MD, Upstate Medical University, Department of Medicine, 750 East Adams Street, Syracuse, NY 13210E-mail: [email protected] received February 13, 2006; revised May 12, 2006; accepted June 1, 2006

www.lejacq.com ID: 5351

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

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THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 9 SEPTEMBER 2006660

pressure (BP) measurements in patients. To do this we will: (1) define the different components of BP and discuss their measurement problems, (2) clarify the relationships of these BP components to CV risks, and (3) assess the reduction of central BP vs peripheral BP and arterial stiffness as important factors for further reduction of CV risk.

THE COMPONENTS OF BP: DEFINITIONS AND ASSESSMENTThe decision regarding who is or is not hypertensive is vital to any decision regarding treatment. Yet the definition for the normal values of BP is almost totally arbitrary. Early on, consensus indicated that the upper limit of the normal value was 140 mm Hg for brachial systolic BP (SBP) and 90 mm Hg for brachial diastolic BP (DBP). Although these values are well established, there is no definition in the literature of normal values for the mean BP (MBP), which is nearly the same in all parts of the arterial tree, or pulse pressure (PP), which differs depending on the arterial measurement site. MBP and PP are recognized as important risk predictors but are not yet included in the hypertension definition3,4 despite their use in several recent outcome trials.9,15–19 Thus, hypertension now remains narrowly defined based only on the upper and lower points of the cyclic BP curve and excludes those measurements

that help describe the shape of the entire BP curve. MBP can be easily determined as one third PP plus DBP, or from a regression equation using PP,20 but with isolated systolic hypertension in the elderly, the arterial pulse shape is changed and the calculated MBP may no longer be appropriate (Figure 1). In recent years, many studies have reported the respec-tive contributions of SBP, DBP, MBP, and PP in the development of CV risk. Increased PP may be due either to disproportionately increased SBP, increased SBP with low DBP (<90 mm Hg), or to low DBP with normal SBP (<140 mm Hg). The last is not considered hypertensive since it does not satisfy the criteria of either increased SBP or DBP. In summary, the best single BP for clinical use in the assessment of CV risk is probably the PP, particularly in the older population.21

For many years, the SBP/DBP definition of hypertension was considered to be independent of age, but in our industrialized countries, life has become increasingly prolonged. SBP is known to increase markedly with age, while DBP rises until age 50–60 years, after which it spontaneously falls (Figure 2). The Framingham study22 was the first to suggest that in hypertensive subjects younger than 50 years, an elevated systemic vascular resis-tance raised the DBP and made it most predictive of CV risk. Above that age, the predictive value

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Figure 1. Effect of different causes of systolic hypertension on the arterial pulse and the induced error of the calculated mean blood pressure in isolated systolic hypertension. BP indicates blood pressure.


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of the DBP is lost because stiffening of the central aorta produces a rise in SBP as well as a fall in DBP, with or without a concomitant increase in systemic vascular resistance. This makes SBP a better risk predictor in patients older than 50 and PP better in those older than 69 years.23 Since the population is aging, the interest of physicians in the treatment of hypertension should be redirected from patients in middle age to the elderly, where hypertension has become increasingly prevalent and most com-plications have been observed.10 Therefore, to account for the normal BP changes with aging, the definition of hypertension had to be modified to individually relate the elevations of DBP, SBP, and PP to age.3,4,24,25

Because of the variability of the BP, a variety of techniques have been used to avoid the interactions of the brachial BP level with the environment (phy-sicians’ office, home, work) using the mercury or aneroid sphygmomanometer, semiautomatic oscil-lometric BP recording, home BP, or 24-hour ambu-latory BP.3,4 Although there is considerable scatter, all these BP methods adequately approximate SBP but generally overestimate DBP when compared with intra-arterial brachial BP values.26 This error makes the calculated PP, an accepted risk predictor, falsely low. How these errors influence the assess-ment of BP as a CV risk is unknown. It is unsettling to realize that all the studies of risk assessment and risk reduction are based on convenient but variable and inaccurate noninvasive brachial BP measure-ments. Nonetheless, these measurements are still the best presently available for such purposes.

Recent guidelines have combined the evalua-tion of hypertension severity and CV risk. The guidelines now take into account not only the BP level, but also the associated CV risk factors, such as diabetes mellitus, hyperlipidemia, obesity, and alcohol and tobacco consumption.3,4 It is widely accepted that none of these CV risk factors directly affect the circulatory control of the BP. But this belief may not be true, since obesity, diabetes, and smoking act independently on tensile arterial wall stress, while hyperlipidemia has an effect on shear stress.27 Both shear stress (the viscous drag of blood flow on the arterial wall) and tensile stress (the wall tension induced directly by the pressure pulse) are ultimately linked to the BP itself.26,27 Nevertheless, in epidemiology and clinical prac-tice, algorithms have been developed to evaluate CV risk that do not address the interactions of the different metabolic and mechanical factors involved. These considerations have prompted changes in the recent guidelines that indicate in the

presence of metabolic abnormalities affecting CV risk, threshold BP values lower than those previ-ously considered normal should be used to define hypertension and recommend therapy.3,4 These decisions, however, have been based on consensus and not on demonstrated epidemiologic results and will considerably increase the size of the treatable population without certainty of benefit.

THE IMPORTANCE OF BRACHIAL BP MEASUREMENTSDespite the heterogeneity of the different classes of antihypertensive agents, the resulting changes in BP were quite similar in the early trials. DBP was lowered to ≤90 mm Hg in approximately 80% of treated patients (Figure 3), but SBP in many trials remained ≥140 mm Hg in nearly 60% of patients,28,29 although the more recent trials have achieved somewhat better SBP control.8,9 The relative difficulty in decreasing the SBP when compared with the DBP has left many patients with persistently widened PP. Furthermore, with increasing age, a secondary increase in SBP and PP may occur as a result of the usual aortic stiffen-ing8,9,15,30 (Figure 2). During the course of therapy, this elevated PP, aggravated by aging, may lead to a significant residual CV risk31 and could represent an important prospective problem in the total eval-uation of antihypertensive drug therapy.9,15,16,22,23 Thus far these concerns, suggesting an increased CV risk of a PP incompletely corrected by therapy, are untested.28,31,32

The consistent reduction of CV risk in the over-all hypertensive population and the similarity of the changes in BP contrasts with the heterogeneity and number of antihypertensive agents. This dis-parity has suggested a substantial cause-and-effect relationship between the reduction of the mechani-cal factors represented by BP and the occurrence of CV events3,5–7,28,30,31 rather than a pleiotropic effect of the drugs. Alone, this perspective suggests that the best way to improve the results of anti-hypertensive therapy is to improve BP control in more people. But BP measurement itself as well as the assessment of risk and the end points of treat-ment can also be improved.

THE RELATION BETWEEN BRACHIAL BP AND CV RISKEpidemiologic studies usually claim that the relationship between CV complications (stroke, congestive heart failure, myocardial infarction, and renal failure) and BP is log-linear (a straight line when plotted semilogarithmically) from


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the higher to the lower BP levels for SBP, DBP, MBP, or PP (Figure 4). These plots have been interpreted to show no low BP threshold for CV

risk and imply that BP even in the normoten-sive range could be lowered to reduce CV risk. This opinion has been recently reinforced in a

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Figure 2. Framingham study: relationship between age and systolic blood pressure (SBP), diastolic blood pressure, mean blood pressure, and pulse pressure. The level of baseline SBP is graded from 1 to 4. MI indicates myocardial infarction; CHF, conges-tive heart failure; and MAP, mean arterial pressure. Reproduced with permission from Circulation. 1997;96:308–315.22


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meta-analysis involving 1 million subjects—both men and women of all ages.33 Despite the advan-tage of large study size, the described log-linear relationship between CV risk and BP level is dif-ficult to interpret for several reasons.

These semilogarithmic plots (Figure 4)2,33 are in fact curvilinear and asymptotic when plotted on linear coordinates, with little change in CV risk at low BPs and exponentially increasing risk at high BPs. Although there may be no risk threshold at low BPs, the CV risk reduction of further BP reduction would be virtually nonexistent, with probably little change in the frequency or sever-ity of side effects. In addition, cuff BP is not a precise measurement, and the variability in the slope calculated from the relation between CV risk

and BP may be greatest at the highest and lowest BP values. Furthermore, the populations at the extremities of the curves are comparatively small, particularly for DBP in younger and older subjects, when compared with the populations at the middle part of the curve. The inclusion of the aging popu-lation is relatively recent,34 making the application of these early curves to older people uncertain. In addition, several studies use substantial extrapola-tions of the extremities of the curves relating CV risk to BP level.33 Finally, these data arise from meta-analyses and therefore are generated from retrospective rather than prospective studies. These limitations call into question the clinical meaning of the relationship of CV risk to BP in the higher and lower BP groups.

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Figure 3. Effects of antihypertensive drug treatment on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in trials of patients with essential hypertension. For each trial indicated, blood pressures at trial entry (B) and those achieved during treatment (T) are shown. Dashed horizontal lines indicate target blood pressures to be achieved during treatment, according to international guidelines. Difference between the SBP and DBP responses would be amplified considerably in individuals with diabetes. HOPE indicates Heart Outcomes Prevention Evaluation; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; CAPPP, Captopril Prevention Project; INSIGHT, International Nifedipine Study on Intervention as a Goal in Hypertension Treatment; NORDIL, Nordic Diltiazem study; HOT, Hypertension Optimal Treatment study; STONE, Shanghai Trial of Nifedipine in the Elderly; STOP-2, Swedish Trial in Old Patients With Hypertension-2 Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension. Reproduced with permission from J Hypertens Suppl. 2002;20:S21–S27.28


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THE RELATIONSHIPS BETWEEN BRACHIAL BP, CENTRAL BP, ARTERIAL STIFFNESS, AND ANTIHYPERTENSIVE THERAPYThe site of the BP measurement is most important in understanding the relationship between CV risk and hypertension. Physiologically, MBP and DBP are nearly identical in central (aorta) and periph-eral (brachial) arteries, whereas SBP and PP are significantly higher (approximately 14 mm Hg for SBP or PP) in peripheral than in central arteries.27 This phenomenon, called SBP and PP amplifica-tion, is the physiologic consequence of progres-sively increased vascular stiffness along the arterial tree and the resulting changes in the transit time of both the primary wave and wave reflections. The timing of normally reflected waves raises SBP

in peripheral arteries but lowers it in the aorta and contributes to the reduction in cardiac work in young normal subjects. With aging, the aortic SBP rises to equal peripheral SBP, thus favoring the development of cardiac hypertrophy and conges-tive heart failure.

The differences between central and peripheral BP are important in CV epidemiology, since only brachial BP has been measured—while target organ damage is determined by local, and not brachial, BP. Furthermore, in recent years it has been clearly shown that central aortic BP is more predictive of cardiac risk than brachial BP.16,18 This means that the traditional relation between CV risk and BP will have to be revised should noninvasive central BPs become widely available.

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Figure 4. Relationship between ischemic heart disease and stroke mortality and systolic and diastolic blood pressure accord-ing to age. CHD indicates coronary heart disease. Reproduced with permission from J Hypertens. 2003;21:1635–1640.32


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Some of these methods are now on the horizon. MBP, similar throughout the arterial tree, is also a good risk predictor and can now be measured directly using the oscillometric technique (pressure at maximum oscillation).19 Efforts should there-fore be directed to include MBP whenever cuff measurements are made; however, there are as yet no studies to validate the accuracy and precision of oscillometric MBP. It may not work in patients with rigid arteries or irregular rhythms, and it suf-fers from inaccuracies similar to those of SBP and DBP.35 Nonetheless, MBP has potential advantages that suggest it be included in future studies of risk assessment and therapeutic risk reduction.

As described earlier, the major findings of comparative antihypertensive drug trials have demonstrated a dissociation between the reduc-tion of DBP and the much smaller reduction of SBP.28,29 Since the resultant wide PP may reflect an increase in arterial stiffness associated with aging, drugs that selectively reduce SBP should be developed. At this time, a selective reduction of SBP has been clinically demonstrated for only 3 therapeutic groups: nitrates,36,37 combinations of angiotensin-converting enzyme inhibitors/diuret-ics9 and angiotensin-converting enzyme inhibitors/calcium channel blockers,16,38 and collagen cross-link breakers.39 But the effectiveness of such drugs for the reduction of CV risk over other regimens, such as those containing atenolol, has been shown thus far only in the Anglo-Scandinavian Cardiac Outcomes-Conduit Artery Function Evaluation (ASCOT-CAFE) trial,38 where central SBP and PP were selectively lowered over brachial BPs.

Because the major effect of drug treatment on CV risk is due to the prevention of stroke and congestive heart failure, and because stroke and congestive heart failure seldom occur before the age of 50, it is important to determine whether hypertension should be treated earlier in adult life, as has been suggested by recently published guidelines.3,4 Alternatively, it is possible that in the most common forms of hypertension, simple modifications of lifestyle alone might be sufficient in patients younger than 50 to prevent complica-tions in later life.5 Opinionated answers to these questions are now available, but answers based on data will require large, long-term prospective studies of population subgroups (age, gender, race, diabetes), different drug classes and combinations, and better noninvasive means of estimating central BP. This is a tall order, but a necessary one if the current trial-and-error method of selecting drug treatment is to be improved.

Disclosures and acknowledgment: This study was per-formed with the help of INSERM and GPH-CV (Groupe de Pharmacologie et d’Hémodynamique Cardiovasculaire). We thank Anne Safar for fruitful discussions.

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blood pressure components in clinical hypertension

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