Management of hypertension in clinical practice: can we forget about diastolic blood pressure?



1. T. Albassam, Saudi Arabia

2. A. Coca, Spain

3. S. Filipova, Slovakia

4. S. A. Golwalla, India

5. I. Barna, Hungary

6. L. F. Martins, Portugal

7. A. Öncül, Turkey

8. A. R. A. Rahman, Malaysia

9. E. B. Reyes, Philippines

10. B. Trimarco, Italy

11. J. Widimský Jr, Czech Republic





1. T. Albassam, Saudia Arabia

Tawfik ALBASSAM, MD
Consultant in Internal Medicine
Clinical Hypertension Specialist
King Fahd General Hospital
Jeddah, SAUDI ARABIA
(e-mail: albassamt@hotmail.com)

Until early middle age, systolic and diastolic blood pressure (SBP/DBP) move in parallel, both tending to increase. However, at about the age of 55 years, their paths diverge. The two components of blood pressure (BP) move in opposite directions: SBP tends to climb on upwards, while DBP tends to decline. The resulting increase in pulse pressure (PP) has attracted attention as a risk factor in its own right.

In the last two decades, SBP has been coming to the fore as the main BP variable, in particular in the elderly, in whom isolated systolic hypertension is the most important BP abnormality.1 However, the picture is not simple. One complication is the J-curve phenomenon, according to which patients with very low DBP are also at increased risk of cardiovascular death. The introduction of ambulatory BP generated a fresh profusion of parameters: daytime BP, nocturnal BP, morning surge BP, average 24-hour BP, and masked hypertension. These were supplemented by central BP, pulse wave velocity, augmentation pressure, and augmentation index. Consequently, it was good news to hear that international hypertension experts wanted to simplify life for the practicing physician. They recommended focusing mainly on SBP, with less emphasis on DBP.2 This view was also supported by studies showing that SBP is the more difficult parameter to control.3 In addition, SBP contributes more to the global burden of BPrelated disease than DBP. However, a number of concerns remain.

Arguments against ignoring DBP

1. DBP data come free of charge with every BP measurement device. There are no instruments that solely record SBP. Thus no cost saving is involved in concentrating on a single parameter; indeed, there may be wastage in ignoring the free contribution of DBP.
2. Blood pressure clinics are typically attended by a mix of young,middle-aged, and elderly.We need tomaintain the DBP parameter in the minds of physicians so that they can offer optimal treatment to these heterogeneous hypertensive populations.
3. The J-curve phenomenon relates to DBP levels in the many hypertensive patients who have coronary artery disease. The concern is that DBP levels may fall too low to provide adequate myocardial perfusion. It is therefore important to monitor DBP carefully in order to prevent unnecessary coronary accidents.4
4. Cardiovascular risk assessment in young and middle-aged hypertensives is more accurate if informed by SBP and DBP together than by SBP, DBP, or PP alone.5
5. Combining SBP with DBP and PP with mean arterial pressure produces models that are superior to single BP components for predicting cardiovascular disease.6
6. Systolic and diastolic hypertension differ in their pathogenesis. The first is related mainly to large artery stiffness while the second relates to arteriolar vasoconstriction. It is important to bear this difference in mind in order to provide optimal patient care.
7. Both SBP and DBP are used in the definition of hypertensive emergencies.
8. We currently stage hypertension using systolic and diastolic values, either separately or in combination. Will the new emphasis on SBP require revision of the staging conventions?

Personally, I feel it is too early to drop the DBP component. The time is not yet ripe. DBP is a simple and easy parameter to measure and remember. Physicians were brought up with it. Taking DBP into account enhances the view of overall risk when combined with SBP, improves hypertensive care, and does so at no extra charge. _

References
1. Dunstan HP. Isolated systolic hypertension: a long neglected cause of cardiovascular complications. Am J Med. 1989,86:368-386.
2. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters. Lancet. 2008:371:2219-2221.
3. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:1461-1464.
4. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-893.
5. Domanski M, Mitchell G, Pfeffer M, et al; MRFIT Research Group. Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 2002;287:2677-2683.
6. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation. 2009;119:243-250.

2. A. Coca, Spain

Antonio COCA, MD, PhD, FRCP
Professor of Internal Medicine
Director of the Vascular Risk Prevention Unit
Department of Internal Medicine
Institute of Medicine and Dermatology
Hospital Clinic (IDIBAPS
University of Barcelona, SPAIN
(e-mail: acoca@clinic.ub.es)

The history of clinical medicine shows how advances in scientific knowledge have shaped physician attitudes to disease and treatment objectives. In cardiovascular medicine, clinicians traditionally gave more importance to diastolic blood pressure (DBP) than to systolic blood pressure (SBP) in the induction and maintenance of arterial disease and its complications in target organs.1 This was because DBP was viewed as reflecting the systemic resistance offered by small arterioles.2. An increase in this resistance was considered the fundamental pathophysiological mechanism of hypertension. In addition, in clinic or home blood pressure (BP) measurements, DBPwasmuchmore stable and reproducible than SBP.

For these and other reasons, even though epidemiologic studies had shown a direct linear relationship between both BP components and cardiovascular mortality and morbidity,3 the first operative definition of hypertension by the World Health Organization in 1978 included DBP as the most important distinctive element in hypertension and its classification of severity. SBP was assumed to be less important.1 It is not therefore surprising that, in all studies on the prevention of morbidity and mortality by antihypertensive treatment carried out during these years, efficacy should have been evaluated by changes in DBP and that regulatory agencies such as the Food and Drug Administration or the European Medicines Agency use this type of design to the present day. Thus the Hypertension Optimal Treatment (HOT) study4 was designed to determine the optimal DBP treatment objective, regardless of the SBP levels achieved.

These concepts strongly influenced physician education in hypertension in the final 30 years of the 20th century. All therapeutic options considered by physicians were designed to normalize DBP. Once this objective was achieved it was generally considered that the patient was controlled, regardless of SBP levels. Due to the training received and hence physicians’ mind-sets, current control rates for DBP are practically double those for SBP in all countries.5 The disparity between SBP and DBP control is also due to the fact that hypertension affects >60% of over 65s, isolated systolic hypertension affects between 10% and 20%, and while the control of DBP increases with age, that of SBP declines.

For these reasons, in recent years, SBP control has been promoted as the great challenge in hypertension. The importance of DBP risks being forgotten. Evidence of this importance can be found in the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) study, in which patients treated with the fixed combination of perindopril and indapamide for a mean of 4.3 years had a mean reduction of 5.6 mm Hg in SBP and 2.2 mm Hg in DBP compared with those receiving placebo plus standard therapy. Strikingly, this reduction of only 2.2 mm Hg in DBP was associated with a significant relative risk reduction of 9% (P=0.04) in combined major macrovascular or microvascular events, with significant reductions of 21% in renal events (P<0.0001) and microalbuminuria (P<0.0001). The relative risk of cardiovascular death was also significantly reduced by 18% (P=0.03) and all-cause mortality by 14% (P=0.03).6

In summary: Both components of BP are important in loweringmorbidity andmortality. Normalization of DBP should therefore continue to be a priority, in addition to normalization of SBP. _

References
1. World Health Organization. Arterial Hypertension: Report of the Experts Committee. Geneva, Switzerland: WHO;1978:1-78.
2. O’Rourke M. Mechanical principles in arterial disease. Hypertension. 1995;26:2-9.
3. Sytkowski PA, D’Agostino RB, Belanger AJ, Kannel WB. Secular trends in longterm sustained hypertension, long-term treatment, and cardiovascular mortality. The Framingham Heart Study 1950 to 1990. Circulation. 1996;93:697-703.
4. Hansson L, Zanchetti A, Carruthers SG, et al; HOT Study Group. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762.
5. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2157.
6. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.

3. S. Filipova, Slovakia

Slavomira FILIPOVA, MD, PhD, FESC
Associate Professor, Department of
Cardiology, Slovak Medical University,
National Institute of Cardiovascular Diseases
Pod Krasnou horkou 1, 833 48 Bratislava
SLOVAK REPUBLIC
(e-mail: filipova@nusch.sk)

In the core trio of hemodynamic values that govern clinical practice (systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate), DBP is—to use a fairytale analogy—the less favored princess, the one whose story evokes less interest. We have less clinical information and evidence- based medicine data on the role of normal and elevated DBP.1 On the other hand, the physiology and pathophysiology of DBP contain a mine of information on blood pressure (BP) regulation and the development of all types of hypertension: essentially, DBP rises with increased systemic vascular resistance and falls with increased arterial stiffness.2 Isolated diastolic hypertension resulting from dysautoregulation of systemic vascular resistance and elevated pulse pressure is more frequent in younger and middle-aged hypertensives (typically 30 to 50 years old). DBP elevation with a normal SBP is the classic presentation of essential hypertension, progressing to systo-diastolic hypertension if untreated. The underlying hemodynamic abnormality is the elevation of systemic vascular resistance and hence of mean arterial pressure, with no corresponding increase in cardiac output. The result is an isolated increase in DBP.2,3 Such diastolic hypertensives are frequently obese and exhibit higher sympathetic and reninangiotensin- aldosterone system activation. The condition has been characterized as prehypertension, but is unfortunately rarely picked up in everyday practice.

Extensive trial data have shown a close and continuous relationship between coronary risk and DBP: risk is continuous over the range 115/75 to 185/115 mm Hg, and doubles with each 20/10 mm Hg increment.4,5 Although lower DBP generally reflects lower risk, a level below the lower limit of coronary autoregulation may actually increase coronary risk, presumably due to lower coronary filling pressures. This would produce a J shape for the DBP coronary risk curve, except no such shape has yet been satisfactorily confirmed. In patients with coronary artery disease, hypertension, and left ventricular hypertrophy, DBP levels either above or below the normal range increase myocardial oxygen demand. Data are too few to characterize the autoregulatory threshold.4,5 The Hypertension Optimal Treatment (HOT) trial found a minimal increase in major cardiovascular events (myocardial infarction, cardiovascular mortality, but not stroke or renal failure) at DBP levels below 70 mm Hg.1 Such myocardial susceptibility to low diastolic perfusion pressures is consistent with the data that stroke morbidity and mortality are best correlated with SBP, while the best predictor of coronary events may be pulse pressure.1,4,5

There are no data for characterizing the appropriate rate of DBP lowering or target DBP values in patients with coronary heart disease. The consensus is that DBP should be lowered continuously, but maintained above 60 mm Hg if the patient has diabetes or is over 60 years of age.4 In older hypertensive patients with a wide pulse pressure, lowering SBP may lower DBP below 60 mm Hg,5 thereby accentuating myocardial ischemia.

An important clinical consideration is the relationship between hypothyroidism and hypertension. Many patients with hypothyroidism have DBP elevation, even in the early stages of the disorder, although no relationship between thyroid-stimulating hormone levels and DBP has been found,6 at least in the elderly. Thyroxine replacement lowers both SBP and DBP in hypertensive patients with hypothyroidism, including during the subclinical (or oligosymptomatic) phase of disorder. Diastolic hypertension could be a marker of incipient hypothyroidism.

Conclusion: The differential diagnosis of hypertension comprisesmany syndromes other than essential hypertension that influence DBP. They form an important part of everyday practice in internal medicine, cardiology, and geriatrics. _

References
1. Hansson L, Zanchetti A, Carruthers SG, et al. Effect of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1988;351:1755-1762.
2. Kara T, Soucek M, Jurak P, Halamek J. Regulacni mechanizmy krevniho tlaku. In: Soucek M, Kara T, et al, eds. Klinicka patofysiologie hypertenze. Prague, Czech Republic: Grada Publishing; 2002:235-264.
3. Victor RG, Kaplan NM. Systemic hypertension: mechanisms and diagnosis. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald E, eds. Braunwald’s Heart disease. A textbook of cardiovascular medicine. Philadelphia, Pa: Saunders Elsevier; 2008:1027-1048.
4. Rosendorff C, Black HR, Cannon CP, et al. AHA scientific statement: the treatment of hypertension in the prevention and management of ischemic heart disease. Circulation. 2007;115:2761-2788.
5. Rosendorff C. Treatment of hypertensive patients with ischemic heart disease. In: Izzo JL Jr, Sica DA, Black HR, eds. Hypertension Primer. The Essentials of High Blood Pressure. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008:496-501.
6. Shenker Y. Hypertension caused by thyroid and parathyroid abnormalities, acromegaly, and androgens. In: Izzo JL Jr, Sica DA, Black HR, eds. Hypertension Primer. The Essentials of High Blood Pressure. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008:168-170.

4. S. A. Golwalla, India

Dr Sharukh A. GOLWALLA, MD
Consultant Cardiologist
Breach Candy Hospital
Mumbai, INDIA
(e-mail: golwallas@hotmail.com)

Meta-analysis of prospective epidemiologic observations in a total of one million adults with no previous vascular disease recorded at baseline has shown an association between an increased risk of vascular mortality, essentially from ischemic heart disease and stroke, and elevation of both diastolic blood pressure (DBP) and systolic blood pressure (SBP).1 Although the average of DBP and SBP is slightly more informative than either alone in predicting vascular mortality from a single blood pressure measurement, the evidence also suggests that risk lies more with SBP than with DBP.

Presently, the definition of essential hypertension is based on the level of both DBP and SBP. As with other biological characteristics, these pressures change with an individual’s age. Whereas SBP increases continuously with age, DBP rises till about the age of 50 years and decreases thereafter.2 It is for this reason that after the fifth decade of life the frequency of high SBP in the community is much greater than that of high DBP.3 The majority of hypertensive patients are above the age of 50 years, and because of an increasing lifespan, the distribution of hypertension is likely to shift further towards the later decades. This is why the burden of elevated cardiovascular risk rests more with SBP than it does with DBP. As age advances, atherosclerotic changes to conduit arteries become a more important determinant of blood pressure (reflected in the SBP) than peripheral resistance (which determines DBP).4

Clinical trials in the elderly with predominantly isolated systolic hypertension have shown the benefit of cardiovascular risk reduction by concentrating on the reduction of SBP. A particularly large trial, the randomized, double-blind, placebocontrolled Hypertension in the Very Elderly Trial (HYVET), was performed in 3845 patients aged 80 years or above with hypertension defined essentially by SBP (160 mm Hg or higher). DBP was initially required to be between 90 and 109 mm Hg, but this was subsequently relaxed to include any value below 110 mm Hg, allowing the inclusion of many patients with isolated SBP. Treatment with a sustained release formulation of the diuretic indapamide 1.5 mg, augmented as necessary with the angiotensin-converting enzyme inhibitor perindopril 2 mg or 4 mg, was targeted to a BP of <150/80 mm Hg. Active treatment was associated with a 39% reduction in the rate of fatal stroke (P=0.05), a 21% reduction in the rate of death from any cause (P=0.02), and most strikingly a 64% reduction in the rate of heart failure (P<0.001). Serious adverse events were also fewer in the active-treatment group (P=0.001).5 Such a study provides evidence of the vascular benefits of treatment targeted primarily at SBP in the very elderly.

It has also been observed that it is more difficult to lower SBP than it is to reduce DBP. The control rate of SBP is about half that achieved with DBP.6 This suggests that control of both would be achieved in more patients if SBP were targeted rather than DBP. Presently, physicians and patients are expected to monitor two parameters of blood pressure. It would be simpler and more practical for all concerned to base management decisions on a single parameter. This is particularly important because despite treatment, about a third of all patients fail to achieve long-term blood pressure control. Perhaps the time has now come to jettison DBP in the day to day management of essential hypertension, and focus our energies on the control of SBP alone. _

References
1. 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.
2. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US population. Hypertension. 1995;25:305-313.
3. Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapeurta P. Predominance of isolated systolic hypertension among middle aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES III). Hypertension. 2001;37:869-874.
4. O’Rourke M. Mechanical principles in arterial disease. Hypertension. 1995;26: 2-9.
5. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898.
6. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:1461-1464.

5. I. Barna, Hungary

Dr István BARNA, MD, PhD
SOTE I, Korànyi S. u. 2/a
H-1083 Budapest, HUNGARY
(e-mail: barpis@bel1.sote.hu)

Diastolic blood pressure (DBP) increases with age to 55 years, then decreases, whereas systolic blood pressure (SBP) increases steadily with age to at least 80 years. Elevated DBP is thus more common in youth and middle age.

Other physiological determinants of BP fluctuation include pregnancy and weight reduction. Early in the first trimester, active vasodilatation induced by local mediators such as prostacyclin and nitric oxide lowers blood pressure (BP), primarily DBP. A drop of 10 mm Hg is usual by 13 to 20 weeks, reaching a nadir at 20 to 24 weeks; fluctuation is similar in both normotensive and hypertensive women. As for weight reduction, a review of randomized controlled trials reported a short-term fall in DBP of 0.92 mm Hg per kg weight lost1; in the longer term, despite a clear linear relationship, this effect is attenuated: 10 kg weight loss decreases DBP by only 4.6 mm Hg, while decreasing SBP by 6.0 mm Hg (r=0.702; P≤0.01); the results are similar to those for absolute differences (r=0.661; P≤0.01).2

The simple direct relationship between SBP/DBP and cardiovascular risk has recently been complicated by observing that risk is directly proportional to SBP in the elderly and that for any given SBP level, outcome is inversely proportional to DBP, with pulse pressure (PP) proving strongly predictive. PP increases due to stiffening of the major arteries. BP fails to increase during diastole. Left ventricular workload is increased, while the lower DBP reduces coronary flow. Arterial stiffening and the resulting increase of PP with age are well-recognized. PP was first reported as a cardiovascular risk marker in 1989 and confirmed as such in several epidemiologic studies.3 It is associated with other risk factors for atherosclerotic vascular disease, such as obesity, inflammation, the micro- and macrovascular complications of type 2 diabetes, and plasma natriuretic peptide levels. There are several theoretical reasons for considering PP an excellent indicator of cardiovascular and mortality risk.

The Veterans Administration and other treatment studies were based on DBP, although SBP may well also have been clearly increased at baseline. The classic meta-analyses of BP and cardiovascular risk similarly used DBP. However, for over 30 years the Framingham investigators have been telling us that SBP is the more important component. Three large placebo- controlled interventional studies—Systolic Hypertension in the Elderly Program (SHEP), Systolic Hypertension in Europe (Syst-Eur), and Systolic Hypertension in China (Syst- China)—reinforced this idea during the 1990s, showing that drug treatment of isolated systolic hypertension reduced cardiovascular events in elderly patients. Elevated SBP is themain target of antihypertensive therapy. It is also the most common and poorly treated component. In the largest available meta-analysis of observational data (61 studies in one million subjects, 70% from Europe, without overt cardiovascular disease), both SBP and DBP were independently and similarly predictive of stroke and coronary mortality. The contribution of PP in this case was slight, particularly in those under 55 years.4

Adequate SBP therapy normally corrects DBP simultaneously. Patients with elevation of SBP and PP are at special risk. Central PP as assessed from the augmentation index is significantly related to cardiovascular events.5 However, more large-scale observational and interventional studies are required to confirm the prognostic role of central as opposed to peripheral BP. Elevation of SBP, DBP, and PP causes target organ damage and increases cardiovascular morbidity and mortality, but SBP is a superior predictor of coronary heart disease and congestive heart failure than DBP.6

Conclusion: An increase in SBP is made more dangerous by either a concomitant increase or concomitant reduction in DBP (especially in the elderly), whereas pure diastolic hypertension may be less harmful. _

References
1. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42:878-884.
2. Aucott L, Poobalan A, Cairns W. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes. A systematic review. Hypertension. 2005;45:1035-1041.
3. Darne B, Girerd X, Safar M, et al. Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis of cardiovascular mortality. Hypertension. 1989;13:392-400.
4. 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.
5. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function valuation (CAFE) study. Circulation. 2006;113:1213-1225.
6. Wang KL, Cheng HM, Chuang SY, et al. Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality? J Hypertens. 2009,27:461-467.

6. L. F. Martins, Portugal

Luis F. MARTINS, MD, PhD, FESC
Professor of Medicine and Cardiology
Director of Health Sciences Faculty
Fernando Pessoa University
Porto, PORTUGAL
(e-mail: luismartinsphd@netcabo.pt)

For decades, hypertension was classified on the basis of diastolic blood pressure (DBP) and the consensus was that DBP was the main determinant of cardiovascular risk (CVR).1 More recently, however, prospective epidemiological studies, clinical trials, andmeta-analyses have focused attention on systolic blood pressure (SBP), showing a stronger association with CVR and suggesting that SBP is a better guide to risk than DBP, especially in older subjects.2-6

Although there is no doubt that lowering elevated blood pressure is highly effective in reducing CVR, the relative importance of pressure components as determinants of risk and the possible existence of J-shaped relationships between mortality and pressure levels have prompted considerable debate.2,5,6

Resolving these issues is methodologically complex, which explains why we still have no conclusive answer about the importance of DBP as a CVR predictor. Elements of the answer include: (i) the linear correlation between SBP, DBP, and pulse pressure; (ii) the age dependency of normal BP levels, reflecting aging of the arterial system: SBP increases to the eighth/ ninth decade, whereas DBP increases only until the sixth decade, then decreases slightly; (iii) the contrasting effects on DBP of increases in peripheral arterial resistance and large conduit artery stiffness; (iv) the close correlation between SBP and DBP in subjects aged ≤55 years—increased arterial resistance is the hallmark of systo-diastolic hypertension; (v) increased arterial stiffness as the dominant hemodynamic factor with advancing age, leading to a fall in DBP and hence isolated systolic hypertension; (vi) difficulties in interpreting the effect of BP components due to their interdependency (if only one component is used to model risk, it is unclear how much of the effect is due to its correlation with the other—if both are introduced in a regression model, the interpretation of coefficients is uncertain because they partly reflect the effect of pulse pressure); (vii) the dynamic effect of aging on the complex interactions between BP and cardiovascular disease (coronary heart disease is much commoner in old age, and the absolute annual difference in coronary mortality associated with a given difference in BP increases with increasing age); (viii) the failure of arterial stiffness to respond readily to drug treatment, with the result that antihypertensive drugs often reduce DBP more than SBP in the elderly; (ix) the possibility in interventional studies that a fall in DBP can be due to aging as well as to active treatment; (x) absence of a proven J-shaped relationship between cardiovascular risk and DBP in coronary patients receiving antihypertensive therapy (several mechanisms may be involved); and (xi) failure of conventional (brachial artery) BP determination to take into account the difference between peripheral and central BP and the age-related amplification of SBP.

At present, the levels of evidence for answers to the initial question are low, there are serious gaps in the data available, and many specific issues remain open to debate. In particular, no matter how difficult they may be to design, clinical studies are needed to determine the importance of DBP in determining CVR. In the meantime, DBP levels remain important for (i) classifying hypertension; (ii) targeting specific intervention in younger patients (≤55 years); (iii) informing antihypertensive therapy options (differing effects in peripheral and central arteries); and (iv) guarding against excessive reduction in the elderly (especially those with comorbidity) since a low DBP may increase coronary risk and related mortality.

On this basis our short answer is: no, we cannot neglect DBP in clinical practice! _

References
1. Kannel WB, Stokes JL. Hypertension as a cardiovascular risk factor. In: Robertson JIS, ed. Handbook of hypertension epidemiology of hypertension. New York, NY: Elsevier Science Publishing Co Inc; 1985:6;15-34.
2. Black HR. The paradigm has shifted to systolic blood pressure. Hypertension. 1999;34:386-387.
3. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355:865-872.
4. Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapuerta P. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 2001;37:869-874.
5. Madhavan S, Ooi WL, Cohen H, Alderman MH. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension. 1994;23:395-401.
6. Domanski M, Mitchell G, Pfeffer M, et al; for the MRFIT Research Group. Pulse pressure and cardiovascular disease-related mortality. Follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA.2002;287:2677-2683.

7. A. Öncül, Turkey

Aytaç ÖNCÜL, MD
Professor of Cardiology
Istanbul Faculty of Medicine
Department of Cardiology
34390 Capa / Istanbul
TURKEY
(e-mail: aytac@istanbul.edu.tr)

Diastolic blood pressure (DBP) came to be considered the most important determinant of cardiovascular risk in the mid-20th century. The first three Reports of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure staged hypertension according to DBP levels.1 DBP was viewed as a better predictor of cardiovascular risk than systolic blood pressure (SBP), which was seen as a natural corollary of aging, while DBP was seen as dependent on peripheral resistance. It remained clinical scientists’ focus for many decades.

Reporting the Framingham data in 1971, Kannel et al showed clearly that SBP was more accurate than DBP in predicting cardiovascular risk,2 but it took nearly 20 years before the JNC used SBP in staging hypertension. The Fourth JNC Report acknowledged the prognostic role of isolated systolic hypertension in 1988.1

Since the Fifth JNC Report, hypertension has been staged according to the elevation of SBP and/or DBP, with both pressure components being accepted as indices of increased cardiovascular risk.1 The key messages of the Seventh JNC Report published in 2003 were that SBP levels over 140 mm Hg are a more important cardiovascular risk factor than DBP in subjects over 50 years of age: risk begins at 115/75 mm Hg and doubles for each 20/10 mm Hg increment of SBP/DBP; until age 50, DBP is the more potent cardiovascular risk factor; it is then overtaken by SBP, with systolic hypertension becoming the most common form of hypertension in the over-50s.

In 2008, Williams et al proposed expressing the thresholds for the diagnosis and treatment of hypertension in the single dimension of SBP on the grounds that this is far the more important of the two blood pressure components, especially among the over-50s.3 They argued that with population aging and hence an increase in the number of subjects with systolic hypertension, it was reasonable to classify and treat hypertension solely on the basis of SBP in the over-50s. However, the 2007 guidelines of the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and European Society of Cardiology stressed the importance of high cardiovascular risk in patients with a high SBP and low DBP, ie, a high pulse pressure. More recently still, in 2009, the European Society of Hypertension Task Force Reappraisal of European Guidelines on Hypertension Management also expressed treatment targets in terms of SBP and DBP.4

In 2008, Kelly et al published a Chinese database comprising 169 871 men and women aged ≥40 years. Compared with normotensives, the relative risks of cardiovascular disease and mortality in patients with isolated diastolic hypertension (≥90 mm Hg and SBP <140 mm Hg) were 1.59 and 1.45, respectively, thus confirming DBP as an independent cardiovascular risk factor.5

A 2009 analysis by Franklin et al of the Framingham data in 9557 individuals, all free of cardiovascular events and antihypertensive therapy at baseline, showed the combination of high SBP and low DBP to be a superior predictor of future adverse cardiovascular events. As to be expected, given the role of pulse pressure, lowering DBP below 70 mm Hg increased cardiovascular risk.6

Conclusion: In evaluating, detecting, and treating hypertensive patients, the combination of SBP and DBP remains superior to either component alone in predicting cardiovascular risk. Although there is considerable evidence to suggest that SBP outperforms DBP in gauging cardiovascular risk in the over-50s, the time has not yet come to jettison DBP. _

References
1. Schillaci G, Pirro M, Mannarino E. Assessing cardiovascular risk. Should we
discard diastolic blood pressure? Circulation. 2009;119:210-212.
2. KannelWB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and
risk of coronary heart disease. The Framingham Study. Am J Cardiol. 1971;27:
335-346.
3. Williams B, Lindholm LH, Sever P. Systolic blood pressure is all that matters.
Lancet. 2008;371:2219-2221.
4. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines
on hypertension management: a European Society of Hypertension Task Force
document. J Hypertens. 2009 Oct 15. Epub ahead of print.
5. Kelly TN, Gu D, Chen J, et al. Hypertension subtype and risk of cardiovascular
disease in Chinese adults. Circulation. 2008:118:1558-1566.
6. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure
components and risk for cardiovascular disease: the Framingham Heart
Study. Circulation. 2009;119:243-250.

8. A. R. A. Rahman, Malaysia

Abdul Rashid Abdul RAHMAN
MBChB, PhD, FRCPI, FRCPEd, FNHAM
Dean of Research and Graduate Studies
Professor of Medicine and Clinical Pharmacology
Cyberjaya University College of Medical Sciences
Unit 2, Street Mall 2, 63000 Cyberjaya
Selangor DE, MALAYSIA
(e-mail: rashid@cybermed.edu.my)

The short answer is no. Although the paradigm has shifted over the last decade with regard to the relative importance of the blood pressure (BP) components, elevated diastolic blood pressure (DBP) does have prognostic implications. For example, although a relatively large study in 1913 subjects aged >40 years using home BP measurement showed that isolated DBP had the same prognosis as normotension,1 a larger study in the elderly (>65 years; n=5888) showed otherwise: systolic blood pressure (SBP) was indeed the best individual predictor of cardiovascular (CV) events, but DBP was also strongly and directly related to the risk of coronary and CV events.2

Furthermore, clinical trials up to the end of the last decade using DBP as the surrogate end point showed clear clinical benefit, in particular for high-risk patients.3 Some may argue that over-reliance on DBP as the surrogate may have contributed to the somewhat attenuated benefits of BP reduction seen in many earlier trials. Others will say that SBP is not only prognostically more important, it is also more difficult to control and therefore deserves more emphasis. While these viewpoints have merits, it does not mean that they should be pursued at the expense of neglecting diastolic control.

In clinical practice, we encounter patients whose SBP is controlled, but whose diastolic readings remain suboptimal, particularly among younger patients. We do not currently have enough evidence to allow us to neglect such cases of isolated diastolic hypertension. On the contrary, forgetting that their DBP remains suboptimal is likely to expose such patients to higher than acceptable long-term risk. Admittedly, we also have no hard evidence of clinical benefit from lowering DBP in this category of patient, but there is epidemiologic evidence that neglecting their DBP could expose them to unnecessary risk. It must also be remembered that in contrast to the case with DBP, there have never been any outcome trials examining the benefits of lowering SBP to different pressure levels. Indeed, recent trials have shown that aggressive BP lowering in high-risk patients is more likely to optimize DBP than SBP. In the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) trial,4 despite efforts to lower BP in the diabetic population to <130/80 mm Hg as recommended by most guidelines, the achieved BP was 135/75 mm Hg. Nevertheless, patients still clearly benefited, as shown by the improved clinical outcomes. It can be plausibly argued that this was due at least in part to achieving the target DBP level with 5 mm Hg to spare, despite the mean end of study SBP remaining suboptimal.

Overreliance on SBP control at the expense of diastolic control has the indirect effect of focusing excessive attention on the elderly as the archetypal patients in whom diastolic control is seldom an issue. However, even in this group, DBP cannot be forgotten, albeit for a slightly different reason: too low a DBP may signify a stiffer conduit artery system, and a worse prognosis.5,6 So whichever way one looks at it, neglecting DBP and its importance may not be such a wise step “forward.” _

References
1. Hozawa A, Ohkubo T, Nagai K, et al. Prognosis of isolated systolic and isolated diastolic hypertension as assessed by self-measurement of blood pressure at home: the Ohasama study. Arch Intern Med. 2000;160:3301-3306.
2. Psaty BM, Furberg CD, Kuller LH, et al. Association between blood pressure level and the risk of myocardial infarct, stroke and total mortality. Arch Intern Med. 2001;161:1183-1192.
3. Hannson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755-1762.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
5. Somes GW, Pahor M, Shorr RI, Cushman WC, Applegate WB. The role of diastolic blood pressure when treating isolated systolic hypertension. Arch Intern Med. 1999;159:2004-2009.
6. O’Rourke M. Mechanical principles in arterial disease. Hypertension. 1995;26: 2-9.

9. E. B. Reyes, Philippines

Eugenio B. REYES, MD
Director, Philippine Heart Association
Room 223, MAC 2 Building
Manila Doctors Hospital
#667 United Nations Avenue
Ermita, Manila, PHILIPPINES 1000
(e-mail: eugene@reyes.ph)

Do you treat a patient who has a blood pressure of 130/100 mm Hg on repeated measurement and no other risk factors? This question may seem silly for many, yet profound for those familiar with the epidemiologic data on hypertension and cardiovascular (CV) risk reduction.

Current hypertension guidelines (Joint National Committee 7, European Society of Hypertension 2007, European Association for Cardiovascular Prevention and Rehabilitation 2007) focus on systolic blood pressure (SBP) as the more accurate predictor of CV outcome and mortality.1-3 Many well-designed clinical trials and observational cohort studies have indeed shown strong associations between SBP and CV events, and between SBP treatment and event reduction.4 Diastolic blood pressure (DBP) was predictive only in cases of combined systolic and diastolic hypertension, but not in isolated diastolic hypertension.5 These findings influenced the current guidelines. As a result, the global risk scoring index of individual patients includes only SBP.1,2

However, DBP remains an integral part of the description of hypertensive status, eg, >140 and/or >90 mm Hg.1,2 Nor do the guidelines rule out a potential contribution of diastolic hypertension to CV risk. The attitude is that hypertension is defined as elevated SBP and/or DBP, but that it is SBP that must be treated. This is not the message that the data are giving us: an elevated DBP is a predictor of CV events. It is simply that SBP is more predictive. Meta-analysis has shown a doubling of CV mortality for every 20/10 mm Hg increase in blood pressure.4 There are many explanations for the discordance between SBP and DBP. For a start, the absolute difference in untreated SBP between hypertensive and control groups exceeds that in DBP. In cohort studies most (but not all) patients were already being treated for hypertension before enrolment and classification into different risk categories. DBP is much easier to control than SBP. This further reduces the absolute difference in DBP while maintaining a relatively high difference in SBP. Naturally, those with uncontrolled SBP will remain at high risk for the entire duration of observation. The same is true in randomized placebo-controlled trials; we see big differences in SBP and small differences in DBP. There is therefore less scope for DBP to predict CV events. In addition,many trials (except those in isolated systolic hypertension) had an inclusion criterion for DBP (eg, >95 mm Hg), but no threshold for SBP. As expected, large falls in SBP were paralleled by much smaller falls in DBP (eg, 30 mm Hg SBP vs 11 mm Hg DBP). Nonetheless, compared with placebo or no treatment, and basing recruitment on DBP alone, treatment reduced CV events and mortality.6

For these reasons, we should not yet recommend the discarding of DBP as a risk factor and treatment target.We also need DBP for determining proven strong predictors of CV events, such as pulse pressure andmean arterial pressure. On this basis, the guidelines recommend treating everyone with stage 1 and 2 hypertension, and point out that DBP is a stronger CV risk factor than SBP in younger hypertensives. In the over-50s, on the other hand, SBP is the more important predictor and the more important treatment target.1

A final point: Few, if any, would disagree with the need to treat DBP to normal levels in any patient with a history of coronary heart disease or stroke and a blood pressure of 130/100 mm Hg. In the final analysis, blood pressure is just one of the multiple risk factors that influence CV outcome and its treatment should be approached in an individualized manner. _

References
1. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572. [Erratum. JAMA. 2003;290:197.].
2. Mancia G, De Backer G, Dominiczak A, et al; ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens. 2007;25:1751-1762. [Erratum. J Hypertens. 2007;25:2184.].
3. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14(suppl 2):E1-E40.
4. Lewington S, Clarke R, Quizilbash 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. [Erratum. Lancet. 2003;361:1060.].
5. Strandberg TE, Salomaa VV, Vanhanen HT, et al. Isolated diastolic hypertension, pulse pressure, and mean arterial pressure as predictors of mortality during a follow-up of up to 32 years. J Hypertens. 2002;20:399-404.
6. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009; 338:b1665.

10. B. Trimarco, Italy

Bruno TRIMARCO, MD
Full Professor of Internal Medicine
Department of Clinical Medicine and
Cardiovascular and Immunological Sciences
Federico II University of Naples
via S. Pansini 5,
80131 Naples, ITALY
(e-mail: trimarco@unina.it)

Diastolic blood pressure (DBP) was long considered the key determinant of the cardiovascular risk associated with hypertension. It was documented as such in the early Reports fromthe Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, which defined hypertension and graded its severity in terms of DBP only. The concept was derived from the knowledge that DBP represents the resistance that the heart has to overcome in order to pump blood into the systemic circulation and also from the strong relationship between diastole and coronary perfusion.

The subsequent finding that systolic blood pressure (SBP) correlates better than DBP with coronary heart disease, stroke, and heart failure have challenged this view, suggesting that SBP outweighs DBP as a predictor of cardiovascular morbidity andmortality. In 1988, the Joint National Committee Report acknowledged the prognostic role of isolated systolic hypertension, and since the Fifth Report published in 1993, hypertension has been defined as elevation of SBP and/or DBP.1 On the evidence that SBP has greater prognostic value than DBP, Williams et al proposed in 2008 a simplified definition of hypertension,2 basing the threshold for the diagnosis and treatment of hypertension on SBP only, discarding DBP values altogether, at least in the 50+ age group that accounts for the great majority of hypertensive patients.

Age plays an important role in modifying the relationship between blood pressure components and cardiovascular risk. In particular, with increasing age, there is a gradual shift fromDBP to SBP and eventually pulse pressure as predictors of cardiovascular events. Under 50 years of age, DBP is a stronger predictor of cardiovascular risk than SBP or pulse pressure. The sixth decade is a transition state during which all three indices are comparable. From age 60 years on, when considered together with SBP, DBP becomes inversely related to cardiovascular risk and pulse pressure emerges as the best predictor. The fact that SBP and DBP both predict risk in the under-50s confirms the concept that increased peripheral resistance is dominant in determining cardiovascular risk in young hypertensives. In the same way, the emergence of pulse pressure and SBP as the dominant predictors of risk from the seventh decade onwards is consistent with the contribution of large artery stiffness to risk in older patients.3

Yet despite the findings relating to age, controversy persists over which blood pressure component is the superior predictor of cardiovascular events. A recent follow-up study of the Framingham data tested the utility of a combination of blood pressure components instead of a single component in predicting cardiovascular risk.4 In a model adjusted for age, sex, and other covariates, the odds of cardiovascular events increased with increasing SBP and DBP, but the relationship between DBP and cardiovascular risk was quadratic and nonlinear. Thus for any given SBP value greater than 120 mm Hg, the odds of cardiovascular events are increased at both the high and low extremes of DBP. In particular, high DBP values are pathogenic because they represent increased vascular resistance, while low DBP values are pathogenic because they reflect increased arterial stiffness.5

Conclusion: We cannot ignore DBP because it has been demonstrated that in patients with isolated diastolic hypertension, who account for 14% of the hypertensive population, cardiovascular risk is twice that in subjects with normal blood pressure. Furthermore, while subjects with SBP ≥180 mm Hg and normal DBP have a 2.4-fold adjusted cardiovascular risk compared to normotensives, those with identical SBP but DBP ≥110 mm Hg have an odds ratio for cardiovascular events of 7.7,4 which more than qualifies DBP as a treatment target. _

References
1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993;153:154-183.
2. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters. Lancet. 2008;371:2219-2221.
3. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001;103:1245-1249.
4. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation. 2009;119:243-250.
5. Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308-315.

11. J. Widimský Jr, Czech Republic

Jiří WIDIMSKÝ Jr, MD
IIIrd Internal Department
Center for Hypertension
General Faculty Hospital
Prague, CZECH REPUBLIC
(e-mail: jiri.widimsky@lf1.cuni.cz)

Long-term epidemiologic studies have shown a relationship between blood pressure (BP) and the risk of cardiovascular (CV) complications.1 Treatment of high BP reduces mortality, morbidity and risk of CV events.2 According to current guidelines all hypertensive patients should be treated to a target BP of <140/90 mm Hg and those at high risk to a target BP of <130/80 mm Hg.2 More intensive BP lowering in high-risk patients has been questioned by the recent Reappraisal of the European Society of Hypertension guidelines on hypertension management.3

Lowering of diastolic blood pressure (DBP) has been traditionally considered the main treatment target for almost 30 years. However, in elderly subjects, systolic blood pressure (SBP) has proved a better predictor of CV complications (coronary artery disease, heart failure, stroke), renal failure, and total mortality. It was also the best predictor of coronary and cerebrovascular events in the Cardiovascular Health Study in subjects 65 years or older.

SBP and pulse pressure rise continuously with age due to age-related changes in arterial stiffness. Pulse pressure is also considered an independent and significant predictor of total CV mortality and all-cause mortality. The prevalence of isolated systolic hypertension increases after the age of 50 years. The majority (approximately 75%) of hypertensive patients are over 50 years of age and have predominantly systolic hypertension. Using DBP to stratify risk in such a population is thus questionable. Some physicians even believe that SBP is “all that matters.”4 Is this really true? Can we afford to discard DBP?

The risks of hypertension were ascribed mainly to DBP until the mid-1980s when SBP also began to be recognized as an important predictor of CV morbidity-mortality. However, metaanalysis of data from over one million adults in 61 prospective studies indicated that the absolute risk of death from ischemic heart disease at least doubled with every decade, with a line of progression that was similar for both SBP and DBP.1 Data from various trials of antihypertensive treatment showed clear clinical benefit and fewer CV complications as a result of lowering DBP. More intensive DBP lowering also translated into clear benefit (especially in diabetics) in the Hypertension Optimal Treatment trial. But treating to DBP levels below 65-70 mm Hg appeared to increase coronary risk. The evidence suggests that this J-curve relationship between DBP and coronary risk applies mainly to older subjects with isolated systolic hypertension.

DBP peaks around 50 years of age and then steadily declines. In younger subjects it depends mainly on peripheral resistance, ie, low DBP means low peripheral resistance. In younger subjects with a hyperkinetic circulation, DBP is less variable than SBP.5 Isolated diastolic hypertension exists in subjects under 50 years of age, but is uncommon.6 In older subjects, low DBP means high arterial stiffness, and is usually associated with high SBP, high pulse pressure, and high CV risk.5 DBP thus appears a better predictor of CV mortality in younger subjects, while SBP and pulse pressure better reflect CV risk in the older population.

Conclusion: DBP is an important predictor of CV morbidity/ mortality in subjects under 50 years of age. Above this age, and in particular from age 60 onwards, SBP (and pulse pressure) become the more important determinants of total risk. However, given the relative importance of each component, treatment of hypertension should continue to focus on lowering both SBP and DBP (where raised), as recommended by the current European guidelines.2 _

References
1. Lewington S, Clarke R, Qizilbash N, et al; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-1913.
2. Mancia G, De Backer G, Dominiczak A, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for theManagement of Arterial Hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Guidelines Committee. J Hypertens. 2007;25:1105-1187. [Erratum. J Hypertens. 2007;25:1749.].
3. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
4. Williams B, Lindholm L, Sever P. Systolic pressure is all that matters. Lancet. 2008;372:2219-2221.
5. Benetos A. Pulse pressure as a cardiovascular risk factor. In: Mancia G, Grassi G, Kjeldsen SE, eds. Manual of Hypertension of the European Society of Hypertension. London, UK: Informa Healthcare; 2008:18-22.
6. Owens P, Lyons S, O’Brien E. Ambulatory blood pressure in the hypertensive population: patterns and prevalence of hypertensive sub-forms. J Hypertens. 1998;16:1735-1743.