Increased Pulse Pressure

Increased pulse pressure

Official reprint from UpToDate® www.uptodate.com©2012 UpToDate®

Print | BackIncreased pulse pressureAuthorRaymond R Townsend, MDSection EditorGeorge L Bakris, MDDeputy EditorJohn P Forman, MD, MScDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Tue Jan 31 00:00:00 GMT 2012. | This topic last updated: Tue Nov 0800:00:00 GMT 2011.

INTRODUCTION — Typical blood pressure measurements include a systolic and diastolic value, whichrepresent the extremes of pressure fluctuation within the circulation during the cardiac cycle. There hasbeen much debate about which increased value alone, either systolic or diastolic hypertension, is morepredictive of adverse cardiovascular outcomes in various patient populations. (See "Technique of bloodpressure measurement in the diagnosis of hypertension" and "Hypertension: Who should be treated?".)

Mean arterial pressure measurements, which provide another indication of overall circulatory pressureload, have also been proposed as predictive for adverse cardiovascular outcomes. This is eitherdetermined directly by catheterization or can be estimated by formulas (such as diastolic blood pressure +1/3 x [systolic pressure – diastolic pressure]). However, the mean arterial pressure provides lessdiscriminatory power as patients age. The diastolic pressure peaks at and subsequently declines after age55 years, while the systolic pressure rises relentlessly with each decade of life [1]. Thus, depending uponthe respective changes in systolic and diastolic pressures with older age, the mean blood pressure mayactually tend to change less as individuals age.

Since the diastolic pressure in a population rises until the sixth decade and then subsequently declineswith increasing age, an elevation in the diastolic pressure alone is less useful as an outcome predictor inolder patients. Increasing emphasis has therefore been placed upon systolic pressure alone as the mostuseful predictor of cardiovascular disease in these individuals. (See "Treatment of hypertension in theelderly patient, particularly isolated systolic hypertension".)

Several guidelines have supported the use of systolic blood pressure (such as JNC-7) and stronglyencourage the use of systolic blood pressure goals in antihypertensive treatment [2].

There is also an enhanced risk for cardiovascular events associated with increases in pulse pressure(defined below). This topic review will discuss the factors that determine pulse pressure and will presentsome of the evidence for and against the suggestion that there is an independent link between an increasedpulse pressure and adverse cardiovascular outcomes.

CLINICAL PERSPECTIVE — The pulse pressure is defined as the systolic minus the diastolic pressure.This value appears, at least in some epidemiologic studies, to be superior in predictive value to the

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systolic or diastolic values alone (see 'Increased pulse pressure and adverse outcomes' below).

However, given the predictive information from the systolic and diastolic pressures, it is unclear, at firstglance, that the pulse pressure provides additional independent information. Among patients with adiastolic pressure of 95 mmHg, for example, a higher pulse pressure simply means that there is a highersystolic pressure which itself is a risk factor for worse outcomes. The pulse pressure also must beconsidered in the context of the absolute values of systolic and diastolic pressures (eg, a blood pressure of120/80 mmHg is not equivalent in risk to 160/120 mmHg) [3].

Pulse pressure and age — To better understand the purported associations among pulse pressure, systolicpressure, diastolic pressure, risk of cardiovascular disease, and increasing age, it is worthwhile to reviewage-related changes in blood pressure measurements and the risk for cardiovascular disease as individualsage.

In patients less than 55 years of age, the diastolic and systolic blood pressures are both predictive ofadverse events from cardiovascular disease. However, because the diastolic blood pressure declines onaverage after the age of 55, its predictive value is diminished in older patients.

By comparison, the systolic pressure continues to rise with every decade of life, resulting in themaintenance of its predictive value for cardiovascular disease. Thus, in older patients, the associationbetween an increased systolic pressure alone and cardiovascular disease becomes much stronger than thatobserved with the diastolic blood pressure alone.

With increasing age, the pulse pressure correlates more closely with the systolic pressure than with thediastolic pressure, and is therefore also a good predictor of cardiovascular disease among the elderly. Anadditional benefit of the pulse pressure is that it incorporates both the systolic pressure increase and thediastolic decrease that is observed with age. In some cases, this measurement has superior predictivepower to that observed with the systolic pressure alone. (See 'Increased pulse pressure and adverseoutcomes' below.)

FACTORS RESULTING IN INCREASED PULSE PRESSURE — Increases in the pulse pressure resultfrom factors that increase and/or decrease the systolic and diastolic pressure, respectively. Since thechanges in pulse pressure are mostly related to changes in systolic blood pressure, factors affectingsystolic pressure are reviewed first.

Increases in systolic pressure — Elevations in systolic pressure, particularly among the elderly, areusually the result of stiffness in the large arteries as well as an early pulse wave reflection [4,5]. Althoughincreases in peripheral vascular resistance appear to be a relatively more important component ofhypertension in younger patients (30 to 49 years old), the role of peripheral vascular resistance inhypertension diminishes progressively with age [1,6]. Given the known effects of aging on vesselstiffness, increases in pulse pressure in older patients (eg, >55 years of age) result from aortic stiffening,while increases in younger patients (ie, <45 years of age) are more likely to result from increases in strokevolume. (See "Treatment of hypertension in the elderly patient, particularly isolated systolichypertension", section on 'Isolated Systolic Hypertension'.)

Decreases in diastolic pressure — Since stiffening of the aorta with age reduces the elastic reservoircapacity, more blood runs off from each stroke volume during systole, resulting in a reduced bloodvolume within the aorta at the onset of diastole. This factor, when combined with diminished elastic recoiland an increased pressure decay rate, causes a fall in the diastolic pressure with age [7]. These changes indiastolic pressure (both in normotensive and hypertensive patients) become evident after age 55 [1].

Genetics — Increased pulse pressure may be a heritable trait [8-12]. As an example, a genome-wideassociation study that included more than 120,000 individuals of European ancestry found five loci that


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were significantly associated with pulse pressure, including three that had opposite effects on systolic anddiastolic pressure [9]. One of these five loci, the figetin gene, was also associated with pulse pressure inan Asian cohort [8]. Other genetic studies have found a high degree of heritability (ranging from 20 to 40percent) [10,11] with linkage to chromosome 18 in all ethnic groups, chromosome 19 in whites, andchromosome 17 in Hispanics [10].

Other considerations — Since a portion of the systolic pressure depends on the height of the patient,shorter patients tend to have a higher pulse pressure. In addition, slower heart rates result in a greaterpulse pressure.

In general, women are shorter than men but tend to have faster heart rates. As a result, differences in pulsepressure with gender are generally lacking since the effect of height on pulse pressure may be counter-balanced by the effect of heart rate.

Increasing evidence suggests that patients with metabolic syndrome have stiffer vessels, resulting in anincreased pulse pressure [13].

Although it is generally thought that the aorta increases in size with age, some studies suggest thatincreases in pulse pressure are associated with reductions, not increases, in aortic diameter [14]. In onestudy of more than a thousand non-diabetic individuals who were free of cardiac disease, aortic rootdiameter determined by echocardiography was inversely related to pulse pressure [14]. These data suggestthat aortic dimensions may contribute to, rather than result from, increased pulse pressure.

INCREASED PULSE PRESSURE AND ADVERSE OUTCOMES — An increase in the pulse pressureplaces greater stress on arteries, resulting in fatigue and an increased fracture rate in the elasticcomponents of the vessel wall. The vascular intima becomes prone to damage, thereby increasing the riskof atherosclerosis and thrombosis.

Pulse pressure and cardiovascular disease — In addition to damage to the vascular wall, an increasedpulse pressure is associated with increased stress on the left ventricle, which can result in ventricularhypertrophy and failure [15]. Heightened pressure during systole increases myocardial oxygen need, andthe lower diastolic value may become a limiting factor for coronary perfusion, resulting in ischemia.

The net result of these combined effects is that increases in pulse pressure may be a predictor of a varietyof adverse cardiovascular outcomes. This association has been observed in numerous population basedcohort studies [3,16-24], as well as in randomized trials of hypertension treatment [25,26].

The following studies illustrate the range of findings from population based cohorts, several of whichincluded individuals with and without hypertension:

In the Framingham Heart Study, for example, each 10 mmHg increment in pulse pressure wasassociated with a 23 percent higher risk of developing coronary heart disease (figure 1) [16]. Thisassociation with pulse pressure was primarily seen in patients over age 50, particularly over age 60[17]. The adverse outcomes observed with an elevated pulse pressure in patients over age 50 appearto apply to both normotensive and hypertensive patients, including those with low diastolic butnormal systolic blood pressure [18].The association between pulse pressure and cardiovascular mortality was analyzed in over 340,000men in the MRFIT trial aged 35 to 57 years without pre-existing diabetes or coronary heart diseasefollowed for 22 years [19]. Systolic and diastolic pressures were stronger predictors ofcardiovascular death than pulse pressure. However, pulse pressure was independently associatedwith risk, particularly among older men (aged 45 to 57 years). Among men younger than 45 years,pulse pressure was associated with mortality only in those with hypertension; among older men,pulse pressure was associated with an increased risk of death at any level of blood pressure. As an


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example, there was a 22 percent increased risk of cardiovascular mortality in the highest comparedwith lowest quartile of pulse pressure in men aged 45 years or older who had optimal bloodpressure (defined as less than 120/80 mmHg).Other studies, such as the second National Health and Nutrition Examination Survey (NHANES),found that pulse pressure added little predictive value compared with either systolic or diastolicpressure [3]. Among 7830 individuals followed for 15 years, a higher pulse pressure was associatedwith either increased, decreased, or no change in the risk of cardiovascular and all-cause mortalitydepending upon age, systolic, and diastolic pressure.

An association between pulse pressure and cardiovascular endpoints has also been observed inhypertension treatment trials, as illustrated by the following [25,26]:

In the SHEP trial of elderly patients with isolated systolic hypertension, each 10 mmHg elevation inpulse pressure in the active treatment group was associated with increases in the risk for heartfailure or stroke by 32 and 24 percent, respectively, after controlling for systolic pressure and otherknown risk factors [25]. However, pulse pressure was not associated with risk in patients assignedto placebo.Twenty-four hour ambulatory blood pressure recordings were obtained in the Syst-Eur trial, also ofolder patients with isolated systolic hypertension [26]. In the placebo group, the ambulatory pulsepressure predicted all cardiovascular end points and stroke, as each 10 mmHg increase in pulsepressure was associated with a hazard ratio ranging from 1.25 to 1.68. In contrast to the findingfrom the SHEP trial, this relation was not significant in patients assigned active treatment.

Pulse pressure and diabetes — The association between pulse pressure and the incidence of type 2diabetes was examined in 2685 initially nondiabetic patients aged 20 to 84 years enrolled in theCandesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial [27]. Higher pulse pressurewas significantly associated with an increased risk of developing diabetes (relative risk 1.44 for each 16mmHg higher pulse pressure, 95% CI 1.15-1.79). Similarly, the pulse pressure divided by the meanarterial pressure, as a measure of vascular stiffness, was directly associated with diabetes risk. Themechanism underlying this association is unclear.

Consistent findings were observed in a cross-sectional study of 528 hypertensive patients from Italy whohad both clinic and 24 hour ambulatory blood pressure measurements [13]. Clinic pulse pressure wassignificantly higher in patients with the metabolic syndrome compared with patients without themetabolic syndrome (61 versus 49 mmHg); results were similar for 24 hour ambulatory pulse pressure.Higher pulse pressure was also associated with individual components of the metabolic syndrome,including higher fasting serum glucose.

Pulse pressure and progression of chronic kidney disease (CKD) — Pulse pressure, as a reflection ofarterial stiffness, may be an independent risk factor for progression of CKD [28-31]. The followingstudies illustrate the range of findings:

The association between blood pressure components and risk of end-stage renal disease (ESRD)was analyzed among 1513 patients with diabetic nephropathy in a post-hoc analysis of theRENAAL trial [30]. After controlling for multiple potential confounders, a 10 mmHg higher pulsepressure was significantly associated with a 17 percent higher relative risk of developing ESRD. Asimilar association was found for systolic but not diastolic pressure.Among 329 patients with CKD (mean estimated glomerular filtration rate of 39 mL/min per 1.73m2), a 10 mmHg higher pulse pressure was significantly associated with a 10 percent greaterrelative risk of kidney function decline after approximately six months of follow-up [29].

PULSE PRESSURE AND ANTIHYPERTENSIVE THERAPY — Limited data suggest that


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antihypertensive agents differ in their effects on pulse pressure [32].

In the Losartan Intervention For Endpoints trial (LIFE) comparing an ARB (losartan) to abeta-blocker (atenolol), the risk of the composite endpoint (stroke, MI and CV death) rosesignificantly as pulse pressure increased in the atenolol group [33]. In the losartan group, the risk ofthe composite endpoint also rose across the pulse pressure quartiles, but the increase was notsignificant.In a retrospective analysis of a VA Cooperative hypertensive trial including 1292 men with adiastolic blood pressure of 95 to 109 mm Hg at randomization, after one year of treatment,hydrochlorothiazide reduced pulse pressure by 8.6 mm Hg, clonidine by 6.3 mm Hg, diltiazem by5.5 mm Hg, prazosin by 5 mm Hg, captopril by 4.1 mm Hg, and atenolol by 4.1 mm Hg [34].In a substudy of the ASCOT trial (Conduit Artery Functional Evaluation [CAFÉ]), 2073participants underwent radial artery applanation tonometry and measurement of pulse wave velocityto calculate pulse pressure and central blood pressures [35-38]. The results suggested thatatenolol had less central blood pressure reduction and improvement in pulse pressure, despitesimilar typical brachial artery blood pressure reduction, than a calcium channel blocker regimen[35-37]. Central pulse pressure was also associated with clinical outcomes [38].An analysis of data from clinical trials including more than 28,000 subjects suggested that thecardiovascular benefit of antihypertensive therapy was mostly linked to systolic blood pressurecontrol [39]. In addition, the reduction in systolic pressure with treatment was found to beprogressively larger than the reduction in diastolic blood pressure with increasing age (eg, greaterfall in pulse pressure with increasing age) [39].In the REASON trial, patients randomly assigned to the perindopril/indapamide regimen showedgreater pulse pressure decreases with treatment when metabolic syndrome was present (10 to 11mm Hg) than when metabolic syndrome was absent (2 to 3 mm Hg) [40,41].In a post hoc analysis of the CALM II trial, which compared lisinopril 40 mg to lisinopril 20 mgplus candesartan 16 mg daily in hypertensive diabetics, combination therapy produced a greaterreduction in the pulse pressure compared to lisinopril alone as determined by ambulatory bloodpressure monitoring [42]. The differences in pulse pressure were principally due to greaterreductions in systolic pressure in the combination group. This study was not powered to assessoutcome differences [42]. Further discussion of the CALM II trial can be found elsewhere. (See"Treatment of hypertension in patients with diabetes mellitus".).

It is premature to use pulse pressure, however, as a factor in deciding which antihypertensive agent toemploy or to use the measurement as a treatment end point itself [43]. Further prospective research isrequired to define pulse pressure as a predictor of cardiovascular outcomes, and to determine whetherpulse pressure is a better index of response to therapy [44,45]. The pulse pressure probably best serves asa tool in clinical trials, to better illustrate the pharmacodynamic effects of drugs, and possibly to provide asharpened estimate of overall cardiovascular disease risk [44].

CONCLUSIONS — The literature appears to be divided on the prognostic values of the four measures ofblood pressure: systolic, diastolic, mean, and pulse pressures. This arises in part because they are,basically, related to one another as they are all measures of the response in the circulation to eachheartbeat. The value of one measure over another is strongly age dependent, and is also related to howvariables are entered into statistical models that help predict cardiovascular outcomes.

The best use of pulse pressure at this time appears to be in providing help in revising the risk estimate ofthe systolic pressure in older individuals. Since systolic pressure predicts cardiovascular morbidity andmortality in older patients, clinicians are encouraged to revise upward the estimate of cardiovascular riskin older patients when the pulse pressure is increased [46]. A reasonable summation of our knowledge isthat diastolic blood pressure is the best predictor of cardiovascular disease risk in the young (<50 years),all three blood pressure components are equally predictive at ages 50 to 59 years, and pulse pressure is the


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best predictor from age 60 years and beyond.

Limited data also suggest that antihypertensive agents differ in their effects on pulse pressure [32].However, it is premature to use pulse pressure as a factor in deciding which antihypertensive agent toemploy or to use the measurement as a treatment end point itself [43].

SUMMARY

Pulse pressure is defined as the systolic minus the diastolic pressure. (See 'Clinicalperspective' above.)Increased pulse pressure may be due to either or both an increase in systolic or a decrease indiastolic blood pressures. (See 'Factors resulting in increased pulse pressure' above.)Among older patients, increased systolic pressure results from increased stiffness in the aorta andother large arteries; among younger patients, increased stroke volume plays a more important role.(See 'Increases in systolic pressure' above.)Decreased diastolic pressure results from a reduction in aortic blood volume at the onset of diastole.This is related to the age-related decrease in elasticity of the aorta which causes more blood to runoff during systole. (See 'Decreases in diastolic pressure' above.)The pulse pressure is a good predictor of cardiovascular events among elderly patients and in somecases has superior predictive capability to that provided by systolic pressure alone. The best use ofpulse pressure is in revising upward the risk estimate provided by the systolic pressure in olderindividuals. (See 'Increased pulse pressure and adverse outcomes' above and 'Conclusions' above.)Limited data suggest that different hypertensive agents may have varying effects on pulse pressure.(See 'Pulse pressure and antihypertensive therapy' above.)

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Increased Pulse Pressure