Scientific Contributions
Isolated Systolic Hypertension
Prognostic Information Provided by Pulse Pressure
Michael J. Domanski, Barry R. Davis, Marc A. Pfeffer, Mark Kastantin, Gary F. Mitchell Abstract—Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave
velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse
cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure
has also been associated with thickening of the carotid intima and media. However, the relationship between pulse
pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is
an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in
the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The
independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality
was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other
variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a
16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in
mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the
risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness,
as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial
pressure, in elderly patients with isolated systolic hypertension. (Hypertension. 1999;34:375-380.)
Key Words: pulse pressure Ⅲ stroke Ⅲ hypertension Ⅲ elderly Ⅲ compliance
The association between hypertension, particularly systol- sure (SBP) and pulse pressure as well as a decrease in ic hypertension, and cerebrovascular disease, including diastolic blood pressure (DBP). In addition, the increased carotid atherosclerosis and stroke, has been established.1 stiffness causes an increase in pulse wave velocity. A more Once thought to be a benign accompaniment of aging, rapid pulse wave velocity results in premature return of the isolated systolic hypertension is now known to increase the reflected pressure wave to the central aorta in systole rather risk of stroke and other adverse cardiovascular events. Fur- than diastole, which further increases the pulse pressure.
thermore, the Systolic Hypertension in the Elderly Program Because of these relationships, pulse pressure has been used (SHEP) clearly demonstrated that effective treatment of as a crude index of aortic stiffness even though left ventric- isolated systolic hypertension in elderly patients markedly ular ejection rate and stroke volume may also influence pulse reduced this risk of stroke.2 Evidence that implicates in- creased conduit vessel stiffness and elevated pulse pressure as An association between increased pulse pressure and important correlates of the cerebrovascular pathophysiology adverse cardiovascular events, presumably due to a detri- of hypertension, especially isolated systolic hypertension, is mental influence of increase in stiffness of the conduit accruing.1,3–14 In a substudy of the SHEP population, in- vessels, has been demonstrated in normotensive and hy- creased pulse pressure was shown to be an independent pertensive patient populations17–21 as well as in patients predictor of carotid stenosis.5 That study provides a rationale with reduced left ventricular function.15,16 This adverse for an association between pulse pressure and the clinical end association has been shown to be independent of age, mean point of stroke in this patient population, although such an arterial pressure (MAP), and other covariates thought to influence pulse pressure or outcome in patients with Increased conduit vessel stiffness results in increased cardiovascular disease. Although a recent population- characteristic impedance of the aorta and decreased arterial based study speculated that increased pulse pressure may compliance, which cause an increase in systolic blood pres- help to explain the higher incidence of stroke in patients Received February 4, 1999; first decision March 1, 1999; revision accepted April 14, 1999.
From the Clinical Trials Group, National Heart, Lung, and Blood Institute, Bethesda, Md (M.J.D., M.K.); Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.A.P.); University of Texas School of Public Health, Houston (B.R.D.); and Cardiovascular Engineering, Inc (G.F.M.),Dover, Mass.
Correspondence to Michael J. Domanski, MD, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, RM 8146, Bethesda, MD 20892-7936.
1999 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
September 1999
Baseline Characteristics by Pulse Pressure Tertile
with isolated systolic hypertension as opposed to those population (Table 1). Evaluation by tertiles of pulse with diastolic or mixed systolic/diastolic hypertension,3 pressure demonstrated an inverse association between the direct relationship between pulse pressure and stroke pulse pressure and MAP, indicating that higher pulse has not been established. The present study examined the pressure could not be attributed to an increase in distend- association of pulse pressure and stroke as well as total ing pressure alone. A higher pulse pressure was associated mortality in patients randomized into SHEP.
with more advanced age, a higher proportion of women,greater frequency of previous use of antihypertensive medication, history of diabetes, baseline ECG abnormali- The SHEP trial was a randomized, controlled study of the effective- ties, and lower prevalence of alcohol use. There were ness of antihypertensive drug treatment in the prevention of stroke in minimal trends toward lower body mass index and de- 4736 people with isolated systolic hypertension.2 Blood pressure readings at the first and second baseline visits were creased prevalence of current smokers in patients with averaged to establish a baseline blood pressure for each participant.
higher pulse pressure. Among the female patients, higher Treatment goals were established on the basis of this baseline blood pulse pressure was also associated with less frequent pressure as previously described in detail.2 Initial therapy was chlorthalidone, which was followed by atenolol or reserpine asneeded. Pulse pressure was calculated as the difference between Univariate analysis was used to assess the impact of a baseline and prerandomization SBP and DBP. MAP was calculated variety of baseline variables on stroke (nϭ262) and total according to the formula MAPϭ(2ϫDBPϩSBP)/3. Fatal or nonfatal mortality (nϭ455). The effects of pulse pressure and MAP stroke, according to previously described criteria,2 was the primary on stroke, the primary end point of SHEP, were evaluated with a Cox proportional hazards model that adjusted for Statistical Methods
significant univariate predictors of stroke (Table 2). In this Differences in baseline characteristics by tertile of pulse pressure multivariate analysis, for each 10-mm Hg increase in pulse were evaluated by ANOVA for continuous variables and by a test pressure, there was an 11% (95% confidence interval, 1% for linear trends for categorical variables. Baseline variables, to 22%) increase in the risk of stroke (Table 2). Further- including randomization assignment, age, pulse pressure, MAP, more, for each 10-mm Hg increase in MAP, there was an SBP, DBP, heart rate, race, gender, body mass index, educationalattainment, serum uric acid, HDL cholesterol, hematocrit, current independent 20% increase in the risk of stroke, confirming smoking status, history of intermittent claudication, presence of the additive prognostic effects of the mean and pulsatile carotid bruits, history of cardiovascular disease, presence of ECG components of blood pressure on the risk of stroke.
abnormality, presence of left ventricular hypertrophy by ECG To determine whether pulse pressure and MAP provide criteria, history of stroke, history of diabetes, alcohol consump- independent prognostic information concerning the risk of tion Ն1 drink per week, and history of myocardial infarction,were evaluated as predictors of stroke and total mortality with a death in this population, a Cox proportional hazards model Cox proportional hazards model. All univariate predictors asso- was constructed that included these variables as well as ciated with an end point (PϽ0.10) were included in a preliminary variables that were significant predictors of all-cause multivariate analysis. Those that remained significant (PϽ0.10) mortality on univariate analysis. In this mortality analysis, were included in the final models along with pulse pressure andMAP.
pulse pressure was again independently predictive of totalmortality (Table 2). For each 10-mm Hg increase in pulse pressure, there was a 16% (95% confidence interval, 8% to Higher pulse pressure was associated with both an increase 24%) increase in the risk of death. MAP was also predic- in SBP as well as a decrease in DBP in this elderly patient tive of increased mortality. For each 10-mm Hg increase in Domanski et al
Pulse Pressure in Systolic Hypertension
Risk Ratios for Factors Examined
HDL cholesterol (per 0.39-mmol/L increase) MAP, there was a 14% increase in the risk of total conduit vessels. However, the selection criteria for SHEP, increased SBP with normal or low DBP, effectivelyeliminated patients whose pulse pressure was elevated Discussion
solely as a result of increased MAP. Consequently, the This analysis demonstrates that MAP and pulse pressure, relationship between MAP and pulse pressure was inverted calculated with data derived from sphygmomanometry, are in SHEP patients, with increasing tertiles of pulse pressure independent predictors of stroke and all-cause mortality.
associated with lower levels of MAP. Therefore, increased The usefulness of a physiological interpretation of blood pulse pressure in this patient population was not simply pressure in terms of both its pulsatile (pulse pressure) and secondary to, or a surrogate for, elevated MAP but rather nonpulsatile (MAP) components is emphasized by the was more likely an indicator of a primary increase in results of this analysis. The well-characterized population of patients in SHEP permitted quantitative estimates of theprognostic implications of pulse pressure and MAP by use Physiological Considerations
of an analysis that adjusts for a large number of potentially With aging and repetitive cyclical stress, there is a break- confounding covariates. Each 10-mm Hg increase in pulse down of the elastin in the walls of conduit vessels, which pressure resulted in an 11% increase in the risk of stroke leads to reduced compliance of the vessel.22 This process and a 16% increase in the risk of death independent of appears to be accelerated by diseases such as diabetes23 other covariates, including MAP. MAP was also indepen- and hypertension24,25 as well as by dietary factors, includ- dently associated with risk of adverse cardiovascular ing high salt intake,25,26 and menopause.27 Heart failure is events, with a 20% increase in the risk of stroke and a 14% also associated with increased conduit vessel stiffness, increase in the risk of death associated with each 10- possibly because of the effect of neurohumoral activa- mm Hg rise in MAP. SBP is also an important predictor of tion.28 Stiffening results in increased aortic impedance and stroke and mortality in this population. On the other hand, an increase in pulse wave velocity. The increase in in the Studies of Left Ventricular Dysfunction (SOLVD),15 impedance causes a larger pulsatile pressure wave for a SBP was not a significant predictor of mortality. DBP was given pulsatile flow. Increased pulse wave velocity causes significantly, although inversely, associated. In the Sur-vival and Ventricular Enlargement (SAVE) trial, both SBP premature return of the pulse wave reflection from the and DBP were significantly associated with survival.16 In periphery. The reflected wave, therefore, arrives in the each of these studies, pulse pressure was predictive. This central aorta during systole rather than diastole, further emphasizes the utility of the use of pulse pressure to increasing central SBP and pulse pressure. This late integrate the effects of both SBP and DBP and its physi- augmentation of SBP progressively reduces, and ulti- ological importance as a measure of conduit vessel mately eliminates, the normal augmentation of the pressure waveform that occurs as the pressure wave travels from the Of interest is the relationship between pulse pressure central aorta to peripheral arteries, such as the brachial and MAP across the tertiles of pulse pressure in SHEP.
artery, where blood pressure is usually evaluated. Thus, the Because large conduit vessels are nonlinearly elastic, an increase in pulse pressure in the brachial artery is indica- increase in MAP could lead to an increase in conduit vessel tive of, but systematically and substantially underesti- stiffness, which could lead to an increase in pulse pressure, mates, the increase in central aortic pulse pressure with regardless of the intrinsic stiffness or composition of the advancing age and increasing conduit vessel stiffness.
September 1999
Increased central aortic pulse pressure may play an confounding covariates. We recently studied the prognostic important role in the pathogenesis and manifestation of importance of pulse pressure in patients with left ventricular carotid and coronary atherosclerosis rather than simply dysfunction entered in the SOLVD trial.16 In this population serving as a marker of the presence of disease. Increased with left ventricular dysfunction and heart failure, pulse pulse pressure has been shown to promote the development pressure was again associated with increased mortality. In of atherosclerosis in a primate model29 and may increase contrast, in this heart failure–left ventricular dysfunction the likelihood of plaque rupture as a result of the fatiguing population, MAP was inversely correlated with increased risk effects of pulsatile strain.30 Several studies have docu- of death, further emphasizing the independent nature of mented the independent association between pulse pres- changes in MAP and pulse pressure and their effects on sure and measures of carotid artery disease, including intima-media thickness and plaque area.5–10,12–14 Pulse The studies discussed have examined patients across a pressure has also been related to small-vessel disease in the wide range of left ventricular function, from low in SOLVD cerebral circulation in animal models.31,32 Furthermore, to intermediate in SAVE to normal in SHEP. Together, they resolution of small-vessel remodeling in those studies was support the importance of aortic stiffening as an independent more closely related to changes in pulse pressure than to risk factor for adverse cardiovascular events. They raise the changes in MAP. Increased prevalence and severity of question of whether interventions that reduce conduit vessel white matter lesions, which are thought to be related to stiffness will have improved efficacy with respect to cardio- small-vessel disease, was associated with increased pulse vascular end points. Also, they emphasize the need for a more pressure in 1920 men and women 55 to 72 years of age direct measure of aortic stiffness, particularly if studies of the who were evaluated by magnetic resonance imaging as part therapeutic effectiveness of reducing aortic stiffness are of the Atherosclerosis Risk in Communities (ARIC) This is the first analysis to evaluate the direct effects of Clinical Implications
pulse pressure as a risk factor for a cerebrovascular The observation that increased pulse pressure is associated accident. Prior reports from the Framingham Heart Study1 with a higher risk of stroke and total mortality becomes and more recently from the Copenhagen City Heart Study3 particularly relevant as therapeutic options are shown to were consistent with a role of pulse pressure as a predictor have a differential effect on conduit vessel stiffness. This of stroke. Both studies found that SBP was superior to differential effect may translate into improved efficacy DBP as a determinant of stroke risk; however, neither with agents that preferentially reduce conduit vessel stiff- evaluated the quantitative effect of pulse pressure. Further- ness. Furthermore, such therapy may be preferentially more, the Framingham analysis established the connection targeted to patients with documented elevations of pulse between increased SBP and conduit vessel stiffness by pressure or conduit vessel stiffness. There is evidence that assessing an oscillometric finger-pulse tracing. They found currently available therapeutic interventions may be able that an abnormal pulse waveform, indicative of premature to modify conduit vessel stiffness. Lifestyle interventions, arrival of the reflected wave, was associated with an such as lower sodium intake33 and increased exercise,34,35 increased prevalence of isolated systolic hypertension.
are associated with improved aortic compliance. Convert- Additional studies have suggested the importance of pulse ing enzyme inhibitors have a highly favorable effect on pressure as an independent prognostic indicator for other conduit vessels.36 Low-dose diuretics effectively reduce cardiovascular end points, including myocardial infarction conduit vessel stiffness37 and pulse pressure38,39 in elderly and death.15–21 The effects of SBP, DBP, and pulse pressure patients. In contrast, ␤-blockers, as monotherapy, have were studied in the Hypertension Detection and Follow-up been shown to increase conduit vessel stiffness and the Program.21 In patients who were untreated at baseline, pulse magnitude of the reflected wave.40,41 Results with calcium pressure was a significant predictor of total mortality. In a channel blockers have been mixed.42– 44 Additional long- multivariate analysis, Madhaven et al19 found that increased term studies with direct, repeated measurements of conduit pulse pressure was an independent predictor of myocardial vessel stiffness are needed to further refine the role of infarction in a 5-year follow-up study of hypertensive indi- therapy targeted to reducing conduit vessel stiffness.
viduals. In a large sample of a general population, Darne et Another important clinical implication is that by use of al,17 and later Benetos et al18 in a follow-up analysis, found only SBP or DBP for study inclusion criteria and thera- that increased pulse pressure was associated with adverse peutic decisions, trialists and clinicians may be underesti- cardiovascular events, independent of MAP and other cardiac mating risk in patients with moderately increased SBP and The relationship between pulse pressure and adverse events was evaluated in the Survival and Ventricular Enlarge- Limitations
ment trial.15 Patients entered in the trial had recently had a Pulse pressure is an imperfect measure of vascular com- myocardial infarction and a left ventricular ejection fraction pliance. It seems unlikely, however, that other potential Յ0.40. Despite the reduction in ejection fraction, pulse determinants of increased pulse pressure, such as increased pressure emerged as a strong independent predictor of both peak ejection rate or stroke volume, would be associated total mortality and recurrent myocardial infarction in multi- with an adverse prognosis. Nonetheless, it is clear that variate analyses that adjusted for a number of potentially more direct measures of conduit vessel stiffness would be Domanski et al
Pulse Pressure in Systolic Hypertension
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analysis apply to elderly patients with isolated systolic 16. Domanski MJ, Mitchell GF, Norman J, Pitt B, Exener D, Pfeffer MA.
hypertension, specifically the population randomized into Independent prognostic information provided by sphygmomano-metrically determined pulse pressure and mean arterial pressure in SHEP. However, the prognostic importance of pulse pres- patients with left ventricular dysfunction. J Am Coll Cardiol. 1999;33: sure on total mortality has now been demonstrated across a wide range of patient populations.
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