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Circulation. 1997;96:4254-4260

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(Circulation. 1997;96:4254-4260.)
© 1997 American Heart Association, Inc.

Articles

Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function

Gary F. Mitchell, MD; Lemuel A. Moyé, MD, PhD; Eugene Braunwald, MD; Jean-Lucien Rouleau, MD; Victoria Bernstein, MD; Edward M. Geltman, MD; Greg C. Flaker, MD; Marc A. Pfeffer, MD, PhD; ; for the SAVE Investigators

From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (G.F.M., E.B., M.A.P.); the University of Texas Health Science Center and the School of Public Health, Houston (L.A.M.); the Institut de Cardiologie de Montreal, Québec (J.-L.R.), the University of British Columbia, Vancouver, British Columbia (V.B.); Washington University School of Medicine, St Louis, Mo (E.M.G.); and the University of Missouri Health Science Center, Columbia (G.C.F.).

Correspondence to Gary F. Mitchell, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail gfmitchell{at}bics.bwh.harvard.edu


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post–myocardial infarction patient population.

Methods and Results We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17; P<.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23; P<.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with ß-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy.

Conclusions These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.


Key Words: hemodynamics • arteriosclerosis • risk factors • atherosclerosis • aging


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
There is increasing evidence of a link between stiffness of the conduit vessels and cardiovascular morbidity. Measures of aortic stiffness have been demonstrated to be associated with left ventricular hypertrophy,1 myocardial infarction,2,3 and stroke4 in normotensive and hypertensive populations. The association between conduit vessel stiffness and recurrent cardiac events after myocardial infarction has not been evaluated, despite a number of factors that suggest such an association. Stiffening of the conduit vessels increases pulse-wave velocity, which results in premature return of the reflected pressure wave to the heart during systole. The reflected pressure wave adds to the forward wave and increases load on the heart, whereas the reflected flow wave diminishes forward flow and stroke volume.5 The impaired ventricle, with a reduced end-systolic elastance, may be sensitized to this incremental late-systolic load, resulting in a reduction in stroke volume.6 Movement of the reflected wave from diastole into systole diminishes coronary perfusion pressure and has been shown to produce ischemia in animal models both with7 and without8 epicardial coronary stenoses. This is particularly important in impaired hearts, in which elevated filling pressures may further limit coronary perfusion pressure and vasodilatory reserve.9 Finally, increased levels of pulse pressure have been implicated in the development and progression of large-vessel atherosclerosis10 and small-vessel disease.11–13 The present study evaluates the relationship between pulse pressure determined by sphygmomanometry, a simple and readily obtainable correlate of conduit vessel stiffness, and recurrent cardiovascular events in a large, prospectively followed population of survivors of a myocardial infarction.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
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The Survival and Ventricular Enlargement (SAVE) trial was a randomized, double-blind, placebo-controlled trial designed to determine whether long-term therapy with the ACE inhibitor captopril would improve survival in patients with significant left ventricular dysfunction but without overt heart failure after myocardial infarction.14 Patients 21 to 80 years of age with a radionuclide left ventricular ejection fraction of <=40% were randomized 3 to 16 (mean, 11) days after infarction and followed for an average of 42 months. Prospectively defined end points of the study considered in this analysis included mortality from all causes, mortality from cardiovascular causes, and recurrence of a myocardial infarction. A single seated blood pressure was measured by sphygmomanometry at the time of randomization, and pulse pressure was calculated as the difference between systolic and diastolic pressures. A standard formula was used to calculate mean arterial pressure from the sphygmomanometric blood pressure: systolic pressure and twice diastolic pressure were summed and then divided by three. The relationship between calculated mean arterial pressure and clinical outcome was then assessed. Clinical variables considered as potential correlates of adverse events included a prior history of hypertension, defined as a clinical history of elevation in blood pressure sufficient to require drug therapy at some point before the index infarction.

Statistical Analysis
The relationship between baseline characteristics and pulse pressure was determined by a general linear model. Patients were categorized by tertiles of systolic, diastolic, and pulse pressures. The relationship between end points and tertiles of systolic, diastolic, and pulse pressures was determined by the {chi}2 test. The association between pulse pressure as a continuous variable and time-dependent end points was evaluated with Cox proportional-hazards models that controlled first for mean arterial pressure alone and then for all baseline characteristics found to influence pulse pressure as well as other known predictors of outcome after myocardial infarction.


*    Results
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 up arrowMethods
 *Results
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Baseline Characteristics of the Study Population
Baseline characteristics of the study population according to level of pulse pressure are presented in Table 1Down. Significant positive relationships were found between pulse pressure and age, left ventricular ejection fraction, and mean arterial pressure. There was no relationship between pulse pressure tertile and heart rate or years of smoking, although there was a weak linear correlation between pulse pressure and years of smoking when both were treated as continuous variables (r=.062, P<.01). The proportion of the patients who were female increased with increasing pulse-pressure tertile. In addition, there were significant linear trends across tertiles of pulse pressure for increasing proportions of patients with histories of prior myocardial infarction or diabetes or a history of hypertension requiring drug therapy before the index infarction. There were significant positive associations between pulse pressure and use of calcium channel blockers, digoxin, diuretics, and nitrates within the 24 hours before randomization, whereas there was a negative association with use of ß-blockers. With increasing pulse pressure, there was an unexpected decrease in the proportion of patients who were smokers at the time of their index myocardial infarction.


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  		Table 1. Characteristics of the Patient Population When Segregated by Tertiles of Pulse Pressure

To evaluate the independent association of each of these covariates with pulse pressure, a general linear model was constructed that controlled for age, years of smoking, mean arterial pressure, and ejection fraction. Nonlinearity in the relationship between pulse pressure and age was evaluated by including a quadratic (age2) term. When the potential covariates were individually tested in this model, the associations with diuretic and nitrate use and current smoking status were not statistically significant. A final multivariate analysis of significant univariate correlates of pulse pressure revealed that use of digoxin (P=.01) or calcium channel blocking agents (P=.001), a history of diabetes (P<.001) or hypertension (P=.011), and female sex (P<.05) were independently associated with increased pulse pressure.

Adverse Cardiovascular Events
Patients were followed for an average of 42±10 months (range, 24 to 60 months), during which time there were 503 deaths, 422 cardiovascular deaths, and 303 recurrent myocardial infarctions. Systolic and pulse pressures had positive linear relationships with each of the end points (FigureDown). In contrast, diastolic pressure had no apparent relationship with any of the end points. Whereas previous studies have focused on systolic pressure as a prognostic indicator, from a physiological and therapeutic perspective, it is important to establish the relative effects of steady flow and pulsatile load on adverse events. Mean pressure correlates with steady flow load, which is a function of resistance vessel tone and cardiac output, whereas pulse pressure is an indicator of conduit vessel function and pulsatile load. Furthermore, because of the nonlinearity of arterial stiffness, pulse pressure is somewhat dependent on the level of mean arterial pressure. To determine which components of load were related to time-dependent end points, a proportional-hazards model was constructed that included both mean and pulse pressure (Table 2Down). Pulse pressure remained a highly significant predictor of each of the clinical end points independent of the level of mean arterial pressure. In contrast, mean arterial pressure remained independently predictive of an adverse outcome only for recurrent myocardial infarction.



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  		Figure 1. Relationship between baseline systolic, diastolic, and pulse pressure tertile and subsequent mortality, cardiovascular mortality, and recurrence of myocardial infarction (MI). P values represent a test for linear association.


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  		Table 2. Results of Cox Regression: Joint Effects of Pulse Pressure and Mean Arterial Pressure

To determine whether pulse pressure provides independent prognostic information in this already well-characterized patient population, a proportional-hazards model was constructed that included the correlates of pulse pressure identified above (age, years of smoking, ejection fraction, mean arterial pressure, sex, history of diabetes or hypertension, and use of calcium channel blockers or digoxin) as well as several other factors known to influence survival after myocardial infarction (use of aspirin, thrombolytic therapy, or ß-blockers; history of prior myocardial infarction; current smoking status; and randomization to captopril therapy). Pulse pressure remained independently predictive of total mortality (Table 3Down) and recurrence of myocardial infarction (Table 4Down).


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  		Table 3. Cox Proportional-Hazards Model for Mortality From All Causes1


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  		Table 4. Cox Proportional-Hazards Model for Recurrent Myocardial Infarction1


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The principal finding of this analysis is that a single, casual determination of pulse pressure, a readily obtainable correlate of pulsatile hemodynamic load, measured 3 to 16 days after myocardial infarction, was a powerful and independent predictor of adverse cardiovascular events in a large population of post–myocardial infarction patients with impaired left ventricular function. There were strong univariate associations between increased pulse pressure and total mortality, cardiovascular mortality, and recurrence of myocardial infarction. A multivariate analysis, which included an extensive list of factors thought or known to contribute to outcome after myocardial infarction, confirmed the independent prognostic implications of increased pulse pressure on total mortality and recurrence of myocardial infarction.

Pathophysiological Implications of Increased Vascular Stiffness
There are several potential explanations for the association between a higher pulse pressure and cardiac events in patients with coronary artery disease. Because it is unlikely that stroke volume or peak aortic flow was increased in these patients with left ventricular dysfunction after myocardial infarction, it may be presumed that the increased pulse pressure was a result of increased conduit vessel stiffness. Furthermore, it is likely that the increased load associated with conduit vessel stiffening contributed to a reduction in stroke volume in the patients with elevated pulse pressure. Conduit vessel stiffening increases the amplitude of the pressure pulse produced by a given flow wave, resulting in higher systolic and lower diastolic pressures for any given mean pressure. Pulse-wave velocity is increased in stiffened conduit vessels, and this shortens the time required for the forward pressure wave to travel down the aorta and peripheral conduits to the various reflecting sites and back to the heart. The resulting movement of the reflected wave from diastole into systole has no effect on mean arterial pressure. However, the premature reflected wave further increases the systolic pressure-time integral and decreases the diastolic pressure-time integral, thereby increasing systolic load while decreasing coronary perfusion pressure. The diastolic perfusion pressure gradient is further compromised if ventricular filling pressures are elevated.9 The latter is exacerbated by premature return of the reflected wave, which impairs left ventricular relaxation.15

Animal models have confirmed the enhanced susceptibility to ischemia of ventricles coupled to stiff aortas, both in the presence7 and absence8 of epicardial stenoses. Furthermore, the functional implications of regional ischemia are enhanced in animals with artificially stiffened aortas, with threefold greater reductions in systolic pressure and ejection fraction after coronary artery occlusion.16 Ischemia adequate to impair ventricular function and reduce systolic pressure may have a direct and immediate impact on global coronary blood flow that would otherwise be moderated by a more compliant arterial system with a higher diastolic pressure and predominantly diastolic coronary flow. An associated increase in heart rate and filling pressures during an ischemic episode could further impair coronary flow17 and initiate a catastrophic vicious cycle in these patients.

In addition to increasing left ventricular load and diminishing coronary perfusion pressure, conduit vessel stiffness correlates with the presence and severity of atherosclerosis. Because atherosclerosis modifies the physical properties of the conduit vessel wall,18,19 increased pulse pressure may simply serve as a marker for advanced or rapidly advancing atherosclerotic disease. Alternatively, stiffening of the conduit vessels may play a primary role in the development and progression of atherosclerosis. Age-related increases in pulse-wave velocity occur in populations in which the prevalence of atherosclerosis is low,20 indicating that atherosclerosis is not a necessary precursor of arterial stiffening. Increased vascular stiffness, independent of the presence of clinically apparent atherosclerosis, is associated with several established risk factors for coronary artery disease, including diabetes,21 hypertension,20 age,4,22–24 and a family history of myocardial infarction.25 Arterial stiffening could represent a component of the association between these risk factors and development of atherosclerosis. Pulse pressure and pulsatile diameter changes from diastole to systole have been shown to be important in the development of atherosclerosis of the aorta in a primate model.10 A 41% reduction in pulse pressure at constant mean pressure decreased aortic diameter change by 52% and reduced intimal plaque area by 82%. Stiffening of the peripheral conduits reduces the transit time of the reflected wave, resulting in progressive overlap between forward and reflected waves in the proximal aorta. This produces a disproportionately large increase in pulse pressure and pulsatile strains in the proximal aorta22,26 and thus in the coronary and carotid arteries and may thereby favor development of atherosclerosis in these vascular beds.

Clinical Correlates of Increased Pulse Pressure
Well-known correlates of conduit vessel stiffness, including age24,27 and a history of diabetes21 or hypertension,20 were found to be related to pulse pressure in the present analysis. Two additional important associations that deserve further comment were the finding of a higher pulse pressure in women and in patients treated with calcium channel blockers. The finding of a higher pulse pressure in the female patients in this study is consistent with the observation that systolic pressure increases more rapidly with age in women than in men.4,27 Elevated pulse pressure may represent one additional risk factor that must be considered when differences in outcome in men and women with coronary artery disease are compared.

The association between use of calcium channel blockers and increased pulse pressure is intriguing in light of recent controversies regarding an increased frequency of ischemic events in hypertensive patients treated with these agents.28 Calcium channel blockade has been shown to have a favorable short-term effect on conduit vessel function and pulsatile hemodynamics in hypertensive patients in some studies29 but not in others.30 Longer-term studies in animals31 and in humans32 have suggested that favorable acute effects of calcium channel blockade on conduit vessel function may be offset over time by compensatory changes in left ventricular contractility and arterial structure and function. It is important to note that calcium channel blockade in our patients was not randomized. Therefore, differences in pulse pressure may be related to a bias toward prescribing these agents in patients with refractory or long-standing hypertension. Ongoing randomized, double-blind clinical trials designed to evaluate the relationship between calcium channel blocker therapy and clinical events in hypertensive patients will provide an opportunity to determine whether pulse pressure is relatively higher in patients treated with calcium channel blockers as opposed to other antihypertensive agents.

Pulsatile Load and Adverse Clinical Events
A number of small studies have related left ventricular mass to various measures of pulsatile load.1,33–38 Because increased left ventricular mass has been correlated with adverse events,39–41 it may be hypothesized that pulsatile load is related to clinical outcome, although few studies have directly evaluated this relationship. A recently proposed vascular overload index, which sums the increments in mean and pulse pressure (relative to a normal blood pressure of 120/80 mm Hg), was shown to have a direct linear relationship with adverse events that was qualitatively superior to the relationship between events and systolic or diastolic pressure alone.42 In a study of nonhypertensive adults, the pulsatile component index, a strong correlate of pulse pressure, was derived by a principal-components analysis of systolic and diastolic pressures.2 An association between the pulsatile component index and ECG evidence of left ventricular hypertrophy was observed. During follow-up, the pulsatile component index was associated with an increased risk of death from coronary artery disease. However, a significant relationship was found only in women >55 years old. In a prospective evaluation of hypertensive patients, those in the highest tertile of pulse pressure before the initiation of therapy (>=63 mm Hg) had an increased risk of myocardial infarction and stroke during an average follow-up of 5 years.3 In the latter study, multivariate analysis revealed that pulse pressure as a categorical variable (although not as a continuous variable) was an independent predictor of myocardial infarction.

The relative effects of diastolic, systolic, and pulse pressures on 5-year mortality were evaluated in the Hypertension Detection and Follow-up Program.43 Pulse pressure was shown to be a significant predictor of total mortality in a logistic regression model that included age, race, sex, randomized antihypertensive therapy, diabetes, hypertensive end-organ damage, and smoking. The relative risk of 1.11 per 10 mm Hg increment in pulse pressure exceeded that of diastolic (1.05) and systolic (1.08) pressures. In a model that included only patients who were untreated at baseline, pulse pressure remained significant even when the model included systolic pressure, although the two variables are highly correlated. Furthermore, in that model, pulse pressure had a relative risk (1.19) that was >1, whereas systolic pressure had a relative risk (0.93) that was quantitatively <1 after the effects of pulse pressure had been considered. These data suggest an important role for pulse pressure as a predictor of adverse outcome in hypertensive patients, even though the authors concluded that the data lent no strong support to such a notion. Our study adds to the foregoing observations and suggests an even stronger relationship between conduit vessel stiffness and adverse events in patients with known coronary artery disease and impaired left ventricular function.

Therapeutic Implications
Abnormalities in conduit vessel function are modifiable.35,44–48 For example, a low-salt diet followed for an average of 24.8 months by normotensive patients produced a pressure-independent decrease in pulse-wave velocity, suggesting a modification of the intrinsic properties of the aorta.44 ACE inhibition has been shown to decrease blood pressure, wave reflection, and pulse-wave velocity and to increase arterial compliance and conduit vessel diameter.35,45–48 Over the course of several weeks, the effects on conduit function are enhanced, resulting in normalization of conduit vessel function in a hypertensive patient population. Further studies are needed to determine whether a reduction in pulse pressure should be a goal of therapy in the postinfarction patient population.

The observed reduction in recurrent myocardial infarction with ACE inhibition has been associated with only modest reductions in blood pressure, leading to investigation of potential nonhemodynamic effects of treatment.49 It is likely, however, that the change in peripheral blood pressure with therapy reported in the foregoing studies underestimated the reduction in central aortic systolic and pulse pressures, especially in patients with stiff conduit vessels. In young adults with highly compliant central conduits, there is considerable amplification of the pressure pulse as it propagates distally into the progressively stiffer peripheral conduits. As the central conduit vessels stiffen, the reflected wave returns to the heart prematurely and becomes an important determinant of peak systolic and pulse pressure in the central aorta. In contrast, peak systolic pressure in the brachial artery is determined by the primary pressure wave well into the eighth decade of age.22 This disproportionate increase in central aortic systolic pressure obscures normal amplification of the primary pressure pulse with distal propagation. Vasodilators decrease the amplitude and delay the return of the reflected wave and thereby decrease or eliminate the late systolic peak in central aortic pressure.50–55 The normal differences between central and peripheral pressures are thereby restored. Because the reflected wave determines neither systolic nor diastolic pressure in the peripheral artery, changes in the amplitude and timing of the reflected wave go unnoticed by sphygmomanometry. Consequently, vasodilators have been shown to reduce central systolic pressure an average of 5 to 10 mm Hg more than is indicated by the change in peripheral pressure, with discrepancies ranging as high as 40 mm Hg. Accounting for this discrepancy by use of more sophisticated measures of conduit vessel function in future studies should considerably narrow the gap between hemodynamic effect and clinical benefit.

Limitations
The dependence of pulse pressure on stroke volume and peak aortic blood flow, both of which may be decreased after extensive infarction, could potentially obscure a relationship between conduit vessel stiffening and mortality after infarction. Despite this, we found a relationship between pulse pressure as a continuous variable and clinical events, including a reduction in event rate in patients with a pulse pressure substantially below the median value of 40 mm Hg. In contrast, the observed association between ß-blocker usage and reduced pulse pressure should strengthen the relationship between the latter and adverse events, because the selection bias for use of ß-blockers in healthier patients and the protective effect of the therapy are both likely to favorably impact prognosis. However, pulse pressure remained independently predictive of events even after these potentially confounding factors were controlled for. Heart rate might also influence pulse pressure because of the inverse relationship with stroke volume. However, we found no association between heart rate and pulse pressure or between heart rate and subsequent events.

The dependence of pulse pressure on hemodynamic factors (stroke volume, peak aortic blood flow) other than aortic and peripheral conduit vessel stiffness per se makes this an imperfect indicator of conduit vessel function. Conversely, several important parameters are integrated into this single, easily obtainable measurement. Future studies will need to assess more direct measures of conduit vessel stiffness, such as pulse-wave velocity, proximal aortic compliance, characteristic impedance, and waveform morphology, to determine to what extent increased pulse pressure is a measure of conduit vessel stiffness. The transfer function (alteration in waveform morphology) between central aorta and radial artery has been shown to be remarkably consistent across a wide range of ages.56,57 As a result, calibrated noninvasive recordings of radial arterial pressure waveforms using arterial tonometry and a generalized transfer function may allow for accurate determination of central aortic pressure amplitude and morphology and their change under therapy.56

It is important to note that this analysis is exploratory in nature and was not a prespecified analysis of the SAVE study. As a result, prospective confirmation of our results is needed. These observations apply to a highly selected population of patients with a recent myocardial infarction and impaired left ventricular function.

Clinical Implications
The importance of risk stratification and targeted secondary prevention after myocardial infarction is clear, although the proper algorithm to optimize cost and benefit continues to evolve. In the present era, the potential benefits of technologically advanced evaluations must be balanced against their cost. It is interesting to note that a century after the description by Riva-Rocci of the modern sphygmomanometer,58 pulse pressure, a long-overlooked measurement provided by this simple, cheap, and universally available instrument, should prove so valuable in risk stratification after myocardial infarction. Further studies will be needed to establish whether pulse pressure and other measures of conduit vessel function can be used as tools for targeting primary and secondary prevention in a broader segment of the population.


*    Acknowledgments
 
The SAVE study was supported by a grant from the Bristol-Myers Squibb Institute for Pharmaceutical Research, which was not involved in the acquisition or management of data and did not have access to unblinded information during the conduct of the study.

Received May 30, 1997; revision received September 1, 1997; accepted September 15, 1997.


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 up arrowDiscussion
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