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Clinical Investigations: CARDIOLOGY |

Pulse Pressure and Cardiovascular Events in Postmenopausal Women With Coronary Heart Disease* FREE TO VIEW

Girish V. Nair, MD, MS; Lily A. Chaput, MD, MPH; Eric Vittinghoff, PhD; David M. Herrington, MD, MHS; for the Heart and Estrogen/Progestin Replacement Study Investigators
Author and Funding Information

*From the Department of Internal Medicine/Cardiology (Drs. Nair and Herrington), Wake Forest University School of Medicine, Winston-Salem, NC; and the Department of Epidemiology and Biostatistics (Drs. Chaput and Vittinghoff), University of California-San Francisco, CA.

Correspondence to: David M. Herrington, MD, MHS, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: dherring@wfubmc.edu



Chest. 2005;127(5):1498-1506. doi:10.1378/chest.127.5.1498
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Published online

Background: Pulse pressure (PP) has been shown to predict risk for cardiovascular events in men; however, this association has not been well established in women. Hormone replacement therapy may improve arterial compliance, but findings from cross-sectional and prospective studies report inconsistent results. We sought to examine the relationship between PP and risk for cardiovascular events, and to determine the effect of hormone therapy on PP in postmenopausal women with coronary heart disease (CHD).

Methods and results: A total of 2,763 postmenopausal women (mean age, 66 ± 7 years [± SD]) with CHD in the Heart and Estrogen/Progestin Replacement Study, a randomized, placebo-controlled, secondary CHD prevention trial of estrogen plus progestin, were followed up on average for 4.1 years. BP was measured at baseline and annually. Mean baseline PP was 62 ± 16 mm Hg. There were 361 myocardial infarctions (MIs) or CHD deaths, 265 hospitalizations for congestive heart failure (CHF), and 215 strokes or transient ischemic attacks (TIAs). Women in the highest quartile of PP at baseline had a 47% increase in risk for MI or CHD death and more than a twofold increase in risk for stroke and TIA events or hospitalization for CHF (p < 0.01 for each outcome). After adjustment for other cardiovascular risk factors and mean arterial pressure, PP remained significantly associated with incident stroke or TIA events (odds ratio, 1.25; p = 0.02) and hospitalizations for CHF (odds ratio, 1.31; p < 0.01) but not with MI or CHD death. After adjustment for diastolic BP, systolic BP was similarly associated with stroke or TIA (odds ratio, 1.30; p < 0.01) and hospitalized CHF (odds ratio, 1.30; p < 0.01) and was also weakly associated with risk for MI and CHD death (odds ratio, 1.18; p = 0.02). Mean PP was 1- to 2-mm Hg higher in women randomized to hormone replacement therapy vs those receiving placebo (p < 0.01).

Conclusions: PP had predictive value for CHF and stroke or TIA, but not MI or CHD death in this cohort of postmenopausal women with CHD. Use of hormone replacement therapy produced a small, statistically significant increase in PP. Further research is necessary to determine the clinical utility of PP as a potential therapeutic target.

Figures in this Article

Brachial pulse pressure (PP), a noninvasive indirect index of arterial stiffness, is a significant predictor of risk for myocardial infarction (MI),12 congestive heart failure (CHF),35 stroke,56 restenosis following percutaneous coronary intervention,7 and total mortality.6,89 However, most large cohort studies examining the association between PP and cardiovascular risk have included few, if any, women. Even in studies46,10 with moderate numbers of women, gender-specific analyses are not always provided.

The relationship between PP and cardiovascular events may be more complex in women because of the potential effects of estrogen on arterial stiffness.

Several small clinical studies1114 of estrogen effects on arterial stiffness have produced conflicting results. Additional data are needed to clarify the association of PP with cardiovascular disease risk in postmenopausal women and to determine the effect of postmenopausal hormone therapy use on PP.

In this study, we examined the association between baseline brachial PP and the incidence of MI or coronary heart disease (CHD) death, hospitalization for CHF, and stroke or transient ischemic attack (TIA) in postmenopausal women with known CHD enrolled in the Heart and Estrogen/Progestin Replacement Study (HERS)15 during the 4.1 years of follow-up. In addition, the effects of hormone replacement therapy on PP were assessed to explore additional mechanisms by which estrogen may influence cardiovascular health.

Subjects

The design, methods, and primary results of the HERS have been published previously.1516 Briefly, 2,763 postmenopausal women aged < 80 years with an intact uterus and established CHD were randomized to receive either a single tablet containing 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate or identical placebo and followed up on average for 4.1 years. CHD was defined as prior MI, coronary artery bypass graft surgery, percutaneous coronary intervention, or angiographic evidence of ≥ 50% luminal diameter narrowing of any one or more major coronary artery segments. Women were excluded for the following: a clinical cardiac event within 6 months of randomization, uncontrolled hypertension (systolic BP > 200 mm Hg or diastolic BP > 105 mm Hg), uncontrolled diabetes mellitus, elevated serum triglycerides (> 300 mg/dL), New York Heart Association class IV or severe class III CHF, a contraindication to hormone therapy, or a disease that was judged to be fatal within 4 years. One participant was excluded from this analysis because of incomplete BP data, yielding a total sample of 2,762 subjects.

BP Measurements

BP was measured using standard methods with a mercury sphygmomanometer. Measurements were taken in the seated position by trained and certified staff. Baseline and annual follow-up systolic and diastolic BP readings were derived from the average of two measurements. Subjects were asked to refrain from caffeine, eating, heavy physical activity, smoking, and alcohol for 30 min before each examination. PP was calculated as the difference between the averaged systolic and diastolic readings. Mean arterial pressure was calculated as the sum of one third the systolic reading plus two thirds the diastolic reading.

Outcomes

Follow-up visits occurred every 4 months over a mean of 4.1 years. Data pertaining to outcome measures were collected by the Coordinating Center at the University of California, San Francisco. Two physicians at the Coordinating Center who were unaware of treatment assignment independently reviewed all outcome events. An independent committee of cardiologists, blinded to treatment assignment, adjudicated all primary outcomes. The three HERS end points considered in the analysis included MI or CHD death, hospitalization for CHF, and stroke or TIA.

Statistical Analysis

Baseline PP was divided into approximate quartiles by 10-mm Hg increments (< 50, ≥ 50 to 60, ≥ 60 to 70, and ≥ 70 mm Hg). Differences in baseline variables according to PP quartile were assessed using Mantel-Haenszel χ2 test for proportions for categorical variables and analysis of variance for continuous variables. Analysis of covariance was performed to identify baseline variables that remained independently associated with PP (p < 0.05) in a multivariable model. Time to first event by PP quartile was compared using Kaplan-Meier survival curves for each of the three outcomes. The log-rank test was used to test for differences in the survival curves. The association between baseline PP and subsequent risk for cardiovascular events was evaluated using Cox proportional hazards models after adjusting for demographic factors, cardiovascular risk factors and treatment assignment, baseline medications, and factors that modify PP independent of the intrinsic stiffness of the central aorta and brachiocephalic artery (ie, mean arterial pressure, height, and heart rate).

To investigate the effects of hormone therapy, on-trial PP was modeled as a function of time, treatment assignment (intention-to-treat), baseline PP, and on-trial mean arterial pressure using generalized estimating equations. Qualitatively similar results were obtained when all follow-up PPs were averaged together to produce a single estimate of postrandomization PP. Similarly, on-trial systolic and diastolic BPs were modeled after adjusting for time, treatment, and baseline systolic and diastolic BPs, respectively. A nominal, two-tailed p value < 0.05 was considered statistically significant. All analyses were conducted using software (Version 6.12; SAS Institute; Cary, NC).

Baseline Characteristics and Predictors of Baseline PP

The mean baseline PP was 62 ± 16 mm Hg. Mean systolic and diastolic BPs were 135 ± 19 mm Hg and 73 ± 10 mm Hg, respectively. Based on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (HTN-JNC VI) criteria,17 39% of the women were hypertensive at baseline (Table 1 ).

In multivariable models, the best predictor of baseline PP was mean arterial pressure (partial R2 = 0.24, p = 0.0001) [Table 1]. Other significant predictors included age, race, education level, previous MI, history of diabetes, calcium channel blocker use, height, and heart rate. A trend toward significance was seen with serum creatinine and α-blocker use. Collectively, these variables accounted for 37% of the variance in PP (p = 0.0001).

Relationship Between Baseline PP and Subsequent Cardiovascular Events

Women in the highest quartile of baseline PP (≥ 70 mm Hg) had a significantly higher risk of MI or CHD death compared to women in the lowest quartile (p < 0.01) [Table 2] . Kaplan-Meier curves demonstrated an overall difference in times to MI or CHD death among PP quartile (log-rank p value = 0.01) [Fig 1] , with increased levels of PP associated with an increased rate of MI or CHD death. Similarly, the highest quartile of PP was significantly associated with increased rates of hospitalizations for CHF (log-rank p value = 0.0001) [Table 2, Fig 2] and stroke or TIA (log-rank p value = 0.0001) [Table 2, Fig 3] .

In the Cox proportional hazards models, adjusting for demographic and cardiovascular risk factors, baseline medications, and factors known to influence PP (height, heart rate, and mean arterial pressure), a 1-SD increase in PP (16 mm Hg) was associated with a nonsignificant 13% increased risk for subsequent MI or CHD death (Table 3 ). In contrast, a similar increase in PP was associated with a significant 25% increased risk for stroke or TIA and a 31% increased risk for hospitalization for CHF. In similar models, systolic BP was associated with a 15% increased risk for MI or CHD death and hospitalization for CHF, and a 22% increased risk of stroke. Diastolic BP was not significantly associated with any of the three outcomes. When models of systolic BP were further adjusted for diastolic BP (the arithmetic equivalent of PP adjusted for mean arterial pressure), the association between systolic BP and all three outcomes was similar to that for PP (data not shown).

Effects of Hormone Therapy on BP

At randomization, mean PP, and systolic and diastolic BPs were the same in the two treatment groups. However, at 1 year of follow-up, women randomized to receive hormone therapy had a 2-mm Hg increase in mean PP vs women in the placebo group (64 ± 17 mm Hg vs 62 ± 17 mm Hg, p = 0.04), a difference that persisted to the end of the trial (p < 0.01) [Fig 4] . The effects of hormone therapy on PP were driven by an increase in systolic BP among those women randomized to active therapy (Fig 5 ; p value for treatment < 0.0001, p value for time trend < 0.01). Diastolic BP remained unchanged during follow-up (p value for time trend = 0.21) and did not differ between the treatment groups (p value for treatment = 0.78).

In this study of postmenopausal women with CHD, brachial PP was a significant predictor of stroke and TIA, and hospitalization for CHF in univariate analysis. An association was also present between PP and MI or CHD death, but this association was greatly attenuated with adjustment for other potential confounders. PP was roughly equivalent to systolic BP as a predictor of MI and CHD death or stroke and TIA events. However, PP was more strongly associated with risk for hospitalization for CHF than was systolic BP. After adjusting for mean arterial pressure, a 1-SD increase in PP was associated with a 25 to 30% increase in risk for stroke and TIA or hospitalization for CHF. Hormone replacement therapy was associated with a small but statistically significant increase in PP; however, the clinical significance of this effect is questionable.

The stiffness of the aorta is determined by the distending pressure of the aorta (mean arterial pressure) and the mechanoelastic properties of the vessel wall.1819 Glycation of vascular matrix proteins from nonenzymatic cross-links between glucose and amino groups produces advanced-glycation end products,20which are thought to be associated with increased collagen cross-linking and subsequent increased arterial stiffness.2122 There is also aging-associated disorganization and fracture of aortic elastin fibers that contribute to increases in arterial stiffness.18Increased aortic stiffness results in higher systolic and lower diastolic BPs because of shifts in the pressure-volume relationship in the aorta, loss of elastic recoil in diastole, and more rapid return of reflected pressure waves, resulting in pressure augmentation during end-systole. Thus, PP is often considered an indirect measure for central aortic stiffness. This is true despite the well-documented effect of pressure amplification in the upper extremities leading to overestimation of central aortic pressure from brachial recordings.19 Height and heart rate also influence PP owing to their effects on timing of the reflected wave and stroke volume, respectively.19 Where possible PP/stroke volume index may provide a superior estimate of arterial stiffness.23 The apparent association between calcium channel blocker use in the current study may be a consequence of the drug or due to greater rates calcium channel blocker use in subjects with increased PP.

Increased vascular stiffness is likely associated with risk for coronary or cerebrovascular thrombotic events because it is a marker for generalized vascular atherosclerosis and because of the effects of increased stiffness on intimal shear stress.24 However, for CHF, increased arterial stiffness is not simply a marker of generalized vascular risk, but rather a central mechanism in the pathogenesis of heart failure due to increased myocardial work, stimulation of left ventricular hypertrophy, and subsequent impaired diastolic filling. This may account for the stronger association of PP with CHF than CHD events in the current study.

Results from the few previous studies of PP and CHD events in women are inconsistent and difficult to interpret. For example, several studies have reported on the association between PP and cardiovascular events after adjustment for systolic BP.2526 Similarly, extremely large studies that examine the association between PP and cardiovascular events without adjusting for mean arterial pressure27 do not effectively isolate the component of arterial stiffness embedded in PP measurements and may therefore fail to detect significant associations. However, statistical models that contain both PP and systolic BP may produce biased or unstable estimates due to overadjustment or collinearity between PP and systolic BP. One study25 excluded women with diastolic BP < 60 mm Hg, potentially excluding subjects with the highest PPs, and many prior studies are limited by modest sample size.12 Similar issues exist for the few previously published studies of PP and cerebrovascular events 8,2627 or CHF3 in women.

There is also no clear consensus from the literature concerning the effects of hormone therapy on arterial compliance in postmenopausal women. Numerous observational or small uncontrolled intervention studies2830 have suggested that hormone therapy had favorable effects on various measures of arterial stiffness. However, a similarly large number of studies,14,3136 including several small randomized clinical trials, have failed to find any evidence of benefit. Differences in study populations, comorbid conditions (eg, diabetes, hypertension, coronary disease), or type, dose, or duration of therapy do not appear to account for the variability in the results of these previous studies. In contrast to the previous studies, HERS,16 was a randomized clinical trial with > 2,500 women; in this study, hormone therapy caused a small but significant increase in PP, primarily as a result of increases in systolic BP. The difference in on-trial PP between the hormone therapy and placebo study arms was not affected by cardiovascular disease state (CHD, CHF, and diabetes). Although differential dropout in the active vs placebo arms of hormone therapy trials can bias results, it is hard to imagine that selective dropout of women with low PP could account for the observed difference in PP by treatment arm. Based on these data, hormone therapy does not appear to improve PP in postmenopausal women with CHD and may, in fact, have an adverse effect. Certain antihypertensive therapies,3740 statins,41and newly developed thiazolium derivatives that are designed to decrease advanced-glycation end product cross-links4244 improve vascular compliance, although their efficacy in women compared to men is not yet well established.

Our examination of the association between PP and cardiovascular events was observational, and confounding from unmeasured variables may bias results. In addition, BP was not a primary outcome in the HERS. Although BP was measured using standard methods and reflects the average of two readings, these were casual measures and may not reflect an individual’s usual BP. Brachial PP overestimates central PP because of pressure amplification in the upper extremities19; however, this is less likely in older individuals due to increased peripheral resistance and earlier return of the reflected wave.38 Finally, the subjects in this study were primarily white, all had established CHD, and were participants in a randomized trial; therefore, these data may not be generalizable to all women.

In summary, in this cohort of postmenopausal women with established CHD, brachial PP was a significant predictor of cardiovascular events, most notably hospitalizations for CHF. Hormone therapy resulted in a small, but statistically significant, increase in PP, although the clinical significance of this change is uncertain. With new therapies specific for arterial stiffness now available, future randomized clinical studies will be needed to determine if PP is a useful therapeutic target in women as well as men.

Abbreviations: CHD = coronary heart disease; CHF = congestive heart failure; HERS = Heart and Estrogen/Progestin Replacement Study; HTN-JNC VI = sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; MI = myocardial infarction; PP = pulse pressure; TIA = transient ischemic attack

The Heart and Estrogen/Progestin Study was supported by a contract from Wyeth-Ayerst Research (Radnor, PA). This work was also supported in part through a grant from Eli Lilly and Company, Indianapolis, IN.

Table Graphic Jump Location
Table 1. Baseline Characteristics of Participants and Predictors of PP*
* 

Data are presented as mean ± SD or No. (%). LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein; ACE = angiotensin-converting enzyme; CCB = calcium channel blocker; MAP = mean arterial pressure.

 

Multivariate adjusted for pulse pressure as a continuous variable.

 

Adjusted for all variables except HTN-JNC VI.

§ 

p Values are based on this model except for HTN-JNC VI.

Table Graphic Jump Location
Table 2. Event Rate (Per 1,000 Person-Years) and Relative Hazard by Baseline PP*
* 

RH = relative hazard; CI = confidence interval.

 

p Value < 0.01.

 

p Value < 0.001 relative to participants with a PP < 50 mm Hg.

Figure Jump LinkFigure 1. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for fatal CHD and MI in the HERS cohort (overall log-rank p = 0.01).Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for hospitalization for CHF in the HERS cohort (overall log-rank p = 0.0001).Grahic Jump Location
Figure Jump LinkFigure 3. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for hospitalization for stroke or TIA in the HERS cohort (overall log-rank p = 0.0001).Grahic Jump Location
Table Graphic Jump Location
Table 3. Association of PP, Systolic BP, and Diastolic BP With Cardiovascular Events*
* 

See Table 2 for expansion of abbreviations. After adjustment for age, race (white vs nonwhite), years of education, marital status, diabetes, previous MI, New York Heart Association level I–III heart failure class, exercise, smoking, alcohol consumption, serum creatinine, serum triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol level, waist-hip ratio, treatment assignment, and baseline medications (statins, aspirin, angiotensin-converting enzyme inhibitors, α- and β-blockers, calcium channel blockers, diuretics, height, and heart rate). Models containing pulse pressure are also adjusted for mean arterial pressure.

 

Relative hazard for 1-SD increase in PP, systolic BP, or diastolic BP.

Figure Jump LinkFigure 4. Mean PP over time in the placebo (circles) and hormone treatment (HT) [squares] arms in the HERS cohort (treatment p < 0.01; time p < 0.0001). Adjusted for mean arterial pressure and baseline PP.Grahic Jump Location
Figure Jump LinkFigure 5. Mean systolic BP (SBP) over time in the placebo (circles) and hormone treatment (squares) arms in the HERS cohort (treatment p < 0.0001; time p < 0.001). Adjusted for baseline systolic BP (mean arterial pressure was removed). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location

We are indebted to Bonny P. McClain, MS, for editorial contributions.

Madhavan, S, Ooi, WL, Cohen, H, et al (1994) Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.Hypertension23,395-401. [CrossRef] [PubMed]
 
Mitchell, GF, Moye, LA, Braunwald, E, et al Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function.Circulation1997;96,4254-4260. [CrossRef] [PubMed]
 
Chae, CU, Pfeffer, MA, Glynn, RJ, et al Increased pulse pressure and risk of heart failure in the elderly.JAMA1999;281,634-639. [CrossRef] [PubMed]
 
Vaccarino, V, Holford, TR, Krumholz, HM Pulse pressure and risk for myocardial infarction and heart failure in the elderly.J Am Coll Cardiol2000;36,130-138. [CrossRef] [PubMed]
 
Vaccarino, V, Berger, AK, Abramson, J, et al Pulse pressure and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program.Am J Cardiol2001;88,980-986. [CrossRef] [PubMed]
 
Blacher, J, Staessen, JA, Girerd, X, et al Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients.Arch Intern Med2000;160,1085-1089. [CrossRef] [PubMed]
 
Nakayama, Y, Tsumura, K, Yamashita, N, et al Pulsatility of ascending aortic pressure waveform is a powerful predictor of restenosis after percutaneous transluminal coronary angioplasty.Circulation2000;101,470-472. [CrossRef] [PubMed]
 
Benetos, A, Rudnichi, A, Safar, M, et al Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects.Hypertension1998;32,560-564. [CrossRef] [PubMed]
 
Domanski, MJ, Norman, J, Wolz, M, et al Cardiovascular risk assessment using pulse pressure in the first National Health and Nutrition Examination Survey (NHANES I).Hypertension2001;38,793-797. [CrossRef] [PubMed]
 
Franklin, SS, Khan, SA, Wong, ND, et al Is pulse pressure useful in predicting risk for coronary disease? The Framingham Heart Study.Circulation1999;100,354-360. [CrossRef] [PubMed]
 
McGrath, BP, Liang, Y-L, Teede, H, et al Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy.Arterioscler Thromb Vasc Biol1998;18,1149-1156. [CrossRef] [PubMed]
 
Bui, MN, Arai, AE, Hathaway, L, et al Effects of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women.Am J Cardiol2002;90,82-85. [CrossRef] [PubMed]
 
Angerer, P, Kothny, W, Stork, S, et al Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial.J Am Coll Cardiol2000;36,1789-1796. [CrossRef] [PubMed]
 
Hayward, CS, Samaras, K, Campbell, L, et al Effect of combination hormone replacement therapy on ambulatory blood pressure and arterial stiffness in diabetic postmenopausal women.Am J Hypertens2001;14,699-703. [CrossRef] [PubMed]
 
Hulley, SB, Grady, D, Bush, T, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA1998;280,605-613. [CrossRef] [PubMed]
 
Grady, D, Applegate, W, Bush, T, et al Heart and Estrogen/Progestin Replacement Study (HERS): design, methods and baseline characteristics.Control Clin Trials1998;19,314-335. [CrossRef] [PubMed]
 
Joint National Committee on Prevention. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med1997;157,2413-2416. [CrossRef] [PubMed]
 
Nichols, W, O’Rourke, M Contours of pressure and flow waves in arteries. Nichols, WW O’Rourke, MF eds.McDonald’s blood flow in arteries1998,180-185 Edward Arnold. London, UK:
 
Dart, AM Pulse pressure: a review of mechanisms and clinical relevance.J Am Coll Cardiol2001;37,975-984. [CrossRef] [PubMed]
 
Vasan, S, Zhang, X, Kapurniotu, A, et al An agent cleaving glucose-derived protein crosslinksin vitroandin vivo.Nature1996;382,275-278. [CrossRef] [PubMed]
 
Lee, AT, Cerami, A Role of glycation in aging.Ann NY Acad Sci1992;663,63-70. [CrossRef] [PubMed]
 
Airaksinen, KE, Salmela, PI, Linnaluoto, MK, et al Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen.Cardiovasc Res1993;27,942-945. [CrossRef] [PubMed]
 
Palmieri, V, Bella, JN, Roman, MJ, et al Pulse pressure/stroke index and left ventricular geometry and function: the LIFE Study.J Hypertens2003;21,781-787. [CrossRef] [PubMed]
 
Jiang, Y, Kohara, K, Hiwada, K Low wall shear stress contributes to atherosclerosis of the carotid artery in hypertensive patients.Hypertens Res1999;22,203-207. [CrossRef] [PubMed]
 
Miura, K, Dyer, AR, Greenland, P, et al Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: The Chicago Heart Association Detection Project in Industry Study.Hypertension2001;38,232-237. [CrossRef] [PubMed]
 
Antikainen, RL, Jousilahti, P, Vanhanen, H, et al Excess mortality associated with increased pulse pressure among middle-aged men and women is explained by high systolic blood pressure.J Hypertens2000;18,417-423. [CrossRef] [PubMed]
 
Lewington, S, Clarke, R, Qizilbash, N, et al Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet2002;360,1903-1913. [CrossRef] [PubMed]
 
Kawecka-Jaszcz, K, Czarnecka, D, Olszanecka, A, et al The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension.J Hum Hypertens2002;16,509-516. [CrossRef] [PubMed]
 
Rajkumar, C, Kingwell, BA, Cameron, JD, et al Hormonal therapy increases arterial compliance in postmenopausal women.J Am Coll Cardiol1997;30,350-356. [CrossRef] [PubMed]
 
Liang, YL, Teede, H, Shiel, LM, et al Effects of oestrogen and progesterone on age-related changes in arteries of postmenopausal women.Clin Exp Pharmacol Physiol1997;24,457-459. [CrossRef] [PubMed]
 
Rodriguez-Macias, KA, Naessen, T, Bostrom, A, et al Arterial stiffness is not improved in long-term use of estrogen.Am J Obstet Gynecol2002;186,189-194. [CrossRef] [PubMed]
 
Vehkavaara, S, Westerbacka, J, Hakala-Ala-Pietila, T, et al Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women.J Clin Endocrinol Metab2000;85,4663-4670. [CrossRef] [PubMed]
 
Teede, HJ, Liang, YL, Kotsopoulos, D, et al Placebo-controlled trial of transdermal estrogen therapy alone in postmenopausal women: effects on arterial compliance and endothelial function.Climacteric2002;5,160-169. [PubMed]
 
Weinberger, MH, Fineberg, NS, Fineberg, SE Effects of age, race, gender, blood pressure, and estrogen on arterial compliance.Am J Hypertens2002;15,358-363. [CrossRef] [PubMed]
 
Teede, HJ, Liang, YL, Kotsopoulos, D, et al A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.Clin Endocrinol (Oxf)2001;55,673-682. [CrossRef] [PubMed]
 
Westendorp, IC, de Kleijn, MJ, Bots, ML, et al The effect of hormone replacement therapy on arterial distensibility and compliance in perimenopausal women: a 2-year randomised trial.Atherosclerosis2000;152,149-157. [CrossRef] [PubMed]
 
Et-Taouil, K, Schiavi, P, Levy, BI, et al Sodium intake, large artery stiffness, and proteoglycans in the spontaneously hypertensive rat.Hypertension2001;38,1172-1176. [CrossRef] [PubMed]
 
Franklin, SS Is there a preferred antihypertensive therapy for isolated systolic hypertension and reduced arterial compliance?Curr Hypertens Rep2000;2,253-259. [CrossRef] [PubMed]
 
Kelly, RP, Millasseau, SC, Ritter, JM, et al Vasoactive drugs influence aortic augmentation index independently of pulse-wave velocity in healthy men.Hypertension2001;37,1429-1433. [CrossRef] [PubMed]
 
Van Bortel, LM, Struijker-Boudier, HA, Safar, ME Pulse pressure, arterial stiffness, and drug treatment of hypertension.Hypertension2001;38,914-921. [CrossRef] [PubMed]
 
Ferrier, KE, Muhlmann, MH, Baguet, J-P, et al Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension.J Am Coll Cardiol2002;39,1020-1025. [CrossRef] [PubMed]
 
Wolffenbuttel, BH, Boulanger, CM, Crijns, FR, et al Breakers of advanced-glycation end products restore large artery properties in experimental diabetes.Proc Natl Acad Sci U S A1998;95,4630-4634. [CrossRef] [PubMed]
 
Asif, M, Egan, J, Vasan, S, et al An advanced glycation end product cross-link breaker can reverse age-related increased in myocardial stiffness.Proc Natl Acad Sci U S A2000;97,2809-2813. [CrossRef] [PubMed]
 
Vaitkevicius, PV, Lane, M, Spurgeon, H, et al A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys.Proc Natl Acad Sci U S A2001;98,1171-1175. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for fatal CHD and MI in the HERS cohort (overall log-rank p = 0.01).Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for hospitalization for CHF in the HERS cohort (overall log-rank p = 0.0001).Grahic Jump Location
Figure Jump LinkFigure 3. Kaplan-Meier estimate of event-free survival by quartiles of baseline PP (unadjusted) for hospitalization for stroke or TIA in the HERS cohort (overall log-rank p = 0.0001).Grahic Jump Location
Figure Jump LinkFigure 4. Mean PP over time in the placebo (circles) and hormone treatment (HT) [squares] arms in the HERS cohort (treatment p < 0.01; time p < 0.0001). Adjusted for mean arterial pressure and baseline PP.Grahic Jump Location
Figure Jump LinkFigure 5. Mean systolic BP (SBP) over time in the placebo (circles) and hormone treatment (squares) arms in the HERS cohort (treatment p < 0.0001; time p < 0.001). Adjusted for baseline systolic BP (mean arterial pressure was removed). See Figure 4 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Baseline Characteristics of Participants and Predictors of PP*
* 

Data are presented as mean ± SD or No. (%). LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein; ACE = angiotensin-converting enzyme; CCB = calcium channel blocker; MAP = mean arterial pressure.

 

Multivariate adjusted for pulse pressure as a continuous variable.

 

Adjusted for all variables except HTN-JNC VI.

§ 

p Values are based on this model except for HTN-JNC VI.

Table Graphic Jump Location
Table 2. Event Rate (Per 1,000 Person-Years) and Relative Hazard by Baseline PP*
* 

RH = relative hazard; CI = confidence interval.

 

p Value < 0.01.

 

p Value < 0.001 relative to participants with a PP < 50 mm Hg.

Table Graphic Jump Location
Table 3. Association of PP, Systolic BP, and Diastolic BP With Cardiovascular Events*
* 

See Table 2 for expansion of abbreviations. After adjustment for age, race (white vs nonwhite), years of education, marital status, diabetes, previous MI, New York Heart Association level I–III heart failure class, exercise, smoking, alcohol consumption, serum creatinine, serum triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol level, waist-hip ratio, treatment assignment, and baseline medications (statins, aspirin, angiotensin-converting enzyme inhibitors, α- and β-blockers, calcium channel blockers, diuretics, height, and heart rate). Models containing pulse pressure are also adjusted for mean arterial pressure.

 

Relative hazard for 1-SD increase in PP, systolic BP, or diastolic BP.

References

Madhavan, S, Ooi, WL, Cohen, H, et al (1994) Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.Hypertension23,395-401. [CrossRef] [PubMed]
 
Mitchell, GF, Moye, LA, Braunwald, E, et al Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function.Circulation1997;96,4254-4260. [CrossRef] [PubMed]
 
Chae, CU, Pfeffer, MA, Glynn, RJ, et al Increased pulse pressure and risk of heart failure in the elderly.JAMA1999;281,634-639. [CrossRef] [PubMed]
 
Vaccarino, V, Holford, TR, Krumholz, HM Pulse pressure and risk for myocardial infarction and heart failure in the elderly.J Am Coll Cardiol2000;36,130-138. [CrossRef] [PubMed]
 
Vaccarino, V, Berger, AK, Abramson, J, et al Pulse pressure and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program.Am J Cardiol2001;88,980-986. [CrossRef] [PubMed]
 
Blacher, J, Staessen, JA, Girerd, X, et al Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients.Arch Intern Med2000;160,1085-1089. [CrossRef] [PubMed]
 
Nakayama, Y, Tsumura, K, Yamashita, N, et al Pulsatility of ascending aortic pressure waveform is a powerful predictor of restenosis after percutaneous transluminal coronary angioplasty.Circulation2000;101,470-472. [CrossRef] [PubMed]
 
Benetos, A, Rudnichi, A, Safar, M, et al Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects.Hypertension1998;32,560-564. [CrossRef] [PubMed]
 
Domanski, MJ, Norman, J, Wolz, M, et al Cardiovascular risk assessment using pulse pressure in the first National Health and Nutrition Examination Survey (NHANES I).Hypertension2001;38,793-797. [CrossRef] [PubMed]
 
Franklin, SS, Khan, SA, Wong, ND, et al Is pulse pressure useful in predicting risk for coronary disease? The Framingham Heart Study.Circulation1999;100,354-360. [CrossRef] [PubMed]
 
McGrath, BP, Liang, Y-L, Teede, H, et al Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy.Arterioscler Thromb Vasc Biol1998;18,1149-1156. [CrossRef] [PubMed]
 
Bui, MN, Arai, AE, Hathaway, L, et al Effects of hormone replacement therapy on carotid arterial compliance in healthy postmenopausal women.Am J Cardiol2002;90,82-85. [CrossRef] [PubMed]
 
Angerer, P, Kothny, W, Stork, S, et al Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial.J Am Coll Cardiol2000;36,1789-1796. [CrossRef] [PubMed]
 
Hayward, CS, Samaras, K, Campbell, L, et al Effect of combination hormone replacement therapy on ambulatory blood pressure and arterial stiffness in diabetic postmenopausal women.Am J Hypertens2001;14,699-703. [CrossRef] [PubMed]
 
Hulley, SB, Grady, D, Bush, T, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA1998;280,605-613. [CrossRef] [PubMed]
 
Grady, D, Applegate, W, Bush, T, et al Heart and Estrogen/Progestin Replacement Study (HERS): design, methods and baseline characteristics.Control Clin Trials1998;19,314-335. [CrossRef] [PubMed]
 
Joint National Committee on Prevention. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med1997;157,2413-2416. [CrossRef] [PubMed]
 
Nichols, W, O’Rourke, M Contours of pressure and flow waves in arteries. Nichols, WW O’Rourke, MF eds.McDonald’s blood flow in arteries1998,180-185 Edward Arnold. London, UK:
 
Dart, AM Pulse pressure: a review of mechanisms and clinical relevance.J Am Coll Cardiol2001;37,975-984. [CrossRef] [PubMed]
 
Vasan, S, Zhang, X, Kapurniotu, A, et al An agent cleaving glucose-derived protein crosslinksin vitroandin vivo.Nature1996;382,275-278. [CrossRef] [PubMed]
 
Lee, AT, Cerami, A Role of glycation in aging.Ann NY Acad Sci1992;663,63-70. [CrossRef] [PubMed]
 
Airaksinen, KE, Salmela, PI, Linnaluoto, MK, et al Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen.Cardiovasc Res1993;27,942-945. [CrossRef] [PubMed]
 
Palmieri, V, Bella, JN, Roman, MJ, et al Pulse pressure/stroke index and left ventricular geometry and function: the LIFE Study.J Hypertens2003;21,781-787. [CrossRef] [PubMed]
 
Jiang, Y, Kohara, K, Hiwada, K Low wall shear stress contributes to atherosclerosis of the carotid artery in hypertensive patients.Hypertens Res1999;22,203-207. [CrossRef] [PubMed]
 
Miura, K, Dyer, AR, Greenland, P, et al Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: The Chicago Heart Association Detection Project in Industry Study.Hypertension2001;38,232-237. [CrossRef] [PubMed]
 
Antikainen, RL, Jousilahti, P, Vanhanen, H, et al Excess mortality associated with increased pulse pressure among middle-aged men and women is explained by high systolic blood pressure.J Hypertens2000;18,417-423. [CrossRef] [PubMed]
 
Lewington, S, Clarke, R, Qizilbash, N, et al Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet2002;360,1903-1913. [CrossRef] [PubMed]
 
Kawecka-Jaszcz, K, Czarnecka, D, Olszanecka, A, et al The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension.J Hum Hypertens2002;16,509-516. [CrossRef] [PubMed]
 
Rajkumar, C, Kingwell, BA, Cameron, JD, et al Hormonal therapy increases arterial compliance in postmenopausal women.J Am Coll Cardiol1997;30,350-356. [CrossRef] [PubMed]
 
Liang, YL, Teede, H, Shiel, LM, et al Effects of oestrogen and progesterone on age-related changes in arteries of postmenopausal women.Clin Exp Pharmacol Physiol1997;24,457-459. [CrossRef] [PubMed]
 
Rodriguez-Macias, KA, Naessen, T, Bostrom, A, et al Arterial stiffness is not improved in long-term use of estrogen.Am J Obstet Gynecol2002;186,189-194. [CrossRef] [PubMed]
 
Vehkavaara, S, Westerbacka, J, Hakala-Ala-Pietila, T, et al Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and preresistance and resistance vessel function in healthy postmenopausal women.J Clin Endocrinol Metab2000;85,4663-4670. [CrossRef] [PubMed]
 
Teede, HJ, Liang, YL, Kotsopoulos, D, et al Placebo-controlled trial of transdermal estrogen therapy alone in postmenopausal women: effects on arterial compliance and endothelial function.Climacteric2002;5,160-169. [PubMed]
 
Weinberger, MH, Fineberg, NS, Fineberg, SE Effects of age, race, gender, blood pressure, and estrogen on arterial compliance.Am J Hypertens2002;15,358-363. [CrossRef] [PubMed]
 
Teede, HJ, Liang, YL, Kotsopoulos, D, et al A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.Clin Endocrinol (Oxf)2001;55,673-682. [CrossRef] [PubMed]
 
Westendorp, IC, de Kleijn, MJ, Bots, ML, et al The effect of hormone replacement therapy on arterial distensibility and compliance in perimenopausal women: a 2-year randomised trial.Atherosclerosis2000;152,149-157. [CrossRef] [PubMed]
 
Et-Taouil, K, Schiavi, P, Levy, BI, et al Sodium intake, large artery stiffness, and proteoglycans in the spontaneously hypertensive rat.Hypertension2001;38,1172-1176. [CrossRef] [PubMed]
 
Franklin, SS Is there a preferred antihypertensive therapy for isolated systolic hypertension and reduced arterial compliance?Curr Hypertens Rep2000;2,253-259. [CrossRef] [PubMed]
 
Kelly, RP, Millasseau, SC, Ritter, JM, et al Vasoactive drugs influence aortic augmentation index independently of pulse-wave velocity in healthy men.Hypertension2001;37,1429-1433. [CrossRef] [PubMed]
 
Van Bortel, LM, Struijker-Boudier, HA, Safar, ME Pulse pressure, arterial stiffness, and drug treatment of hypertension.Hypertension2001;38,914-921. [CrossRef] [PubMed]
 
Ferrier, KE, Muhlmann, MH, Baguet, J-P, et al Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension.J Am Coll Cardiol2002;39,1020-1025. [CrossRef] [PubMed]
 
Wolffenbuttel, BH, Boulanger, CM, Crijns, FR, et al Breakers of advanced-glycation end products restore large artery properties in experimental diabetes.Proc Natl Acad Sci U S A1998;95,4630-4634. [CrossRef] [PubMed]
 
Asif, M, Egan, J, Vasan, S, et al An advanced glycation end product cross-link breaker can reverse age-related increased in myocardial stiffness.Proc Natl Acad Sci U S A2000;97,2809-2813. [CrossRef] [PubMed]
 
Vaitkevicius, PV, Lane, M, Spurgeon, H, et al A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys.Proc Natl Acad Sci U S A2001;98,1171-1175. [CrossRef] [PubMed]
 
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