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The Interaction of Vascular Stiffness and Cardiovascular Events in Women : Insights From the Heart and Estrogen/Progestin Replacement Study FREE TO VIEW

Hector O. Ventura, MD; Mandeep R. Mehra, MD
Author and Funding Information

Affiliations: New Orleans, LA
 ,  Dr. Ventura is Chairman, Graduate Medical Education Committee, and Dr. Mehra is Vice Chair, Department of Cardiovascular Medicine, Cardiomyopathy and Heart Transplantation Center, Ochsner Clinic Foundation, New Orleans, LA.

Correspondence to: Hector O. Ventura, MD, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121; e-mail: Hventura@ochsner.org



Chest. 2005;127(5):1477-1480. doi:10.1378/chest.127.5.1477
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Published online

The matter regarding hormone replacement therapy and cardiovascular events has been the subject of multiple publications. While observational studies depicted a protection from coronary events in patients receiving hormone replacement therapy, recent randomized trials have failed to show that promising evidence.1The Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled trial of 4.1 years in duration, and a subsequent, open-label, observational follow-up for 2.7 years (HERS II) enrolled 2,763 women with documented coronary artery disease to receive either conjugated equine estrogens (0.625 mg) and progestin medroxyprogesterone (2.5 mg) or placebo.24 The results of HERS demonstrated that hormone replacement therapy did not have a positive overall effect on cardiovascular outcomes, such as nonfatal infarction and mortality from coronary heart disease. A more detailed analysis of this trial demonstrated that during the first year of treatment, there was a significant increase in adverse coronary heart disease events (52% excess cardiovascular events); and during the follow-up period, including an additional 2.7 years, hormone replacement therapy did not confer any protective effects. Although the underlying mechanisms by which this may occur are speculative, a prothrombotic, proarrhythmic, or proischemic effect of hormonal replacement therapy could account for the early increased risk of coronary heart disease. These early detrimental effects, however, are steadily offset by the favorable changes in low- and high-density lipoprotein cholesterol of hormone replacement therapy, thus delaying the progression of underlying atherosclerosis. The large cohort of postmenopausal women included in HERS and the long-term follow-up have allowed the investigation of other issues that are relevant to women cardiovascular disease. Recently, a prospective substudy form the HERS cohort5 demonstrated that although randomization to hormone replacement did not increase the risk of heart failure, the presence of diabetes, myocardial infarction, atrial fibrillation, creatinine clearance of 40 mL/min, systolic BP of 120 mm Hg, current smoking, body mass index of 35, left bundle-branch block, and left ventricular hypertrophy were identified as strong risk factors for the development of heart failure in women. Of all the predictors, diabetes was the strongest risk factor (adjusted hazard ratio, 3.1; 95% confidence interval, 2.3 to 4.2). In the issue of CHEST (see page 1498), Nair et al report another very interesting observation from the HERS cohort. The authors examined the potential role of pulse pressure in the development of cardiovascular events in the HERS cohort. In addition, the authors explore another interesting and controversial issue: the effects of hormone replacement therapy on pulse pressure and vascular stiffness.

As Mahomed6wrote, “since the information which the pulse affords is of so great importance and so often consulted, surely it must be to our advantage to appreciate fully all it tells us, and to draw from every detail that is capable of imparting.” Although the study of the pulse dates back to Egypt, it was Frederick Akbar Horatio Mahomed, late in the nineteenth century, who recognized the importance of study in detail the radial pulse waveform. Utilizing a quantitative self-developed sphygmograph, Mahomed7 recognized the characteristics of the pulse waveform in hypertension:

The characteristic features of a pulse of high tension may be enumerated as follows: (1) a pressure above one ounce, and sometimes as high as ten ounces, is employed to develop the pulse tracing to its greatest extent; (2) the percussion wave is usually well marked and distinctly separated from the tidal; (3) the dicrotic wave is very small, and often scarcely perceptible; the vessels, however, are full during the diastolic period and collapse slowly; (4) the tidal wave is prolonged and too much sustained.

More recently, pulse waveform and indexes of vascular compliance and stiffness have been clinical and prognostic tools in patients with cardiovascular disease. For example, in patients with hypertension the combination of increased vascular stiffness and peripheral resistance produces a disproportionate increase in systolic pressure compared to mean diastolic pressure in the major central arteries, leading also to an increase in pulse pressure. The increase in systolic BP and pulse pressure has been shown to be a major risk factor for heart failure, myocardial infarction, and stroke, underscoring not only vascular stiffness as a important clinical measurement, but also as a prognostic factor for an increase in cardiovascular risk.811

Several methods have been evaluated to measure arterial stiffness in humans. However, pulse pressure, as the difference between systolic BP and diastolic BP, is a simple albeit indirect and clinically relevant measure of vascular stiffness.1213

Pulse pressure rises markedly after the fifth decade of life due to arterial stiffening with age, as the elastic function of the aorta lessens. The rise in vascular stiffness leads to several aberrations, such as an increase in ventricular afterload and myocardial oxygen demand, impairment of ventricular relaxation, and subendocardial ischemia. Hence, the aging heart is most susceptible to left ventricular dysfunction and ischemia.10,12,14 Increased pulse pressure is a prognostic factor for multiple cardiovascular events in prospective cohorts. Thus, it is associated with risk of myocardial infarction and mortality for cardiovascular disease in normotensive and hypertensive populations. Higher pulse pressures in patients after myocardial infarction and left ventricular dysfunction confer a greater risk for the future development of reinfarction and cardiovascular mortality.811,1517

The role of pulse pressure as a risk factor for the development of heart failure was studies in the community based East Boston Senior Health Project.18 The population studied consisted of 1,621 elderly men and women (66%) without heart failure who had complete BP measurements and were followed up prospectively for 3.8 years. At baseline evaluation, hypertension was present in 54.6%, diabetes in 19.3%, coronary heart disease in 10.3%, atrial fibrillation in 2.8%, and valvular heart disease in 1.8% of the patients. Mean systolic BP was 137 ± 19 mm Hg [± SD], mean diastolic BP was 75 ± 10 mm Hg, and pulse pressure was 62 ± 17 mm Hg. The authors demonstrate in this cohort that for each 10-mm Hg elevation of pulse pressure, there was a 14% increase in risk of heart failure (95% confidence interval, 1.05 to 1.24; p = 0.003). Patients in the highest tertile of pulse pressure (> 67 mm Hg) had a 55% increased risk of heart failure compared with those in the lowest tertile. These data support the concept that a rise in pulse pressure is a very significant risk factor for the development of heart failure.

The data regarding pulse pressure as cardiovascular risk factor in women are inconsistent and somewhat difficult to interpret for several reasons, including sample size, underrepresentation of women in cardiovascular clinical trials, and other confounding factors.1921 The results of the article reported herein add evidence to the existing literature on pulse pressure as a risk factor in women, since it analyzes the relationship between pulse pressure and cardiovascular events in HERS. The authors demonstrated that women in the highest quartile of baseline pulse pressure (> 70 mm Hg) have a significantly higher of myocardial infarction or coronary heart disease death compared in women in the lowest quartile. The highest quartile of pulse pressure was associated with increased rates of hospitalization for heart failure and stroke or transient ischemic attacks. After adjusting for other confounding variables, the association between pulse pressure and myocardial infarction and coronary heart disease death was attenuated. The robust association of increased pulse pressure with heart failure support the data previously reported in the East Boston Senior Health Project,18 which included 66% women. Since the study did not investigate the underlying mechanisms by which this relationship may occur, the authors speculate that in the analysis of HERS, the convincing relationship between the rise in pulse pressure and heart failure can be related to the fact that the increase in vascular stiffness in heart failure is not only a marker of generalized atherosclerosis, but also a reflection of left ventricular hypertrophy, increased myocardial work, and impairment of diastolic filling. Although clinically relevant and confirmatory, these data should be interpreted with caution. First, the population included in HERS consisted of women with underlying coronary artery disease, and therefore it should not generalized to all women; second, the inherent limitations of pulse pressure measurement are an indicator of vascular stiffness; third, BP was not a primary outcome of HERS; and finally, there may be observational biases in the analysis of these data.

The effects of hormone replacement therapy on vascular stiffness measured by different methodologies have been investigated in several small observational and randomized studies.2225 Similar to the controversies between observational and randomized trials evaluating cardiovascular events in women receiving hormone replacement therapy, the studies on the effects of hormonal replacement therapy on vascular stiffness have also achieved disparate results. The analysis of a nonrandomized study23utilizing estrogen alone and estrogen plus progestogen in 56 normotensive postmenopausal women demonstrated a decrease in pulse wave velocity; this an improvement in vascular stiffness in the hormonal replacement therapy group. Conversely, in a 2-year, double-blind, placebo-controlled, cross-over study24in 34 healthy postmenopausal women randomized to transdermal estrogen alone (50 μg) or placebo, there was no improvement in BP, lipid profiles, or vascular stiffness, compared with placebo, suggesting that there might not be a beneficial effect of transdermal hormone replacement therapy on the vasculature in postmenopausal women. Another 2-year randomized trial25 of 99 perimenopausal women utilizing oral 17β-estradiol and desogestrel (17βE[2]-D), conjugated equine estrogens and norgestrel, and placebo failed to demonstrate an improvement in arterial compliance after 6 months and 24 months of follow-up. Whether differences in study populations, the presence of diabetes, hypertension, race or type dose, and duration of hormone replacement therapy are the culprit for the disparate effects on vascular stiffness observed in the above-discussed trials is a matter of debate but it seems unlikely.

In HERS, hormone replacement therapy caused a small but significant increase in BP due to an increase in systolic BP. In addition, this difference in pulse pressure between the hormone replacement therapy and the placebo groups was not affected by other comorbidities, such as heart failure and diabetes. To the best of our knowledge, even with the limitations of this analysis, these results are the first to demonstrate in a large number of women with coronary artery disease that hormone replacement therapy does not improve vascular stiffness and perhaps may be deleterious. Future trials are needed to confirm these results.

This valuable observation in postmenopausal women obtained from the HERS cohort lends support to the value of an increase in pulse pressure, a measure of vascular stiffness, as a significant predictor of cardiovascular events. Women randomized to hormone replacement therapy had an increase in vascular stiffness compared to women in the placebo group. It will be important in the future not only to confirm these results but also to investigate in large clinical trials the potential utilization of pulse pressure as a therapeutic target in men and women with cardiovascular diseases. Furthermore, it will be also essential to explore the underlying mechanisms, including the particular contribution of hormone replacement therapy, by which vascular stiffness occurs in women. Studies1,26 have suggested that components of the renin-angiotensin system, matrix metalloproteinases, intracellular signaling, and extracellular matrix may be implicated in increasing vascular stiffness. Interventions intended at these targets may reduce vascular stiffness and may improve outcomes for men and women with cardiovascular diseases.

Dubey, R, Imthurm, B, Zacharia, L, et al (2004) Hormone replacement therapy and cardiovascular disease: what went wrong and where do we go from here?Hypertension44,789-795. [CrossRef] [PubMed]
 
Hulley, S, Grady, D, Bush, T, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group.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]
 
Grady, D, Herrington, D, Bittner, V, et al Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II).JAMA2002;288,49-57. [CrossRef] [PubMed]
 
Bibbins-Domingo, K, Lin, F, Vittinghoff, E, et al Predictors of heart failure among women with coronary disease.Circulation2004;110,1424-1430. [CrossRef] [PubMed]
 
Mahomed, FA The physiology and clinical use of the sphygmograph.Med Times Gazette (Lond)1872;1,62-65
 
Mahomed, FA The etiology of Bright’s disease and the prealbuminuric stage.Med Chir Trans1874;57,197-228. [PubMed]
 
O’Rourke, MF Arterial stiffness and hypertension. Izzo, JL Black, HR eds.Hypertension primer: the essentials of high blood pressure 2nd ed.1999,160-162 Lippincott, Williams, and Wilkins. Baltimore, MD:
 
Franklin, SS, Khan, SA, Wong, ND, et al The importance of pulse pressure and systolic blood pressure in predicting coronary heart disease in older adults: The Framingham Study.Circulation1999;100,354-360. [CrossRef] [PubMed]
 
O’Rourke, MF Isolated systolic hypertension, pulse pressure, and arterial stiffness as risks for cardiovascular disease.Curr Hypertens Rep1999;3,204-211
 
Smulyan, H, Safar, ME Systolic blood pressure revisited.J Am Coll Cardiol1997;29,1407-1413. [CrossRef] [PubMed]
 
O’Rourke, MF, Staessen, JA, Vlachopoulos, C, et al Clinical applications of arterial stiffness: definitions and reference values.Am J Hypertens2002;15,426-444. [CrossRef] [PubMed]
 
Ventura, H, Messerli, FH, Oigman, W, et al Impaired systemic arterial compliance in borderline hypertension.Am Heart J1984;108,132-136. [CrossRef] [PubMed]
 
Wang, YX, Fitch, RM Vascular stiffness: measurements, mechanisms and implications.Curr Vasc Pharmacol2004;2,379-384. [CrossRef] [PubMed]
 
Madhavan, S, Ooi, WL, Cohen, H, et al Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.Hypertension1994;23,395-401. [CrossRef] [PubMed]
 
Fang, J, Madhavan, S, Cohen, H, et al Measures of blood pressure and myocardial infarction in treated hypertensive patients.J Hypertens1995;13,413-419. [PubMed]
 
Benetos, A, Safar, M, Rudnichi, A, et al Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population.Hypertension1997;30,1410-1415. [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]
 
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]
 
Miura, S, Tanaka, E, Mori, A, et al Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women.Maturitas2003;45,293-298. [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]
 
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]
 
Schiffrin, EL Vascular stiffening and arterial compliance: implications for systolic blood pressure.Am J Hypertens2004;17,S39-S48
 

Figures

Tables

References

Dubey, R, Imthurm, B, Zacharia, L, et al (2004) Hormone replacement therapy and cardiovascular disease: what went wrong and where do we go from here?Hypertension44,789-795. [CrossRef] [PubMed]
 
Hulley, S, Grady, D, Bush, T, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group.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]
 
Grady, D, Herrington, D, Bittner, V, et al Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II).JAMA2002;288,49-57. [CrossRef] [PubMed]
 
Bibbins-Domingo, K, Lin, F, Vittinghoff, E, et al Predictors of heart failure among women with coronary disease.Circulation2004;110,1424-1430. [CrossRef] [PubMed]
 
Mahomed, FA The physiology and clinical use of the sphygmograph.Med Times Gazette (Lond)1872;1,62-65
 
Mahomed, FA The etiology of Bright’s disease and the prealbuminuric stage.Med Chir Trans1874;57,197-228. [PubMed]
 
O’Rourke, MF Arterial stiffness and hypertension. Izzo, JL Black, HR eds.Hypertension primer: the essentials of high blood pressure 2nd ed.1999,160-162 Lippincott, Williams, and Wilkins. Baltimore, MD:
 
Franklin, SS, Khan, SA, Wong, ND, et al The importance of pulse pressure and systolic blood pressure in predicting coronary heart disease in older adults: The Framingham Study.Circulation1999;100,354-360. [CrossRef] [PubMed]
 
O’Rourke, MF Isolated systolic hypertension, pulse pressure, and arterial stiffness as risks for cardiovascular disease.Curr Hypertens Rep1999;3,204-211
 
Smulyan, H, Safar, ME Systolic blood pressure revisited.J Am Coll Cardiol1997;29,1407-1413. [CrossRef] [PubMed]
 
O’Rourke, MF, Staessen, JA, Vlachopoulos, C, et al Clinical applications of arterial stiffness: definitions and reference values.Am J Hypertens2002;15,426-444. [CrossRef] [PubMed]
 
Ventura, H, Messerli, FH, Oigman, W, et al Impaired systemic arterial compliance in borderline hypertension.Am Heart J1984;108,132-136. [CrossRef] [PubMed]
 
Wang, YX, Fitch, RM Vascular stiffness: measurements, mechanisms and implications.Curr Vasc Pharmacol2004;2,379-384. [CrossRef] [PubMed]
 
Madhavan, S, Ooi, WL, Cohen, H, et al Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction.Hypertension1994;23,395-401. [CrossRef] [PubMed]
 
Fang, J, Madhavan, S, Cohen, H, et al Measures of blood pressure and myocardial infarction in treated hypertensive patients.J Hypertens1995;13,413-419. [PubMed]
 
Benetos, A, Safar, M, Rudnichi, A, et al Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population.Hypertension1997;30,1410-1415. [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]
 
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]
 
Miura, S, Tanaka, E, Mori, A, et al Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women.Maturitas2003;45,293-298. [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]
 
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]
 
Schiffrin, EL Vascular stiffening and arterial compliance: implications for systolic blood pressure.Am J Hypertens2004;17,S39-S48
 
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