Sex Difference in Cardiovascular Risk: Role of Pulse Pressure Amplification

Abstract

Objectives

Our aim was to explore whether the carotid/brachial pulse pressure (C/B-PP) ratio selectively predicts the gender difference in age-related cardiovascular death.

Background

Hypertension and cardiovascular complications are more severe in men and post-menopausal women than in pre-menopausal women. C-PP is lower than B-PP, and the C/B-PP ratio is a physiological marker of PP amplification between C and B arteries which tends toward 1.0 with age.

Methods

The study involved 72,437 men (aged 41.0±11.1 years, mean±SD) and 52,714 women (39.5±11.6 years). C-PP was calculated for each gender by a multiple regression analysis including B-PP, age, height and risk factors, a method validated beforehand in a subgroup of 834 subjects. During the 12 years of follow-up, 3028 men and 969 women died.

Results

In the total population, the adjusted hazard ratios (HR, 95% CI) of C/B-PP ratio were: (i) for all cause mortality: men, 1.51 (1.47–1.56), women, 2.46 (2.27–2.67) (p<0.0001); (ii) for cardiovascular mortality: men, 1.81 (1.70–1.93), women, 4.46 (3.66–5.45) (p<0.0001). The C/B-PP impact on mortality did not significantly increase from younger men to those over 55, from: 1.44 (1.31–1.58) to 1.65 (1.48–1.84), but increased significantly with age in women: 3.19 (2.08–4.89) vs 5.60 (4.17–7.50) (p<0.01). Thus the mortality impact of C/B-PP ratio was 3-fold higher in women than in men over 55.

Conclusions

The C/B amplification is highly predictive of differences in cardiovascular risk between men and women. In post-menopausal women, the attenuation of PP amplification, mainly related to increased aortic stiffness, contributes to the significant increase in cardiovascular risk.

Introduction

A greater incidence of hypertension and cardiovascular (CV) complications is widely observed in men and post-menopausal women when compared with pre-menopausal women. This epidemiological finding has suggested that the female sex hormone estrogen and, to a lesser extent, the sex hormones progesterone and testosterone, possess under clinical situations significant vascular protective properties which disappear after the menopause.(1–7) However, recently, the effects of menopausal hormonal therapy (MHT), as well as data from randomized clinical trials such as the Women’s Health Initiative study, have challenged the hypothesis of the potential CV benefits of estrogen treatment.(6,7) In these studies, the potential negative role of the participants’ age, preexisting CV disease and the type of estrogen used were suggested(6) but the major role of blood pressure (BP) was poorly taken into consideration: most of the patients were hypertensive (38%).

Studies of pulsatile arterial hemodynamics have shown that BP in women presents very particular hemodynamic characteristics. First, there are classically two distinct components of BP: mean arterial pressure (MAP) and pulse pressure (PP).(8) Whereas MAP refers exclusively to steady pressure, vascular resistance and hence small arteries, PP refers to pulsatile pressure which has three determinants, stroke volume, arterial stiffness and wave reflections. Only the latter two factors impinge on PP in large arteries and, in post-menopausal women, the role of PP predominates over that of MAP in the mechanism of high BP. Second, physiologically, PP and systolic BP (SBP) are consistently higher in peripheral than in central arteries for the same MAP and diastolic BP (DBP).(8,9) This aspect, called SBP or PP amplification, is due to the changes in arterial stiffness, principally affecting the propagation of the pressure wave and wave reflections along the arterial tree.(9) In post-menopausal women,(10–12) SBP and PP amplification are considerably attenuated because central SBP and PP increase more rapidly with age than do brachial SBP or PP. Consequently the carotid to brachial PP ratio (C/B ratio) increases and tends towards 1.0 with aging and arterial stiffness.

Recently, our group has shown that brachial (B) PP, carotid (C) PP, and carotid PP/brachial PP ratio (or C/B ratio), are all significant and independent CV risk factors and that the most powerful predictor of CV death is the C/B ratio.(13) In the present study, our working hypothesis is that the C/B ratio should be significantly associated with the gender difference in age-dependent cardiovascular risk. In order to assess the observed mortality rates in both genders in the general low-to-moderate risk population, we have at our disposal a large sample of 125,151 subjects. We determined mathematically the central carotid artery PP by an equation established in an independent sample of 834 subjects.

Methods

Subjects

Subjects were examined at the IPC (“Investigations Preventives et Cliniques”) Center (Paris-France). This medical center, which is subsidized by the French national health care system (Sécurité Sociale-CNAMTS), offers a free medical examination to working and retired individuals and their families and thus carries out approximately 25000 health examinations per year for inhabitants of the Paris area.

The IPC study population consisted of 72,437 (41.0±11.1 years) men and 52,714 (39.5±11.6 years) women who had a health checkup at the IPC Center between January 1981 and December 1988 (Table I). Subjects with previous CV disease were excluded, in order to focus on primary prevention. Although the specific date of menopause was not available in our global database, in a more recent cohort of 35,000 women explored in the IPC center, we found that after the age of 55, 98% had gone through menopause (data not shown). As a consequence, in the present study women over 55 were considered as being post-menopausal.

Table 1.

Characteristics of the population according to gender and age

	Men		Women		Age effect	Gender effect	Age* gender interaction
	<55 years	≥55 years	<55 years	≥55 years
n	62888	9549	46187	6527
Age (years)	38.3 (9.1)	58.9 (4.7)	36.8 (9.5)	58.9 (4.9)
Weight (kg)	73.7 (10.6)	75.4 (10.8)	58.1 (9.4)	61.2 (10.2)	<0.0001	<0.0001	<0.0001
Height (cm)	174.2 (6.7)	171.2 (6.6)	161.1 (6.2)	158.0 (6.0)	<0.0001	<0.0001	<0.0001
Body mass index (kg/m2)	24.3 (3.2)	25.7 (3.2)	22.4 (3.5)	24.5 (3.9)	<0.0001	<0.0001	<0.0001
Plasma glycemia (g/l)	1.02 (0.12)	1.07 (0.20)	0.95 (0.10)	1.03 (0.14)	<0.0001	<0.0001	<0.0001
Plasma creatinine (mg/l)	10.41 (1.25)	10.66 (1.48)	8.46 (1.15)	8.76 (1.35)	<0.0001	<0.0001	0.0008
Plasma cholesterol (g/l)	2.17 (0.45)	2.37 (0.42)	2.00 (0.39)	2.49 (0.42)	<0.0001	<0.0001	<0.0001
Systolic blood pressure (mmHg)	133.8 (12.8)	142.5 (16.3)	126.6 (12.9)	139.9 (17.2)	<0.0001	<0.0001	<0.0001
Diastolic blood pressure (mmHg)	82.2 (9.8)	87.8 (10.6)	77.3 (9.6)	85.3 (10.4)	<0.0001	<0.0001	<0.0001
Mean arterial pressure (mmHg)	99.4 (10.2)	106.0 (11.9)	93.8 (10.1)	85.3 (10.4)	<0.0001	<0.0001	<0.0001
Heart rate ≥80 beats/min (%, n)	16.1 (10 142)	17.0 (1626))	20.1 (9269)	18.0 (1173)	<0.0001	<0.0001	<0.0001
Brachial PP (mmHg)	51.6 (8.3)	54.7 (10.1)	49.3 (8.1)	54.7 (10.9)	<0.0001	<0.0001	<0.0001
Carotid PP (mmHg)	33.5 (7.0)	38.8 (8.8)	39.9 (7.1)	47.2 (9.4)	<0.0001	<0.0001	<0.0001
Carotid/Brachial PP	0.64 (0.05)	0.70 (0.04)	0.81 (0.03)	0.86 (0.01)	<0.0001	<0.0001	<0.0001
Hypertensive subjects (%, n)	42.2 (26530)	68.1 (6495)	22.3 (10301)	59.7 (3883)	<0.0001	<0.0001	<0.0001
Antihypertensive treatment* (%, n)	2.32 (1459)	10.1 (967)	2.46 (1134)	14.4 (939)	<0.0001	<0.0001	<0.0001
Current smokers (%, n)	35.4 (22 238)	23.8 (2269)	25.3 (11670)	10.8 (702)	<0.0001	<0.0001	<0.0001
Subjects with aspirin treatment or anti inflammatory agent (%, n)	7.8 (4879)	10.4 (990)	14.0 (6468)	20.2 (1318)	<0.0001	<0.0001	<0.0001
All-cause mortality (‰, n)	31 (1929)	115 (1099)	13 (604)	56 (365)	<0.0001	<0.0001	<0.0001
Cardiovascular mortality (‰, n)	5 (313)	30 (287)	1.2 (57)	12 (78)	<0.0001	<0.0001	<0.0001

Mean (SD), PP=pulse pressure.

^*with or without antidiabetic or hypolipidemic agent

Antihypertensive drug therapy (present or past) concerned 4,499 patients (3.60% of the IPC population). The follow-up ended in 1998. During this period (mean duration: 12.1±2.2 years), 3028 men and 969 women died; Among these deaths, CV disease was responsible in 600 men and 135 women. The measurement methods employed have been described in detail elsewhere.(14) Briefly, supine BP was measured in the right arm using a manual mercury sphygmomanometer, after a 10-minute rest period. The first and the fifth Korotkoff sounds were used to define SBP and DBP. The mean of three measurements was considered as the peripheral blood pressure value. Brachial PP was calculated as SBP-DBP. Height (using a wall-mounted stadiometer) and weight (using calibrated scales) were recorded by a nurse. Standard biological parameters, including total plasma cholesterol, triglycerides, and glycemia, were measured under fasting conditions, and a resting electrocardiogram (ECG) was recorded. Heart rate was measured on the ECG. Tobacco consumption (present: yes/no), physical activity (exercising more than one hour of walking per day: yes/no), personal medical history, were assessed using a self-administered questionnaire. All clinical and biological parameters were evaluated on the same day of the examination.

Brachial and central carotid BP measurements

To assess the mortality rates associated with CV causes in such a low-to-moderate CV risk population, we needed a large sample of subjects. As direct measurements of central carotid artery PP cannot be available in such a large population, at least in our institution, we determined this parameter mathematically from brachial PP, using an equation first evaluated in an independent sample of 834 subjects and then validated in a second independent population of 285 individuals.

In order to assess a method of calculating carotid PP, a population of 834 subjects, taken from the Hotel Dieu Hospital population (ME.S.), for whom carotid PP was measured by applanation tonometry, was selected. The aim was to develop a method to determine carotid PP by calculation, using multiple regression analysis associating brachial PP (measured by sphygmomanometry), some significant risk factors and other hemodynamic and biochemical variables,(11,12,15,16) and to validate the method by comparison with carotid PP values measured directly by tonometry. A complete description of the procedure is given in reference(13) of this paper.

Briefly, in 834 subjects, brachial BP determinations were performed in the supine position after a 15-minute rest in the laboratory by traditional mercury sphygmomanometry. Central BP determinations were made by performing radial and carotid artery applanation tonometry using a high-fidelity Millar strain gauge transducer (SPT-301; Millar Instruments, Houston, Texas, USA).(8,11,12,17–19) The derived pressure waveforms were recorded on a Gould 8188 recorder (Gould Electronic, Boulainvilliers, France) at a paper speed of 100 mm/s. Radial artery pressure waveform, calibrated from brachial artery SBP and DBP, was used for the determination of peripheral MAP via application of an integration method. Since DBP and MAP differences throughout the arterial tree do not exceed 2–3 mmHg,(8,17,20,21) the resulting carotid BP wave was calibrated using brachial DBP and MAP. MAP, computed from the area method, was assumed to be equal to peripheral mean BP in order to calculate the amplitude of the carotid pressure waveform as well as carotid PP and SBP. Carotid PP is considered as a close surrogate of aortic PP.(22,23)

The reproducibility of hemodynamic measurements has been published in detail elsewhere, particularly regarding carotid PP.(22,23) PP amplification between carotid PP and brachial PP (mmHg) was calculated as the C/B ratio. In the present subpopulation, the carotid PP measured by tonometry and pulse wave analysis was compared with the values calculated from a gender-specific multiple regression analysis deduced from the same 834 patients studied, including 480 men and 354 women (equations are shown in the expanded methods). To further validate the carotid PP evaluation we applied these equations to another distinct population of 285 individuals (147 men, 138 women), investigated in the Nancy Hospital (France)(24,25) (see the expanded methods). We calculated the correlation between the evaluated carotid PP and the measured carotid PP using the same methodology (applanation tonometry) but performed by another trained investigator. The observed R² were 0.888 (p<0.0001) in men and 0.889 (p<0.0001) in women. The Bland-Altman analysis for comparison of both methods for central PP determination has shown that 2 SDs for individual differences was 12.18 mmHg in men and 12.45 mmHg in women, without any drift of the regression lines (see the expanded methods). The mean value for the individual difference in carotid PP was −0.50 mmHg in men and −6.45 mmHg in women. After this validation, the calculation of carotid PP was then applied to the total IPC population.

Statistical analysis

The impact of brachial and carotid PP and PP amplification (C/B ratio) on all-cause and CV mortality was evaluated using Cox regression models including age, gender, height, weight and risk factors (smoking, physical activity, cholesterol and diabetes mellitus). Additional adjustment for MAP in the Cox regression model was also performed. Because the C/B ratio is known to be highly influenced by pulse rate,(13) models also included pulse rate as an adjusting factor. Hazard ratios for all-cause and CV mortalities (HR, and 95% confidence interval) were calculated for each increase of 1 SD of brachial PP, carotid PP and the C/B ratio. All quantitative variables used in the regression model or in the carotid PP equation were normally distributed and colinearity assessment was taken into account in multivariate analysis. The presence or absence of anti-hypertensive therapy did not modify the results. To evaluate the effect of gender, Cox regression models were carried out separately in men and women.

Secondly, the effect of age was investigated by dividing men and women into 2 categories (<55 or ≥55 years of age) and analysing men and women separately. The threshold of 55 years of age was chosen for this analysis because of its link with the menopause. Hazard ratios (HR) were adjusted for height, weight, risk factors (smoking, physical activity, cholesterol and diabetes mellitus) and heart rate. The inclusion of MAP as a covariate did not alter the results (data not shown). The interaction of age was calculated.

All statistical analyses, including interactions, were performed with the version 8.2 of the SAS statistical software and a p value below 0.05 was considered as significant.

Results

Clinical characteristics of the population

The population was composed of 72,437 men (41.0±11.1 years) and 52,714 women (39.5±11.6 years). MAP was respectively 100.3±10.7 in men and 95.0±10.8 mm Hg in women. Brachial PP was respectively 52.0±8.6 and 49.9±8.7 mmHg, calculated carotid PP was 34.2±7.5 mm Hg and 40.8±7.8 mmHg and the C/B ratio was 0.65±0.05 in men and 0.82±0.03 in women (p<0.0001).

Table 1 shows the characteristics of the population divided into two categories of age. The younger men presented the lowest mean value of C/B ratio (0.64±0.05) while the older women showed the highest (0.86±0.01). The gender-age interaction was significant with a greater increase in C/B ratio with age in men than in women. An age-gender interaction was also observed for brachial and carotid PP separately. The mortality risk increased with age, particularly the CV risk of death: 5°/°° in men under 55, and 30°/°° in men over 55, and in women: 1.2°/°° and 12°/°° respectively. The age-gender interaction was significant with a greater increase in CV mortality with age in women than in men.

Risk of mortality according to gender

For all-cause mortality and CV mortality (Table 2) the HR for brachial PP, calculated carotid PP, and C/B ratio were highly significant in the overall population.

Table 2.

Adjusted risk (HR) of all-cause mortality and CV mortality according to gender in the overall population.

All-cause mortality MHR
	Men	Women	p*
Brachial PP	1.17 (1.14–1.21)	1.07 (1.01–1.14)	0.31
Carotid PP	1.39 (1.35–1.44)	1.35 (1.28–1.42)	0.88
C/B ratio	1.51(1.47–1.56)	2.46 (2.27–2.67)	<0.0001

CV mortality HR MHR
	Men	Women	p*
Brachial PP	1.18 (1.11–1.25)	1.25 (1.12–1.40)	0.02
Carotid PP	1.50 (1.42–1.59)	1.72 (1.57–1.89)	0.01
C/B ratio	1.81 (1.70–1.93)	4.46 (3.66–5.45)	<0.0001

Adjusted risk of all-cause mortality and cardiovascular (CV) mortality (hazard ratio (HR) and 95% confidence interval) associated with the increase of 1 SD in brachial pulse pressure (PP), carotid PP and carotid/brachial (C/B) ratio. Adjustments were made for age, height, weight, smoking, physical activity, cholesterol, diabetes mellitus and heart rate. Additional adjustment for gender was performed for the overall group analysis.

^*Men vs Women

Concerning all-cause mortality, the C/B ratio HR was significantly different between men and women after full adjustment, being higher in women than in men (p<0.0001). However, the differences observed for brachial PP and carotid PP HR between genders were not statistically significant. The CV mortality risk associated with the C/B ratio was also higher in women than in men (p<0.0001) and moreover, similar significant gender differences in HR were observed for both brachial PP and carotid PP.

Gender-interaction of risk according to age

Table 3 summarizes the p values of gender interactions in the total population. For overall mortality, a gender interaction was observed for the C/B ratio in patients both under and over 55 years of age (p<0.0001). For CVD mortality, p values were significant for carotid PP (p=0.04) above 55 years of age and for the C/B ratio both under and over 55 years of age (p=0.008 and p<0.0001 respectively).

Table 3.

Gender effect (p) for all-cause and cardiovascular mortality according to age

All cause mortality
	<55 years	≥55 years
Model:
gender*PP	0.09	0.79
gender*carotid PP	0.09	0.52
gender*C/B ratio	<0.0001	<0.0001

Cardiovascular mortality
	<55 years	≥55 years
Model:
gender*PP	0.33	0.31
gender*carotid PP	0.37	0.04
gender*C/B ratio	0.008	<0.0001

Adjustments were made for height, weight, smoking, physical activity, cholesterol, diabetes mellitus and heart rate.

Figure 1 shows values of HR for CV risk associated with the C/B ratio and gender interactions in men and women in the two age groups (below and above 55 years of age). This HR was higher for women than for men. In men, the change in HR with age was not statistically significant: HR = 1.44 (1.31–1.58) vs 1.65 (1.48–1.84) but for women it significantly increased: 3.19 (2.08–4.89) vs 5.60 (4.17–7.50), (p<0.01). The mortality impact of the C/B ratio was 3-fold higher in women than in men over 55 years of age (p<0.0001). A supplementary adjustment on MAP did not alter these results: men <55 years: HR: 1.29 (1.17–1.42), ≥55 years: 1.56 (1.39–1.74); women, <55 years: 2.59 (1.67–4.02), ≥55 years: 5.83 (4.29–7.92).

Figure 1. Adjusted risk of CV mortality associated with carotid/brachial (C/B) PP ratio according to gender and age (gray bars: men and black bars: women).

Hazard ratio (95% confidence interval) associated with the increase in carotid/brachial (C/B) PP ratio of 1 SD.

The gender effect (p) adjusted for height, weight, risk factors (smoking, physical activity, cholesterol and diabetes mellitus) and heart rate as well as hazard ratio are indicated above the bars.

Discussion

In this study, we investigated a large population of outpatients in whom we measured brachial PP non-invasively and also calculated carotid PP. The validation of the methodological basis of the carotid PP calculation has already been published.(13) Carotid PP was measured using a tonometric sensor in a first unrelated population of 834 patients in order to evaluate the determinants of carotid PP, among the classical parameters available in a large cohort of subjects. We further confirmed this validation in a second unrelated population.

Both carotid PP and brachial PP individually had significant predictive value on overall and CV mortality, independently of standard CV risk factors. Furthermore, PP amplification, expressed as the C/B ratio, was strongly associated with both CV and overall mortality risk, with a much higher HR for the C/B ratio by comparison with that of brachial PP or carotid PP alone. Thus, after adjustment for age, gender, standard risk factors and presence of antihypertensive treatment, an increase in PP amplification of 1 SD was associated with an increase of 51% for all-cause mortality and of 81% for CV mortality in men, and in women, a 146% increase for overall mortality and a 346% increase for CV mortality. All results were independent of any other confounding variables, including pulse rate and drug treatment. Finally, the disappearance of PP amplification indicates a significantly higher risk of CV mortality in women than in men. Because only a relatively small number of subjects, particularly women, died during the observation period, this finding was probably slightly underestimated.

An important advantage of the present carotid PP calculation results from the use of a validated stepwise multiple regression, which associates hemodynamic and biological variables with a very high proportion of explained variance (86%).(13) When PP amplification is calculated as the C/B ratio, this ratio becomes independent of brachial artery calibration and is influenced only by the reliability of detection of the brachial pressure pulse by the auscultatory method and the methodology used to estimate the central aortic or carotid pulse.(9,20,21)

The contribution of the C/B ratio to the mechanism of CV risk is clearly superior to that of brachial or carotid PP alone but this parameter is difficult to determine. Because body height and heart rate have been already used as adjustments in the calculations of the ratio, it does not seem likely that these parameters played a major role in the mechanisms of PP amplification and CV risk. It seems rather, from the statistical findings, that gender and age played predominant roles.(26)

The present study confirms that all-cause mortality and CV mortality (Table 1) are higher in men than in women, both before and after 55 years of age. However, there is a greater increase in CV mortality with age in women than in men and the major finding of this study concerns the impact of the C/B ratio on CV mortality. This impact is largely increased in women over 55 years by comparison with younger women. Such an increase was not observed in men. Over 55, the impact of the C/B ratio on CV mortality was threefold higher in women than in men. The main putative cause of this gender difference is the menopausal change, particularly via its effects on large artery behavior(1–7) and CV events. The fact that the most important observations of this study concerned the large arteries of older women (≥55 years), suggests that, independently of the standard aging process, the loss of estrogenic action in the carotid and brachial arterial wall might play a specific deleterious role, increasing arterial stiffness and reducing elasticity, as previously observed by others.(27,28) Estrogen receptors are present and effectively active on central large arteries, but only before menopause.(6) The loss of their vascular protective action would favor the development of pro-fibrotic and pro-inflammatory effects in the arterial tissue,(7) thereby disturbing the amplitude and timing of central wave reflections and contributing to the deterioration of CV structure and function. In post-menopausal women, an increased incidence of systolic hypertension as well as increased arterial stiffness (mostly in its structural aspects) is commonly observed.(27,28) What is currently less established, however, is the relationship between estrogens and the aortic wave reflection in women. A recent study on women taking oral hormonal contraception has shown that they had higher SBP and aortic pulse wave velocity compared with non users and this occurred possible passively since there was no difference in augmentation index.(29) But the true impact of hormonal removal with menopause (and aging process) on intrinsic aortic wave reflection is less clear.

C/B amplification is highly predictive of the difference in CV risk of death between men and women. We propose that in post-menopausal women, the attenuation of PP amplification, mainly related to increased aortic stiffness, contributes to the significant increase in CV risk. We show, for the first time, that in men, the well established increase in aortic stiffness with age(26,30) does not result in the same epidemiological consequences as in women. We propose that the C/B ratio should be interpreted taking into account the estrogenic status as recently demonstrated by our group in the metabolic syndrome which is mainly associated with hormonal changes and inflammation.(31)

Some limitations of the study should be acknowledged. As mentioned, we were not able to directly measure the carotid artery pulse pressure by applanation tonometry in these 125.151 subjects. However we tried hard to circumvent this limitation by a calculation based on a subgroup of 834 subjects of both genders and to validate the gender equations in 285 individuals explored in the Nancy Hospital (V.R., P.L.). A second limitation is the lack of data on morbidity for these 125.151 subjects, particularly in the cardiovascular domain. Our data-base does not include such data. However, the mortality data is robust and has been previously validated. The cause of death is drawn from the only official French institution which documents French mortality, the Cepid INSERM (SC8 department of the National French Institute of Health and Medical Research). It is clear that in the field of cardiovascular disease, particularly in the 80’s, the cardio-vascular mortality rate does not correspond to the general impact of the disease because of the many successful interventional coronary and arterial procedures. But we are convinced of the robustness of the data, in spite of this limitation, particularly in view of the large size of the sample studied. The menopause status was not specifically assessed in our questionnaire. However we have obtained data in a different subpopulation of the IPC cohort, suggesting that at 55 years of age 98% of women have gone through menopause. The last limitation is the lack of HDL and LDL cholesterol data for assessing risk factors and cardiovascular mortality. Unfortunately, our data base at the period of this cohort did not include the measurement of HDL cholesterol. We thus adjusted for Total cholesterol in our analysis.

In conclusion, this epidemiological study shows that a large scale evaluation of central to peripheral pulsatility amplification is independently associated with cardiovascular mortality.

Perspectives

In the past, studies of BP in menopausal and post-menopausal women have largely been based on its steady component, MAP, and consequently on its principal determinant, total peripheral resistance (small arteries).(32) Using the C/B ratio in men and women, we showed for the first time that in vivo, cardiovascular risk is not related only to the steady component of BP but rather to its pulsatile component (large arteries), i.e. arterial stiffness and, mostly in women >55 years, wave reflections.(26,33) For this reason, the effects of MHT in controlled trials should be analyzed in older women on the following basis: 1/the choice of drugs acting on arterial stiffness and wave reflections, which depends on the status of preexisting CV disease, 2/the specific analysis of the type of estrogen used, and its dose and mode of administration (probably acting differently on small and large arteries), 3/epidemiological findings principally evaluated in women. We speculate on such a basis that the optimal anti-hypertensive drug therapy of hypertension should differ markedly between men and women.

List of abbreviations

B

brachial

C

carotid

CV

cardiovascular

DBP

diastolic blood pressure

HR

hazard ratio

MAP

mean arterial pressure

MHT

menopausal hormonal therapy

PP

pulse pressure

SBP

systolic blood pressure