Hypertension and cardiovascular disease in women: Progress towards better understanding of gender‐specific differences?

There is an increasing recognition that there are gender specific characteristics of cardiovascular disease, the commonest cause of death in most developed countries [1,2]. Men and women differ considerably in the etiology, pathogenesis, clinical manifestations and outcomes of cardiovascular disease [3,4]. Female gender, particularly in younger subjects, has been associated with a worse prognosis after acute myocardial infarction, including a greater recurrence of acute coronary syndrome and higher mortality [5]. Furthermore, women might have less favorable short‐term outcome after myocardial revascularization procedures than do their male counterparts [6]. The increasing prevalence of cardiovascular pathology in women has created a clear and compelling need for identification of those variables specifically relevant to cardiovascular health in women.

In young to middle‐aged subjects, hypertension and cardiovascular disease are more common in men than in women [7–9]. Cardiovascular risk then increases with age in both sexes. However, this increase is sharper in women, so that in old age women have similar rates of cardiovascular disease, and even higher prevalence of hypertension than men. In other words, there is a gradual, but striking loss of the “protective effect” of female gender, both for cardiovascular disease and for hypertension. More women than men have congestive heart failure, and overall, more women than men die from cardiovascular disease in most developed countries [10,11]. The mechanisms underlying this differential age effect are not well understood. Changes in serum total cholesterol level, body mass index and diabetes prevalence explain only 50% of the age‐related increase in cardiovascular morbidity and mortality among women [12]. Thus, other factors are implicated in the high prevalence of hypertension and cardiovascular disease in older women [13].

Autonomic mechanisms may contribute importantly to gender‐related differences and the more marked influence of age on cardiovascular disease in women. Such mechanisms may include less effective baroreflex buffering of blood pressure in women than men [14] and stronger heart rate responses reflecting increased β₁‐receptor responsiveness in females [15]. Gender‐related differences in vagal mechanisms may also be implicated, as the parasympathetic contribution to heart rate variability is greater in females than in males [16,17]. Interestingly, faster heart rates are linked to higher blood pressure in males, but not female subjects [18]. In younger subjects, sympathetic nerve traffic to the vessels is higher in men than women [19], offering a plausible mechanism explaining male predominance among younger hypertensives. However, aging has a more striking effect on increasing sympathetic traffic in women than in men [19]. This marked increase is independent of body mass index, waist‐to‐hip ratio and menopause status. In addition to hypertension, sympathetic activation might predispose to cardiovascular events by several other mechanisms. These include metabolic, hemodynamic, trophic and rheologic abnormalities [20–22]. Thus, the marked age‐related increase in sympathetic drive may contribute to a higher prevalence of cardiovascular events in older women by mechanisms other than hypertension per se.

Gender‐specific hemodynamic and metabolic factors might also play an important role. Shorter arterial tree, as a consequence of shorter stature in women, induces faster heart rates and earlier reflection of arterial pulse waves [23]. The age‐related rise in aortic stiffness is steeper in women than in men [24]. Furthermore, prognostic implications of left ventricular hypertrophy may be more profound in women than in men. Both hypertension and obesity contribute to the development of left ventricular hypertrophy. However, obesity and hypertension appear to have an additive effect in men but a synergistic effect in women [25]. Therefore, obese hypertensive women are at particular risk of developing left ventricular hypertrophy. Glucose intolerance might contribute to cardiovascular disease in gender‐dependent fashion. Indeed, diabetes increases cardiovascular risk threefold to sevenfold in women compared with a twofold to threefold increase in risk in men.

Despite the protective effects of female gender against cardiovascular disease, smoking may be especially harmful to women [26–30]. Middle‐aged female smokers have a 50% increase in relative risk for myocardial infarction than males, and increased risk for vascular mortality. Acute effects of smoking in women are more important than chronic exposure in development of coronary thrombosis. Heavy smoking in women is associated with a fourfold increased risk of sudden cardiac death, similar to that conferred by a history of myocardial infarction [31].

It is likely that the multiple possible environmental and genetic mechanisms interact, possibly strengthening their individual effects in raising blood pressure and in increasing cardiovascular risk. The current issue of Blood Pressure features two articles that are focusing on cardiovascular risk factors in women. Sigurjonsdottir et al. [32] observed that the liquorice‐induced inhibition of aldosterone secretion is less pronounced in females than in males. Suwazano et al. [33] have shown that low‐density lipoprotein receptor‐related protein 5 variant Q89R is associated with hypertension in Japanese females but not males. Senti et al. have recently provided genetic evidence for the different impact of the beta₁‐subunit of the large‐conductance, Ca²⁺‐dependent K⁺ (BK) channel, in the control of human blood pressure in men and women, with particular relevance in aging women [34]. Taken together, these studies provide support for gender‐selective role of certain genetic variants in pathogenesis of hypertension. These gene variants may alter some metabolic pathways, thereby influencing interactions with environmental factors that affect the development and progression of cardiovascular disease.

Whether gender should influence the diagnosis and clinical management of hypertension remains a topic of intense debate [13],[23]. There is evidence that hypertensive females, in comparison to male patients, are more likely to benefit from salt reduction and aggressive blood pressure lowering. On the other hand, they are more prone to develop side‐effects (particularly cough during ACE‐I treatment) and are less likely to benefit from aspirin treatment. These issues were covered in more details in a previous Blood Pressure review [13]. The recently published ASCOT trial [35] indicates that the amlodipine/perindopril antihypertensive treatment regimen prevents more major cardiovascular events and induced less diabetes than an atenolol/thiazide regimen. The benefits of treatment with newer drugs in females were similar to those in male patients.

The rate of public awareness of cardiovascular disease as the leading cause of death in women has nearly doubled between 1997 and 2005 (from 30% to 55%) [36]. Previously reported bias against performing coronary revascularization in women has been acknowledged. Women with abnormal non‐invasive tests are currently more likely to be referred to coronary angiography as compared with a decade ago [37]. Despite better understanding of the mechanisms and growing awareness of gender‐specific differences, several issues remain to be solved. For example, much of the evidence supporting current recommendations for non‐invasive diagnostic studies in women is extrapolated from studies conducted predominantly in cohorts of middle‐aged men [37]. Furthermore, there is still a strong predominance of male patients in clinical trials. In particular, few hypertension trials included elderly women, in whom cardiovascular disease is common. Further research in this area holds promise for prevention of cardiovascular disease and improving quality of life in the aging female population.