Hypertension in women: latest findings and clinical implications

Abstract

Cardiovascular disease claims more women’s lives than any other disease. Hypertension is an important risk factor for cardiovascular disease in women but is often underestimated and undiagnosed and there is an ongoing misperception that women are at a lower risk of cardiovascular disease than men. The attainment of clinical blood pressure goals can markedly reduce cardiovascular morbidity and mortality, yet approximately two-thirds of treated hypertensive women have uncontrolled blood pressure. Furthermore, there are special risk factors that are unique for women that needs acknowledgement in order to help prevent the great number of hypertension-related events in women. Guidelines for treatment of hypertension are similar for men and women. More studies on the interaction between gender and response to antihypertensive drugs would be of interest.

Introduction

Hypertension is a major risk factor for cardiovascular disease (CVD) and outcomes in women [Smith et al. 2006]. Even though substantial progress has been made in the awareness, treatment, and prevention of CVD in women in the last decade, hypertension is often underestimated and undiagnosed [Maas et al. 2011; Mosca et al. 2011]. It is no longer true that CVD is a ‘man’s disease’. Heart disease is the leading cause of death in women in every major developed country and most emerging economies [Gholizadeh and Davidson, 2008]. In 2007, CVD caused about one death per minute among women in the United States, more women’s lives than were claimed by cancer, chronic lower respiratory disease, Alzheimer’s disease, and accidents combined [Roger et al. 2011]. Acknowledging those facts might reduce hypertension-related morbidity and mortality in women.

Epidemiology

The prevalence of hypertension has increased over the last decade [Fields et al. 2004]. Essential hypertension accounts for more than 90% of cases of hypertension [Mancia et al. 2007; Oparil et al. 2003] and in a recent review, the lifetime risk of becoming hypertensive in industrialised countries was estimated to exceed 90% [Messerli et al. 2007]. The gender difference in blood pressure levels appears during adolescence [Himmelmann et al. 1994] but a shift in relative prevalence of hypertension occurs in the elderly [Kotchen et al. 1982]. Premenopausal women have lower risk and incidence of hypertension compared with age-matched men but this advantage for women gradually disappears after menopause. After 65 years of age, a higher percentage of women than men have hypertension, and the gap will likely increase with the continued aging of the female population [Roger et al. 2011]. In women between the ages of 65 and 74 years, the prevalence of hypertension is as high as 58%. The prevalence of hypertension among black women is particularly high and CVD rates in the United States are significantly higher for black females compared with their white counterparts [Hertz et al. 2005]. Approximately 40% of stroke cases, 39% of myocardial infarction cases and 28% of end-stage renal diseases are attributable to hypertension [Jones and Nagpal, 2001; Os et al. 1993]. Furthermore, hypertension, due to its greater prevalence, contributes more to the population burden of heart failure than does myocardial infarction [Bui et al. 2011; Lloyd-Jones et al. 2002] and The Rotterdam study indicated that hypertension was more of a contributing factor in women than in men [Mosterd et al. 1999]. The 5-year mortality after the onset of hypertensive heart failure in women is high, about 69% [Levy et al. 1996]. Treatment of hypertension, however, can reduce the incidence of heart failure by almost 50% [Chapman and Neal 2001; Psaty et al. 1997]. In The Women’s Health Initiative, the major determinants of hypertension prevalence were found to be black race, lower socioeconomic status, history of CVD, and concomitant CVD risk factors of physical inactivity, overweight/obesity, and excess alcohol consumption [Wassertheil-Smoller et al. 2000]. Furthermore, it is of great concern that there is a reverse trend in death rate of coronary heart disease (CHD) in US women aged 35–54 years, most likely due to the obesity epidemic [Ford et al. 2007].

Pathophysiological mechanisms

The reason for gender difference in blood pressure levels is multifactorial and incompletely understood. There are several hypotheses including the potential role of sex hormones, the renin–angiotensin system (RAS), oxidative stress, endothelin, weight gain and sympathetic activation [Nuzzo et al. 2010; Reckelhoff, 2001].

Premenopausal hypertensive women with regular menstrual cycles appear to have lower plasma estradiol levels than age-matched normotensive women [Nordby et al. 1992], and the protective function of oestrogen has been suggested to account for the 10- to 15-year delay in presentation of CVD in women compared with men [Oparil, 2009]. Natural oestrogens and natural progesterone protect the vasculature from oxidative and inflammatory injury, preventing CVD as reviewed by Dubey and colleagues [Dubey et al. 2002]. Oestrogen increases angiotensinogen levels, and decreases renin levels, angiotensin-converting enzyme (ACE) activity, angiotensin AT-1 receptor density and aldosterone production. Oestrogen also activates counterparts of the RAS as well as improving endothelial function [Fischer et al. 2002]. New intracellular signalling pathways and actions for the cardiovascular protective properties of oestrogen have been proposed [Yang and Reckelhoff, 2011]. Randomized controlled trials have failed to confirm that hormone replacement therapy affords cardioprotection and have even shown evidence of harm [Rossouw et al. 2002]. However, recent Women’s Health Initiative studies restricted to younger postmenopausal women showed that initiation of hormone replacement therapy closer to menopause reduced the risk of CVD [Oparil, 2006; Wassertheil-Smoller et al. 2000). More studies are needed if we are to understand the divergent published findings regarding hormone replacement therapy for women.

There is epidemiological [Burt et al. 1995; Kotchen et al. 1982] and experimental evidence [Dubey et al. 2002; Reckelhoff, 2001] that androgens can impact blood pressure regulation in multiple ways [Dubey et al. 2002; Reckelhoff, 2001], through activation of the RAS, blunting of the pressure–natriuresis relationship, and increased endothelin and oxidative stress [Reckelhoff, 2001], and through the increase of visceral fat [Janssen et al. 2010].

Gender differences in the activity of the RAS could, at least in part, explain the differences in blood pressure levels between men and women [Schunkert et al. 1997]. Lower plasma renin levels have been reported in women with essential hypertension compared with normotensive women [Nordby et al. 1992] and to men [Lewis, 1996; Os et al. 1993]. Furthermore, plasma renin activity increases after menopause [Duerrschmidt et al. 2000], and the upregulation of angiotensin II receptors and downregulation of angiotensin I receptors after menopause might influence response to therapy.

An interaction between gender and vascular responsiveness has been shown during angiotensin II infusion [Miller et al. 1999]. The Copenhagen City Heart Study showed association between different polymorphism of the angiotensinogen gene and elevated blood pressure in women only [Sethi et al. 2003]. It has also been suggested that ACE, or a nearby gene, could be a sex-specific candidate gene for hypertension [O’Donnell et al. 1998].

Endothelin levels and oxidative stress increase after menopause [Nuzzo et al. 2010], and may affect blood pressure through increased sodium reabsorption and vasoconstriction [Fortepiani et al. 2003; Mortensen et al. 1990].

Obesity and being overweight are increasing more in postmenopausal women than in men [Rappelli, 2002], and are associated with risk of hypertension and mortality more than in men of the same age [Wilson et al. 2002]. How obesity favours development of hypertension is still a matter of debate, but overactivity of the sympathetic nervous system, insulin resistance, leptin resistance, overactivity of the renin–angiotensin–aldosterone system and a blunted activity of the natriuretic peptides have been implicated [Jarvie and Foody, 2010]. Increased physical activity and avoidance of excess weight may have large effects on women’s health both on an individual and population level.

Gender appears to be a determinant of autonomic function measured as baroreceptor reflex sensitivity (BRS) and heart rate variability (HRV) in both hypertensive and normotensive subjects [Sevre et al. 2001]. Both hypertensive and normotensive women seem to have attenuated cardiovascular response to stress compared with men [Mundal et al. 1993; Ross et al. 2001]. Sevre and colleagues showed that BRS reduction was more pronounced in women than in men and that systolic blood pressure correlated significantly with BRS in the female hypertensive group only, suggesting that autonomic dysfunction may play a more important role in hypertension in women [Sevre et al. 2001]. The authors speculate on the putative effect of female sex hormones on arterial compliance and modelling, and thus on arterial blood pressure buffer capacity [Sevre et al. 2001]. HRV seems reduced in men and women with hypertension [Singh et al. 1998], and Sevre and colleagues observed that overall HRV was reduced in hypertensive subjects, particularly in women, perhaps through a more pronounced withdrawal of autonomic heart rate control in females.

Cardiovascular risk

Hypertension is an important risk factor for CVD in women. There are specific risk factors in women which may contribute to CVD risk. Preeclampsia has been shown to increase the risk for future hypertension by fourfold, and doubling the risk of future CHD compared with women with uncomplicated pregnancy [Jonsdottir et al. 1995; Nilsson et al. 2009; Tan et al. 2010]. It has also been shown that preeclampsia is a risk factor for subsequent end-stage renal disease, although the absolute risk is low [Vikse et al. 2008]. Another important aspect of hypertension in pregnancy is the increased risk of having a low-birthweight infant. As low birthweight is a risk factor for future CHD [Barker et al. 1989; Eriksson et al. 2001; Eriksson, 2005; Frankel et al. 1996; Leon et al. 1998; Rich-Edwards et al. 1997], hypertension in pregnancy can influence the health of the next generation.

Furthermore, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have been associated with increased risk of CVD. Whole blood viscosity is closely related to blood pressure and left ventricular hypertrophy (LVH) [de Simone et al. 1991; Letcher et al. 1981], and considered a determinant of cardiovascular risk [de Simone et al. 1990]. Whole blood viscosity is lower in women, both before and after menopause, than in men [Fossum et al. 1997; Hoieggen et al. 2000]. Activation of the sympathetic nervous system during stress may increase whole blood viscosity differently in men and women [Ross et al. 2001]. During stress, platelet function is affected in hypertensive men [Lande et al. 1987, 1988], but not in hypertensive women [Mundal et al. 1993].

Several studies have reported that left ventricular (LV) systolic and diastolic function are gender dependent [Aurigemma and Gaasch 1995; Bech-Hanssen et al. 1999; Bella et al. 2002; Gerdts et al. 2001; Legget et al. 1996]. How gender may influence cardiac adaptation to chronic pressure overload is not fully understood, however, increased hypertrophic response to chronic pressure overload is associated with higher LV ejection fraction in women than in men [Carroll et al. 1992; Gerdts et al. 2001]. Experimental data indicate that myocardial hypertrophy is related to oestrogen in rats, while levels of testosterone do not seem to alter the hypertrophic response [Wallen et al. 2000]. In a study by Gerdts and colleagues, female gender was associated with better LV function [Gerdts et al. 2001]. Obesity, particularly in women, may potentiate the effect of hypertension on LVH [de Simone et al. 1994; Gerdts et al. 2001]. Another explanation could be the difference in LV growth from the first years of life to adulthood. Thus, a relative cardiac hypertrophy in men could contribute to a reduced hypertrophic reserve, and thereby lead to reduced ability to normalize wall stress and less capacity to maintain normal systolic function [Koren et al. 1991].

Microalbuminuria is a marker of cardiovascular and renal risk, and is a sign of target organ damage in essential hypertension [European Society of Hypertension and European Society of Cardiology, 2003]. Albumin excretion is related to blood pressure levels [Mimran et al. 1994], even in the normoalbuminuric range [Bulatov et al. 2001]. In a recent large-scale population-based study of hypertensive subjects, the association between microalbuminuria and all-cause mortality was found to be stronger in treated males compared with females [Romundstad et al. 2003]. This was the first study to demonstrate a stronger association between microalbuminuria, a marker of endothelial function, and total mortality in hypertensive men than in hypertensive women, and the findings might indicate that hypertensive women tolerate microalbuminuria better than men.

Treatment of hypertension

The attainment of clinical blood pressure goals can markedly reduce cardiovascular morbidity and mortality, yet approximately two-thirds of treated hypertensive women have uncontrolled blood pressure. Data from the National Health and Nutrition Examination Survey (NHANES) showed that hypertensive women were more likely to be treated than men, but less likely to have achieved blood pressure control [Gu et al. 2008]. An interesting observational study from Sweden concluded that female physicians appeared more often to reach the treatment goal for blood pressure in female patients than did male physicians [Journath et al. 2008]. Furthermore, several studies have shown that the blood pressure control rates in women decline dramatically with age [Olsen et al. 1999; Wassertheil-Smoller et al. 2000]. Whether this decline in blood pressure control rates in women is related to biological determinants or to less aggressive treatment is not clear [Oparil, 2006]. In The Women’s Health Initiative cohort, predictors of lack of blood pressure control were older age, nonwhite race, and the present of insulin-dependent diabetes [Wassertheil-Smoller et al. 2000].

Guidelines for treatment of hypertension are similar for men and women and most do not include a risk stratification for gender. Studies have indicated that with lifestyle modification alone, blood pressure control was worse in women than in men [August and Oparil, 1999; Lewis et al. 1996], perhaps because weight reduction is harder to obtain in females. Obesity is an important cause of elevated blood pressure in women [Wilsgaard et al. 2000] and with the trend in ongoing increase in average body weight [Roger et al. 2011], focus on weight reduction is extremely important and should be encouraged. Based on the findings of low plasma renin in hypertensive women, salt restriction would be expected to be important for controlling blood pressure in women [Os et al. 2004]. The Dietary Approaches to Stop Hypertension (DASH) trial [Sacks et al. 2001] showed a pronounced antihypertensive effect in women during dietary sodium restriction. This is in accordance with earlier study showing an enhanced depressor response to sodium restriction in elderly normotensive women [Nestel et al. 1993].

In general, antihypertensive efficacy of pharmacological agents is similar in both genders [Os et al. 2004] and the recommendations to prevent CVD are similar for women and men, with few exceptions [Mosca et al. 2011]. Nevertheless, gender differences in prescription pattern occur in Norway and in other countries with the greater use of diuretics in women [Klungel et al. 2000; Olsen et al. 1999]. One could argue that low plasma renin activity [Nordby et al. 1992] in hypertensive patients favours the use of diuretics, but ACE inhibitors have been shown to have similar antihypertensive efficacy in men and women [Os et al. 1991]. Furthermore, the LIFE study, provided evidence that treatment based on the angiotensin receptor blocker (ARB), losartan, with the addition of thiazide diuretic was superior to the β-blocker, atenolol, plus thiazide diuretic in preventing CVD outcomes in women with LVH, and that the favourable adverse effect profile of losartan-based treatment in hypertensive women at high cardiovascular risk, made it a particularly attractive choice. The treatment effect was consistent in men and women for all of the endpoints tested, with the exception of hospitalization for angina [Os et al. 2008]. On the other hand, in an Australian study, the superior effect of ACE inhibitors compared with hydrochlorthiazide in preventing myocardial infarction was observed only in hypertensive men [Wing et al. 2003]. Other large-scale clinical trials on the effect of antihypertensive treatment on cardiovascular complications have not exposed any gender differences [Kjeldsen et al. 2000, 2002]. In contrast, only hypertensive men had a reduction in cardiovascular events in response to acetylsalicylic acid (ASA) treatment in the Hypertension Optimal Treatment (HOT) study [Kjeldsen et al. 2000]. Although antihypertensive efficacy of pharmacological agents is similar in both genders and guidelines may be applied across all groups, recognizing specific aspects of race and ethnicity when approaching women with hypertension may be beneficial. Black women have higher prevalence of hypertension, they develop hypertension at an earlier age, and their average blood pressure tends to be higher [Lloyd-Jones et al. 2010], contributing to an increased cardiovascular and renal risk in this population [Lloyd-Jones et al. 2010]. African Americans tend to have low plasma renin activity [Rahman et al. 1997] and it has been reported that they respond better to calcium channel blockers and diuretics than to β-blockers or RAS inhibitors. It has been suggested that combination therapy with RAS agents along with calcium channel blockers (CCBs) or diuretics may reduce the differential effect of race/ethnicity on antihypertensive efficacy [Ferdinand and Ferdinand, 2008]. However, an important fact to bear in mind is that the blockers of RAS are contraindicated in pregnancy due to their teratogenic effect and ought to be used with caution in women who may become pregnant.

Hormone replacement therapy related changes in blood pressure are likely to be modest and should not preclude hormone use in normotensive or hypertensive women when indicated. However, hormone replacement therapy does not appear to reduce blood pressure significantly and should not be prescribed for that indication, nor should it be prescribed for the primary or secondary prevention of CVD [Mosca et al. 2004; Oparil, 2006] .

Hypertension is one of the most important cardiovascular risk factors in women with diabetes [Cederholm et al. 2010]. The importance of strict blood pressure control has proved effective in reducing the risk of stroke and diabetes-related mortality and guidelines have so far advocated a treatment target blood pressure of < 130/80 mmHg [Mansia et al. 2007]. There is, however, an ongoing debate on the advocated blood pressure goal, based on evidence from both randomized controlled trials and observational studies, showing that the benefit for stroke reduction remains at lower blood pressure levels, but the risk of coronary events may be uninfluenced or even increased at lower systolic blood pressure levels [Cederholm et al. 2010; Cushman et al. 2010]. This is reflected in a less strict wording in the reappraisal of the European Society of Hypertension guidelines recommending a systolic blood pressure goal of ‘well below’ 140 mmHg in diabetic patients [Mancia et al. 2009].

It has been suggested that some antihypertensive drugs have gender-specific adverse profiles and it is of interest that in the LIFE study and in the THOMS study, women reported side-effects more often than men [Neaton et al. 1993; Os et al. 2008]. Women develop cough related to ACE-inhibitor therapy three times more often than men [Os et al. 1994]. Although men are more likely to develop gout, women are more likely to develop hyponatremia and hypokalemia associated with diuretic therapy [August and Oparil, 1999]. Furthermore, there is evidence that sexual dysfunction related to antihypertensive therapy may be a problem in women, as well in men [Grimm et al. 1997; Wassertheil-Smoller et al. 1991].

Conclusion

Hypertension is an important risk factor for CVD in women. Even though women are more at risk to die from hypertension-related CVD than men, women do not perceive CVD as an important health problem. The perception by both patients and physicians that women are at substantial lower risk than men could explain the poorer outcome in women. Better education and information on the importance of treating hypertension is needed and more studies on the interaction between gender and response to antihypertensive drugs are of interest. Furthermore, acknowledgement of risk factors that are unique for women could help preventing the great number of hypertension-related events in women.