Atherosclerosis xxx (2015) 1e8
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Sex differences in cardiovascular risk factors and disease prevention Yolande Appelman a, *, Bas B. van Rijn b, c, Monique E. ten Haaf a, Eric Boersma d, Sanne A.E. Peters e, f a
Department of Cardiology, VU University Medical Center, Boelelaan 1117, 1081 HV Amsterdam, The Netherlands Department of Obstetrics, Division Woman and Baby, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands c Academic Unit of Human Development and Health, Princess Anne Hospital, University of Southampton, Coxford Rd, Southampton, Hampshire SO16 5YA, United Kingdom d Thoraxcenter Cardiology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands e The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, United Kingdom f Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 November 2014 Received in revised form 22 January 2015 Accepted 22 January 2015 Available online xxx
Cardiovascular disease (CVD) has been seen as a men's disease for decades, however it is more common in women than in men. It is generally assumed in medicine that the effects of the major risk factors (RF) on CVD outcomes are the same in women as in men. Recent evidence has emerged that recognizes new, potentially independent, CVD RF exclusive to women. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with accelerated development of CVD and impaired CVD-free survival. With the recent availability of prospective studies comprising men and women, the equivalency of major RF prevalence and effects on CVD between men and women can be examined. Furthermore, female-specific RFs might be identified enabling early detection of apparently healthy women with a high lifetime risk of CVD. Therefore, we examined the available literature regarding the prevalence and effects of the traditional major RFs for CVD in men and women. This included large prospective cohort studies, cross-sectional studies and registries, as randomised trials are lacking. Furthermore, a literature search was performed to examine the impact of female-specific RFs on the traditional RFs and the occurrence of CVD. We found that the effects of elevated blood pressure, overweight and obesity, and elevated cholesterol on CVD outcomes are largely similar between women and men, however prolonged smoking is significantly more hazardous for women than for men. With respect to female-specific RF only associations (and no absolute risk data) could be found between preeclampsia, gestational diabetes and menopause onset with the occurrence of CVD. This review shows that CVD is the main cause of death in men and women, however the prevalence is higher in women. Determination of the CV risk profile should take into account that there are differences in impact of major CV RF leading to a worse outcome in women. Lifestyle interventions and awareness in women needs more consideration. Furthermore, there is accumulating evidence that female-specific RF are of influence on the impact of major RF and on the onset of CVD. Attention for female specific RF may enable early detection and intervention in apparently healthy women. Studies are needed on how to implement the added RF's in current risk assessment and management strategies to maximize benefit and cost-effectiveness specific in women. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular disease Risk factors Gender Atherosclerosis Prevention Sex-differences
* Corresponding author. VU University Medical Center, Meibergdreef 1117, 1081 HV Amsterdam, The Netherlands. E-mail addresses: [email protected] (Y. Appelman), [email protected] (B.B. van Rijn), [email protected] (M.E. ten Haaf), [email protected] (E. Boersma), [email protected] (S.A.E. Peters).
1. Introduction Despite enormous declines in the burden of cardiovascular disease (CVD) in the past decades, mainly due to improvements in
http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis (2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
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Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
primary and secondary prevention, CVD disease remains a main cause of premature death and disability among men and women worldwide. Statistics from the World Health Organization (WHO) show that an estimated 17.3 million people died of CVD in 2008 of which 80% occurred in low- and middle income countries [1]. About 7.3 million deaths were due to coronary heart disease (CHD) and 6.2 million were due to stroke [2]. It is expected that the number of people who die from CVD, mainly from CHD and stroke, will increase to reach 23.3 million by 2030 [1,3]. Although CVD has been seen as a men's disease for decades, it is actually more common in women. In the European population, 38% of deaths in women before the age of 75 years are due to CVD - in men this figure is 37% - a figure that is partly explained by a higher risk of competing events, i.e. the risk of dying from other causes (Fig. 1) [4]. Most of the burden of CVD can be explained by a set of traditional risk factors that affect both men and women, including elevated blood pressure, smoking, overweight and obesity, diabetes, and elevated cholesterol. Already in 1999 the American Heart Association (AHA) developed the first women-specific clinical recommendations for CVD prevention, which led to increased awareness of women's CVD risk, and to improved risk factor management and treatment of CVD in women [5]. However, despite these women-specific guidelines and accruing evidence for clinically important sex differences in the prevalence of traditional CVD risk factors, and in the effects of these risk factors on CVD outcomes sex-specific risk remains poorly understood and the prevention and management of stroke and cardiovascular risk factors is essentially still the same for men and women. Recent evidence has emerged that recognizes new, potentially independent, CVD risk factors exclusive to women [6]. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with accelerated development of CVD and impaired CVD-free survival [7,8]. Other risk factors, although not exclusive to women, have a much higher prevalence in women than men. As an example, migraine occurs 3 times more often in women, and is associated with an increased risk of stroke [9,10]. The most recent AHA guideline (2011) and AHA/American Stroke Association (ASA) guideline (2014) for the prevention of cardiovascular complications and stroke in women recommends CVD risk assessment in women with certain reproductive manifestations of CVD risk, such as adverse pregnancy outcomes, and suggests that female-specific risk factors may improve current CVD risk assessment strategies [11,12]. The purpose of this review is to examine the available literature regarding the prevalence and effects of the traditional risk factors
on the risk for CVD in men and women. Furthermore, the impact of the female specific risk factors on the occurrence of CVD is examined. 2. Major risk factors that affect both men and women 2.1. Elevated blood pressure Elevated blood pressure is a major public-health challenge worldwide; it is estimated to be responsible for an annual 7.5 million deaths, about 12.8% of the total of all deaths and to account for 57 million disability adjusted life years (DALYS), about 3.7% of all DALYS [14]. The prevalence of hypertension is broadly similar in men and women, and is projected to increase with population growth and aging in both sexes. In 2000, nearly a billion adults, 27% of all men and 26% of all women, had hypertension; these estimates are projected to increase to 1.5 billion adults, 29% of men, and 30% of women, in 2025 [14,15,16]. The Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group recently conducted large-scale analyses to estimate the global trends in systolic blood pressure (SBP) levels between 1980 and 2008 [17]. In 2008, the age-standardized systolic blood pressure worldwide was 4 mmHg higher in men than in women; men on average had an SBP of 128.1 mmHg compared to 124.4 mmHg in women. Between 1980 and 2008, global levels of mean SBP had decreased by 0.8 mmHg in men and by 1.0 mmHg per decade in women and the prevalence of uncontrolled hypertension had fallen from 33% in 1980 to 29% in 2008 in men and from 29% to 25% in women. These trends, however, varied markedly among men and women living in different regions of the world. Where SBP levels had fallen considerably by about 3e4 mmHg per decade in men and women living in higher-income countries, most likely due to successful implementation of lifestyle and therapeutic interventions [18], opposite trends were seen in many lower and middle-income countries including countries in Oceania, east Africa, and south and southeast Asia were SBP levels rose with 0.8e1.6 mmHg per decade in men and 1.0e2.7 mmHg per decade for women, with no evidence that trends were curbing [17]. Studies have reported conflicting results on whether the strength of the association between increments in SBP and future risk for CVD is the same for men as for women [19,20,21,22]. A recent pooled analysis that included data from prospective cohort studies on more than 1.2 million individuals and over 50,000 cardiovascular events systematically examined whether the magnitude of the association between SBP and risk of CHD and stroke was similar in women and men [23]. After consideration of differences in other major cardiovascular risk factors, every 10 mmHg
Fig. 1. Death rates in Europe 2012. Death rates in Europe, men and women 20 cigarettes per day) [30]. Two recent meta-analyses provided reliable estimates of the association between smoking and CHD and stroke in men and women [31,32]. The first metaanalysis with data from 74 prospective cohort studies, nearly 2.4 million men and women and 44,000 coronary events, showed that, while the beneficial effects of smoking cessation on coronary risk were similar in women and men, women who smoke had a 25%
Fig. 2. Relative risk for coronary heart disease and stroke. Relative risk for coronary heart disease (CHD) and stroke in women and in men per 10-mm Hg increase in systolic blood pressure (A); for current smokers versus non-smokers (B); for people with diabetes versus without diabetes (C) and per 5 kg/m2 in body mass index (D). Lines show 95% confidence intervals.
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis (2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
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Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
greater relative risk of CHD than men, independent of differences in baseline characteristics (Fig. 2B) [31]. In the second meta-analysis, involving data from nearly 4 million individuals and more than 42,000 strokes, there was no clear evidence for a greater excess risk of smoking in women compared with men; the pooled relative risk for stroke associated with current smoking was 1.83 (95% CI: 1.58; 2.12) in women and 1.67 (95% CI: 1.49; 1.88) in men (Fig. 2B) [32]. In a sensitivity analysis that explored the association in Occidental cohorts (where the smoking epidemic is known to be relatively mature) versus Oriental cohorts, smoking conferred a 10% greater risk of stroke in women than in men in the Occidental populations. This finding suggests that there is a small but real sex difference in the effect of smoking on stroke risk, which is currently not visible due to the relative immaturity of the smoking epidemic in women in most parts of the world [25,27,28]. Alternatively, it might be that the mechanisms driving the excess risk of smoking in women, such as a potentially greater absorption of toxic chemicals from the same amount of cigarettes in women [33], may be more pronounced for CHD than for stroke. Future studies are required to examine the effects of prolonged smoking in women and men, independent of the attenuating but persisting sex differences in smoking behavior, and if confirmed, to clarify the mechanisms underpinning these differences. 2.3. Diabetes mellitus Prevalence rates of diabetes rates are rising globally; where 8.3% of all men and 7.5% of all women had diabetes in 1980, estimates from 2008 were 9.8% in men and 9.2% in women [14,34]. The total number of individuals dying from the consequences of high fasting blood sugar or diabetes was 3.4 million in 2004, with more than 80% of these deaths occurring in low- and middle income countries [3,35]. There is substantial evidence that diabetes is a more potent risk factor for CHD and stroke in women than in men, i.e. the presence of diabetes negates the biological female advantage that is often used to explain why women have lower absolute rates of CHD and stroke compared to men [36,37]. In a pooled analysis of over 850,000 individuals and 28,000 coronary events, it was demonstrated that the presence of diabetes nearly tripled the risk of CHD in women (RR: 2.82 [95% CI: 2.35; 3.38]) whereas it more than doubled the risk in men (RR: 2.16 [95% CI: 1.82; 2.56]); the relative risk for CHD thus being 44% greater in women with diabetes than in similarly affected men (Fig. 2C) [36]. In addition, a similarly large meta-analysis including data from over 750,000 individuals and more than 12,500 strokes showed that the relative effect of diabetes on stroke risk was 27% greater in women compared with men: the RR of stroke associated with diabetes was 2.28 (95% CI 1.93; 2.69) in women and 1.83 (95% CI 1.60; 2.08) in men, independent of sex differences in other major cardiovascular risk factors (Fig. 2C) [37]. This sex differential was seen consistently across major predefined stroke, study, and participant subtypes, which included a comparison of individuals from Asian and non-Asian populations. The mechanisms by which diabetes confers a greater excess risk for CHD and stroke in affected women than in affected men remain unclear. A sex disparity in the management and treatment of cardiovascular risk factors in individuals with diabetes, to the detriment of women, is possibly involved [38,39,40,41,42,43,44]. Most recently, data on nearly 2 million individuals with diabetes from the in the United Kingdom suggested that women with diabetes were less likely than men with diabetes to receive care processes recommended by the national guidelines and to meet treatment targets [45]. Standard care processes, including annual checks for the effectiveness of diabetes treatment, management of
cardiovascular risk factors and the emergence of early complications, were received by 58% of women and 62% of men, and 34% of women and 37% of men met all treatment targets for HbA1c, blood pressure, and cholesterol. While evidently of importance, these sex disparities in the treatment and management of individuals with diabetes alone, however, may be too small to explain all of the excess relative risk for CVD in women with diabetes. Alternatively, as the detrimental effects of glucose already occur at glycemic levels below the threshold for the diagnosis of diabetes, it might be that the transition from normoglycemia, to impaired glucose tolerance and overt diabetes is more detrimental in women than in men. As diabetes may remain undetected for many years (about 183 million people with diabetes, 50% of all people with diabetes, are undiagnosed) [46], its diagnosis is often made at an advanced stage when major metabolic alterations and vascular complications have already occurred in most patients [47,48]. Accumulating evidence suggests that these adverse changes in metabolic and vascular risk factor profile in pre-diabetic individuals are greater in women than they are in men [49,50,51,52,53,54,55]. Consequently, the diabetes-related excess risk of cardiovascular disease in women may not be due to any significant sex difference in the effects and complications of diabetes itself, but rather the result of the combination of both a greater deterioration in cardiovascular risk factor levels and a chronically elevated, but undiagnosed and untreated, cardiovascular risk profile in the prediabetic state [56,57]. Future studies will be needed to determine the role of sexspecific cardiovascular risk factor trajectories and their contribution to cardiovascular risk. 2.4. Overweight and obesity Excess body weight is estimated to cause nearly 3 million deaths worldwide each year [14,58]. In 2008, nearly 1.5 billion individuals were overweight (i.e. body mass index (BMI) 25e30), a third of all adults; of these more than 300 million women and nearly 200 million men were obese (i.e. BMI 30) [59]. Estimates from the Global Burden of Disease group indicated that the world's average had increased with 0.5 kg/m2 per decade in women and 0.4 kg/m2 in men to an average level of BMI of 24.1 kg/m2 for women and of 23.8 kg/m2 for men in 2008. The prevalence of overweight in men and women differs according to the level of development of a country; levels of BMI are typically higher in men than women in most high-income countries whereas the reverse is more common in lower and middle-income countries. Regions with almost flat trends or even potential decreases in mean population BMI level are Central and Eastern Europe for women, and Central Africa and South Asia for men. Out of all of the high-income countries, men and women from the USA had, with a mean BMI of over 28 kg/m2 in both sexes, the highest mean population level of BMI [59]. Large-scale analyses of the Prospective Studies Collaboration (PSC) and the Emerging Risk Factors Collaboration (ERFC) have shown that the association between BMI and CHD is broadly identical between men and women whereas the risk for stroke associated with increments in BMI may be higher in men than in women [60,61]. In the PSC, each 5 kg/m2 higher BMI was associated with an increased risk for CHD of 1.35 (95% CI: 1.28; 1.43) in women and 1.42 (95% CI: 1.35; 1.48) in men and with an increased risk for fatal stroke of 1.30 (95% CI: 1.19; 1.42) in women and 1.50 (95% CI: 1.38; 1.65) in men (Fig. 2D). Analyses from the Asian-Pacific Cohort Studies Collaboration (APCSC) also demonstrated the approximately equal strength of the association between the presence of overweight or obesity and the risk of CHD between men and women in both Asian and Australasian populations [62,63]. Moreover, despite the widely recognised sex dimorphism in the body fat
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis (2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
Y. Appelman et al. / Atherosclerosis xxx (2015) 1e8
distribution there is no evidence that measures of abdominal adiposity, such as waist circumference or waist-to-hip-ratio have a different relationship with risk for CHD or stroke than BMI as measure of general adiposity, nor that the associations between excess CHD or stroke risk induced by measures of abdominal adiposity are differential between men and women [61]. 2.5. Raised cholesterol Raised cholesterol is responsible for over 2.6 million deaths (4.5% of the total deaths), and for 29.7 Disability Adjusted Life Years (DALY's) each year [14]. Women of younger age tend to have more favorable lipid profiles than men, but cholesterol rises after the menopausal transition to levels higher than in men [64]. Globally, mean total cholesterol changed little between 1980 and 2008, falling by less than 0.1 mmol/L per decade in men and women; the global mean age-standardized total cholesterol is 4.76 mmol/L in women and 4.64 mmol/L in men [65]. The prevalence of raised total cholesterol is generally similar between sexes, but is strongly related to the income level of the country. Around a quarter of adults in low income countries, a third of adults in lower middle income countries, and over half of all adult population from highincome countries had raised total cholesterol [14]. To date, there has been no systematic evaluation of the sexspecific effects of major lipids on cardiovascular risk. Results from large-scale individual participant data meta-analyses, however, generally suggest that the associations between several major lipids and the risk of CHD or stroke are similar between men and women [66,67,68]. Analyses from the PSC on almost 900,000 individuals and over 33,000 coronary deaths demonstrated that, in both men and women, each 1 mmol/L lower total cholesterol reduced the risk of mortality from CHD with about a half lower in early middle age (40e49 years), about a third lower in later middle age (50e69 years), and about a sixth lower in old age (70e89 years) [67]. The APCSC also showed no evidence of a sex difference in total
Table 1 Female-Specific Risk Factors associated with Cardiovascular Disease. Female-specific risk factor a
PCOS [89,90,95,96] POIb [93] PIHc [71] Preeclampsia [71] GDMd [76,77,81] Parity 1 [85] Parity 5 [85] Miscarriage 1 [97] Miscarriage 2þ/3þ [98] Preterm birth < 37 w [84,99,100,101,102] SGA < 10th centilee [82] Stillbirth [98]
CVDf
CHDg HTh
C CC CC CC CC CC CCC e e CC
e CC C CC CC e e C CC C
CC e
CC e CC e
C e CCC CCC CCC e e e e C
Stroke T2DMi e e C CC e e e e e CC
CCC e CC CC CCC e e e e CC
CC e
e e
C weak association, Relative Risk (RR) between 1 and 1.5 in cohort studies CC moderate association, RR between 1.5 and 2.5 in cohort studies CCC strong association, RR 2.5 in cohort studies. a PCOS, Polycystic Ovary Syndrome, diagnosis according to the 2003 Rotterdam consensus criteria. b POI, Primary Ovarian Insufficiency, defined as spontaneous (non-surgical) menopause before the age of 40 years. c PIH, Pregnancy-Induced Hypertension, defined by ISSHP criteria (BP 140/ 90 mm Hg without significant proteinuria). d GDM, Gestational Diabetes Mellitus, different criteria combined. e SGA, Small-for-Gestational Age, i.e. birth weight
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Sex differences in cardiovascular risk factors and disease prevention Yolande Appelman a, *, Bas B. van Rijn b, c, Monique E. ten Haaf a, Eric Boersma d, Sanne A.E. Peters e, f a
Department of Cardiology, VU University Medical Center, Boelelaan 1117, 1081 HV Amsterdam, The Netherlands Department of Obstetrics, Division Woman and Baby, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands c Academic Unit of Human Development and Health, Princess Anne Hospital, University of Southampton, Coxford Rd, Southampton, Hampshire SO16 5YA, United Kingdom d Thoraxcenter Cardiology, Erasmus MC, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands e The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, United Kingdom f Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 November 2014 Received in revised form 22 January 2015 Accepted 22 January 2015 Available online xxx
Cardiovascular disease (CVD) has been seen as a men's disease for decades, however it is more common in women than in men. It is generally assumed in medicine that the effects of the major risk factors (RF) on CVD outcomes are the same in women as in men. Recent evidence has emerged that recognizes new, potentially independent, CVD RF exclusive to women. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with accelerated development of CVD and impaired CVD-free survival. With the recent availability of prospective studies comprising men and women, the equivalency of major RF prevalence and effects on CVD between men and women can be examined. Furthermore, female-specific RFs might be identified enabling early detection of apparently healthy women with a high lifetime risk of CVD. Therefore, we examined the available literature regarding the prevalence and effects of the traditional major RFs for CVD in men and women. This included large prospective cohort studies, cross-sectional studies and registries, as randomised trials are lacking. Furthermore, a literature search was performed to examine the impact of female-specific RFs on the traditional RFs and the occurrence of CVD. We found that the effects of elevated blood pressure, overweight and obesity, and elevated cholesterol on CVD outcomes are largely similar between women and men, however prolonged smoking is significantly more hazardous for women than for men. With respect to female-specific RF only associations (and no absolute risk data) could be found between preeclampsia, gestational diabetes and menopause onset with the occurrence of CVD. This review shows that CVD is the main cause of death in men and women, however the prevalence is higher in women. Determination of the CV risk profile should take into account that there are differences in impact of major CV RF leading to a worse outcome in women. Lifestyle interventions and awareness in women needs more consideration. Furthermore, there is accumulating evidence that female-specific RF are of influence on the impact of major RF and on the onset of CVD. Attention for female specific RF may enable early detection and intervention in apparently healthy women. Studies are needed on how to implement the added RF's in current risk assessment and management strategies to maximize benefit and cost-effectiveness specific in women. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular disease Risk factors Gender Atherosclerosis Prevention Sex-differences
* Corresponding author. VU University Medical Center, Meibergdreef 1117, 1081 HV Amsterdam, The Netherlands. E-mail addresses: [email protected] (Y. Appelman), [email protected] (B.B. van Rijn), [email protected] (M.E. ten Haaf), [email protected] (E. Boersma), [email protected] (S.A.E. Peters).
1. Introduction Despite enormous declines in the burden of cardiovascular disease (CVD) in the past decades, mainly due to improvements in
http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis (2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
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primary and secondary prevention, CVD disease remains a main cause of premature death and disability among men and women worldwide. Statistics from the World Health Organization (WHO) show that an estimated 17.3 million people died of CVD in 2008 of which 80% occurred in low- and middle income countries [1]. About 7.3 million deaths were due to coronary heart disease (CHD) and 6.2 million were due to stroke [2]. It is expected that the number of people who die from CVD, mainly from CHD and stroke, will increase to reach 23.3 million by 2030 [1,3]. Although CVD has been seen as a men's disease for decades, it is actually more common in women. In the European population, 38% of deaths in women before the age of 75 years are due to CVD - in men this figure is 37% - a figure that is partly explained by a higher risk of competing events, i.e. the risk of dying from other causes (Fig. 1) [4]. Most of the burden of CVD can be explained by a set of traditional risk factors that affect both men and women, including elevated blood pressure, smoking, overweight and obesity, diabetes, and elevated cholesterol. Already in 1999 the American Heart Association (AHA) developed the first women-specific clinical recommendations for CVD prevention, which led to increased awareness of women's CVD risk, and to improved risk factor management and treatment of CVD in women [5]. However, despite these women-specific guidelines and accruing evidence for clinically important sex differences in the prevalence of traditional CVD risk factors, and in the effects of these risk factors on CVD outcomes sex-specific risk remains poorly understood and the prevention and management of stroke and cardiovascular risk factors is essentially still the same for men and women. Recent evidence has emerged that recognizes new, potentially independent, CVD risk factors exclusive to women [6]. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g. polycystic ovary syndrome (PCOS) and early menopause) are associated with accelerated development of CVD and impaired CVD-free survival [7,8]. Other risk factors, although not exclusive to women, have a much higher prevalence in women than men. As an example, migraine occurs 3 times more often in women, and is associated with an increased risk of stroke [9,10]. The most recent AHA guideline (2011) and AHA/American Stroke Association (ASA) guideline (2014) for the prevention of cardiovascular complications and stroke in women recommends CVD risk assessment in women with certain reproductive manifestations of CVD risk, such as adverse pregnancy outcomes, and suggests that female-specific risk factors may improve current CVD risk assessment strategies [11,12]. The purpose of this review is to examine the available literature regarding the prevalence and effects of the traditional risk factors
on the risk for CVD in men and women. Furthermore, the impact of the female specific risk factors on the occurrence of CVD is examined. 2. Major risk factors that affect both men and women 2.1. Elevated blood pressure Elevated blood pressure is a major public-health challenge worldwide; it is estimated to be responsible for an annual 7.5 million deaths, about 12.8% of the total of all deaths and to account for 57 million disability adjusted life years (DALYS), about 3.7% of all DALYS [14]. The prevalence of hypertension is broadly similar in men and women, and is projected to increase with population growth and aging in both sexes. In 2000, nearly a billion adults, 27% of all men and 26% of all women, had hypertension; these estimates are projected to increase to 1.5 billion adults, 29% of men, and 30% of women, in 2025 [14,15,16]. The Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group recently conducted large-scale analyses to estimate the global trends in systolic blood pressure (SBP) levels between 1980 and 2008 [17]. In 2008, the age-standardized systolic blood pressure worldwide was 4 mmHg higher in men than in women; men on average had an SBP of 128.1 mmHg compared to 124.4 mmHg in women. Between 1980 and 2008, global levels of mean SBP had decreased by 0.8 mmHg in men and by 1.0 mmHg per decade in women and the prevalence of uncontrolled hypertension had fallen from 33% in 1980 to 29% in 2008 in men and from 29% to 25% in women. These trends, however, varied markedly among men and women living in different regions of the world. Where SBP levels had fallen considerably by about 3e4 mmHg per decade in men and women living in higher-income countries, most likely due to successful implementation of lifestyle and therapeutic interventions [18], opposite trends were seen in many lower and middle-income countries including countries in Oceania, east Africa, and south and southeast Asia were SBP levels rose with 0.8e1.6 mmHg per decade in men and 1.0e2.7 mmHg per decade for women, with no evidence that trends were curbing [17]. Studies have reported conflicting results on whether the strength of the association between increments in SBP and future risk for CVD is the same for men as for women [19,20,21,22]. A recent pooled analysis that included data from prospective cohort studies on more than 1.2 million individuals and over 50,000 cardiovascular events systematically examined whether the magnitude of the association between SBP and risk of CHD and stroke was similar in women and men [23]. After consideration of differences in other major cardiovascular risk factors, every 10 mmHg
Fig. 1. Death rates in Europe 2012. Death rates in Europe, men and women 20 cigarettes per day) [30]. Two recent meta-analyses provided reliable estimates of the association between smoking and CHD and stroke in men and women [31,32]. The first metaanalysis with data from 74 prospective cohort studies, nearly 2.4 million men and women and 44,000 coronary events, showed that, while the beneficial effects of smoking cessation on coronary risk were similar in women and men, women who smoke had a 25%
Fig. 2. Relative risk for coronary heart disease and stroke. Relative risk for coronary heart disease (CHD) and stroke in women and in men per 10-mm Hg increase in systolic blood pressure (A); for current smokers versus non-smokers (B); for people with diabetes versus without diabetes (C) and per 5 kg/m2 in body mass index (D). Lines show 95% confidence intervals.
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greater relative risk of CHD than men, independent of differences in baseline characteristics (Fig. 2B) [31]. In the second meta-analysis, involving data from nearly 4 million individuals and more than 42,000 strokes, there was no clear evidence for a greater excess risk of smoking in women compared with men; the pooled relative risk for stroke associated with current smoking was 1.83 (95% CI: 1.58; 2.12) in women and 1.67 (95% CI: 1.49; 1.88) in men (Fig. 2B) [32]. In a sensitivity analysis that explored the association in Occidental cohorts (where the smoking epidemic is known to be relatively mature) versus Oriental cohorts, smoking conferred a 10% greater risk of stroke in women than in men in the Occidental populations. This finding suggests that there is a small but real sex difference in the effect of smoking on stroke risk, which is currently not visible due to the relative immaturity of the smoking epidemic in women in most parts of the world [25,27,28]. Alternatively, it might be that the mechanisms driving the excess risk of smoking in women, such as a potentially greater absorption of toxic chemicals from the same amount of cigarettes in women [33], may be more pronounced for CHD than for stroke. Future studies are required to examine the effects of prolonged smoking in women and men, independent of the attenuating but persisting sex differences in smoking behavior, and if confirmed, to clarify the mechanisms underpinning these differences. 2.3. Diabetes mellitus Prevalence rates of diabetes rates are rising globally; where 8.3% of all men and 7.5% of all women had diabetes in 1980, estimates from 2008 were 9.8% in men and 9.2% in women [14,34]. The total number of individuals dying from the consequences of high fasting blood sugar or diabetes was 3.4 million in 2004, with more than 80% of these deaths occurring in low- and middle income countries [3,35]. There is substantial evidence that diabetes is a more potent risk factor for CHD and stroke in women than in men, i.e. the presence of diabetes negates the biological female advantage that is often used to explain why women have lower absolute rates of CHD and stroke compared to men [36,37]. In a pooled analysis of over 850,000 individuals and 28,000 coronary events, it was demonstrated that the presence of diabetes nearly tripled the risk of CHD in women (RR: 2.82 [95% CI: 2.35; 3.38]) whereas it more than doubled the risk in men (RR: 2.16 [95% CI: 1.82; 2.56]); the relative risk for CHD thus being 44% greater in women with diabetes than in similarly affected men (Fig. 2C) [36]. In addition, a similarly large meta-analysis including data from over 750,000 individuals and more than 12,500 strokes showed that the relative effect of diabetes on stroke risk was 27% greater in women compared with men: the RR of stroke associated with diabetes was 2.28 (95% CI 1.93; 2.69) in women and 1.83 (95% CI 1.60; 2.08) in men, independent of sex differences in other major cardiovascular risk factors (Fig. 2C) [37]. This sex differential was seen consistently across major predefined stroke, study, and participant subtypes, which included a comparison of individuals from Asian and non-Asian populations. The mechanisms by which diabetes confers a greater excess risk for CHD and stroke in affected women than in affected men remain unclear. A sex disparity in the management and treatment of cardiovascular risk factors in individuals with diabetes, to the detriment of women, is possibly involved [38,39,40,41,42,43,44]. Most recently, data on nearly 2 million individuals with diabetes from the in the United Kingdom suggested that women with diabetes were less likely than men with diabetes to receive care processes recommended by the national guidelines and to meet treatment targets [45]. Standard care processes, including annual checks for the effectiveness of diabetes treatment, management of
cardiovascular risk factors and the emergence of early complications, were received by 58% of women and 62% of men, and 34% of women and 37% of men met all treatment targets for HbA1c, blood pressure, and cholesterol. While evidently of importance, these sex disparities in the treatment and management of individuals with diabetes alone, however, may be too small to explain all of the excess relative risk for CVD in women with diabetes. Alternatively, as the detrimental effects of glucose already occur at glycemic levels below the threshold for the diagnosis of diabetes, it might be that the transition from normoglycemia, to impaired glucose tolerance and overt diabetes is more detrimental in women than in men. As diabetes may remain undetected for many years (about 183 million people with diabetes, 50% of all people with diabetes, are undiagnosed) [46], its diagnosis is often made at an advanced stage when major metabolic alterations and vascular complications have already occurred in most patients [47,48]. Accumulating evidence suggests that these adverse changes in metabolic and vascular risk factor profile in pre-diabetic individuals are greater in women than they are in men [49,50,51,52,53,54,55]. Consequently, the diabetes-related excess risk of cardiovascular disease in women may not be due to any significant sex difference in the effects and complications of diabetes itself, but rather the result of the combination of both a greater deterioration in cardiovascular risk factor levels and a chronically elevated, but undiagnosed and untreated, cardiovascular risk profile in the prediabetic state [56,57]. Future studies will be needed to determine the role of sexspecific cardiovascular risk factor trajectories and their contribution to cardiovascular risk. 2.4. Overweight and obesity Excess body weight is estimated to cause nearly 3 million deaths worldwide each year [14,58]. In 2008, nearly 1.5 billion individuals were overweight (i.e. body mass index (BMI) 25e30), a third of all adults; of these more than 300 million women and nearly 200 million men were obese (i.e. BMI 30) [59]. Estimates from the Global Burden of Disease group indicated that the world's average had increased with 0.5 kg/m2 per decade in women and 0.4 kg/m2 in men to an average level of BMI of 24.1 kg/m2 for women and of 23.8 kg/m2 for men in 2008. The prevalence of overweight in men and women differs according to the level of development of a country; levels of BMI are typically higher in men than women in most high-income countries whereas the reverse is more common in lower and middle-income countries. Regions with almost flat trends or even potential decreases in mean population BMI level are Central and Eastern Europe for women, and Central Africa and South Asia for men. Out of all of the high-income countries, men and women from the USA had, with a mean BMI of over 28 kg/m2 in both sexes, the highest mean population level of BMI [59]. Large-scale analyses of the Prospective Studies Collaboration (PSC) and the Emerging Risk Factors Collaboration (ERFC) have shown that the association between BMI and CHD is broadly identical between men and women whereas the risk for stroke associated with increments in BMI may be higher in men than in women [60,61]. In the PSC, each 5 kg/m2 higher BMI was associated with an increased risk for CHD of 1.35 (95% CI: 1.28; 1.43) in women and 1.42 (95% CI: 1.35; 1.48) in men and with an increased risk for fatal stroke of 1.30 (95% CI: 1.19; 1.42) in women and 1.50 (95% CI: 1.38; 1.65) in men (Fig. 2D). Analyses from the Asian-Pacific Cohort Studies Collaboration (APCSC) also demonstrated the approximately equal strength of the association between the presence of overweight or obesity and the risk of CHD between men and women in both Asian and Australasian populations [62,63]. Moreover, despite the widely recognised sex dimorphism in the body fat
Please cite this article in press as: Y. Appelman, et al., Sex differences in cardiovascular risk factors and disease prevention, Atherosclerosis (2015), http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.027
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distribution there is no evidence that measures of abdominal adiposity, such as waist circumference or waist-to-hip-ratio have a different relationship with risk for CHD or stroke than BMI as measure of general adiposity, nor that the associations between excess CHD or stroke risk induced by measures of abdominal adiposity are differential between men and women [61]. 2.5. Raised cholesterol Raised cholesterol is responsible for over 2.6 million deaths (4.5% of the total deaths), and for 29.7 Disability Adjusted Life Years (DALY's) each year [14]. Women of younger age tend to have more favorable lipid profiles than men, but cholesterol rises after the menopausal transition to levels higher than in men [64]. Globally, mean total cholesterol changed little between 1980 and 2008, falling by less than 0.1 mmol/L per decade in men and women; the global mean age-standardized total cholesterol is 4.76 mmol/L in women and 4.64 mmol/L in men [65]. The prevalence of raised total cholesterol is generally similar between sexes, but is strongly related to the income level of the country. Around a quarter of adults in low income countries, a third of adults in lower middle income countries, and over half of all adult population from highincome countries had raised total cholesterol [14]. To date, there has been no systematic evaluation of the sexspecific effects of major lipids on cardiovascular risk. Results from large-scale individual participant data meta-analyses, however, generally suggest that the associations between several major lipids and the risk of CHD or stroke are similar between men and women [66,67,68]. Analyses from the PSC on almost 900,000 individuals and over 33,000 coronary deaths demonstrated that, in both men and women, each 1 mmol/L lower total cholesterol reduced the risk of mortality from CHD with about a half lower in early middle age (40e49 years), about a third lower in later middle age (50e69 years), and about a sixth lower in old age (70e89 years) [67]. The APCSC also showed no evidence of a sex difference in total
Table 1 Female-Specific Risk Factors associated with Cardiovascular Disease. Female-specific risk factor a
PCOS [89,90,95,96] POIb [93] PIHc [71] Preeclampsia [71] GDMd [76,77,81] Parity 1 [85] Parity 5 [85] Miscarriage 1 [97] Miscarriage 2þ/3þ [98] Preterm birth < 37 w [84,99,100,101,102] SGA < 10th centilee [82] Stillbirth [98]
CVDf
CHDg HTh
C CC CC CC CC CC CCC e e CC
e CC C CC CC e e C CC C
CC e
CC e CC e
C e CCC CCC CCC e e e e C
Stroke T2DMi e e C CC e e e e e CC
CCC e CC CC CCC e e e e CC
CC e
e e
C weak association, Relative Risk (RR) between 1 and 1.5 in cohort studies CC moderate association, RR between 1.5 and 2.5 in cohort studies CCC strong association, RR 2.5 in cohort studies. a PCOS, Polycystic Ovary Syndrome, diagnosis according to the 2003 Rotterdam consensus criteria. b POI, Primary Ovarian Insufficiency, defined as spontaneous (non-surgical) menopause before the age of 40 years. c PIH, Pregnancy-Induced Hypertension, defined by ISSHP criteria (BP 140/ 90 mm Hg without significant proteinuria). d GDM, Gestational Diabetes Mellitus, different criteria combined. e SGA, Small-for-Gestational Age, i.e. birth weight
