Obesity and cardiovascular disease in women

Abstract

As the prevalence of obesity continues to grow worldwide, the health and financial burden of obesity-related comorbidities grows too. Cardiovascular disease (CVD) is clearly associated with increased adiposity. Importantly, women are at higher risk of CVD when obese and insulin resistant, in particular at higher risk of developing heart failure with preserved ejection fraction and ischemic heart disease. Increased aldosterone and mineralocorticoid receptor activation, aberrant estrogenic signaling and elevated levels of androgens are among some of the proposed mechanisms explaining the heightened CVD risk. In addition to traditional cardiovascular risk factors, understanding nontraditional risk factors specific to women, like excess weight gain during pregnancy, preeclampsia, gestational diabetes, and menopause are central to designing personalized interventions aimed to curb the epidemic of CVD. In the present review, we examine the available evidence supporting a differential cardiovascular impact of increased adiposity in women compared with men and the proposed pathophysiological mechanisms behind these differences. We also discuss women-specific cardiovascular risk factors associated with obesity and insulin resistance.

Introduction

The global burden of excess adiposity continues to accrue with about one third of the world’s population being now classified as either overweight or obese [1]. Alarmingly, women are particularly affected by the obesity epidemic [2]. Per recent estimates, the prevalence of obesity will reach 18% in men and 21% in women by 2025 [2]. Health wise, obesity increases the risk of cardiovascular disease (CVD), type 2 diabetes mellitus (T2D), systemic hypertension, obstructive sleep apnea (OSA), cancer, and mental disorders. Across the globe, the obesity pandemic also represents a significant financial burden. Only in the US, obesity is estimated to cost $149.4 billion annually in healthcare related expenditures [3].

In spite of the fact that both sexes are affected by the obesity burden, women manifest heightened CVD risk, particularly when overweight/obese and insulin resistant [4–6]. In the present review, we examine the available evidence supporting a differential cardiovascular impact of increased adiposity in women compared with men and the proposed pathophysiological mechanisms behind these differences. We also discuss women- specific cardiovascular risk factors associated with obesity and insulin resistance.

Epidemiology of obesity in women

Between 1980 and 2015, the global prevalence of a body mass index (BMI) ≥ 25 kg/m² rose from 27.8 to 39.4% in women, and from 25.4 to 38.5% in men. In parallel, the global prevalence of obesity increased from 8.9 to 14.8% in women, and from 5 to 10.1% in men [7]. Interestingly, the greater prevalence of obesity in women becomes only manifested in adulthood, with peak prevalence occurring between 60 and 64 years of age [8]. These sex-related differences in obesity prevalence have been attributed to nutrition, lifestyle, behavior, and environmental differences between men and women [9, 10].

Although BMI is routinely used in both clinical and research settings to stratify at-risk individuals, it does not accurately reflect the actual location of excess adiposity. Mounting evidence suggests that it is not only fat mass per se, but also the distribution of fat mass in the various compartments that influences vascular morbidity [11, 12], particularly in women. A recent study by Chen et al. analyzed data from 2683 postmenopausal women with normal BMI, and showed that after adjustment for demographic, lifestyle, and clinical risk factors, whole fat mass expressed as percentage of body weight was not associated with CVD. However, higher percentage of trunk fat combined with a lower percentage of leg fat was strongly associated with CVD [13]. Hence, the prevalence of at-risk women is likely more elevated than what is currently recognized through BMI alone.

T2D is the major comorbidity associated with increased adiposity [14, 15]. In this regard, sex-related differences have been identified in the association of elevated BMI, T2D, and CVD. Compared with men, a higher proportion of women with T2D are obese, and have higher central adiposity indices, which likely contributes to cardiovascular risk [16]. Indeed, a recent report from the Bogalusa Heart Cohort that included 1530 participants confirms that women who become diabetic exhibit a greater myriad of cardiovascular risk factors, including higher BMI and higher rates of hypertension [17].

As the rate of increase in obesity continues to grow worldwide, surveillance of the epidemiology of obesity among males and females is necessary to better understand the pathophysiology and risk factors involved. This in turn could be used to design prevention and treatment modalities specific to the individual sexes.

Risk factors associated with obesity

In addition to traditional cardiovascular risk factors, attention has been directed toward understanding nontraditional risk factors specific to women, such as excess weight gain during pregnancy, preeclampsia, gestational diabetes, preterm delivery, and menopause [18]. In the following sections, we review some of these CVD risk factors as they relate to female sex and increased adiposity.

Nontraditional risk factors

Pregnancy

A risk factor unique to women is pregnancy. Obesity during pregnancy is associated with adverse short-term and long-term consequences for both mother and offspring [19]. Ramsay et al. showed that obesity during pregnancy is associated with endothelial dysfunction, insulin resistance, and a low-grade inflammatory state, all of which predispose to vascular disease [20]. Further, the degree of weight gain during pregnancy relates with the amount of weight retention after delivery [21, 22]. A study examining 305 postpartum women showed that an adverse cardiometabolic profile characterized by elevation of diastolic blood pressure, LDL, and apo B levels was already present at 12 months in women that did not achieve adequate weight loss between 3 and 12 months after delivery [23]. During a women’s lifetime, the weight retained from each pregnancy has a cumulative effect on the cardiometabolic risk including higher risk of hypertension, T2D, and vascular disease [24, 25]. Therefore, appropriate weight loss strategies should be instituted in the early postpartum period intervention to modify cardiovascular risks in women.

Preeclampsia

New onset hypertension after 20 weeks of gestation along with proteinuria and end-organ damage are the criteria for the presence of preeclampsia. Notably, preeclampsia markedly increases the risk of maternal death [26]. Prepregnancy obesity significantly augments the risk of developing preeclampsia [27, 28]. Different mechanisms have been postulated to explain the link between adiposity and preeclampsia including placental ischemia, pro-inflammatory and procoagulant milieu, and maternal endothelial dysfunction [29, 30]. Preeclampsia exaggerates the “physiological” manifestations of pregnancy, including insulin resistance, hyperlipidemia, inflammation, and hypercoagulability, which in turn could be translated to a “metabolic syndrome” in pregnancy [31], and can result in both short-term and long-term maternal consequences [32]. A meta-analysis by Bellamy et al. that included data from 198,252 subjects concluded that there was an overall significantly increased risk of hypertension, ischemic heart disease (IHD), and stroke in preeclamptic women compared with the control population [33].

Gestational diabetes

The obesity and overweight pandemic have led to more women entering child bearing age with preexisting T2D, and more and more women surfacing with undiagnosed T2D in the first trimester. However, gestational diabetes mellitus is defined as new onset diabetes diagnosed beyond the first trimester [34]. Gestational diabetes becomes an independent risk factor for CVD in women later in life [35]. Weight loss along with other lifestyle modifications become necessary in the postpartum period to reduce the incidence of overt T2D and eventually CVD [36–38].

Menopause and hormone replacement therapy

As discussed earlier, menopause increases the risk of CVD, and even among postmenopausal women with a normal BMI (18–24 kg/m²), increased truncal adiposity increases CVD risk [13]. Although the use of hormone replacement therapy was considered a logical intervention in light of multiple beneficial preclinical studies, evidence from a landmark large clinical trial does not support the use of estrogen therapy for prevention of CVD [39–41]. Further, a recent Cochrane meta-analysis that included 22 studies in postmenopausal women indicated that there is an increased risk in coronary artery disease and stroke with combined hormone replacement therapy [42]. The American College of Obstetricians and Gynecologists, as well as the North American Menopause Society, currently discourage the routine use of estrogen replacement therapy in most post-menopausal women. However, there is still a debate about the time line of introducing hormone replacement therapy, since there might still be benefits among women in early menopause. Additional studies are warranted to more precisely identify the signaling pathways by which estrogen loses its cardiovascular protective power in the post-menopausal state. With the advent of novel transdermal routes of hormone replacement delivery, which have lower risks, estrogen therapy may still be considered as a viable and effective option.

Traditional risk factors

Hypertension

Obesity is a modifiable risk factor clearly associated with hypertension in women [43]. An analysis of the Framingham cohort showed that the attributable risk related to excess weight (BMI ≥ 25 kg/m²) for hypertension was 26% in men and 28% in women [44]. The presence of hypertension results in greater cardiovascular morbidity and mortality risk even after adjusting for other classic risk factors [44]. Women are protected from hypertension until later in life, a phenomenon related to the vasodilatory effects of estrogens [45, 46]. However, exogenous estrogen therapy in postmenopausal does not result in improved blood pressure control. Further, obesity offsets estrogen benefits, as BMI and age of onset of hypertension share an inverse relationship [47]. Extant clinical trials have not been specifically designed to address the higher risk that obesity and hypertensive disorders of pregnancy impose on women, but there is evidence that women attain antihypertensive treatment therapeutic goals at lower rates [48]. For instance, a continuous cross-sectional survey from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 showed that while men and women are effectively placed on antihypertensive treatment, women are less likely to attain targeted blood pressure reductions [48].

Type 2 diabetes

T2D is an important potentiator of IHD in women [49, 50]. Possible mechanisms to explain the increased burden of CVD among diabetic women can be explained by the clustering of obesity, elevated triglycerides, and the influence of sex hormones [51]. Women accumulate greater adipose mass before developing T2D in comparison to males and this can potentially result in greater cardiometabolic burden, endothelial dysfunction, and hypercoagulability [52, 53]. Interestingly, sex-related differences in the prescription of medications and adherence to treatment also have been postulated to contribute to this sex-related divergent effect [51].

Obstructive sleep apnea

OSA is a common disorder with nearly one billion people affected worldwide, and is closely related to the epidemic of obesity [54]. Further, OSA increases the risk of CVD, particularly by increasing blood pressure [55, 56], and differences in attributable risk of sleep disorders differs between men, pre- and postmenopausal women [57–59]. OSA has been classically considered to mainly affect men and, as such, women have been underrepresented in clinical trials [55]. In this regard, menopause is a significant risk factor for OSA [60], and hormonal replacement therapy appears to reduce the risk of OSA [61]. In the Wisconsin sleep cohort, 24% of men and 9% of women were found to have an apnea–hypopnea index of >5 per hour of sleep (the cut-off value indicative of disease), while 4% of the men and 2% of the women had symptoms associated with OSA [62]. Despite the finding that women are less frequently diagnosed with OSA [63], they have higher healthcare consumption and significantly more frequent physician visits and hospitalizations before the diagnosis of OSA than men [64]. Data from some studies suggest that women with OSA tend to have a lower Epworth Sleepiness Scale score [65], more complaints of insomnia, symptoms of restless legs syndrome, depression and nightmares, and less complaints of snoring and apneic episodes [66] than men. The differential clinical presentation might be a cause for delayed diagnosis.

Untreated severe OSA is strongly associated with CVD morbidity and mortality in both men and women [67–72], and even though continuous positive airway pressure (CPAP) is an effective therapy for treatment of OSA, its impact on decreasing CVD remains a matter of debate. CPAP therapy has been shown to have a positive effect on hypertension [73, 74] but randomized-clinical trials have failed to demonstrate a beneficial effect on cardiovascular outcomes [75–78]. Further, a recent meta-analysis found that CPAP treatment decreases daytime sleepiness and improves quality of life scores, but does not appear to impact cardiovascular outcomes. However, these studies have limitations that preclude their translation to the clinic such as outcomes examined, poor adherence to CPAP therapy, limited geographic representation, and hetero-geneity of the subjects examined [79]. Overall, CPAP is a safe therapy that should be advocated to patients with OSA, and strong pragmatic trials powered to detect sex-related differences are needed to confirm its efficacy in preventing CVD.

Pathophysiology of CVD in obese women

Awareness of the existence of sex-related differences in the prevalence and presentation of CVD has increased over the last decades [17, 80, 81]. Importantly, research aimed at unveiling key pathophysiological events behind heightened CVD risk in obese and T2D women has provided important cues. Nondiabetic premenopausal women are protected against CVD when compared with age-matched men [82]. However, once obese and diabetic, women exhibit worsened cardiovascular outcomes [13, 17, 80, 83, 84]. Multiple potential contributing factors could be operationally involved in this dyad; the more salient are discussed below.

Adipokines

Obesity is characterized by chronic low-grade inflammation and dysregulation of the endocrine and immune milieu in the adipose tissue [85]. Aberrant production of adipokines and inflammatory molecules have been associated with the genesis of CVD.

Adiponectin is an adipokine produced preferentially in the subcutaneous white adipose tissue [85] and its circulating levels are inversely related to the size of the visceral fat depot [86, 87]. As multiple preclinical studies have shown that adiponectin has cardioprotective, vasodilatory, anti-inflammatory, antiatherogenic, and insulin sensitizing effects [85, 88], the finding that adiponectin is associated with cardiovascular mortality seems paradoxical. However, different analyses of large cohorts have consistently found that adiponectin levels correlate positively with CVD events and mortality [89–92]. Furthermore, studies using Mendelian randomization have further questioned the role of low adiponectin levels in the pathogenesis of cardiometabolic disease [93, 94]. Notably, a recent meta-analysis by Scarale et al. pooling all-cause mortality data from 61,676 subjects and cardiovascular mortality data from 43,979 subjects support these findings, and show that there is a significant increase in all-cause and cardiovascular mortality with elevated total adiponectin levels [92]. Potential explanations for these paradoxical results include resistance to the beneficial vascular effects of adiponectin, and an increase in adiponectin levels secondary to elevation of natriuretic peptides [95]. Natriuretic peptides are a known marker of increased CVD risk [96]. Nevertheless, the association of adiponectin with mortality remains significant even after controlling for natriuretic peptides [97]. In regard to sex-related differences, data from the Rancho Bernardo study found that higher adiponectin levels were associated with a significant increase in cardiovascular death in both men and women, independently of age, waist circumference, lipids or blood glucose [97]. On the other hand, Menzagui et al. have reported, using data from different populations, that serum adiponectin levels predict CV mortality in men, but not in women with T2D [98].

Another adipokine that has been related to increased CVD risk is leptin. Leptin is primarily produced by white adipocytes, and under physiological conditions, suppresses appetite and increases energy expenditure [85]. Leptin levels correlate with adiposity in both rodents and humans [99]. A cross-sectional analysis of the Dallas Heart Study revealed that after adjusting for fat mass and fat distribution, leptin was higher in women than in men across different BMI values [100]. Similarly, a recent report by Lau et al. examining 7184 Framingham Heart Study participants found significant sex-related differences in CVD biomarkers; specifically leptin was found to be higher in women than in men regardless of postmenopausal status or use of hormone replacement therapy [101]. Elevated circulating levels of leptin have been associated with IHD, stroke, and peripheral artery disease [102–104], and as we discuss later, leptin has also been implicated in the pathogenesis of CVD in obese women via increased mineralocorticoid activity [105, 106].

C-reactive protein (CRP) is an acute phase reactant produced by the liver in response to different pro-inflammatory stimuli (mainly IL-6) [107]. Women are known to have higher levels of CRP. Ridker et al. reported in a population of postmenopausal overweight women that several inflammatory markers may serve as independent predictors of risk of future CVD events, with CRP showing the strongest association in the univariate analysis [108]. Khera et al. later showed using data from the Dallas Heart Study cohort that women have significantly higher levels of CRP when compared with men (3.3 vs. 1.8 mg/l), and that the elevation in CRP associated with obesity was greater for women than for men [109]. However, and despite elevated levels of CRP in obesity [110], the role of CRP as a causative agent of the cardiovascular complications of obesity is unclear [107].

Sex steroids

The classical protection against CVD in premenopausal lean women has been attributed to the effects of estrogen on the vasculature. Estrogens exert their effects via the intracellular receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), and the membrane bound receptor (G protein-coupled estrogen receptor-1; GPER-1) [45]. Estrogen receptors are present in different cardiovascular cells, including endothelial and vascular smooth muscle cells, as well as cardiomyocytes [45]. Under physiological conditions, estrogenic signaling in endothelial cells results in increased production of nitric oxide (NO) [111–113]. Increased NO bioavailability reduces arterial tone, arterial stiffness, blood pressure, and prevents adverse vascular remodeling [114]. These vascular estrogenic effects are widely considered to be mediated by ERα [112]. ERα signaling also exerts protective anti-inflammatory, antioxidant, and antiatherogenic effects [45, 112]. In the heart, estrogens are known to modulate prosurvival signaling and antioxidant mechanisms [115, 116], predominantly via ERα [111, 117]. However, recent evidence also highlights the cardioprotective role of GPER-1 in models of aging and ischemia–reperfusion [118–120]. Notably, the favorable effects of estrogens in the vasculature are lessened when conditions such as obesity, insulin resistance, and T2D are concurrently present [121, 122]. In this regard, our research group has explored the role of ERα signaling in conditions of overnutrition and obesity. We have shown that absence of ERα in endothelial cells of both insulin resistant female and male mice is protective against arterial stiffening, when compared with wild-type mice [123, 124]. These findings highlight the fact that the classical beneficial effects of estrogens are lost in conditions of overnutrition. Furthermore, the abrogation of the protective vascular effects of estrogen in the setting of obesity and insulin resistance appears to be mediated by activation of the epithelial sodium channel in endothelial cells [125].

Limited data are available regarding the vascular effects of estrogen replacement in obese or T2D women. Koh et al. treated T2D women with conjugated estrogens for 2 months and reported lack of improvement on endothelial-dependent dilation in diabetic subjects despite beneficial effects on lipid profile [122]. Nonetheless, long-term clinical trials examining the impact of hormone replacement therapy in populations at high risk of CVD such as obese and T2D women are missing.

Androgen excess can also play a role in the pathogenesis of CVD in obese women [126–128]. Hyperandrogenemia is seen in conditions of increased adiposity like polycystic ovarian syndrome and postmenopausal state [126, 127]. Further, elevated levels of androgens correlate with obesity, hypertension, insulin resistance, and endothelial dysfunction [128]. Wang et al. examined a cohort of 4720 T2D subjects in China, and reported that in postmenopausal overweight women total testosterone levels were associated with diabetic CVD [129]. Similarly, using data from the MESA study (Multi-Ethnic Study of Atherosclerosis), Zhao et al. reported that in postmenopausal women a higher testosterone/estradiol ratio is related to incident CVD and IHD [130]. The mechanisms involved in the deleterious vascular effects of androgens in women are not completely understood. Wenner et al. have shown that vasodilation in response to endothelin-1 receptor B (ET_B) activation in the skin microvasculature of women with polycystic ovarian is blunted [131], and that androgen suppression results in improved ET_B-induced vasodilation, as well as in reduced ET_A-mediated vasoconstriction [132]. In addition, androgens are also known to upregulate components of the renin–angiotensin system with consequent elevation in blood pressure and enhanced oxidative stress [133].

More recent studies also point toward a deleterious effect of progesterone in the vasculature of obese females. Faulkner et al. recently reported that in a female rodent model of obesity, activation of the progesterone receptor drives mineralocorticoid receptor (MR) expression in endothelial cells [134], and that deletion of progesterone receptors in endothelial cells protects against leptin-induced endothelial dysfunction.

Aldosterone and mineralocorticoid receptor (MR) activation

Aldosterone (Aldo) plays a central role in the pathogenesis of CVD in the setting of obesity, insulin resistance, and T2D [135–138]. Aldo binds and activates the MR in epithelial and nonepithelial tissues [139]. MR activation was originally described to contribute to blood pressure regulation in the distal nephron [139]. During the last couple of decades, copious amounts of evidence have accumulated delineating the role of MR activation in both endothelial and vascular smooth muscle cells as central to the pathogenesis of hypertension, atherosclerosis, cardiovascular fibrosis, and remodeling [139, 140]. MR activation in vascular smooth muscle promotes vasoconstriction, vascular fibrosis, and remodeling [139, 141, 142]. Further, MR is also present in endothelial cells, where it upregulates genes that result in transcription of inflammatory molecules and ion channels [143]. MR also induces vascular remodeling via micro-RNAs acting as posttranscriptional regulators of genes [144].

Conditions of increased adiposity are characterized by elevated Aldo levels and enhanced MR activation [145–148]. Both preclinical and clinical investigations support a greater role for MR activation in the genesis of vascular disease in obese and insulin resistant women. A decade ago, Touyz et al. described Aldo production by adipose tissue [149]. Later, Aldo production by adipose tissue was characterized as dependent on calcineurin dependent signaling [146]. Subsequently, it was demonstrated that adipocytes express aldosterone synthase, and via the angiotensin II (Ang II) receptor type 1, adipocytes secrete Aldo in response to Ang II stimulation [146]. However, the increased production of Aldo characteristic of obesity states is not exclusive of adipose tissue. Leptin, an adipokine that is elevated in obesity, increases Aldo levels in females, and results in augmented expression of aldosterone synthase in the adrenal gland [150]. In addition, leptin-related endothelial dysfunction and cardiac fibrosis is ameliorated by MR blockade [150], and in females, both leptin antagonism and MR blockade improve endothelial function and blood pressure [151].

Preclinical studies have also shown that female mice develop diastolic dysfunction when obese and that such changes develop earlier than in male mice [152]. Furthermore, MR antagonism prevents the development of diastolic dysfunction [153]. Similarly, another investigation demonstrated that obese and hyperlipidemic female mice have higher susceptibility to microvascular dysfunction in comparison to males [154]. Notably, both MR pharmaco-logical blockade and MR transgenic deletion result in amelioration of arterial stiffening, endothelial dysfunction, and aortic remodeling in obese female rodents [155, 156]. In older adults, MR blockade has been shown to lead to greater improvements in endothelial function, the latter assessed by brachial artery flow-mediated dilation, in subjects with greater adiposity [157].

Clinical evidence also supports the impactful relationships of obesity, female sex, and Aldo. In a cohort of nonhypertensive adults, Garg et al. reported that overweight subjects have greater Aldo responses to Ang II stimulation when compared with lean counterparts [147], with a significant negative correlation emerging between insulin sensitivity and Aldo levels [158]. Further, in an analysis of the Framingham offspring cohort, female sex was correlated with elevated Aldo levels only in premenopausal women and in postmenopausal women using hormone replacement therapy, which points toward an effect of sex steroids on Aldo production [159]. A contemporary study found that the elevation of plasma Aldo in response to Ang II infusion was greater in women when compared to men [160], and that similar to the Framingham cohort findings, elevations in Aldo production were greater in premenopausal women [160]. Notably, interventions resulting in weight loss will lower plasma Aldo and reduce blood pressure [161].

Clinical manifestations of CVD in overweight and obese women

Despite remarkable improvements in CVD outcomes in the last 40 years, the toll of obesity-related CVD continues to grow [162]. In 2015, CVD related to elevated BMI was the leading cause of death and disability-adjusted life years, accounting for 2.7 million deaths and 66.3 million disability-adjusted life years (composite metric used to assess burden of disease computed as the sum of years lived with disability and years of life lost due to high BMI) [8]. The association of CVD and obesity is particularly impactful for women. CVD is the leading cause of death for women in every major developed country and in most developing countries. Data from the Framingham Heart Study shows that obesity increases the risk of coronary artery disease by 64% in women when compared with 46% in men [44]. This heightened cardiovascular risk has been considered as responsible for the recent stagnation in the rate of improvement of cardiovascular mortality indices, particularly in younger women [163].

Ischemic heart disease

The prevalence of IHD is higher in men that in women, across different racial and age groups [164]. This higher prevalence is likely related to a greater burden of CVD risk factors in men throughout their lifespan [165]. Nevertheless, IHD is the leading cause of death in women with a marked increase in frequency after menopause, highlighting the impact of reduced sex hormones on metabolic profile and fat redistribution [165]. Importantly, recent data show that younger women with premature IHD exhibit a higher prevalence of CV risk factors (hypertension, obesity, and T2D), as well as increased mortality rates [166].

The angiographic presentation of IHD differs between women and men, as women tend to present less obstructive lesions and more coronary vasospasm [167, 168]. Recent analysis of 10-year mortality data of the Women’s Ischemia Syndrome Evaluation study showed that women with nonobstructive lesions had higher mortality rates, and that cardiometabolic abnormalities related to increased adiposity, such as dyslipidemia, hypertension, and T2D were significant predictors of the accrued mortality rates [169].

Studies recently showed that in a cross-sectional post hoc analysis, obese T2D women with good metabolic control have lower coronary blood reserve, higher resting myocardial blood flow, and worse diastolic function compared with T2D men [170]. This is highly relevant when considering that impaired microvascular coronary function correlates with CVD mortality [171, 172].

Data from the Nurse’s Health Initiative study showed that the incidence of IHD among women who follow a healthy lifestyle accompanied by a lower BMI was significantly lower compared with women who have increased adiposity, high cholesterol levels, and lack of regular physical activity [173]. Hence, it can be argued that the promotion of obesity-preventing strategies has a crucial role in the primary prevention of IHD among women. In this same regard, data are available indicating that women are less likely to receive aggressive medical therapy to address classical cardiovascular risk factors once the diagnosis of IHD has been established [174].

Heart failure

Heart failure (HF) has become a global epidemic [164]. Recent data from the NHANES reported that in the United States alone, 6.5 million adults carried the diagnosis of HF between 2011 and 2014 [164]. Populations with a higher BMI had a greater risk of HF occurrence in a lifetime [164]. Indeed, obesity is a well-known risk factor for HF, as it is associated with hypertension, dyslipidemia, and insulin resistance [175]. Moreover, when obesity is combined with female sex, HF with preserved ejection fraction (HFpEF) stands out as a special phenomenon [176–180]. In this regard, Savji et al. showed that women demonstrated a stronger correlation between obesity associated cardiometabolic parameters, such as insulin resistance, with incident HFpEF [181]. This association is less pronounced in men, who demonstrated occurrence of both types of HFpEF and reduced EF in the presence of the same parameters [181]. Similarly, Kim et al. showed in a Korean cohort that the prevalence of diastolic dysfunction was greater in women than in men with metabolic syndrome [182].

Arterial stiffness is a phenomenon associated with vascular aging, but obese and insulin resistant women exhibit increased arterial stiffening when compared with men [183–187]. Importantly, arterial stiffening has a greater negative impact on diastolic function in women than in men [170]. Similarly, a recent subanalysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial reported that in women, arterial stiffening has a greater negative effect in long-term outcomes when compared with men, despite similar blood pressure control [188].

Different pathophysiological mechanisms have been proposed as central to the appearance of HFpEF, and include increased inflammation and disruption of the nitric-oxide–cyclic guanosine monophosphate-protein kinase G pathway leading to endothelial dysfunction and mitochondrial disruption, as well as amplification of the angiotensin–aldosterone system signaling leading to myocardial injury. Furthermore, as HFpEF prevalence increases in postmenopausal women, the lack of the estrogenic vasodilatory signaling and the differential use of myocardial energy substrates have been proposed as important contributors to the pathogenesis of HFpEF [189].

Clinical manifestations of HF in obese women also differ from obese men, with women exhibiting worsened quality of life due to greater fatigue, dyspnea, and decreased exercise capacity compared with their male counterparts [190, 191]. Women have been underrepresented in earlier clinical trials concerning HF [192]. These observations warrant the need to establish female-specific outlines in the approach, diagnosis, and treatment of HF [193].

More recently, clinical trials addressing the effectiveness of MR blockade on HFpEF patients have been completed with variable results. The Aldo-DHF trial examined the effect of MR blockade with spironolactone on patients with HFpEF. In this study, over 50% of the subjects were females with a mean BMI of 28. Twelve months of MR blockade improved left ventricular diastolic function, but did not favorably impact exercise capacity or quality of life [194]. Another landmark trial, the TOPCAT, assigned 3445 patients with symptomatic HF and a left ventricular EF ≥45% to receive spironolactone or placebo. Fifty-one percent of the subjects were women, and the median BMI was 31. Treatment did not result in significant differences in the primary outcomes of cardiovascular death, aborted cardiac arrest or HF hospitalization [188]. In an exploratory post hoc analysis of the TOPCAT trial, Merril et al. reported that there was a significant interaction between sex and treatment arm in regards to all-cause mortality, with women exhibiting a greater benefit [195].

Peripheral artery disease

The identification of peripheral arterial disease (PAD) in the population is important, as it illustrates the atherosclerotic plaque burden for an individual, and hence the risk of IHD [196–198]. Also, given that PAD itself has a significant impact on the quality of life, it is important to identify those at risk. The global burden of PAD is particularly significant among the older populations, and the prevalence is similar among both men and women [1, 199]. Conditions associated with obesity such as T2D, hypertension, and hyperlipidemia increase the risk of PAD [200]. How sex plays a role in affecting these pathways specifically in PAD is still an open question that will undoubtedly be hotly debated over the next several years. Women tend to have higher prevalence of pain as well as a greater impairment in lower extremity function from PAD when compared with men [201]. Unfortunately and similar to IHD, women also do not seem to present with the classic symptoms of PAD, which may delay diagnosis and lead to more limb amputations [202]. These findings seem to indicate that PAD imposes a greater burden among females. Whether sex and obesity are to be included in the guidelines considering PAD risk stratification is a matter of debate as current evidence is not particularly strong in this regard.

Stroke

The incidence and prevalence of stroke have declined worldwide among both men and women, but stroke related deaths continue to rise, ranking only second to IHD in global mortality [164, 203]. Ischemic stroke, which constitutes the vast majority of cerebral strokes, has similar etiology to other forms of atherosclerotic disease [203]. Men have greater prevalence of ischemic stroke than women [204], but this trend changes with age-based stratification [205, 206], possibly due to the fact that women develop ischemic stroke at a later age, and also because women have a longer lifespan than men.

When considering the risk attributable to obesity per se, several cohort studies among Asian, European, and American populations have identified increased adiposity as an independent risk factor for stroke among women [207–210]. A large Chinese cohort study of 67,000 women found a relative increase in the risk of stroke with every 1 cm increase in waist circumference [211]. However, as per the statement for healthcare professionals from the American Heart Association/American Stroke Association, the stroke risk from obesity among men and women was not clearly evident after adjusting for comorbid conditions [212]. Another important risk factor for ischemic stroke is the presence of atrial fibrillation. The Women’s Health Study showed that, in otherwise healthy women, the risk of atrial fibrillation increases linearly with BMI [213]. Importantly, the use of oral contraceptives, as well as a previous history of preeclampsia also increase the risk of stroke [214–216].

The obesity paradox

Although a significant amount of evidence supports the association between excess adiposity with CVD, a contrarian observation, the so called “obesity paradox” proposes that the prognosis of certain established CVD manifestations, particularly HF, is better in overweight and obese individuals in comparison with leaner ones [11, 217–220]. Horwich et al. originally described this finding in a cohort of subjects with HF and reported that higher BMI was not associated with increased mortality with a trend toward greater survival [221]. Different analyses have further supported these observations in patients with either HFpEF or HF with reduced EF [222–224]. Nevertheless, the potential benefit of increased adiposity seems to disappear on long-term follow-up [225] and in severely obese groups [226, 227]. There are limited amount of data examining the “obesity paradox” in women. Vest et al. reviewed data from 3811 HF subjects with decreased EF, and found that the survival advantage disappeared in obese and overweight males when confounders were controlled, but overweight women retained a lower adjusted mortality [228].

Different potential explanations behind the paradoxical findings have been postulated and highlight the inherent limitations of assessing adiposity by BMI alone. As studies usually categorize patients based on BMI, the possibility exists that the groups that showed benefit may have a relative healthier fat distribution and higher muscle mass [229]. It is also hypothesized that unaccounted confounding factors like cardiorespiratory fitness are responsible for the obesity paradox [230–232]. Accumulating adipose tissue worsens insulin resistance and exercise capacity eventually leading to poor outcomes. Hence, it is important to carefully validate the plausible factors explaining the obesity paradox before concluding that overweight and obesity are beneficial states.

Future directions and key areas of interest

As the prevalence of obesity continues to increase worldwide, the burden of obesity-related CVD follows a similar trajectory. Women are particularly affected by CVD in this setting (Fig. 1), as the protection naturally afforded by sex hormones is diminished. Even though different mechanisms have now been identified as mediators of the heightened CVD risk in men and women, interventions specifically tailored to target women are lacking. Aggressive control of classical risk factors such as obesity, hypertension, T2D, and dyslipidemia becomes a central focus for curbing down the CVD epidemic. Moreover, clinical studies need to address long-term follow-up and treatment strategies for women with a history of preeclampsia and gestational diabetes to ameliorate the cardiovascular consequences of these conditions. In addition, we briefly describe below some emerging key areas of interest with a potential sex dependent impact in the pathogenesis of obesity-related CVD.

Fig. 1. Cardiovascular disease manifestations and risk factors in obese women.

MR mineralocorticoid receptor, CPAP continuous positive airway pressure, HFpEF heart failure with preserved ejection fraction.

Microbiota

Increasing amount of data support a role for the microbiome in the genesis and progression of CVD [233]. Sex-related differences in the composition of the microbiota have been described, with a higher ratio of Firmicutes/Bacteroidetes (F/B) in women than in men [234, 235]. Some have associated a higher F/B ratio with gut dysbiosis [236]. Haro et al. showed that microbiota composition can be affected by sex in a BMI-specific manner with obese women exhibiting a higher F/B ratio [237]. Altered production of certain metabolites by the dysbiotic microbiome can result in increased cardiovascular risk. In particular, increased production of trimethylamine-N-oxide [238], a pro-inflammatory, and proatherosclerotic metabolite, has been reported to result in augmented cardiovascular risk [239]. Further, the finding that the enzyme that catalyzes the rate-limiting step in the production of trimethylamine-N-oxide is down-regulated by androgens [240], suggests that sex differences in obesity-related-CVD can be associated with sex differences in gut microbiota.

Metabolic surgery

Obese women account for the majority of patients that undergo metabolic surgery procedures [241]. Importantly, surgery for obesity management is well-known to result in regression of different metabolic and cardiovascular risk factors, while lowering risk of major cardiovascular events [242–248]. Likewise, the incidence of pregnancy-related complications, such as gestational diabetes and pre-eclampsia, decreases in obese women that undergo metabolic surgery [249, 250]. However, further clinical trials are needed to better delineate the optimal choice and timing of surgery in obese women as it relates to its impact on both pregnancy-related complications as well as long-term CVD risk [251, 252].

Pollutants

An area of increase public and research interest is that of the impact of air pollutants on cardiovascular health [253]. Hoffman et al. analyzed data from the from German Heinz Nixdorf Recall Study, and reported that residential exposure to highly trafficker roads was associated with coronary artery calcification [254]. An analysis of a cohort of 65,893 postmenopausal women without known CVD demonstrated that long-term exposure to polluted air was related with cardiovascular events and cardiovascular mortality [255]. Further, Bell et al. used Bayesian hierarchical modeling to estimate the association between fine particles and CVD. These authors found that women were more susceptible than men to hospitalizations related to cardiovascular causes on days with higher fine particles count [256].

Depression

Women are known to have higher rates of depression than men [257]. Significantly, depression and CVD frequently co-exist [258, 259], and women with IHD have a higher prevalence of depression that men [260]. In the Nurses’ health initiative cohort, presence of depression symptoms was also associated with increased cardiovascular mortality in a previously healthy population [261]. Different mechanisms have been proposed to mediate the association between depression and CVD [262], but further studies are needed to define clinical interventions that positively impact the outcomes of both conditions.