Advanced age is a major risk factor for mortality from CVD, in particular for women over the age of 85 years who have coexisting risk factors, reduced physical activity, and other comorbidities. CVD accounts for 27% of deaths in women over the age of 85 years.¹ CVD appears to have a later onset in
women as compared to men, with estrogen hypothesized to be protective in their early years and CVD more prevalent after menopause—natural or surgical—when the circulating levels of estrogen are decreased.⁴ Estrogen is thought to have a role in vasodilation, inhibition of smooth muscle cellular proliferation, and regulation of blood pressure control. Nevertheless, postmenopausal estrogen replacement therapy is not recommended for prevention of CVD, as it has failed to demonstrate a protective benefit in clinical studies.

Hypertension affects more men than premenopausal women. It is believed that endogenous estrogens help maintain vasodilation and contribute to blood pressure control in premenopausal women. However, after the age of 65 years, the incidence of hypertension increases in women and the associated mortality is higher than at younger years.²,⁵ This is due to the increased risk of CVD, heart failure (HF), and stroke with hypertension as well as the confounded risk with advancing age.

Despite modern advancements in antihypertensive agents, mortality associated with hypertension has increased over the past decade.⁶ Nearly one-third of individuals with hypertension are unaware of their diagnosis. However, women tend to have better awareness of their hypertension diagnosis, receive treatment, and have better blood pressure control compared to men.⁷ It is estimated that with improvement in hypertension, cardiovascular mortality may be improved by 38% in women.⁶ Based on the SPRINT trial, the blood pressure targets should be less than 130 mm Hg systolic and less than 80 mm Hg diastolic in both men and women.

Diabetes mellitus is a well-recognized risk factor for the development of CVD and affects at least 10% of the population.⁸ The prevalence of diabetes mellitus in women is lower compared to men (8.4% vs 9.5%, respectively) and has a lower associated overall mortality.²,⁸,⁹

Interestingly, diabetes is more common in younger women (18-54 years) and associated with a greater risk for CVD compared to similarly aged men.¹⁰ Women with diabetes mellitus have a threefold risk of fatal coronary disease compared to women without diabetes mellitus.¹¹ There is also a known risk for the development of HF with diabetes, which is higher in women than in men. In the CARDIA study, longer duration of diabetes mellitus was associated with higher coronary artery calcium (CAC) scores, worse cardiac function, and higher diastolic filling pressures and diastolic dysfunction.¹² Diabetic women are also known to have a greater number of traditional CVD risk factors than nondiabetic women, with poorer optimization of their risk factors over time.

Given the potential severe cardiovascular complications in diabetic women, medical optimization of glycemic control and concurrent risk factor reduction is crucial. Providing education on the cardiovascular risk associated with diabetes mellitus in women is recommended. Women should have dietary education to optimize glycemic control and target weight loss if they are overweight or obese. Additionally, the addition of diabetic agents that confer a cardiovascular benefit, such as sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonists, should be considered. In general, the presence of diabetes mellitus is an imperative for aggressive CVD risk prevention in women.

Metabolic syndrome is also a significant risk factor for CVD given its known association with diabetes mellitus, myocardial infarction, stroke, and increased all-cause mortality. Metabolic syndrome confers an increased risk of CVD in women compared to men. This may be due to subclinical atherosclerosis, which is a consequence of metabolic syndrome and demonstrated by the higher CAC scores in women with metabolic syndrome compared to those without it. The pathophysiology of associated risk for CVD is thought to be related to microvascular (ie, endothelial) and macrovascular dysfunction, leading to atherosclerotic plaques at high risk of progression and thrombosis, impairment in coronary blood flow reserve, and both systolic and diastolic left ventricular dysfunction. In women, metabolic syndrome is also associated with a number of comorbid autoimmune and inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Gestational diabetes and hypertension, which confer a high risk of CVD progression, are also associated with metabolic syndrome in women.¹³,¹⁴

Hyperlipidemia is a recognized modifiable risk factor for CVD. Women typically have higher total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels compared to men; however, they have lower low-density lipoprotein cholesterol (LDL-C) and triglyceride levels compared to men. The advent of cholesterol-lowering agents, especially statins, has resulted in a significant reduction in hypercholesterolemia within the population. Despite baseline gender differences in cholesterol and triglycerides, treatment recommendations remain the same for both women and men. The 2019 AHA/ACC Guidelines on the Primary Prevention of Cardiovascular Disease includes recommendations for statin therapy based on atherosclerotic CVD (ASCVD) risk scoring and associated risk factor consideration.⁴ The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—evolocumab and alirocumab—has allowed patients with severe statin intolerance or suboptimal cholesterol control despite maximally tolerated statin therapy to achieve desired cholesterol levels. PCSK9 inhibitors reduce LDL-C by approximately 40% to 50% and the risk of ASCVD events by 15%.¹⁵ Women with suboptimal cholesterol control despite maximally tolerated statin therapy or severe statin intolerances are ideal candidates for PCSK9 inhibitor therapy. Providing education to women on target ranges for cholesterol and healthy diet choices is important for long-term cholesterol management and CVD prevention.

Tobacco use remains the most significant cause of preventable death worldwide. Approximately 13.5% of women are tobacco
users but represent a smaller proportion of the population of smokers compared to men.¹⁶ Additionally, up to 7.2% of women continue to smoke during pregnancy, which may increase the overall risk of pregnancy-associated hypertension and preterm birth. Although overall rates for smoking continue to decline, the use of e-cigarettes has substantially risen in recent years, in particular, in younger individuals. The cardiovascular implications of e-cigarette use have not been studied and the long-term CVD effects are not yet known.²

Tobacco is a recognized independent risk factor for CVD and also increases the risk for the development of hypertension, hyperlipidemia, and diabetes mellitus, which further increases the risk for CVD. Women tobacco users are thought to be at a greater risk for CVD compared to men. In a recent meta-analysis of over 75 studies, women had a 25% increased risk for coronary artery disease (CAD) conferred by cigarette smoking compared with men.¹⁷ It is also important to note that the combination of smoking with oral contraceptive use has a synergistic effect on the risk of acute myocardial infarction, stroke, and thromboembolism. Hence, counseling concerning smoking cessation and the risks of CVD with tobacco use should be provided to women. Complete tobacco cessation is important given the increased risk of CVD even with reduced tobacco use: women who smoke one cigarette per day have a 57% higher risk of heart disease and a 31% higher risk of stroke (or 119% and 46% when allowing for multiple confounders) compared with never smokers.¹⁸ In female patients, the risk of smoking with pregnancy should be strongly discouraged. Additionally, education on the increased risk of myocardial infarction, thromboembolism, and stroke associated with tobacco use and oral contraceptive use should be provided to women of childbearing years. Younger tobacco users and e-cigarette users should be warned about the unknown cardiovascular side effects of newer nicotine and tobacco agents.

Obesity is a significant risk factor for CAD, HF, and atrial fibrillation, and its impact on the development of CAD appears to be greater in women than in men. More than two in three adults in the United States are considered to be overweight or obese, and the prevalence of obesity is higher among women than men. According to National Health and Nutrition Examination Survey (NHANES) data, the prevalence of obesity in the United States is 42% in women and 43% in men.¹⁹ The prevalence of obesity in women has continued to rise over the past 15 years and class III obesity (ie, severe or extreme, with body mass index [BMI] of 40 kg/m² or higher) in particular. Conversely, this upward trend in class III obesity is not seen in the male population. Class III obesity rates are highest in women, accounting for 9.7% of the female population versus 5.6% of males. CVD risk is increased in class III obesity compared to classes I or II, which is concerning given the higher prevalence in women.²⁰,²¹ Numerous studies, including data from the Framingham Heart Study, associate a higher risk of CVD in obese women compared to obese men: obesity increased the relative risk of CAD by 64% in women, as opposed to 46% in men.²²

Additionally, obesity has an important role in the development of other risk factors for CVD such as hypertension, diabetes mellitus, and dyslipidemia.²¹,²³ Subclinical atherosclerosis has also been implicated in the obese population, with this group having higher CAC and carotid intima-media thickness compared with patients with normal body size, even after adjustment for traditional CVD risk factors.²⁴ Furthermore, there are data showing obese women who present with ACS have worse outcomes. For patients with ST elevation myocardial infarction, in-hospital mortality rates are highest for individuals with class III obesity, which is of concern given a higher prevalence of class III obesity in women.²⁵

The CVD risk associated with obesity is underappreciated by women. When asked to categorize their weight status, nearly 23% of obese women categorized themselves in a healthier weight status. This behavior has been associated with less weight loss over time.²⁶ Aggressive weight reduction to a normal BMI range of 18.5 to 24 kg/m² in women is important for the reduction of CVD and associated risk factors. Given the increased risk of CVD in women with class III obesity, this subset of patients should be referred for weight management and appropriately counseled on their increased risk for CVD over time.

Physical inactivity is an independent risk factor for CVD and stroke. The AHA guidelines currently recommend at least 150 minutes of moderate-intensity exercise or 75 minutes of vigorous aerobic exercise per week for both men and women.²⁷ Interestingly, only one-third of the population is aware of current physical activity guidelines. Multiple studies have shown all-cause mortality reduction with increased physical activity levels. Physical activity is thought to reduce the incidence and severity of associated CVD risk factors including hypertension, hyperlipidemia, CAD, HF, stroke, and diabetes mellitus. Physical activity declines after the age of 50 years and further at 60 years of age when reportedly only 2% of the female population achieves target physical activity goals: women in the highest risk group for CVD are achieving the lowest physical activity. Hence, patients should be counseled on current AHA recommendations for physical activity on a routine basis to improve adherence.

Numerous population studies have demonstrated an association between inflammatory diseases and increased mortality, in both men and women, mainly as a consequence of CVD. For most systemic autoimmune disorders, there is a clear sex difference in prevalence, making this a more common CVD risk factor in women.

Autoimmune conditions are prevalent in women and are associated with an increased risk of numerous CVDs. CAD is known to be a major source of morbidity and mortality in women with SLE, RA, or psoriatic arthritis.²⁸ However, despite the prevalence of these autoimmune diseases, their association
with CVD is frequently underrecognized. RA is more than twice more common in women than in men and is associated with a twofold increase in risk for myocardial infarction. SLE is nearly nine times more common in women than in men and is associated with a tenfold increased risk for myocardial infarction. CVD is the leading cause for reduced life expectancy in patients with SLE.²⁹ CVD risk in women with SLE is underestimated by traditional risk assessments tools such as the Framingham risk model. The etiology for increased cardiovascular risk with rheumatologic diseases is not well understood. However, it is likely multifactorial due, at least in part, to chronic inflammation in the setting of autoimmune disease. Women with rheumatologic disease should have a thorough cardiovascular risk assessment and aggressive risk factor management given their increased risk of accelerated atherosclerosis and complications of CAD.³⁰