The following are key points to remember about the manifestations, management, and outcomes related to gender in cardiovascular diseases (CVDs):

1. In a majority of CVDs, differences in pathophysiology, clinical presentation, and management have been observed between men and women. Biological differences are termed “sex differences,” whereas those uniquely related to humans including those differences related to environment, lifestyle, and attitudes are termed “gender differences.” Both sex and gender differences are important in the diagnosis and management of CVD. The experts as well as institutions and societies from the European Union and the United States have called for greater reporting of gender-specific outcomes in CVD.
2. Ischemic heart disease (IHD) develops at a later age for women compared to men; however, rates of IHD have been increasing among younger women. Although rates of hypertension and dyslipidemia are lower in men than premenopausal women, with older age, these gender differences disappear. Diabetes appears to be a stronger risk for IHD in women compared to men. Rates of impaired glucose are higher among women than men. Mechanistic studies are needed to understand these differences.
3. Additional risk factors for IHD include depression and other forms of mental stress (anxiety, anger, work, and marital stress). Coronary heart disease risk related to mental stress is similar for men and women; however, the prevalence of these factors is higher among women.
4. Women are more likely to have nonobstructive coronary artery disease (CAD) in the setting of acute coronary syndrome (ACS) compared to men. Women with non−ST-segment elevation myocardial infarction (NSTEMI) are more likely to demonstrate myocardial ischemia independent of coronary stenosis. Microvascular disease, coronary artery spasm, and spontaneous coronary artery dissection are more often seen in women than men. Diagnostic testing of coronary microvascular disease includes measurement of coronary blood flow reserve by echocardiography or positron emission tomography-computed tomography (PET-CT). Calculation of microcirculatory resistance index can be performed during coronary catheterization (i.e., coronary flow reserve). Women with chest pain and nonobstructive CAD have an increased risk for obstructive CAD; thus, diagnosis of microvascular disease is warranted.
5. Women take longer to obtain medical care in the setting of ACS than men. This may be related to differences in presenting symptoms in addition to psychosocial factors. Biomarkers including troponin I may differ by sex. Diagnostic testing for IHD also differs by sex, with reduced specificity of testing in women. The current European Society of Cardiology guidelines recommend stress-echo as a first test for women to evaluate for IHD. Some but not all studies have observed worse outcomes for women compared to men, younger women in particular. These findings may relate to time from first symptom to presentation, and risk factor burden in addition to differences in management.
6. The prevalence of heart failure with preserved ejection fraction (HFpEF) is greater in women than men; while rates of heart failure with reduced ejection fraction (HFrEF) and dilated cardiomyopathies in general are higher in men. Rates of Takotsubo cardiomyopathy are higher among women than men. Understanding differences related to inflammation, sex hormones, hyperglycemia, and ventricular remodeling is warranted. Additionally, health service research related to gender differences in cardiac transplantation referral is needed, along with improved gender-specific reporting of outcomes related to transplantation.
7. Although rates of hypertension are lower among young women compared to young men, rates are higher in women and the elderly. Sex-related differences have been observed related to the renin-angiotensin system; however, no differences related to efficacy of antihypertensive medications have been consistently noted. Polycystic ovarian syndrome and postmenopausal status have been associated with increased incidence of hypertension among women. Left ventricular hypertrophy (LVH) related to hypertension is more difficult to treat among women than men, with less regression of hypertrophy with antihypertensive treatment. Increases in LVH and myocardial stiffness predispose women to HFpEF and stroke at older ages.
8. Aortic stenosis is one of the most common valvular abnormalities among both men and women. Perioperative complications are higher among women than men with aortic valve replacement. Transcatheter aortic valve replacement (TAVR) appears to have similar success rates for men and women with greater short- and mid-term survival for women, and similar stroke rates among women and men. Mitral valve prolapse (MVP) is more common among women than men; however, the need for MV surgery is higher among men. Underdiagnosis of symptomatic MV among women may be present given women often have higher LVEFs and smaller LV dimensions compared to men.
9. Sex and gender differences exist related to the pharmacokinetics of many cardiac drugs. Oral bioavailability, clearance, body fat distribution, plasma protein binding, and metabolism all can differ by sex. Furthermore, women have a longer repolarization phase (longer QT duration on electrocardiogram), which may increase a woman’s risk for ventricular arrhythmias in the setting of certain drugs including antidepressants.
10. The authors call upon cardiovascular societies and research funding institutes to promote sex- and gender-specific research. Decision algorithms, health services, research, and basic and translational research are needed in the area of sex and gender differences. As of June 2015, the National Institutes of Health now requires all animal research and human studies to include sex-specific reporting or to justify why this is not needed in a specific study. Continued health policy, advocacy, and investigation to promote sex- and gender-specific investigation will improve cardiovascular care for both men and women.

Keywords: Acute Coronary Syndrome, Aortic Valve Stenosis, Arrhythmias, Cardiac, Biomarkers, Cardiac Catheterization, Cardiomyopathies, Cardiovascular Diseases, Coronary Artery Disease, Depression, Diabetes Mellitus, Echocardiography, Stress, Heart Failure, Hypertension, Hypertrophy, Left Ventricular, Mitral Valve Prolapse, Myocardial Infarction, Myocardial Ischemia, Risk Factors, Sex Characteristics, Stroke, Tomography, X-Ray Computed, Troponin I

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