The following are key points to remember from this review on sex differences in heart failure (HF):

1. While the lifetime risk of HF is similar in men and women, the prevalence of HF with preserved ejection fraction (HFpEF) is higher in women than in men, and increases with age. In the Swedish HF registry, women constituted 55% of patients with HFpEF.
2. Three HFpEF phenotypes have been identified: (1) a younger predominantly female group with less adverse remodeling and lower natriuretic peptide levels; (2) an obese predominantly female group with higher rates of diabetes and markedly abnormal diastology; and (3) an older, mostly male group with more associated chronic kidney disease, significant adverse left ventricular remodeling, and the highest rates of adverse cardiac outcomes.
3. Both intrinsic sex differences and epidemiologic factors contribute to the higher prevalence of HFpEF in women.
4. Traditional risk factors, such as diabetes, obesity, tobacco, socioeconomic status, and hypertension may impact the risk of heart failure in women to a greater degree than in men. Furthermore, psychological stress, the etiology of HF in Takotsubo cardiomyopathy, may have a greater cardiac impact in women than in men, and it has been shown that higher psychological distress increases the risk of cardiovascular events in women, but not men, with coronary artery disease. A female:male ratio of 9:1 has been reported in Takotsubo cardiomyopathy.
5. Sex-specific risk factors for women include reproductive factors, which may result in peripartum cardiomyopathy, and breast cancer therapy, including anthracyclines, trastuzumab, and radiation.
6. Endothelial inflammation and microvascular dysfunction may be the common link between the spectrum of cardiovascular conditions to which women are predisposed.
7. Endothelial inflammation is caused by altered NO signaling, and animal models have demonstrated sex differences in NO signaling and response to pressure overload, specifically concentric ventricular remodeling in females versus eccentric remodeling in males.
8. While a landmark study demonstrated a link between altered NO signaling and HFpEF, the study only included male mice.
9. Women may be predisposed to age-related ventricular-vascular uncoupling, a key abnormality in HFpEF.
10. Women with HFpEF have lower pulmonary artery compliance than men and have a higher prevalence of pulmonary hypertension, which may be related to sex differences in pulmonary vascular reactivity as well as chronically elevated left atrial pressures.
11. Sex differences in body composition contribute to differences in pharmacokinetics and pharmacodynamics which may result in differential responses to guideline-directed medical therapy for HF.
12. While studies show that plasma concentrations of some beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers can be up to 2.5 times higher in women than in men taking comparable doses, further studies are required to determine the optimal doses required in women to achieve a beneficial response.
13. Women are less likely to receive an implantable cardioverter-defibrillator when compared to men, although the efficacy in women is less clear. On the other hand, women are more likely to respond to cardiac resynchronization therapy and derive a greater survival benefit, possibly due to lower rates of ischemia and myocardial scarring; sex-specific definitions of left bundle branch block should be considered.
14. Women with HF have lower mortality but worse quality of life than men.
15. Under-representation of women in clinical trials remains a barrier to understanding sex-related differences in HF.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Acute Heart Failure, Pulmonary Hypertension, Hypertension, Stress

Keywords: Adrenergic beta-Antagonists, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Breast Neoplasms, Bundle-Branch Block, Cardiac Resynchronization Therapy, Cardiomyopathies, Coronary Artery Disease, Defibrillators, Implantable, Diabetes Mellitus, Heart Failure, Hypertension, Hypertension, Pulmonary, Inflammation, Natriuretic Peptides, Obesity, Peripartum Period, Phenotype, Quality of Life, Renal Insufficiency, Chronic, Risk Factors, Social Class, Stress, Psychological, Stroke Volume, Takotsubo Cardiomyopathy, Tobacco, Ventricular Remodeling

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