Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and exhibits significant disparities between men and women in terms of risk factors, clinical presentation, diagnosis, treatment, and outcomes. Despite advances in cardiovascular medicine, sex differences in CVD have historically been under-recognized and understudied. By embracing medical diversity among individual patients and properly investigating this disparity, we aim to provide more equitable, effective, and efficient cardiovascular care for all patients.Epidemiological studies have consistently shown that women develop CVD later than men 1. However, this delay does not translate into better outcomes, as women often present with more comorbidities and have a worse prognosis after cardiovascular events. Risk factors such as diabetes, smoking, and hypertension have differential impacts on men and women, with some factors conferring a greater risk in women. For instance, diabetes increases the risk of CVD more significantly in women than in men 2, and smoking has been shown to be a more potent risk factor for coronary artery disease (CAD) in younger women compared to men of the same age 3. Moreover, the symptoms and presentation of CVD can differ significantly between genders, with women being more likely to experience underrepresented symptoms, leading to potential delays in diagnosis and treatment and potentially contributing to poorer outcomes.There have been reports of sex-related differences in several specific CVD. First, women with CAD often present with microvascular dysfunction rather than with obstructive coronary lesions, which is associated with poorer diagnosis and management 4. They are more likely to experience nonobstructive myocardial infarction (MI) and have a higher mortality rate after MI than men. Additionally, women are more prone to coronary artery spasms and spontaneous coronary artery dissection, which require different management approaches than those for traditional obstructive CAD. Second, women are more likely to develop heart failure with preserved ejection fraction, whereas men more commonly present with reduced ejection fraction 5. This difference has implications for treatment strategies and outcomes. Heart failure with preserved ejection fraction, which is more prevalent in women, has fewer evidence-based treatment options than heart failure with reduced ejection fraction, highlighting the need for further studies. Women with heart failure tend to be older at presentation and have a higher prevalence of hypertension and diabetes as contributing factors. Third, women with arrhythmias have a higher risk of drug-induced QT prolongation and torsade de pointes 6. They also have a higher incidence of atrial fibrillation but, paradoxically, a lower risk of sudden cardiac death than men. The reasons for these differences are multifactorial and include hormonal influences, differences in ion channel expression, and variations in autonomic tone. Fourth, with respect to aortic diseases, while overall less common in women, certain aortic conditions such as type A aortic dissection are more prevalent in women, particularly in older age groups 7. Women with aortic dissection often present with atypical symptoms, leading to delayed diagnosis and treatment. Finally, women have a higher lifetime risk of stroke and often present with more severe strokes than men as well as with atypical symptoms 8. Unique risk factors for stroke in women include pregnancy, the use of oral contraceptives, and hormone replacement therapy. Moreover, women are more likely to experience certain stroke subtypes such as subarachnoid hemorrhage and cerebral venous thrombosis.The use of ICDs for the primary prevention of sudden cardiac death has shown significant benefits in reducing mortality. However, sex differences in ICD utilization and outcomes have been the subject of ongoing research and debate. In another article in this issue, Srivastava et al. 9 shed new light on this topic. Another study that analyzed data from the National Inpatient Sample found that, while women accounted for approximately 40% of patients admitted with systolic heart failure, they represented less than 30% of those who underwent ICD implantation. This discrepancy highlights potential sex-based disparities in ICD use. Interestingly, this study found no significant differences in age, length of hospital stay, or in-hospital mortality between men and women who underwent ICD implantation. These findings suggest that women may benefit less from ICD treatment despite meeting the ICD eligibility criteria 10 and may be useful background for understanding low ICD implantation rates. The reasons for this disparity are multifactorial and may include differences in disease presentation, physician biases, and patient preferences. Some studies have suggested that women may be more risk-averse and less likely to accept ICD therapy when offered, highlighting the need for improved patient education and shared decision-making.With regard to pharmacotherapy, women are more susceptible to adverse drug reactions and may require different dosing strategies for certain cardiovascular medications. For instance, women have a higher risk of bleeding with anticoagulant therapy and may derive greater benefits from certain antihypertensive medications 11. The reasons for these differences include variations in body composition, drug metabolism, and hormonal effects on pharmacokinetics and pharmacodynamics. However, despite often presenting with more advanced disease, women with CVD have shown better long-term outcomes under certain conditions 12. However, they also face unique challenges such as a higher risk of heart failure following MI and increased mortality after coronary artery bypass grafting. The reasons for these disparities in outcomes are complex and likely involve a combination of biological, social, and healthcare-related factors.The growing recognition of sex differences in CVD underscores the importance of personalized medicine approaches that consider sex as a crucial biological variable in risk assessment, diagnosis, and treatment planning (Fig. 1). These include the development of sex-specific risk calculators, diagnostic criteria, and treatment algorithms. Additionally, the integration of genomic and proteomic data may further enhance our ability to tailor cardiovascular care for individual patients considering both sex and other relevant biological factors.Cardiovascular medicine researchers and practitioners are increasingly recognizing the importance of sex differences in disease presentation, progression, and treatment outcomes. Moving forward, it is crucial that healthcare providers consider sex-related factors in their clinical decision-making processes. Addressing sex differences in cardiovascular care requires a multifaceted approach that includes raising awareness, establishing representative scientific evidence, and developing guidelines that consider sex differences. By acknowledging and actively addressing these differences, we can work toward more equitable and effective cardiovascular care. Ultimately, we should aim to provide personalized, evidence-based care that considers the full spectrum of biological and social factors influencing cardiovascular health. By continuing to investigate and address sex differences in CVD, we may improve the outcomes and quality of life of all patients with CVD.Takahiro Okumura received lecture fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis, Otsuka, and Ono Yakuhin and research grants from Pfizer, Alnylam, Alexion, and Ono Yakuhin. Toyoaki Murohara has received lecture fees and unrestricted research grants from the Department of Cardiology at Nagoya University Graduate School of Medicine, Bayer, Daiichi-Sankyo, Dainippon Sumitomo, Kowa, MSD, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Takeda, Astellas, Otsuka, and Teijin.This study was not supported by any sponsor or funding.T.O. drafted the manuscript. T.M. revised it critically for important intellectual content.
Okumura et al. (2024) studied this question.