Sex-specific insights in atherosclerosis and pulmonary arterial hypertension: an overlooked comorbidity

The mortality rates attributed to cardiovascular diseases (CVD) are increasing within the United States. Atherosclerotic cardiovascular disease (ASCVD) and pulmonary arterial hypertension (PAH) are two severe, life-threatening subtypes of CVD. Although ASCVD and PAH are distinct vascular disorders, they share common mechanisms, including endothelial dysfunction, inflammation, smooth muscle proliferation, fibrosis, and vascular remodeling. It is noteworthy that patients diagnosed with PAH may have underlying atherosclerotic coronary artery disease at a rate of ∼28%, and conversely, patients with ASCVD may present with pulmonary symptoms. PAH is more prevalent among females; however, once the disease is established, males exhibit disproportionately worse right ventricular (RV) adaptation and higher rates of RV failure. Conversely, atherosclerosis is more common in males and less prevalent in females before menopause. Despite advances in understanding the unique pathophysiology of each disease, the relationship between ASCVD and PAH remains poorly elucidated, and current animal models often fail to accurately replicate the complexities of both conditions. This review underscores the key similarities and differences between ASCVD and PAH, with particular emphasis on sex as a significant biological factor in these diseases. Recognition of these sex-specific vascular and cardiac mechanisms has important therapeutic implications, supporting sex-informed risk stratification and the development of targeted interventions for both pulmonary and systemic vascular diseases.