Abstract
Cardiovascular disease remains the leading cause of morbidity and mortality for both women and men. Emerging evidence supports that ischemic heart disease (IHD) may manifest differently in women and men, in ways ranging from the clinical presentation, diagnosis, and management of disease to the basic biology and biomechanics of cardiomyocyte function and the coronary circulation. Women consistently present with a higher burden of symptoms and comorbidities as compared with men and experience worse outcomes. These data have proved perplexing given the decreased likelihood of women to demonstrate obstructive coronary artery disease (CAD) on coronary angiography. Reported sex differences have long been influenced by the practice of defining heart disease primarily as obstructive CAD, but obstructive plaque is now recognized as neither necessary nor sufficient to explain symptoms of IHD, and it is no longer adequate to tailor diagnostic and treatment strategies only to this subset of patients. To date, women remain underrepresented in guideline-changing heart disease research and trials, creating important limitations in the evidence base for cardiovascular medicine. Smaller epicardial coronary arteries in women as compared to men, coupled with differences in shear stress and inflammatory mediators over the life span, may modify the development of CAD in susceptible patients into a diffuse pattern with more contribution from coronary vasomotor dysfunction than focal obstruction. Newer studies corroborate that symptomatic women are more likely than men to present with nonobstructive CAD and coronary microvascular dysfunction. When present, these processes increase cardiovascular risk in both women and men but may constitute an especially malignant phenotype in a subset of severely affected women, with implications for the management of not only CAD but also heart failure with preserved ejection fraction. This represents a state-of-the-art review of sex differences in the coronary system, with an eye toward how diverse pathophysiological processes may contribute to IHD phenotypes prevalent in women and men. Beyond providing women and men with equitable optimal care according to current paradigms, understanding the pathophysiology of IHD beyond a conventional focus on obstructive CAD is needed to address what is likely a combination of biological as well as environmental determinants of their prognosis.