Gender-related differences in heart failure: beyond the “one-size-fits-all” paradigm

Cardiovascular diseases show many sex-related differences in prevalence, etiology, phenotype expression, and outcomes. Complex molecular mechanisms underlie this diverse pathological manifestation, from sex-determined differential gene expression to sex hormones interaction with their specific receptors in different tissues. More recently, differential non-coding RNAs regulation also turned out to be an involved mechanism. This review focuses on sex impact on the various heart failure syndromes, including coronary artery disease, heart failure with preserved ejection fraction and with reduced ejection fraction, with particular attention to dilated cardiomyopathy. Despite similar genetic predisposition in terms of identified causative mutations, other causes, such as cardiotoxic drugs exposure or stress-induced cardiomyopathy, are more prevalent in women. Beyond this, differences in disease presentation and natural history reveal a more severe clinical onset with otherwise better long-term outcomes in women compared to men. Understanding the varying characteristics of disease manifestation and outcomes is warranted for a prompt and tailored treatment for both men and women. This is a mandatory step in the road to the personalized medicine. Moreover, despite a higher enrollment in the last years, the under-representation of females in clinical trials is the first obstacle to overcome in the long way to develop appropriate sex-based therapy approach.