Cardiometabolic HFpEF: mechanisms and therapies

Heart failure with preserved ejection fraction (HFpEF) accounts for at least half of all patients with heart failure (HF) and is projected to be the most common form of HF in the near feature. HFpEF, characterized by high morbidity and mortality, poses an enormous medical and societal burden and lacks evidence-based therapies. Hence, HFpEF has been recognized as the greatest unmet need in cardiovascular medicine. HFpEF is a heterogenous syndrome presenting as several different clinical phenotypes. Among these, metabolic alteration-driven HFpEF - i.e. cardiometabolic HFpEF - is emerging around the globe as the most prevalent form of HFpEF. Pathophysiological mechanisms of cardiometabolic HFpEF are still incompletely understood. However, recent advances in the preclinical modeling of the syndrome, coupled with better definition of its clinical presentations and analysis of human HFpEF myocardial specimens, have unveiled metabolic disturbances and inflammatory burden as 2 key drivers of HFpEF pathophysiology. Here, we summarize evidence in support of a cardiometabolic phenotype of HFpEF and discuss the pivotal biological mechanisms underlying this syndrome in the hope of informing more efficacious therapeutic approaches in the future.