PHENOTYPE-SPECIFIC TREATMENT OF HEART FAILURE WITH PRESERVED EJECTION FRACTION: A MULTIORGAN ROADMAP

摘要

Heart failure (HF) with preserved ejection fraction (EF) (HFpEF) accounts for 50% of HF cases and its prevalence relative to HF with reduced EF (HFrEF) continues to rise. In contrast to HFrEF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, a HFpEF treatment strategy is proposed which addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension and renal insufficiency drive left ventricular (LV) remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects LV diastolic dysfunction through macrophage infiltration resulting in interstitial fibrosis and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Systemic inflammation also affects other organs such as lungs, skeletal muscle and kidneys leading respectively to pulmonary hypertension, muscle weakness and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase (PDE) 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial NO bioavailability by inorganic nitrate-nitrite, myocardial cGMP content by neprilysin or PDE 9 inhibition and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.