Can Nitrite AMPk Up Sirt-ainty to Treat Heart Failure With Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) remains a common yet vexing clinical syndrome, with no approved therapies despite prevalence, morbidity, and mortality on par with those of heart failure with reduced ejection fraction (HFrEF).1 Therapies and devices proven effective in HFrEF have repeatedly fallen short in their application to HFpEF.1 This is no longer surprising, as we increasingly recognize HFpEF as a syndrome characterized by multiple mechanisms and multi-organ engagement. Involved are not just the myocardium, but also the systemic and pulmonary vasculature, kidneys, skeletal muscle, and metabolic state.2 Multiple co-morbidities, including hypertension, obesity, and diabetes mellitus, conspire to increase fluid retention and left ventricular (LV) filling pressures, often with ventricular hypertrophy and diastolic dysfunction. In the pulmonary vasculature, elevated LV filling pressure augments pulsatile loading on the right ventricle (RV)3; this, combined with passive elevations in pressure and pulmonary vasculature remodeling, can lead to pulmonary hypertension in about half the patients.1 Meanwhile, microvascular and metabolic dysfunction in the peripheral skeletal muscle contribute to sarcopenia and exercise intolerance.1 These deficiencies collectively lead to the breathlessness, marked exertional intolerance, and fluid retention that characterize HFpEF.