Sacubitril/valsartan represents the first of a new class of drugs able to act as a
neprilysin inhibitor and as an
angiotensin receptor blocker. This double inhibition has the advantage of concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (
angiotensin receptor blocker component) while stimulating an anti-fibrotic/anti-hypertrophic mechanism (
neprilysin inhibitor component). Furthermore, the novel drug has natriuretic and
diuretic properties, better preserves renal function, provides better blood pressure control as compared to renin angiotensin system inhibitors, and improves ventricular-arterial coupling. Consequently,
sacubitril/valsartan provides greater target organ protection than
angiotensin receptor blocker therapy alone, including cardiac, vascular, and renal protection. Up to now, this drug does not have an indication in patients with
heart failure with preserved ejection fraction (HFpEF). However, its complex mechanism of action and previous experimental and clinical data seem to suggest its possible success in HFpEF. In this review we highlight and discuss the rationale, clinical insights, and perspectives behind the use of
sacubitril/valsartan in HFpEF, specifically referring to its possible efficacy in pathophysiologic mechanisms, such as myocardial
hypertrophy,
fibrosis, and
ischemia, renal dysfunction, impaired ventricular-arterial coupling, which are all tightly related to elevated left ventricular end diastolic pressure, a common hallmark for this multifaceted syndrome.