Cardiac and Hemodynamic Effects of Acute Phosphodiesterase-1 Inhibition in Human Heart Failure

Abstract

Introduction Phosphodiesterase-1 (PDE-1) hydrolyzes cyclic adenosine monophosphate and cyclic guanosine monophosphate, key second messenger molecules in cardiac and vascular tissue. Selective PDE-1 inhibition with ITI-214 resulted in systemic vasodilation and positive inotropic effects (inodilator) in a canine heart failure (HF) model with minimal effects on blood pressure. Hypothesis The specific PDE-1 inhibitor, ITI-214, confers inodilator effects in humans with HF with reduced ejection fraction. Methods ITI-214-104 was a Phase Ib/IIa, multi center, double-blind, randomized, placebo-controlled single ascending dose cohort study of ITI-214 in patients with stable chronic systolic HF (NYHA Class II-III, LVEF ≤ 35%) (NCT03387215). Participants were randomized 9:3 to receive either ITI-214 10, 30, or 90 mg or placebo, with transthoracic echocardiography obtained just before and 120 min after dosing. Safety outcomes included supine and orthostatic BP and HR, telemetry events and blood laboratories. Hemodynamic outcomes included mean LV power index (primary outcome), as well as exploratory outcomes: cardiac output, LV volumes, LVEF, effective arterial elastance (Ea), and estimated systemic vascular resistance (SVR). Results Patient mean age was 54 yr, 57% male and 57% Black with mean LVEF 25% (31% had ischemic HF). Cmax occurred at 90 - 120 min, with area under curve increasing with dose escalation. ITI-214 30 mg increased mean LV power index and cardiac output while SVR and MAP decreased at 30 and 90 mg doses at 120 minutes post dose compared to placebo (Figure). Total LV afterload (Ea) followed the same pattern as SVR change. There were 3 orthostatic hypotension and 3 hypotension adverse events, both mild to moderate. There was no change in arrhythmia on continuous telemetry monitoring and no serious adverse events. Conclusion Single-dose ITI-214 confers inodilator effects in humans with systolic HF. These data confirm our previous findings in the canine HF model. Further investigation of acute and chronic PDE-1 inhibition in HF should be considered.