Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure

Circ Heart Fail. 2021 Sep;14(9):e008236. doi: 10.1161/CIRCHEARTFAILURE.120.008236. Epub 2021 Aug 31.


Background: PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction.

Methods: Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose.

Results: Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm Hg (P<0.001) and heart rate increased 5 to 9 bpm (P≤0.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts/mL2·104 (P=0.03, a +41% rise; 5-71 CI) and cardiac output by 0.83 L/min (P=0.002, +31%, 13-49 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (-564 dynes·s/cm-5, P<0.001) and 90 mg (-370, P=0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events.

Conclusions: Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted. Registration: URL:; Unique identifier: NCT03387215.

Keywords: adenosine; blood pressure; cardiac output; heart failure; inotrope; vasodilation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Female
  • Heart Failure, Systolic / drug therapy*
  • Heart Failure, Systolic / physiopathology*
  • Heart Rate / drug effects
  • Heart Ventricles / physiopathology
  • Hemodynamics / drug effects*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Male
  • Middle Aged
  • Phosphoric Diester Hydrolases / drug effects*
  • Phosphoric Diester Hydrolases / metabolism
  • Stroke Volume / drug effects
  • Vascular Resistance / drug effects
  • Vascular Resistance / physiology
  • Ventricular Dysfunction, Left
  • Ventricular Function, Left / drug effects


  • Heterocyclic Compounds, 4 or More Rings
  • ITI-214
  • Phosphoric Diester Hydrolases

Associated data