Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure

  • JACC Basic Transl Sci. 2018 Nov 12;3(5):625-638. doi: 10.1016/j.jacbts.2018.07.003.
J Craig Hartman  1 ,  Carlos L Del Rio  2 ,  John E Reardon  3 ,  Kefei Zhang  4 ,  Hani N Sabbah  4
Affiliations
  • 1. Pharmaceutical R&D Consulting, LLC, Loveland, Colorado.
  • 2. QTest Labs, LLC, Columbus, Ohio.
  • 3. Revivo Therapeutics, Inc., Durham, North Carolina.
  • 4. Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan.
PMID: 30456334 DOI: 10.1016/j.jacbts.2018.07.003
Abstract

The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time. BMS-986231 significantly decreased LV filling pressures, end-diastolic stiffness, the time-constant of relaxation, end-diastolic wall stress, systemic vascular resistance, and myocardial oxygen consumption. BMS-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects.

Keywords
DT, deceleration time of early mitral inflow velocity; EDPVR, end-diastolic pressure–volume relationship; ESPVR, end-systolic pressure–volume relationship; Ei/Ai, the ratio of early-to-late filling time integrals; HEX, Hextend (plasma volume-expanding solution); LVEDWS, left ventricular end-diastolic circumferential wall stress; LVEF, left ventricular ejection fraction; LVFAS, left ventricular fractional area shortening; MHC, myosin heavy chain; MLC1, myosin light chain 1; PRSW, pre-load-recruitable stroke work; RyR2, ryanodine receptor 2; SH, thiol group; SV, stroke volume; SVR, systemic vascular resistance; Tau, left ventricular relaxation time-constant; canine; cardiomyopathies; heart failure; hemodynamics; nitroxyl.
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