Effects of acute intravenous infusion of nitroxyl donor BMS-986231 on left ventricular function and cardiac rhythm in anaesthetised dogs with intracoronary microembolisation-induced heart failure

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Conference Proceeding

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Eur J Heart Fail


Background: BMS-986231 is a novel nitroxyl donor indevelopment for the treatment of acutedecompensated heart failure (HF). Purpose: Assess the effects of BMS-986231 on left ventricular (LV) function and induction of arrhythmias in dogs withHF. Methods: Chronic LV failure was produced indogs via sequential embolisations until an LV ejection fraction of 30% was achieved. In Study A, seven isoflurane-anaesthetised animals each received continuous intravenous (IV) infusions of three different doses of BMS-986231 (0.7, 2 and 7 μg/kg/min) as well as vehicle for 4 hours; haemodynamic, angiographic and echocardiographic measurements were obtained. Animals were monitored for 1 hour post-infusion. In Study B, another seven animals with induced HF received BMS-986231 (7 μg/kg/min) and vehicle over 2 hours, before undergoing programmed ventricularstimulation (PVS). PVS was terminated when it provoked ventricular fibrillation (VF) or a sustained monomorphic ventricular tachycardia (SVT) lasting >30 seconds. Threshold data for SVT or VF were quantified in which progressively increasing scores were indicative of higher magnitudes of required stimulation. Results: With vehicle, all measured/calculated variables were stable from baseline through 4 hours. At 4 hours, BMS-986231resulted in significant (p<0.05) increases in early-to-late diastolic velocity-time integral ratio (mean Δ from baseline across doses: 1.6 to 2.7) and deceleration time of early mitral valve inflow velocity (Δ10.4 to 12.4 msec), and significant decreases in LV end-diastolic wall stress (Δ-9.3 to -13.4 gm/cm) versus baseline, all suggesting positive lusitropy. BMS-986231 also led to significant increases in LV ejection fraction (Δ5.6 to 8.8%), LV fractional area shortening (Δ6.1 to 11.3%), stroke volume (Δ3.7 to 5.9 ml) and cardiac output (Δ0.24 to 0.47 l/min), suggesting positive inotropy. Systemic vascular resistance was significantly decreased with all doses (Δ-457 to -704 dynes.sec.cm5), suggesting a vasodilatory effect. BMS-986231 had little effect on heart rate (Δ-0.6 to -1.6 bpm, p=NS) and no de novo arrhythmias were detected during infusion. Myocardial oxygen consumption was significantly reduced below baseline with the high dose (Δ-73.1 μmols/min). During PVS, BMS-986231 increased the mean threshold score for SVT or VF twofold versus vehicle (18.0 vs. 9.0) and had no impact on subsequent cardioversion to restore sinus rhythm. Conclusions: BMS-986231 was associated with outcomes suggestive of inotropic, lusitropic and vasodilatory effects without an impact on heart rate, and with a reduction in myocardial oxygen consumption. BMS-986231 did not induce ventricular arrhythmias and significantly increased the threshold for triggering such episodes with PVS. Based on these findings, BMS-986231 may be a suitable candidate for further development in acute decompensated HF.



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