The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and proarrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, preload-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 watt stress, systemic vascular resistance, and myocardial oxygen consumption. BM5-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies. In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca2+ entry via L-type Ca2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.

The reduction of myocardial loading and energetic demand while preserving/enhancing cardiac function are primary needs for the pharmacological treatment of chronic heart failure (HF). Nitroxyl (HNO) has been proposed as potential therapeutic agent for HF, providing cAMP-independent unloading and inotropic/lusitropic support in both laboratory animals and patients with HF; however, due to short half-life, available HNO donors (HNO+) are limited to the treatment of acutely-decompensated patients via parenteral administration. This study assessed the feasibility of non-parenteral HNO delivery, by evaluating the acute cardiovascular response(s) to a novel slow-release HNO-donor when given orally to conscious dogs with induced HF. Dogs (n = 6) were chronically instrumented for arterial pressures and for LV pressure-volume (LVPV) recordings; all animals had HF induced via chronic overdrive pacing (e.g., EF: 38 ± 1%, PRSW: 51.2 ± 0.9 mmHg+, EDP: 23 ± 2 mmHg and NT-proBNP > 2500 pM/L). Data were obtained before/after oral (22.5 mg/kg) and/or intravenously (65 μg/kg/min) treatment with a slow-release HNO+; load-independent systolic/diastolic function was examined by LVPV relationships obtained for up to 180min after the onset of dosing. HNO, when given orally via a slow-release HNO+, reduced LV preload (EDV: -7 ± 1%*), filling (EDP: -29 ± 7%*) and end-systolic pressures (ESP: -17 ± 2 %*) without concomitant changes in rate (HR: -4 ± 2%). Oral HNO increased stroke volume (SV: 14±3%*) and ejection fraction (EF: 22 ± 3%*), while decreasing arterial elastance (Ea: -27±2 %). Oral HNO enhanced load-independent inotropy (e.g., PRSW, +12 ± 2%*) and lusitropy (tau: -15 ± 3 %*, EDPVR: -50 ± 8%*), improving ventriculo-arterial coupling and decreasing estimated myocardial demand (PVA: -66 ± 4%*). These effects were comparable to those obtained via parenteral administration (e.g., PRSW: +12 ± 1%*, Ea: -23 ± 3%*, and PVA: -51 ± 8%*). (*: P < 0.05 vs. pre-dosing). These data support the feasibility/efficacy of novel slow-release HNO donors, when given orally, to improve myocardial loading and enhance systolic/diastolic function when in the setting of HF.

Despite the morbidity and clinical burden of primary diastolic cardiac dysfunction, effective therapies for patients presenting with heart failure with preserved ejection fraction (HFpEF) are limited. Nitroxyl (HNO) produces cAMP-independent functional support, in part by improving myocardial calcium-handling. We hypothesize that HNO can rescue lusitropic function when acutely administered to rats with chronic diastolic dysfunction, mimicking HFpEF. Diastolic dysfunction, as demonstrated by decreased E/A ratios via echocardiography, was induced by either 4 weeks of chronic isoproterenol administration (via a mini-osmotic pump; ISO) or by renoprival hypertension (secondary to renal wrapping; RW) for 5 weeks. In vivo left-ventricular hemodynamics/pressure-volume relationships were assessed before/during a 30 minute IV administration of a HNO pro-drug (CXL-1020, 100 μg/kg/min). Ca2+ handling in isolated cardiomyocytes was also studied (CXL-1020, at 50 μM). In both cases, milrinone (mil) was used as a cAMP-dependent positive control (at a matched-efficacy in healthy rats, i.e., 10 μg/kg/min and 0.5 μM) In the setting of chronic diastolic dysfunction, HNO lowered the LV filling pressures in both models by a combined average of 46 ± 8% versus baseline, accelerated the time-constant (tau) of relaxation (-26 ± 3%) and improved compliance (flattened the end-diastolic PV relationship) (-61 ±3%). In myocytes isolated from dysfunctional hearts, HNO accelerated the time for Ca2+ to decline to 50% of its max amplitude (RT50) by -10 ± 2% and myocyte relengthening by -12 ± 3% in ISO rats. Despite eliciting comparable responses in healthy animals/myocytes, the HNO-mediated effects on both tau (in vivo) (-33 ± 3% vs mil -25 ± 2%) and Ca2+ decline (myocyte) (-10 ± 2% vs mil -6 ± 1%) were greater than those of milrinone in the ISO rats, which had greater impairment at baseline compared to RW rats. In conclusion, acute-therapy with HNO improved ventricular relaxation, compliance and Ca2+ handling, in the setting of chronic diastolic dysfunction. Moreover, these effects were greater than observed with the cAMP-dependent agent milrinone.

Introduction: Reduction of myocardial loading and energetic demand while enhancing function are primary needs for the treatment of heart failure (HF). Nitroxyl (HNO) produces cAMP-independent unloading and inotropic/lusitropic support in both laboratory animals and patients with HF. To date, however, the cardiovascular activity of HNO has only been investigated using short-acting parenteral donors. Aim: This study assessed the feasibility of non-parenteral (oral) HNO delivery, by evaluating the cardiovascular responses to a novel slow-release HNO prodrug given to conscious dogs with induced HF. Methods: Dogs were either used for pharmacokinetic assessments or chronically instrumented for arterial pressures and LV pressure-volume (LVPV) recordings; instrumented dogs had HF induced via chronic pacing (e.g., EF: 38 ± 1%, PRSW: 51.2 ± 0.9 mmHg+, EDP: 23 ± 2 mmHg and NT-proBNP > 2500 pM/L). Data were obtained before/after oral (22.5 mg/kg) and/or before/during continuous IV infusion (65 μg/kg/min) treatment with a slow-release HNO prodrug (~30min in vitro t1/2 for release of HNO); load-independent systolic/diastolic function was examined by LVPV relationships obtained for up to 180min after the onset of dosing. Results: The slow-release HNO prodrug was bioavailable orally (%F: 40 ± 4), presenting rapid absortion (Tmax: 0.1 ± 0.5 hr, Cmax: 3.6 ± 1.3 ug/mL) and clearance (t1/2: 0.40 ± 0.01 hr, AUCinf: 4.1±0.8 hr·ug/mL). Oral HNO reduced LV preload (EDV: -7 ± 1%*), filling (EDP: -29 ± 7%*) and end-systolic pressures (ESP: -17 ± 2 %*), without concomitant changes in heart rate (HR: -4 ± 2%). Oral HNO increased stroke volume (SV: 14 ± 3%*) and ejection fraction (EF: 22 ± 3%*), while decreasing arterial elastance (Ea: -27 ± 2 %). Oral HNO enhanced load-independent inotropy (PRSW, +12 ± 2%*) and lusitropy (tau: -15 ± 3 %*, EDPVR: -50 ± 8%*), improved ventriculo-arterial coupling and decreased estimated myocardial demand (PVA: -66 ± 4%*). These effects were comparable to those obtained via IV administration (PRSW: +12 ± 1%*, Ea: -23 ± 3%*, and PVA: -51 ± 8%*). (*: P < 0.05 vs. pre-dosing). Conclusions: These results demonstrate the feasibility of delivering HNO orally to improve myocardial loading and enhance systolic/diastolic function in the setting of HF.

BACKGROUND:Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS:The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION:These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.