Abstract
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.
Highlights
Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in the United States with ∼1 million hospital admissions per year (Feldman et al, 2008)
CXL-1020 significantly decreased mean arterial pressure (MAP) as well as left ventricular endsystolic (LV-ESP) and end-diastolic (LV-EDP) filling pressures (Table 1 and Figure 1A). These hemodynamic changes were not accompanied by heart rate (HR) increases
The chronic ISO model is a model of mild systolic dysfunction and more significant diastolic dysfunction due to sub-endocardial fibrosis and slowed SR Ca2+ uptake (decreased SERCA2a and PLB Ser16 phosphorylation (PKA site) (Zile et al, 2004; Martos et al, 2007).The present study demonstrated that CXL-1020 improved Ca2+ cycling in vitro by increasing the rate of Ca2+ decline in myocytes (Figures 4A,B) and in vivo by decreasing the end diastolic pressure-volume relationship (EDPVR) slope (Table 6 and Figure 3)
Summary
Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in the United States with ∼1 million hospital admissions per year (Feldman et al, 2008). Heart failure is a complex syndrome, characterized by the inability of the heart to maintain adequate cardiac output without elevated intracardiac filling pressures, leading to pulmonary and peripheral fluid retention and the typical clinical findings of fatigue, dyspnea and edema. Patients with heart failure receive diuretics such as furosemide, vasodilators such as nitrates, and as needed, intravenous inodilators/inotropes such as, milrinone (MIL), and dobutamine (DOB). The goals of in-hospital therapy are to relieve acute patient discomfort (primarily dyspnea) and restore baseline hemodynamics to the extent possible for these often critically ill patients. While existing inodilators and inotropes can improve acute hemodynamics, they confer deleterious side effects and increase mortality (Packer et al, 1991, 2013; Cuffe et al, 2002).
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