Abstract 3705: Acute Intravenous Infusion of CXL-1020, a Nitroxyl Donor, Improves Left Ventricular Function in Dogs With Advanced Heart Failure
Background: Cardiac sarcoplasmic reticulum (SR) Calcium cycling is abnormal in heart failure (HF) and is partly responsible for abnormalities of LV systolic and diastolic function. Nitroxyl (HNO) donors are compounds that improve cardiomyocyte function by directly enhancing SR calcium cycling. The positive inotropic effect of HNO has been shown to be independent of beta-adrenergic receptor signaling. We tested the hypothesis that acute intravenous infusion of CXL-1020, an HNO donor, improves LV systolic function in dogs with advanced HF.
Methods: Studies were performed in 6 dogs with coronary microembolization-induced HF (LV ejection fraction, EF<30%). Each dog underwent 3 acute 4-hour CXL-1020 infusions (doses of 0, 3, and 10 ìg/kg/min); studies performed one week apart and in random order. Heart rate (HR), systolic aortic pressure (SAP), LV end-diastolic (EDV) and end-systolic (ESV) volumes, EF and peak power index (PPI, load-independent index of contractility) were measured at baseline (Base) and at the end of 4 hours of infusion. Myocardial oxygen consumption (MVO2) was measured during infusion of the high dose (10 μg/kg/min) CXL-1020.
Result: CXL-1020 had no effect on HR but tended to reduce SAP, albeit not significantly. Vehicle had no effects on EDV, ESV or EF. In contrast, CXL-1020 significantly reduced EDV and ESV and increased EF and PPI in a dose-dependent manner. At the highest CXL-1020 dose, the improvement in LV function was associated with reduced MVO2 and did not evoke ventricular arrhythmias. CXL-1020 also reduced plasma levels of troponin-I (p<0.01), atrial natriuretic peptide (p<0.05), and n-terminal pro-brain natriuretic peptide(p<0.05).
Conclusions: In dogs with chronic HF, acute intravenous administration of CXL-1020 improves LV function without eliciting any chronotropic effects or de-novo ventricular arrhythmias and without increasing MVO2. This novel HNO donor may be useful in the treatment of patients with acute HF syndromes.