Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure

Abstract

Background: Abnormalities of energy metabolism are often cited as key elements in the progressive worsening of left ventricular (LV) dysfunction that characterizes the heart failure (HF) state. The present study tested the hypothesis that partial inhibition of fatty acids will ameliorate the hemodynamic abnormalities associated with HF.

Methods and results: Chronic HF (LV ejection fraction 27 +/- 1%) was produced in 13 dogs by intracoronary microembolizations. Hemodynamic and angiographic measurements were made before and 40 minutes after intravenous administration of ranolazine, a partial fatty acid oxidation (pFOX) inhibitor. Ranolazine was administered as an intravenous bolus dose of 0.5 mg/kg followed by a continuous infusion for 40 minutes at a constant rate of 1.0 mg / kg / hr. Ranolazine significantly increased LV ejection fraction (27 +/- 1 versus 36 +/- 2, P =.0001), peak LV +dP/dt (1712 +/- 122 versus 1900 +/- 112 mm Hg/sec, P =.001), and stroke volume (20 +/- 1 versus 26 +/- 1 mL). These improvements occurred in the absence of any effects on heart rate or systemic pressure. In 8 normal healthy dogs, ranolazine had no effect on LV ejection fraction or any other index of LV function.

Conclusions: In dogs with HF, acute intravenous administration of the pFOX inhibitor ranolazine improves LV systolic function. The absence of any hemodynamic effects of ranolazine in normal dogs suggests that the drug is devoid of any positive inotropic effects and acts primarily by optimizing cardiac metabolism in the setting of chronic HF.