Acute intravenous infusion of ranolazine (RAN), an anti-ischemic / anti-angina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with RAN alone and in combination with metoprolol or enalapril on LV function and remodeling in dogs with HF. Dogs (n=28) with microembolizations-induced HF were randomized to 3 months oral treatment with RAN alone (375 mg, bid, n=7), RAN (375 mg bid) in combination with metoprolol tartrate (MET, 25 mg bid, n=7), RAN (375 mg bid) in combination with enalapril (ENA 10 mg bid, n=7), or placebo (PL) (RAN vehicle bid, n=7). Ventriculographic measurements of LV end-diastolic (EDV) and end-systolic (ESV) volumes and LV ejection fraction (EF) were obtained before treatment (PRE) and after 3 months of treatment (POST). In PL-treated dogs, EDV and ESV increased significantly. RAN alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly from 35±1 to 37±2 %. When combined with either ENA or MET, RAN prevented the increase in EDV, significantly decreased ESV and markedly increased EF compared to PL. EF increased from 35±1 to 40%