Ranolazine Prevents Heart Failure with Preserved Ejection Fraction; Diastolic Dysfunction and Left Ventricular Hypertrophy in a Hypertensive Murine Model

Background: Recent in vitro studies on failing human heart muscle has suggested that ranolazine (RAN), a novel antianginal drug known to inhibit late sodium current, may improve diastolic dysfunction (DD) caused by hypertension (HTN)-induced oxidative stress. By improving DD, RAN can improve heart failure with preserved ejection fraction (HFPEF). Methods: Amouse model of DDwas developed by inducing mild HTN by unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and substituting drinking water with 1% NaCl. Control animals underwent sham operation and drank regular tap water. RAN 50 (mg/kg) was given orally twice a day. Weekly blood pressures (BPs) and heart rates (HRs) were measured using tail-cuff plethysmography. Cardiac function and left ventricular posterior wall thickness (LVPWd) were measured by echocardiogram under light anesthesia using isoflurane. Treatment durationwas for 3weeks and 7weeks. Pulmonary congestion was assessed by lung to body weight (L/BW) ratio. Results: Compared to controls, DOCA mice were hypertensive (BP 112 ±4 vs. 89±2 mmHg) and had DD evidenced by a low LV inflow propagation velocity Vp (28.1±0.5 vs. 47.2±1 cm/s⁎), a low mitral annulus early longitudinal velocity E' (2.70 vs. 4.40 cm/s⁎), and a high E/E' ratio (29.3±1.5 vs. 18.0±0⁎). DOCA mice had LVH as evidenced by high heart/BW ratio (6.22±0.15 vs. 4.90±0.22 mg/g⁎) and increased LVPWd (0.82±0.22 vs. 0.74±0.01 mm⁎). There was no systolic dysfunction in either group. RAN pretreatment effectively prevented DD and LVH in DOCA mice as evidenced by high E' (3.9 Vs 2.70 cm/s⁎), low E/E' (18.8±1.0⁎), high Vp (41±2Vs 28.1±0.5 cm/s⁎), lowheart/BW ratio (4.79±0.11 mg/g⁎), and low LVPWd thickness (0.76±0.01 vs. 0.82±0.02 mm⁎). RAN had no effect on HR [625±18 vs. 630±20 bpm, P=not significant (NS)]. RAN pretreatment effectively prevented development of heart failure in DOCA mice at 7 weeks as evidenced by significantly lower L/BW ratios when compared with untreated DOCA mice (0.41±0.002 vs. 0.52±0.02 mg/g⁎). Conclusions: RANhas prevented DD, LVH, and HFPEF in a hypertensive murine model of DD. Prevention of heart failure in our model warrants additional animal andhuman studies to further evaluate the therapeutic potential of RAN in HFPEF (Mean±S.E.M., ⁎Pb.05).