Re-print: Ranolazine may be the Best and Safest Pharmacologic Therapy for Congestive Heart Failure, and Safe, Effective for Ventricular and Atrial Arrhythmias

Abstract

Background: Ranolazine (RAN) reduces cardiac sodium channel 1.5’s late sodium current(INaL ) in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular ejection fraction(LVEF) and reducing arrhyth- mogenic after potentials. RAN blocks neuronal sodium channel 1.7(Nav 1.7), potentially altering parasympathetic and sympathetic (P&S) activity. RAN also selectively blocks inactivated atrial Nav 1.8, as well as ventricular IKr and ICaL, affecting atrial and ventric- ular arrhythmias. Methods: (1)Matched CHF patients were given RAN (1000 mg p.o. b.i.d.) added to guideline-driven therapy (RANCHF, 41 systolic, 13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Echocardiographic LVEF and P&S measures were obtained at baseline and follow-up (mean 23.7 months). (2)A total of 59 patients with symptomatic PVCs were identified from full-disclosure Holters. Doses of 500 - 1,000 mg RAN b.i.d. were given to 34% and 66% of patients, respectively, and Holters were repeated (mean 3.1 months). Congestive heart failure (CHF) was defined as symptoms including dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema, with a brain natriuretic peptide > 400. Systolic heart failure with reduced ejection fraction (HFr EF) vs. diastolic CHF (HFpEF) depended upon LVEF≥ 40%. Results: (1)LVEF increased in 70% of RANCHF patients, an average of 11.3 units. Mean LVEF remained unchanged in NORANCHF pa- tients. P&S measures indicated cardiovascular autonomic neuropathy (P<0.10 bpm2) in 20% of NORANCHF patients at baseline and 29% at follow-up (increasing in both groups). At baseline, 28% of patients had high sympathovagal balance (SB), RAN normalized SB in over 50% of these; in contrast, the NORANCHF group had a 20% increase in patients with high SB. (2)Upon repeat Holters at a mean of 3.1 months after initiating RAN, 95% (56/59) of the patients had their PVC count reduced: 24% (14/59) had more than 90% decrease, 34% (20/59) had 71 to 90% decrease, and 17% (10/59) had 50 to 70% decrease. In the entire group, RAN reduced PVCs by 71% (mean 13,329 to 3,837; p < 0.001). Ventricular bigeminy was reduced by 80% (4,168 to 851; p < 0.001), ventricular couplets were reduced by 78% (374 to 81; p < 0.001), and ventricular tachycardia (VT) was reduced by 91% (56 to 5; p < 0.001). The PVC reduction was dose dependent without proarrhythmia. Conclusions: (1)RAN preserves or improves LVEF and decreases high SB in CHF. (2)RAN offers an effective and safe pharmacologic treatment for symptomatic PVCs.