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.
ABNORMAL CARDIAC SODIUM CHANNEL MRNA SPLICING IN HEART FAILURE: A POTENTIAL MARKER FOR THE RISK OF SUDDEN DEATH
