Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol

Abstract

Evidence has accumulated recently about the importance of alterations in Na+ channel function and slow myocardial conduction for arrhythmias in the infarcted and failing heart. The present study tested a hypothesis that Na+ current (INa/C) density decreases in chronic heart failure (HF) and that Na+ channel (NaCh) functional density can be restored by long-term therapy with carvedilol, a mixed alpha- and beta-adrenergic blocker. Studies were performed using a canine model of chronic HF produced in dogs by sequential intracoronary embolizations with microspheres. HF developed approximately 3 months after the last embolization (left ventricle, LV, ejection fraction = 28 +/- 1%). Ventricular cardiomyocytes (VCs) were isolated enzymatically from LV mid-myocardium, and INa was measured by whole-cell patch-clamp. The maximum INa/C was decreased in failing (n = 19) compared to normal (n = 12) hearts (33.1 +/- 1.6 vs 48.5 +/- 5.1 pA/pF, mean +/- SE, p < 0.001). The steady-state inactivation and activation of INa remained unchanged in failing compared to normal hearts. Long-term treatment with carvedilol (1 mg/kg, twice daily for 3 months) normalized INa/C in dogs with HF. INa/C in HF dogs (n = 6) treated with carvedilol was higher compared to that of non-treated HF dogs (n = 6) (49.4 +/- 0.9 vs 29 +/- 4.8 pA/pF, p < 0.007). In vitro culture of VCs of failing hearts for 24 h did not restore INa/C. However, INa/C was partially restored when VCs were incubated for 24 h with BAPTA-AM, an intracellular Ca2+ buffer. Thus, we conclude that experimental chronic HF in dogs results in down-regulation of the functional density of NaCh that can be restored by long-term therapy with carvedilol. The mechanism of NaCh down-regulation in HF may be linked to poor Ca2+ handling in this stage of disease.

Mechanisms of Postinfarction Electrophysiological Abnormality: Sympathetic Neural Remodeling, Electrical Remodeling and Gap Junction Remodeling

“…An angiotensin-converting enzyme inhibitor attenuated increases in refractoriness heterogeneity and prevented afterdepolarization formation in normal zones of rats with prior infarctions . The combined -and -adrenoceptor antagonist carvedilol suppresses downregulation of both Na + (Maltsev et al, 2002) and L-type Ca 2+ currents following myocardial infarction. Protein kinase A activators can partially restore suppressed I Na in the infarct border zone .…”

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

“…Carvedilol's other electrophysiologic effects are underappreciated and include direct membrane-stabilizing activity (Class IA); prolonging repolarization by blocking potassium channels (Class III); and inhibiting L-type calcium channels (Class IV). [9][10][11][12][13] These effects appear to be without any known ventricular proarrhythmic activity.…”

“…By reducing the rate of Phase 0 depolarization, changes in I Na can slow conduction and promote reentrant arrthythmias. 11 In a canine model of chronic HF associated with a decrease in sodium current, long-term carvedilol treatment resulted in a recovery in the density of I Na . 11 Because changes in intracellular calcium modulate the expression of sodium channels in cardiomyocytes, 16 it is believed that chronically heightened sympathetic beta-receptor stimulation, which increases intracellular calcium, may downregulate sodium channels in chronic HF.…”

“…11 In a canine model of chronic HF associated with a decrease in sodium current, long-term carvedilol treatment resulted in a recovery in the density of I Na . 11 Because changes in intracellular calcium modulate the expression of sodium channels in cardiomyocytes, 16 it is believed that chronically heightened sympathetic beta-receptor stimulation, which increases intracellular calcium, may downregulate sodium channels in chronic HF. Carvedilol may increase sodium-channel expression and I Na density by ameliorating the abnormal calcium handling found in the failing cardiomyocyte (spontaneous sarcoplasmic reticulum sodium release, upregulated sodiumcalcium exchange, and increased L-type channel activity), resulting in improved myocardial conduction.…”

“…Carvedilol may increase sodium-channel expression and I Na density by ameliorating the abnormal calcium handling found in the failing cardiomyocyte (spontaneous sarcoplasmic reticulum sodium release, upregulated sodiumcalcium exchange, and increased L-type channel activity), resulting in improved myocardial conduction. 11 Treatment with carvedilol causes electrophysiologic changes in conduction and repolarization; these changes are manifested by improvements in several important parameters. Nonuniform myocardial repolarization that leads to dispersion of refractoriness is well recognized as an important predisposing factor in the genesis of reentry and malignant ventricular arrhythmias.…”