Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure.

Abstract

BACKGROUND:

Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia.

OBJECTIVE:

To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF).

METHODS AND RESULTS:

CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups.

CONCLUSIONS:

In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.

• Authors: Peter Milberg, Christian Pott, Gerrit Frommeyer, Martin Fink, Matthias Ruhe, Toshio Matsuda, Akemichi Baba, Rainer Klocke, Trong Hung Quang, Sigrid Nikol, Jörg Stypmann, Nani Osada, Frank U Müller, Günter Breithardt, Dennis Noble, Lars Eckardt
• Journal: Heart rhythm (Heart Rhythm) Vol. 9 Issue 4 Pg. 570-8 (Apr 2012) ISSN: 1556-3871 [Electronic] United States
• PMID: 22075452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anti-Arrhythmia Agents
• Sodium-Calcium Exchanger
• Veratridine
• Sotalol
• Amiodarone

Topics

• Action Potentials (drug effects)
• Amiodarone (pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Disease Models, Animal
• Heart (drug effects)
• Heart Failure (drug therapy)
• Heart Ventricles (drug effects)
• Humans
• Long QT Syndrome (chemically induced)
• Rabbits
• Sodium-Calcium Exchanger (drug effects)
• Sotalol (pharmacology)
• Tachycardia, Ventricular (drug therapy)
• Torsades de Pointes (chemically induced)
• Veratridine (pharmacology)