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.