Combined Na+/Ca2+ Exchanger and L-Type Calcium Channel Block as a Potential Strategy to Suppress Arrhythmias and Maintain Ventricular Function

VJA Bourgonje, MA Vos, S Ozdemir… - Circulation …, 2013 - Am Heart Assoc
VJA Bourgonje, MA Vos, S Ozdemir, N Doisne, K Acsai, A Varro, A Sztojkov-Ivanov, I Zupko
Circulation: Arrhythmia and Electrophysiology, 2013Am Heart Assoc
Background—L-type calcium channel (LTCC) and Na+/Ca2+ exchanger (NCX) have been
implicated in repolarization-dependent arrhythmias, but also modulate calcium and
contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite
effect. Combined block may, therefore, offer an advantage for hemodynamics and
antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the
dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX …
Background
L-type calcium channel (LTCC) and Na+/Ca2+ exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics.
Methods and Results
Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic.
Conclusions
In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
Am Heart Assoc