ACE Inhibitor Delapril Prevents Ca²⁺-Dependent Blunting of I_K1 and Ventricular Arrhythmia in Ischemic Heart Disease

Title:ACE Inhibitor Delapril Prevents Ca²⁺-Dependent Blunting of I_K1 and Ventricular Arrhythmia in Ischemic Heart Disease

Volume: 15 Issue: 7

Author(s): J. Thireau, S. Zalvidea, P. Meschin, J.-L. Pasquie, F. Aimond and S. Richard

Affiliation:

Keywords: Arrhythmias, angiotensin-converting enzyme inhibitor, heart failure, upstream therapy, I_K1.

Abstract: Angiotensin-converting enzyme inhibitors (ACE-I) improve clinical outcome in patients with myocardial infarction (MI) and chronic heart failure. We investigated potential anti-arrhythmic (AA) benefits in a mouse model of ischemic HF. We hypothesized that normalization of diastolic calcium (Ca²⁺) by ACE-I may prevent Ca²⁺-dependent reduction of inward rectifying K⁺ current (I_K1) and occurrence of arrhythmias after MI. Mice were randomly assigned to three groups: Sham, MI, and MI-D (6 weeks of treatment with ACE-I delapril started 24h after MI). Electrophysiological analyses showed that delapril attenuates MI-induced prolongations of electrocardiogram parameters (QRS complex, QT, QTc intervals) and conduction time from His bundle to ventricular activation. Delapril improved the sympatho-vagal balance (LF/HF) and reduced atrio-ventricular blocks and ventricular arrhythmia. Investigations in cardiomyocytes showed that delapril prevented the decrease of IK1 measured by patch-clamp technique. I_K1 reduction was related to intracellular Ca²⁺ overload. This reduction was not observed when intracellular free-Ca²⁺ was maintained low. Conversely, increasing intracellular free-Ca²⁺ in Sham following application of SERCA2a inhibitor thapsigargin reduced I_K1. Thapsigargin had no effect in MI animals and abolished the benefits of delapril on I_K1 in MI-D mice. Delapril prevented both the prolongation of action potential late repolarization and the depolarization of resting membrane potential, two phenomena known to trigger abnormal electrical activities, promoted by MI. In conclusion, early chronic therapy with delapril after MI prevented Ca²⁺-dependent reduction of I_K1. This mechanism may significantly contribute to the antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death.

Cite this article as:

Thireau J., Zalvidea S., Meschin P., Pasquie J.-L., Aimond F. and Richard S., ACE Inhibitor Delapril Prevents Ca²⁺-Dependent Blunting of I_K1 and Ventricular Arrhythmia in Ischemic Heart Disease, Current Molecular Medicine 2015; 15 (7) . https://dx.doi.org/10.2174/1566524015666150831131459