ACE Inhibitor Delapril Prevents Ca(2+)-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease. - Université de Montpellier
Article Dans Une Revue Current Molecular Medicine Année : 2015

ACE Inhibitor Delapril Prevents Ca(2+)-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease.

Résumé

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 (Ca(2+)) by ACE-I may prevent Ca(2+)-dependent reduction of inward rectifying K(+) current (IK1) 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. IK1 reduction was related to intracellular Ca(2+) overload. This reduction was not observed when intracellular free-Ca(2+) was maintained low. Conversely, increasing intracellular free-Ca(2+) in Sham following application of SERCA2a inhibitor thapsigargin reduced IK1. Thapsigargin had no effect in MI animals and abolished the benefits of delapril on IK1 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 Ca(2+)-dependent reduction of IK1. This mechanism may significantly contribute to the antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death.
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Dates et versions

hal-01762616 , version 1 (10-04-2018)

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Jérôme Thireau, Santiago Zalvidea, Pieere Meschin, Jean Luc Pasquié, Franck Aimond, et al.. ACE Inhibitor Delapril Prevents Ca(2+)-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease.. Current Molecular Medicine, 2015, pp.642-51. ⟨10.2174/1566524015666150831131459⟩. ⟨hal-01762616⟩
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