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 (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 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 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 Ca2+-dependent reduction of IK1. This mechanism may significantly contribute to the
antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death.
Keywords: Arrhythmias, angiotensin-converting enzyme inhibitor, heart failure, upstream therapy, IK1.
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