Résumé
Acute myocardial infarction (AMI) is a major cause of mortality worldwide. Early reperfusion is the only treatment recommended to reduce infarct size. However, reperfusion induces also deleterious secondary effects called ischemia-reperfusion (IR) injury due to irreversible apoptotic death of cardiomyocytes. Most ischemic episodes are triggered by an increase in heart rate that induces an imbalance between myocardial oxygen delivery and consumption. The BEAUTIFUL clinical trial has demonstrated that moderate heart rate reduction diminishes the frequency of AMI episodes in patients with stable coronary artery disease having increased heart rate at rest. The HCN-mediated If current and the Cav1.3- mediated L-type Ca2+ currents play important roles in the generation of automaticity and heart rate, therefore they are interesting targets for selective control of heart rate and cardioprotection during AMI. The aim of this study was to investigate if Cav1.3 channels could be a putative target to reduce infarct size.
Anesthetized C57BL/6J, Cav1.3-/- and Girk4-/- mice were subjected to a surgical protocol of myocardial IR (40min ischemia-60 min reperfusion). Heart rate was measured with a one-lead surface ECG recording, and infarct size with triphenyl tetrazolium chloride staining.
Selective heart rate decrease (26%) in an in vivo mouse model of AMI is associated with reduced IR injury. Ivabradine administration before ischemia significantly reduced infarct size (–33%). Cav1.3-/- mice presented reduced infarct size (–30%) compared to WT mice. In addition, Girk4-/- mice, a genetic model of moderate tachycardia (10%) displayed increased infarct size (+30%) compared to control mice.
These results show a direct relationship between heart rate and IR injury. Heart rate reduction by inhibition of Cav1.3 channels constitutes a promising strategy to reduce infarct size.