Acute myocardial infarction (AMI) is the major cause of cardiovascular mortality worldwide. Early reperfusion is the only treatment recommended to reduce infarct size (IS). However, reperfusion presents also deleterious effects such as ischemia-reperfusion (IR) injury due to irreversible apoptotic death of cardiomyocytes. Most ischemic episodes are triggered by an increase in heart rate (HR) that induces an imbalance between myocardial oxygen delivery and consumption. The BEAUTIFUL clinical trial has demonstrated that moderate HR reduction diminishes the frequency of AMI episodes in patients with stable coronary artery disease and increased HR 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 HR, therefore they are interesting targets for selective control of HR and cardioprotection during AMI.
The aim of our study was to investigate if targeting Cav1.3 channels could be an efficient strategy to reduce IS. Cav1.3 -/- mice was used as a genetic model of Cav1.3 inhibition because of the lack of selective blocker. Ivabradine, the selective f-channel blocker, was used for pure HR reduction as a positive control. Results show that selective HR decrease (40%) in an in vivo mouse model of acute MI is associated with reduced IR injury. Ivabradine administration 30 minutes before ischemia significantly reduced IS (35%). Cav1.3 -/- mice presented reduced IS (30%) compared to WT mice. In addition, preliminary results show that Girk4 -/- mice, a genetic model of moderate tachycardia (10%) displayed increased IS (45%) compared to control mice. In conclusion, results suggest a direct relationship between HR and IR injury and that inhibition of Cav1.3 channels constitutes a promising strategy to reduce both HR and IS.