Background: Mechanical unloading before reperfusion limits infarct size in pre-clinical models and is currently under clinical investigation in acute MI (AMI). The impact of left ventricular (LV) unloading on energetics or mitochondrial function in AMI is unknown. We hypothesised that LV unloading preserves myocardial metabolism and mitochondrial function in AMI.
Methods: AMI was induced by balloon occlusion of the left anterior descending (LAD) artery for 120 minutes in adult male pigs (n=5 per group), followed by reperfusion for 180 minutes. After 90 minutes of occlusion, animals were assigned to 30 minutes of continued occlusion, then immediate reperfusion (IR) or 30 minutes of LV unloading with persistent occlusion before reperfusion. Compared to IR, unloading reduced infarct size normalised to the area at risk by 41 ± 6% (p<0.01). Untargeted metabolomics were performed using tissue from the infarct zone (Metabolon). Compared to IR, unloading preserved glycolytic activity, fatty acid oxidation and amino acid utilisation, and increased tricarboxylic acid cycle metabolites, suggesting preserved mitochondrial function.
To further explore the impact of unloading on mitochondrial function, we performed Seahorse analysis on mitochondria isolated from the infarct zone. Compared to sham controls, IR reduced the function of mitochondrial complex I (CI), increased reactive oxygen species (ROS) levels, decreased adenosine triphosphate (ATP) levels and reduced mitochondrial membrane potential. In contrast, unloading preserved CI function and ATP levels while reducing ROS levels and maintaining membrane potential.
Since ischaemia alone converts CI from an activated to de-activated state, we next studied whether unloading limits ischaemic injury without reperfusion. Adult pigs (n=5–6 per group) were subjected to 120 minutes of LAD occlusion, followed by 120 minutes of occlusion, with or without LV unloading. No reperfusion was performed. Compared to sham controls, ischaemia increased deactivated CI levels and reduced CI activity. In contrast, unloading during ischaemia reduced infarct size, reduced deactivated CI levels and increased CI activity.
Conclusion: We report for the first time that LV unloading limits myocardial injury, preserves energy substrate utilisation and protects mitochondrial function after ischaemia injury, with or without reperfusion.