Abstract
Background: Mitochondrial Complex 1 (MC1) plays a key role in energy metabolism during myocardial ischemia-reperfusion injury (M-IRI). Disruption of MC1 promotes reactive oxygen species (ROS) generation and myocardial damage. We recently reported that first reducing left ventricular (LV) workload using a trans-valvular pump and delaying coronary reperfusion, known as Primary Unloading (PU), reduces infarct size in preclinical models of M-IRI. The Door to Unload Pilot Trial recently demonstrated the safety and feasibility of PU in patients with ST-segment elevation myocardial infarction (STEMI), however the cardioprotective mechanisms of PU remain poorly understood. We hypothesized that compared to immediate reperfusion (IR); PU preserves mitochondrial function in M-IRI. Results: M-IRI was induced by balloon occlusion of the left anterior descending artery for 120 minutes in adult swine followed by reperfusion for 180 minutes. After 90 minutes of occlusion, animals were assigned to 30 minutes of continued occlusion (IR, n=5) or 30 minutes of support with an Impella CP pump (PU, n=5) with persistent occlusion before reperfusion. Compared to IR, PU reduced LV stroke work by 38.4% (p=0.047) and infarct size by 41.3±5.6% (p=0.0052). Compared to IR, PU preserved gene and protein expression of specific MC1 subunits (NDUFA8 and NDUFS3). Using the Agilent Seahorse Platform, we identified that compared to IR, PU preserved function of MC1 and ATP production in mitochondria isolated from the infarct zone by 82.45±12.8% (p=0.0040, IR vs PU). Compared to IR, PU reduced levels of ROS and preserved mitochondrial membrane potential. Next, we studied the activation state of MC1 and observed that compared to IR alone, PU increased the ratio of activated A form versus de-activated D form from 2.79 ± 0.29 to 7.58 ± 0.80 (p=0.005) levels of MC1 within the infarct zone. Conclusion: We report for the first time that compared to IR, mechanically unloading the LV and delaying reperfusion protects the structural and functional integrity of mitochondrial complex 1. These findings provide new insight into the cardioprotective mechanisms of Primary Unloading and support the development of novel therapeutic approaches to improve clinical outcome for patients with STEMI.
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