Left Ventricular Unloading and Delaying Coronary Reperfusion Preserves Energy Substrate Utilisation and Protects Mitochondrial Integrity in a Pre-clinical Model of Acute MI

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Dr Swain began by highlighting that haemodynamic load is a major determinant of acute and chronic ventricular remodelling.1 This led her to question if acute ventricular unloading can be used as a therapeutic strategy to improve myocardial recovery. She recalled the observation by Mann et al. that the myocardial damage due to acute MI (AMI) is reversible following the reduction of left ventricular (LV) pressure and volume.2 Studies have demonstrated that LV unloading reduces myocardial oxygen consumption, which is driven by myocyte cycling, excitation-contraction coupling and basal metabolism. Previous studies have shown that transvalvular pumps, such as Impella, rapidly unload the LV without the need for surgery.3,4 In addition, emerging research comparing reperfusion alone to LV unloading prior to reperfusion has demonstrated that the unloading strategy reduces infarct size, despite delaying reperfusion by 60 minutes in a pig model.4,5 The recent ST-elevation MI Door-To-Unload pilot trial demonstrated the safety and feasibility of LV unloading and delayed reperfusion (U-DR) in patients with ST-elevation MI.6 The results of the subgroup analysis showed that U-DR reduced infarct size compared to unloading and immediate reperfusion.

Given the results of a previous study showing that LV unloading preserves mitochondrial structure and levels of genes associated with mitochondrial function,5 Dr Swain hypothesised that LV unloading before reperfusion preserves mitochondrial structural and functional integrity in AMI. To test the effect of LV unloading on mitochondrial function, adult male pigs subjected to left anterior descending artery (LAD) occlusion for 90 minutes were divided into three groups. In the continued occlusion group, LAD was occluded for an additional 30 minutes, followed by 180 minutes of reperfusion. In the Impella pre-reperfusion group, Impella CP at maximal support was activated with LAD occlusion for an additional 30 minutes, followed by 180 minutes of reperfusion. In the veno-arterial extracorporeal membrane oxygenation (VA-ECMO) pre-reperfusion group, VA-ECMO at 7,500 rpm was activated with LAD occlusion for an additional 30 minutes, followed by 180 minutes of reperfusion.

The results showed that unloading with Impella CP before reperfusion compared to VA-ECMO reduced infarct size, despite equal exposure to LAD occlusion. Also, oxygen consumption rates measured using the Agilent Seahorse Platform on tissue harvested from within the infarct zone showed that primary unloading using Impella CP preserves the function of mitochondrial complex 1 in AMI compared to reperfusion alone. On the other hand, primary unloading with VA-ECMO led to a significant decrease in mitochondrial respiration via complexes I, II and III compared to reperfusion alone. Furthermore, unloading with Impella before reperfusion reduced the increase in complex I deactivation observed in the infarct zone due to ischaemia–reperfusion (IR) injury compared to VA-ECMO or reperfusion alone.

Along the same lines, oxidative stress biomarkers (catalase activity and glutathione levels) in Impella-treated animals were similar to sham-treated animals, indicating the prevention of oxidative stress and subsequent reactive oxygen species production following unloading with Impella in AMI. Dr Swain tested whether unloading with Impella impacted myocardial metabolism. Her findings suggested that unloading with Impella preserved glycolytic and Krebs cycle activity compared to IR injury alone or unloading with VA-ECMO.

Dr Swain also tested if LV unloading during ischaemia without reperfusion reduced infarct size and preserved mitochondrial function. To address this question, adult male swine were subjected to either 90 minutes of LAD occlusion, followed by an additional 120 minutes of occlusion (ischaemia), or 90 minutes of LAD occlusion, followed by 120 minutes of additional ischaemia with concurrent LV unloading with Impella (ischaemia and unloading). The results demonstrate that ischaemia and unloading significantly reduced the infarct size and preserved mitochondrial function compared to ischaemia alone. The results indicate that LV unloading may be able to limit ischaemia-dependent damage.

In summary, these findings suggest that LV unloading prior to reperfusion with Impella reperfusion versus VA-ECMO reduces infarct size and preserves mitochondrial function after IR injury. Also, the results indicate for the first time that unloading with Impella during ischaemia without reperfusion reduces infarct size and preserves mitochondrial function after prolonged ischaemic injury.


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