Abstract Body: Cardiac damage in the aftermath of myocardial ischemia / reperfusion (MI/R) compromises both electrical and mechanical function, predisposing patients to arrhythmia and heart failure. Microvascular obstruction (MVO) is increasingly recognized as a sequela of MI/R and a contributor to proarrhythmic cardiac remodeling. While the benefits of cardiac unloading using trans valvular pump (TV-P) in limiting infarct size and preserving mechanical function are gaining wider appreciation, the benefits for arrhythmia prevention remain unclear. Therefore, we undertook studies in an porcine preclinical model to test the hypothesis that cardiac unloading mitigates MVO, preserves cardiomyocyte nanostructure, and thereby, alleviates arrhythmias acutely following MI/R. Anesthetized domestic swine undergoing acute ischemia (LAD occlusion, 90 mins) and reperfusion (120 mins) were randomized to TV-P unloading (n=5) and sham (control; n=6) treatments. Thioflavin-S was infused into the mid-LAD to enable assessment of coronary microcirculation and quantify MVO. Arrhythmia burden was assessed by in vivo electrocardiography using 3 lead EKG. Cardiac tissues were preserved for histology and optical microscopy studies. Wilcoxon’s ranksum test was applied and p<0.05 considered significant. Compared to sham controls, TV-P unloaded hearts evidenced significantly reduced infarct area (48±5 vs. 59±11%) and MVO (19±4 vs. 27±5%) normalized to area at risk and a higher myocardial salvage index (52±5 vs. 41±11%). Extensive perivascular edema, cellular diapedesis, and neutrophil infiltration observed in controls was markedly reduced in TV-P unloaded hearts. We have previously demonstrated how inflammation-induced vascular leak acutely induces proarrhythmic disruption of sodium channel Na_V1.5-rich nanodomains within cardiomyocyte intercalated discs (IDs). Confocal microscopy and spatial pattern analysis revealed significantly mitigated disruption of gap junctions and Na_V1.5 dissociation from N-cadherin in TV-P unloaded hearts compared to controls. Importantly, severity-adjusted arrhythmia burden during reperfusion was significantly lower in TV-P unloaded hearts (8±1 vs. 16±18 in controls). Our results demonstrate that TV-P unloading effectively prevents arrhythmias during reperfusion by preserving coronary microvasculature and cardiomyocyte nanostructure.