Burkhoff, D. | bioRxiv Science

bioRxiv2026

Cardiac unloading via a transvalvular pump prevents arrhythmias following myocardial ischemia / reperfusion by preserving coronary microcirculation and cardiomyocyte nanostructure

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 transvalvular unloading (TVU) using a percutaneously delivered pump is garnering appreciation as a means of limiting infarct size and preserving mechanical function following percutaneous coronary intervention, its benefits for arrhythmia prevention remain unclear. We used a porcine model to test the hypothesis that cardiac unloading prior to and through reperfusion mitigates MVO, preserves cardiomyocyte nanostructure, and alleviates arrhythmias following MI/R. Anesthetized domestic swine undergoing acute ischemia (LAD occlusion, 90 mins) and reperfusion (120 mins) were randomized to TVU (n=5) and no treatment (control; n=6) treatments. Thioflavin-S was infused into the mid-LAD to assess 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. Compared to no treatment controls, TVU hearts evidenced significantly reduced infarct area (48 +/- 5 % vs. 59 +/- 11 % p = 0.03) and MVO (19 +/- 4 % vs. 27 +/- 5% , p = 0.03) normalized to area at risk and a higher myocardial salvage index (52 +/- 5 % vs. 41 +/- 11% p = 0.03). Extensive perivascular edema, and neutrophil infiltration observed in controls was markedly reduced in TVU hearts. Confocal microscopy and spatial pattern analysis revealed significantly mitigated disruption of gap junctions and NaV1.5 dissociation from N-cadherin in TVU hearts compared to controls. Importantly, severity-adjusted arrhythmia burden during reperfusion was significantly lower in TV-P hearts (8+/-8 vs. 12+/-5 episodes lasting greater than 5seconds in controls). Our results demonstrate that TVU effectively prevents arrhythmias during reperfusion by preserving coronary microvasculature and cardiomyocyte nanostructure.

physiology↗

bioRxiv2021

Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.

pathology↗