Prolonged mast cell stabilization in reperfused myocardial infarction accelerates hemorrhage resorption and improves remodeling

Abstract Background Ischemia-reperfusion (I/R) mast cell (MC) dysfunction refers to a condition where tissue-resident MCs become overstimulated during reperfusion after a period of prolonged ischemia. When excessively activated, MCs release an abnormal amount of harmful chemical mediators in the affected/reperfused area, thus perpetuating the inflammation and tissue damage. Notably, recent in vitro studies have shown that, as opposed to resting/unstimulated MCs, activated MCs act as "scavengers" by actively engulfing and clearing damaged/oxidized erythrocytes (oxRBC). To date, however, the interaction of MCs with stagnant blood/oxydized erythrocytes in reperfused infarcted myocardium (MI) remains grossly unexplored. Purpose Growing body of evidence suggests that MCs play an important role in adverse myocardial remodeling post-MI; however, the role of MC degranulation on post-reperfusion hemorrhage formation/resolution is unknown. In the present study, we investigated the effects of MC stabilization on post-MI hemorrhage resorption/clearance in a clinically relevant porcine model using longitudinal MRI. Methods Female farm pigs (n=14; 30-35kg) underwent 90-minute occlusion of the left anterior descending artery followed by reperfusion. At Day 5, MI and intramyocardial hemorrhage (IMH) were confirmed using a clinical 3T MRI scanner. Pigs with comparable MI, IMH and microvascular obstruction (MVO) sizes were randomized into untreated (MI, n=7) and treated (LORA, n=7) groups, with the latter given daily oral loratadine (10mg) until termination. The animals were followed longitudinally through Weeks 4 and 8. Cardiac function was assessed using cine MRI sequences (short-axis, horizontal, and vertical long-axis). MI and MVO were quantified using LGE, while IMH was assessed using T2*-weighted imaging. Results As seen in Fig 1, no significant differences were observed in infarct (p=0.23), MVO (p=0.21) or IMH (p=0.11) sizes between the untreated MI and LORA groups at Day 5. Hemorrhage resorption from Day 5 to Week 4 and Week 8 was significantly greater in LORA (Week 4: -89.37%; Week 8: -96.53%) than in untreated MI (Week 4: -73.67%, p0.05; Week 8: -88.66%, p=0.02). Notably, at Week 8, while both groups demonstrated similar (p=0.48) reductions in MI scar size, the extent of ventricle volume increase was significantly lower in LORA (ESV: +22.23%; EDV: +25.06%) compared to untreated MI (ESV: +64.55%, p0.01; EDV: +64.11%, p=0.02) group. Conclusions Given that prolonged MC stabilization accelerated hemorrhage resolution and attenuated adverse remodelling in hemorrhagic MI, our findings suggest that activated MCs indeed negatively affect the hemorrhage clearance post MI. However, whether (over)stimulated MCs during myocardial I/R directly exhibit reduced oxRBC scavenging potential, or it is the MC degranulation that indirectly inhibits hemorrhage resolution, remains to be determined.