Abstract 4370326: Modifying Mast Cell Response to Control Inflammation and Optimize Repair in Reperfused Myocardial Infarction

Abstract

Background: While prolonged pro-inflammatory/delayed anti-inflammatory macrophage (MΦ) polarization post-MI promotes adverse cardiac remodeling, the impact of mast cell (MC) polarization on remodeling remains unknown. Timely MΦ infiltration is crucial for beneficial remodeling, but PET/MRI studies in reperfused MI revealed that microvascular obstruction (MVO) impairs early local MΦ influx, delaying “good” inflammation and promoting adverse remodeling. Whether MC degranulation contributes to the formation of MVO, thus delaying “good” inflammation in reperfused MIs is unknown. Purpose: Histamine, a product of MCs, can act as a vasodilator or vasoconstrictor depending on vessel type. Notably, autopsy reports have shown that in the number of degranulated MCs is increased at the site of vasospasm in patients with variant angina, indicating a role for histamine in coronary spasm. In the present study we tested whether loratadine, a commonly used over-the-counter antihistamine and MC stabilizer, attenuates MVO and augments early inflammation in reperfused MIs. Methods: Twelve pigs underwent a closed-chest 90-minute ischemia-reperfusion of the left anterior descending artery and were followed through Day 5-Week 8 with LGE, cine and 18 FDG-PET/MRI. Six pigs (LORA group) were treated with loratadine (10 mg/day PO), while six remained untreated (CTRL group). Remote myocardium FDG uptake was suppressed by 48-hour ketogenic diet, 12-hour fasting, and 2000 U heparin 15 minutes before FDG injection. LGE and PET images were fused to compute target-to-background ratio (TBR) between infarct and remote. Results: Comparing CTRL to LORA at Day 5, there was: (i) no difference in infarct size (IS) (CTRL=26.8±6.8%LV;LORA=20.9±6.2%LV; p=0.08); (ii) a reduction of MVO in LORA (p=0.02)(Fig 1a/b); (iii) an increased TBR in LORA (p=0.04)(Fig 1c); (iv) no difference in end-systolic volume (ESV: p=0.29) and end-diastolic volume (EDV: p=0.22)(Fig 2). Comparing the groups at Week 8, there was: (i) no difference in IS (CTRL=12.8±2.9%LV; LORA=9.5±2.2%LV; p=0.05); (ii) no difference in TBR (p=0.41); (iii) decreased ESV and EDV in LORA (ESV: p=0.03; EDV: p=0.02). Conclusion: Our seemingly paradoxical findings of MC stabilizer-augmented initial inflammatory response and lower subsequent ventricular volumes indicate that fine-tuning of MC degranulation post-MI could be a novel therapeutic strategy for optimized remodeling of reperfused MIs.