Preemptive cardioprotection with a small molecule in rodents that suppresses genes predictive of heart failure.

Ischemic heart disease is a leading cause of death worldwide. While percutaneous coronary intervention (PCI) restores blood flow in acute coronary syndrome (ACS), reperfusion injury exacerbates myocardial damage, contributing to heart failure (HF). Preemptive administration of a cardioprotective agent could help counter the imminent proinflammatory insult of PCI and reperfusion. Administering BT2, a small-molecule MAPK kinase/extracellular signal-regulated kinase inhibitor, 24 hours before and during ischemia in rats before reperfusion reduced infarct size by ~70% and preserved cardiac function 24 hours and 2 weeks postinjury. BT2 prevented adverse left ventricular remodeling and scarring. Single nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq revealed that BT2 modulated genes associated with inflammation, fibrosis, and matrix production, especially within macrophages and myofibroblasts. BT2 suppressed macrophage and neutrophil infiltration. BT2 reduced the expression of genes in rodent hearts predictive of HF in patients with ACS, including many encoding cytokines, inflammasome components, and damage-associated molecular patterns. BT2 is a small molecule that can prevent myocardial ischemia-reperfusion injury, improve heart function, reduce cardiac fibrosis, and favorably modulate multiple key genes and biological processes in rats prognostic of HF when delivered before reperfusion. This strategy could be evaluated with high-risk unstable angina/non-ST-segment elevation myocardial infarction patients or those having an elective PCI.