Recombinant human thymosin beta 4 improves ischemic cardiac dysfunction in mice and patients with acute ST-segment elevation myocardial infarction after reperfusion

Abstract Aims Despite advancements in primary percutaneous coronary intervention (PCI), cardiac dysfunction remains a challenge in patients with ST-segment elevation myocardial infarction (STEMI). Although thymosin beta 4 has shown cardioprotective effects in preclinical MI models, its impact on chronic cardiac functional recovery post ischemia/reperfusion (I/R), especially in STEMI, warrants further investigation. This study aims to explore the therapeutic potential of recombinant human thymosin beta 4 (rhTB4) in both murine models subjected to I/R and in subjects with STEMI post-PCI. Methods and Results In C57BL/6J mice, 7-day rhTB4 treatment prevented cardiac dysfunction and fibrosis 28 days post-I/R surgery and significantly reduced plasma NT-proBNP levels at both 1 day and 28 days post-I/R. Similarly, in a permanent ligation model, rhTB4 improved cardiac function and reduced infarct size at 8 weeks post-MI. RNA-seq analysis of I/R heart tissues revealed that rhTB4 modulated the ErbB signaling pathway. In vitro hypoxia/reoxygenation models (HL-1, neonatal mouse cardiomyocytes, H9C2) demonstrated that rhTB4 activated the ErbB2/Raf1 signaling pathway, attenuated cardiomyocyte apoptosis and suppressed pro-apoptotic protein Bad expression. The cardioprotective effects of rhTB4 on cardiac function and adverse cardiac remodeling in I/R mice were abolished by ErbB2 inhibition. In a randomized, placebo-controlled, double-blind trial involving 96 STEMI patients, the infarcted areas were significantly reduced in the rhTB4 group, which received the first dose of rhTB4 within 8 hours after PCI (n=43), as compared to the placebo group at the 90-day follow-up. However, the overall differences in infarcted areas were not significantly between the rhTB4 group and the placebo group (n=96). Conclusions These findings underscore the crucial role of rhTB4 in mitigating cardiac dysfunction in an ErbB2-dependent manner. The clinical relevance of rhTB4 is demonstrated through a randomized controlled trial, emphasizing its translational potential. Further rigorous randomized studies are needed to assess the significance of early rhTB4 use post-myocardial infarction reperfusion.