Beyond Reperfusion: Early Molecular Drivers and Therapeutic Opportunities in Acute Post-Infarction Cardiac Fibrosis

Heart failure is a leading cause of global morbidity and mortality, often developing as a consequence of acute myocardial infarction. Current management focuses on timely reperfusion via percutaneous coronary intervention. Yet, this approach fails to prevent the molecular cascades that drive the death of viable yet stressed cardiomyocytes within the infarct and peri-infarct zone. Effective antifibrotic therapies remain limited, highlighting a critical gap in current management strategies. This review aims to integrate current understanding of the molecular mechanisms underpinning post-infarct fibrosis and potential interventions for therapeutic development. This emphasis on molecular death signal activation and cell elimination highlights the redundancy of interconnecting fibrosis pathways. Anti-inflammatory and cell-targeted therapies focussing on oxidative stress and haemodynamic load have demonstrated strong preclinical promise. Yet, these approaches have largely failed to translate into clinical benefit. Overall, these limitations emphasise a narrow therapeutic window for intervention. As such, current therapies often fail to preserve metabolically vulnerable myocardium that remains potentially salvageable. Therefore, emerging approaches including RNA-based therapies, cardiac reprogramming, and targeted delivery systems offer new opportunities to improve therapeutic precision. Collectively, these findings support a shift toward early, cell-targeted intervention strategies. This approach aims to prevent progression to heart failure and increases patient quality of life.