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Aim: Inhibition of microRNA (miR)‐132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR‐132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF‐REVERT (Phase 2, multicenter, randomized, parallel, 3‐arm, placebo‐controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post‐acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N‐terminal pro‐B‐type natriuretic peptide. The study consists of a 6‐month double‐blinded treatment period with the primary endpoint LV end‐systolic volume index and relevant secondary endpoints, followed by a 6‐month open‐label observation period. Conclusion: The HF‐REVERT trial may underpin the concept of miR‐132 inhibition to prevent or reverse cardiac remodelling in post‐MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF. [ABSTRACT FROM AUTHOR]