RITA-MI 2 will assess the impact of a novel therapeutic strategy targeting patients’ immune response on the recovery of heart function after myocardial infarction (MI) in a phase 2 clinical trial. Cardiovascular diseases (CVD) represent a major cause of morbidity and mortality worldwide. Despite important advances in the treatment of acute MI, the occurrence of MI still results in left ventricular dysfunction in up to 50% of patients, which leads to the development of heart failure. Left ventricular dysfunction is the strongest predictor of adverse outcome after acute MI, and is associated with a 3 to 4-fold increase in mortality risk. In Westernised countries, heart failure is responsible for 1-2% of all health expenditure, which is mostly driven by repeated hospital admissions. Therefore, there is a considerable need for new therapies to limit the burden of CVD. This application builds on a ground-breaking discovery by a unique team of clinicians and scientists who provided extensive validation for their findings through a series of basic, pre-clinical and translational research. Our goal is to translate this discovery into benefit for patients. The new therapy is based on selective targeting of a specific immune cell subset, mature B lymphocytes, with the aim to limit deleterious cardiac remodelling and improve heart function recovery post-MI. Of note, the drug that targets this pathway, i.e., CD20 monoclonal antibody (mAb) rituximab, is available for testing in a re-purposing scheme, allowing for rapid initiation of proof-of-concept clinical trials. The PIs of the present proposal have successfully completed a phase 1/2a clinical trial (RITA-MI, NCT03072199), which established the safety of rituximab treatment at the acute phase of MI. RITA-MI 2 will conduct a phase 2b randomised double-blind placebo-controlled CT to assess the impact of B cell depletion with the CD20 mAb rituximab on left ventricular dysfunction and cardiac remodelling after acute MI.