Developing endpoints for the cardiac burden in myotonic dystrophy type 1: A workshop report

Cardiac disease is a well-established manifestation of myotonic dystrophy type 1 (DM1), characterized by progressive cardiac conduction slowing with increased risk of atrial and ventricular arrhythmias, heart block, and sudden cardiac death. Multiple disease modifying therapies are in clinical trials for DM1 and show promise in improving skeletal muscle weakness and myotonia. Testing the effects of these medicines, or others, in the heart is of critical importance, but requires identification of endpoints of cardiac function that accurately reflect the state of DM1 cardiac disease. To better define cardiac endpoints, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the Myotonic Dystrophy Foundation (MDF) convened a workshop entitled ''Cardiac Endpoint Workshop'' in May 2025 at the Myotonic Dystrophy Foundation International Conference. Here, we summarize the discussion at the workshop and perform secondary analysis of cardiac outcomes in the published literature to evaluate cardiac endpoints for clinical impact and trial feasibility. This analysis demonstrates that major cardiac events are too infrequent (<1% annual incidence), and alternatives such as composite endpoints or progression of cardiac conduction prolongation would likely be underpowered in a conventional clinical trial. Given these limitations, we identify areas for further natural history study to better describe longitudinal cardiac structural and functional changes to inform specialized patient selection or identify alternative measures with sensitivity to detect therapeutic impact in a trial.