Ion channels in dystrophic cardiac Purkinje cells

Duchenne muscular dystrophy (DMD) is a severe inherited disease caused by mutations in the gene encoding for the intracellular protein dystrophin. Progressive skeletal muscle weakness and wasting leading to loss of ambulation, respiratory failure, and premature death are the hallmarks of the illness. Besides skeletal muscle degeneration, DMD is also associated with severe cardiac complications including cardiomyopathy development and cardiac arrhythmias. These significantly contribute to the morbidity and mortality. Since the specific mechanisms responsible for the cardiac disease phenotype are poorly understood, current therapy approaches are not targeted and render little success. In particular, cardiomyopathy development in DMD patients can neither be prevented, nor can its progression effectively be slowed, and current cardiac arrhythmia management is unsatisfactory. The future goal is the identification and validation of new and better therapeutic targets. The successful exploration of such targets requires a more detailed understanding of the pathophysiology in the human dystrophic heart. In the present project, we will study voltage-gated sodium and calcium channels, intracellular Ca handling, as well as arrhythmia vulnerability in dystrophin-deficient cardiac Purkinje fibers. This cell type is part of the myocardial conduction system, important for the spread and coordination of cardiac excitation, and often responsible for the initiation of ventricular arrhythmias. Based on our previous work and preliminary data, we expect to elaborate ion channel and Ca handling abnormalities in dystrophic Purkinje fibers, which will not only shed light on the involvement of the Purkinje fibre network in the pathophysiology of the dystrophic heart, but also help to explain clinically observed electrocardiogram and conduction abnormalities in DMD patients. Further, the studies should entail a better understanding of the arrhythmia mechanisms in the dystrophic heart as basis for the development of targeted and more effective antiarrhythmic therapies in the future. We expect that the project studies will expose new therapeutic targets for evidence-based and hence effective treatment of the cardiomyopathy and concomitant complications in DMD patients.