Calcium handling properties and arrhythmia vulnerability of cardiomyocytes from dystrophin-deficient mdx mice.

Cardiomyopathy and arrhythmia development significantly contribute to mortality in patients with Duchenne muscular dystrophy (DMD), a fatal muscle disorder caused by dystrophin deficiency. Previous studies suggested that abnormal Ca handling is an important causative factor for cardiac involvement in DMD. Here, we aimed to provide an extensive analysis of Ca handling properties and arrhythmia vulnerability of cardiomyocytes from the dystrophin-deficient mdx mouse, the most common DMD animal model. Whole cell patch clamp experiments showed that currents through L-type Ca channels are similar in wild-type and mdx cardiac Purkinje myocytes. Intracellular Ca measurements revealed that the decay of electrically evoked Ca transients is significantly prolonged in mdx compared to wild-type ventricular cardiomyocytes, thereby suggesting slowed Ca removal from the cytosol by the sarcoplasmic/endoplasmic reticulum Ca ATPase. The diastolic sarcoplasmic reticulum Ca leak and the resting concentration of free Ca in the cytosol were not significantly increased in mdx compared to wild-type ventricular cardiomyocytes. The occurrence of arrhythmogenic delayed afterdepolarizations (DADs), which are provoked by dysregulated Ca handling, was also not enhanced in mdx compared to wild-type ventricular cardiomyocytes. In conclusion, this work provides evidence that the only significant Ca handling abnormality in mdx cardiomyocytes is slowed removal of cytosolic Ca after release from the sarcoplasmic reticulum. Since the susceptibility of mdx ventricular cardiomyocytes to DADs was normal, cardiac arrhythmias in mdx mice might primarily be triggered by other arrhythmogenic mechanisms than DADs.