Cardiomyocyte calcium and stress-induced ventricular arrhythmia

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and is caused by mutations in the dystrophin gene. Subclinical signs of cardiac disease present early and usually progress to dilated cardiomyopathy in late stage DMD patients. Dystrophin deficiency is associated with structural and functional changes of the muscle cell sarcolemma and/or stretch-induced ion channel activation. However, the mechanism of cardiac dysfunction remains poorly understood. In this investigation, we use mice with transgenic cardiomyocyte-specific expression of the GCaMP6f Ca2+ indicator to test the hypothesis that dystrophin deficiency leads to cardiomyocyte Ca2+ handling abnormalities and cardiomyocyte damage following acute ventricular preload challenge. Excessive activity of the potent octapeptide Angiotensin II (Ang II) associates with adverse cardiac remodeling and arrhythmogenesis. While the long-term detrimental effects of Ang II excess on the heart are well-established, the acute effects of Ang II on ventricular arrhythmogenesis remain controversial, particularly in aged populations with associated structural heart disease. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel exhibits increased activity in cardiomyocytes with aging, and Ang II has been shown to increase TRPV4-mediated Ca2+ influx in several cell types. The goal of this investigation was to examine the acute effects of Ang II on cardiomyocyte Ca2+ transients and ventricular arrhythmia in the aged heart.