Taken together, the substantial reduction in Cx43, including phospho-Cx43(S262), its heterogeneous distribution, the increased likelihood of heterotypic Cx43/Cx45 channel formation, and increased levels of ZO-1 contribute to aberrant gap junctional remodeling, and increased fragility in the CRT-TG hearts, leading to calreticulin-dependent ECG abnormalities and cardiomyopathy. This evidence concerns the gene CALR and cardiomyopathy.