Cardiac dysfunction is a primary cause of patient mortality in
Duchenne muscular dystrophy, potentially related to elevated cytosolic
calcium. However, the regional versus global functional consequences of cellular
calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between
calcium mishandling and myocardial fiber/sheet function as a manifestation of
dystrophin-deficient (mdx)
cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx (N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate
calcium concentrations. Optical mapping of
calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular
calcium reuptake, reflected by a 25% increase of decay times (T(50)) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater
fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with
calcium mishandling, ultimately culminating in increased
fibrosis. The preservation of relatively normal
calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic
calcium, points to the significance of regional mechanical factors in the progression of the disease.