Cardiovascular Division, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Am J Physiol Heart Circ Physiol. 2012 Sep 1;303(5):H559-68. doi: 10.1152/ajpheart.00321.2012. Epub 2012 Jul 9.
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.
心脏功能障碍是杜氏肌营养不良症患者死亡的主要原因，可能与细胞溶质钙升高有关。然而，细胞内钙处理不当对整个心脏的局部和整体功能的影响尚未确定。在这里，我们首次试图阐明钙处理不当与心肌纤维/片功能之间的潜在局部依赖性，作为缺乏肌营养不良蛋白（mdx）心肌病的表现。从 16 个月大的 mdx（N = 10）和野生型（WT；N = 10）的离体灌注心脏中依次在舒张期和收缩期停止，以进行心肌片结构和功能的扩散张量 MRI 定量分析。与 WT 心脏相比，mdx 心脏表现出正常的收缩期片结构，但在基底区域的舒张期片角度幅度（|β|）较低。通过降低灌流液钙浓度，可以使区域性舒张片功能障碍正常化。离体心脏（3 只 mdx 和 4 只 WT）的钙瞬变光学映射显示，细胞内钙重摄取的可拉伸诱导的区域性缺陷，反映在 mdx 心脏的半衰期（T（50））和衰减常数增加了 25％。mdx 心脏的基底区域也表现出比心尖更多的纤维化，与区域性片功能障碍相匹配。我们的结论是，最初在基底段观察到心肌舒张片功能障碍，并伴有钙处理不当，最终导致纤维化增加。在心脏的其余部分保留相对正常的钙重摄取和舒张/收缩片力学，以及通过降低细胞溶质钙使功能缺陷迅速逆转，这表明局部机械因素在疾病进展中的重要性。
