Bollen Ilse A E, van der Meulen Marijke, de Goede Kyra, Kuster Diederik W D, Dalinghaus Michiel, van der Velden Jolanda
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands.
Department of Pediatric Cardiology, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, Netherlands.
Front Physiol. 2017 Dec 22;8:1103. doi: 10.3389/fphys.2017.01103. eCollection 2017.
Dilated cardiomyopathy amongst children (pediatric cardiomyopathy, pediatric CM) is associated with a high morbidity and mortality. Because little is known about the pathophysiology of pediatric CM, treatment is largely based on adult heart failure therapy. The reason for high morbidity and mortality is largely unknown as well as data on cellular pathomechanisms is limited. Here, we assessed cardiomyocyte contractility and protein expression to define cellular pathomechanisms in pediatric CM. Explanted heart tissue of 11 pediatric CM patients and 18 controls was studied. Contractility was measured in single membrane-permeabilized cardiomyocytes and protein expression was assessed with gel electrophoresis and western blot analysis. We observed increased Ca-sensitivity of myofilaments which was due to hypophosphorylation of cardiac troponin I, a feature commonly observed in adult DCM. We also found a significantly reduced maximal force generating capacity of pediatric CM cardiomyocytes, as well as a reduced passive force development over a range of sarcomere lengths. Myofibril density was reduced in pediatric CM compared to controls. Correction of maximal force and passive force for myofibril density normalized forces in pediatric CM cardiomyocytes to control values. This implies that the hypocontractility was caused by the reduction in myofibril density. Unlike in adult DCM we did not find an increase in compliant titin isoform expression in end-stage pediatric CM. The limited ability of pediatric CM patients to maintain myofibril density might have contributed to their early disease onset and severity.
儿童扩张型心肌病（小儿心肌病，小儿CM）与高发病率和高死亡率相关。由于对小儿CM的病理生理学了解甚少，治疗主要基于成人心力衰竭疗法。高发病率和高死亡率的原因很大程度上未知，细胞病理机制的数据也很有限。在此，我们评估了心肌细胞收缩力和蛋白质表达，以确定小儿CM的细胞病理机制。研究了11例小儿CM患者和18例对照的心脏移植组织。在单个膜通透的心肌细胞中测量收缩力，并用凝胶电泳和蛋白质印迹分析评估蛋白质表达。我们观察到肌丝的钙敏感性增加，这是由于心肌肌钙蛋白I的低磷酸化所致，这是成人扩张型心肌病中常见的特征。我们还发现小儿CM心肌细胞产生最大力的能力显著降低，以及在一系列肌节长度上被动力发展减少。与对照组相比，小儿CM中的肌原纤维密度降低。将最大力和被动力校正为肌原纤维密度后，小儿CM心肌细胞中的力恢复到对照值。这意味着收缩力降低是由肌原纤维密度降低引起的。与成人扩张型心肌病不同，我们在晚期小儿CM中未发现顺应性肌联蛋白异构体表达增加。小儿CM患者维持肌原纤维密度的能力有限，这可能导致了他们疾病的早期发作和严重程度。
