Multimodal assessment of cardiomyopathy in muscular dystrophy using a combined PET-CMR approach

肌营养不良症（MD）是由肌营养不良蛋白基因突变引起的遗传性孤儿性肌原性疾病。高达90%的MD患者因进行性扩张型心肌病（DCM）导致心衰，并以心肌纤维化/损伤（主要发生在左心室（LV）游离壁）为标志。因此，心脏病——包括心源性猝死——是这些患者死亡的主要原因。MD患者左室心肌纤维化特征性非缺血性模式的详细病理机制尚不清楚。潜在的遗传肌营养不良蛋白缺陷可能导致心肌细胞的结构异常，易导致代谢变化和随后对机械应力的过度易感性。此外，我们怀疑肌营养不良蛋白缺陷的漏性心肌细胞释放细胞因子引发冠状动脉微血管痉挛，进而导致进一步的心肌损伤（局灶性水肿），从而导致细胞因子释放进一步增加、随后的痉挛和加速心肌损伤的恶性循环。相应的形态学改变始于左室后外侧壁，在额外的机械应力下进一步加剧，并可能在后期涉及其他心肌区域。目前，药物治疗的目的是改善营养不良蛋白损伤的后果，但效果有限，或者直接纠正营养不良蛋白损伤（例如通过实验性基因治疗）。然而，众所周知，与相应的动物模型（例如mdx小鼠）相比，MD患者心肌病发展的机制不同。这构成了研究人类MD心肌病分子病因学以及进行适当的临床前药物测试的主要障碍。该项目的目的是在MD患者中进行一项全面的试点研究，并通过同时多参数PET-CMR研究心肌代谢、冠状动脉微循环、心肌水肿和心肌纤维化（区域和全球）变化的因果关系和时间关系。将这些发现与血液标本和心肌活检分析（重点关注miRNA谱）联系起来，并开发一个平台，用于识别和测试未来MD患者的新治疗方法。

Muscular dystrophies (MD) are inherited orphan myogenic disorders caused by mutations in the dystrophin gene. Up to 90% of MD patients suffer from heart failure due to progressive dilated cardiomyopathy (DCM) with myocardial fibrosis/damage - predominantly in the left ventricular (LV) free wall - as a hallmark. Hence, cardiac disease - including sudden cardiac death - represents the leading cause of mortality in these patients. The detailed pathomechanism leading to a characteristic, non-ischemic pattern of LV myocardial fibrosis in MD patients is still unclear. The underlying genetic dystrophin defect may cause structural abnormalities in cardiomyocytes which predispose to metabolic changes and subsequent excessive susceptibility to mechanical stress. In addition, it is suspected that cytokine release by dystrophin-deficient leaky cardiomyocytes triggers coronary microvascular spasm which in turn leads to further myocardial damage (focal edema) thereby resulting in a vicious circle of further increased cytokine release, subsequent spasm and accelerated myocardial damage. The respective morphological changes start in the LV posterolateral wall, are further aggravated by additional mechanical stress and may involve other myocardial regions at a later stage. Currently, pharmacological treatment aims at ameliorating the consequences of the dystrophin impairment with limited effectivity, or by correcting the dystrophin impairment directly (e.g. by experimental gene therapies). However, it is well known that different mechanisms underlie the development of cardiomyopathy in MD patients compared to the respective animal models (e.g. the mdx mouse). This constitutes a major hurdle for studying the molecular etiology of human MD cardiomyopathy as well as for conducting appropriate preclinical drug testing. The objectives of this project are to perform a comprehensive pilot study in MD patients and to investigate the causal and temporal relationship of changes in myocardial metabolism, coronary microcirculation, myocardial edema as well as myocardial fibrosis (regionally and globally) by simultaneous multi-parametric PET-CMR, to correlate these findings to analyses of blood specimens and of myocardial biopsies (focusing amongst others on miRNA profiles) and to develop a platform for identifying and testing novel therapeutic approaches in patients with MD in the future.