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

• Applicants: Professor Dr. Lars Stegger; Professor Dr. Ali Yilmaz
• Subject Area: Cardiology, Angiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399570893

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.

• DFG Programme: Research Grants