Comprehensive evaluation of structural and functional myocardial impairments in Becker muscular dystrophy using quantitative cardiac magnetic resonance imaging.

AIMS: Becker muscular dystrophy (BMD) is a genetic neuromuscular disease characterized by an alteration of the dystrophin protein. Myocardial involvement is frequent, eventually progressing to a dilated cardiomyopathy, and represents the most common cause of death for this pathology. We performed a comprehensive evaluation of myocardial functional and structural alterations encountered in a large cohort of BMD patients using quantitative cardiac magnetic resonance (CMR) imaging. METHODS AND RESULTS: Eighty-eight BMD patients and 26 age-matched volunteers underwent standard cine and tag imaging to assess myocardial function and dyssynchrony, while native T1, T2, and extracellular volume fraction (ECV) were measured for tissue characterization. The left ventricular ejection fraction (LV-EF) was significantly reduced in 26% of the BMD patients. Patients exhibited higher dyssynchrony index than controls (6.94 ± 3.17 vs. 5.09 ± 1.25, P = 0.005). Diastolic dyssynchrony also exists in patients where systolic function was normal. BMD subjects, compared with controls, had significantly higher native T1, T2, and ECV (1183 ± 60 ms vs. 1164 ± 22 ms, 47.5 ± 4.5 ms vs. 45.6 ± 3.4 ms, 0.282 ± 0.050 vs. 0.231 ± 0.027, respectively, P < 0.05). Native T1, T2, and ECV correlated with LV-EF (R = -0.79, -0.70, and -0.71, respectively, P < 0.001) and N-terminal-pro brain natriuretic peptide (R = 0.51, 0.58, and 0.44, respectively, P < 0.001). CONCLUSION: Quantitative CMR represents a powerful tool to evaluate structural and functional impairments in the myocardium of BMD subjects. Native T1, T2, and ECV provided quantitative biomarkers related to inflammation and fibrosis, and could stratify disease severity.

Characterization of Benign Myocarditis Using Quantitative Delayed-Enhancement Imaging Based on Molli T1 Mapping.

Delayed contrast enhancement after injection of a gadolinium-chelate (Gd-chelate) is a reference imaging method to detect myocardial tissue changes. Its localization within the thickness of the myocardial wall allows differentiating various pathological processes such as myocardial infarction (MI), inflammatory myocarditis, and cardiomyopathies. The aim of the study was first to characterize benign myocarditis using quantitative delayed-enhancement imaging and then to investigate whether the measure of the extracellular volume fraction (ECV) can be used to discriminate between MI and myocarditis.In 6 patients with acute benign myocarditis (32.2 ±â€Š13.8 year-old, subepicardial late gadolinium enhancement [LGE]) and 18 patients with MI (52.3 ±â€Š10.9 year-old, subendocardial/transmural LGE), myocardial T1 was determined using the Modified Look-Locker Imaging (MOLLI) sequence at 3 Tesla before and after Gd-chelate injection. T1 values were compared in LGE and normal regions of the myocardium. The myocardial T1 values were normalized to the T1 of blood, and the ECV was calculated from T1 values of myocardium and blood pre- and post-Gd injection.In both myocarditis and MI, the T1 was lower in LGE regions than in normal regions of the left ventricle. T1 of LGE areas was significantly higher in myocarditis than in MI (446.8 ±â€Š45.8 vs 360.5 ±â€Š66.9 ms, P = 0.003) and ECV was lower in myocarditis than in MI (34.5 ±â€Š3.3 vs 53.8 ±â€Š13.0 %, P = 0.004).Both inflammatory process and chronic fibrosis induce LGE (subepicardial in myocarditis and subendocardial in MI). The present study demonstrates that the determination of T1 and ECV is able to differentiate the 2 histological patterns.Further investigation will indicate whether the severity of ECV changes might help refine the predictive risk of LGE in myocarditis.

Ca2+ overload and mitochondrial permeability transition pore activation in living delta-sarcoglycan-deficient cardiomyocytes.

Muscular dystrophies are often associated with significant cardiac disease that can be the prominent feature associated with gene mutations in sarcoglycan. Cardiac cell death is a main feature of cardiomyopathy in sarcoglycan deficiency and may arise as a cardiomyocyte intrinsic process that remains unclear. Deficiency of delta-sarcoglycan (delta-SG) induces disruption of the dystrophin-associated glycoprotein complex, a known cause of membrane instability that may explain cardiomyocytes cytosolic Ca2+ increase. In this study we assessed the hypothesis that cytosolic Ca2+ increase triggers cardiomyocyte death through mitochondrial Ca2+ overload and dysfunction in the delta-SG-deficient CHF147 hamster. We showed that virtually all isolated CHF147 ventricular myocytes exhibited elevated cytosolic and mitochondrial Ca2+ levels by the use of the Fura-2 and Rhod-2 fluorescent probes. Observation of living cells with Mito-Tracker red lead to the conclusion that approximately 15% of isolated CHF147 cardiomyocytes had disorganized mitochondria. Transmission electron microscope imaging showed mitochondrial swelling associated with crest and membrane disruption. Analysis of the mitochondrial permeability transition pore (MPTP) activity using calcein revealed that mitochondria of CHF147 ventricular cells were twofold leakier than wild types, whereas reactive oxygen species production was unchanged. Bax, Bcl-2, and LC3 expression analysis by Western blot indicated that the intrinsic apoptosis and the cell death associated to autophagy pathways were not significantly activated in CHF147 hearts. Our results lead to conclusion that cardiomyocytes death in delta-SG-deficient animals is an intrinsic phenomenon, likely related to Ca2+-induced necrosis. In this process Ca2+ overload-induced MPTP activation and mitochondrial disorganization may have an important role.

Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.

Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.