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Background: Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure., Objectives: The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies., Methods: To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models., Results: At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy., Conclusions: The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Myocardial fibrosis identified by apical core pathology at the time of left ventricular assist device (LVAD) implantation may add information regarding myocardial recovery potential. In this analysis, we report the prevalence of myocardial fibrosis by cardiomyopathy type and its association with other known markers of left ventricular recovery. Left ventricular assist device core pathology was reviewed on 332 patients who underwent LVAD implantation at a single institution between 2005 and 2016. Baseline clinical and echocardiographic characteristics were compared among patients with and without myocardial fibrosis by cardiomyopathy type. Among the 332 LVAD core specimens, myocardial fibrosis was present in 79%. Myocardial fibrosis was more common in ischemic than in nonischemic patients (90% vs. 66%; p < 0.001). Patients with fibrosis were older than those without (58 ± 12 vs. 55 ± 19; p < 0.05). Among the nonischemic cardiomyopathy cases, those with fibrosis were more likely to have an implantable cardioverter defibrillator (ICD) 81% and to be diabetic 81%. Fibrosis was not associated with left ventricular end-diastolic diameter (LVEDD), creatinine, or N-terminal prohormone of brain natriuretic peptide (NT-pro BNP). Myocardial fibrosis by apical core biopsy correlated with several known markers of left ventricular recovery including cardiomyopathy type, age, and presence of an ICD. In nonischemic cardiomyopathy patients, the degree of myocardial fibrosis may add information regarding recovery potential.

Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Inherited cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathies, arrythmogenic right ventricular cardiomyopathy, and other inherited forms of heart failure, represent a unique set of genetically defined cardiovascular disease processes. Unraveling the molecular mechanisms of these deadly forms of human heart disease has been challenging, but recent groundbreaking scientific advances in stem cell technology have allowed for the generation of patient-specific human inducible stem cell (hiPSC)-derived cardiomyocytes (CMs). hiPSC-derived CMs retain the genetic blueprint of the patient, they can be maintained in culture, and they recapitulate the phenotypic characteristics of the disease in vitro, thus serving as a disease in a dish. This review provides an overview of in vitro modeling of inherited cardiomyopathies with the use of patient-specific hiPSC-derived CMs., (Copyright © 2015. Published by Elsevier Inc.)

Background Myotonic dystrophies (DM) are multi-systemic diseases characterized by muscle weakness and myotonia. Despite a growing appreciation for the cardiovascular manifestations in myotonic dystrophy type 1 (DM1), cardiac involvement in myotonic dystrophy type 2 (DM2) has been less well characterized. In patients with DM2, cardiomyopathy has rarely been described. Case summary This case report describes a rare case of DM2 associated cardiomyopathy. A 56-year-old male with DM2 who presented with palpitations and fatigue. Cardiac magnetic resonance (CMR) imaging confirmed a severely enlarged left ventricular cavity with a left ventricular ejection fraction of 28% consistent with severely reduced global systolic function. The lateral wall epicardium exhibited late gadolinium enhancement in a pattern seen in myotonic dystrophy-related cardiomyopathy. Discussion This case highlights the potential for significant cardiovascular involvement in DM2, as well as the importance of screening, including CMR imaging, and therapy in the myotonic dystrophy patient population. [ABSTRACT FROM AUTHOR]