Clinical Management of DMD-Associated Cardiomyopathy

Over the past decade, cardiomyopathy has become the leading cause of mortality among patients with Duchenne muscular dystrophy (DMD). The majority of DMD patients over the age of 18 experience some degree of cardiac involvement. The primary cardiac manifestations of DMD include progressive left ventricular (LV) wall stress leading to LV dilatation and wall thinning, and the development of cardiac fibrosis, all of which culminate in decreased LV contractility and reduced cardiac output. Mortality in these patients is predominantly related to pump failure and fatal arrhythmias leading to sudden cardiac death. While basic guidelines for the management of cardiomyopathy in DMD patients exist, these recommendations are by no means comprehensive, and this chapter aims to provide further insight into appropriate clinical diagnosis and management of DMD-associated cardiomyopathy. Notably, earlier and more frequent cardiac assessment and care can allow for better outcomes for these patients. Pharmacological treatments typically include an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, beta-adrenergic receptor blockers, mineralocorticoid receptor antagonists, and corticosteroids. Non-pharmacological therapies include automated implantable cardioverter defibrillators and left ventricular assist devices, as well as in rare cases cardiac transplantation. Additionally, many emerging therapies show great promise for improving standards of care. These novel therapies, based primarily on applied gene therapy and genome editing, have great potential to significantly alter the DMD care landscape in the near future

Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes*

Cardiac hypertrophy develops in response to a variety of cardiovascular stresses and results in activation of numerous signaling cascades and proteins. In the present study, we demonstrate that cytoglobin is a stress-responsive hemoprotein in the hypoxia-induced hypertrophic myocardium and it is transcriptionally regulated by calcineurin-dependent transcription factors. The cytoglobin transcript level is abundantly expressed in the adult heart and in response to hypoxia cytoglobin expression is markedly up-regulated within the hypoxia-induced hypertrophic heart. To define the molecular mechanism resulting in the induction of cytoglobin, we undertook a transcriptional analysis of the 5′ upstream regulatory region of the cytoglobin gene. Evolutionarily conserved binding elements for transcription factors HIF-1, AP-1, and NFAT are located within the upstream region of the cytoglobin gene. Transcriptional assays demonstrated that calcineurin activity modulates cytoglobin transcription. Increased calcineurin activity enhances the ability of NFAT and AP-1 to bind to the putative cytoglobin promoter, especially under hypoxic conditions. In addition, inhibition of calcineurin, NFAT, and/or AP-1 activities decreases endogenous cytoglobin transcript and protein levels. Thus, the regulation of cytoglobin transcription by calcineurin-dependent transcription factors suggests that cytoglobin may have a functional role in calcium-dependent events accompanying cardiac remodeling