Кардиология

УДК 616.74–007.17−053.1−06:616.127
https://doi.org/10.30702/card:sp.2018.09.033/07

Shirokova N.¹, Niggli E.²

¹Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, USA
²Department of Physiology, University of Bern, Bern, Switzerland

Brief abstract. Duchene Muscular Dystrophy (DMD) is a lethal, X-linked muscle wasting disease with serious cardiac complications. This review article summarizes recent findings on the cellular pathophysiology of dystrophic cardiomyopathy, identifies novel potential therapeutic targets and describes several novel pharmacological agents and genetic approaches that aim to slow down the progression of the disease.

Keywords: dystrophic cardiomyopathy; Ca²⁺ and redox signaling; mitochondria; pharmacological targets; gene therapy.

Introduction

Duchenne Muscular Dystrophy (DMD) is an inherited lethal muscular disease that affects 1 in 3500–6000 live male births. DMD was named after the French physiologist Guillaume-Benjamin Duchenne who presented several cases of infants with dystrophy in the mid 19th century. DMD occurs as a result of an inherited or spontaneous out-of-frame mutation (manly deletions) in dystrophin gene. Mutations lead to the absence of or a defect in the protein dystrophin [1].

Most patients are diagnosed at approximately 5 years of age, when they start to show signs of physical disabilities including walking problems. Later they manifest progressive systemic muscle weakness and become wheelchair dependent before their teens. For a long time DMD was considered to be predominantly a skeletal muscle illness clinically associated with skeletal deformities and breathing disorders. However, myocardial involvement is inevitable in DMD patients as dystrophin serves similar functions in both skeletal and cardiac muscles. The reduction of respiratory disease-related deaths, due to nocturnal ventilation and spinal stabilization, has contributed to the relative increase of DMD cardiomyopathy. Cardiac dysfunction is therefore an increasingly more common cause of death for individuals with DMD [2].

The incidence of cardiomyopathy in DMD increases with age. Whereas about 25 % of boys have cardiac abnormalities at 6 years of age, more than 90 % of young men over 18 years of age exhibit cardiac dysfunction [3]. Pathological changes of the myocardium in DMD patients are quite heterogeneous and probably result from combination of cardiac atrophy and myocardial remodeling. Abnormalities in the electrocardiogram and sinus tachycardia are found in many DMD patients at early age. Later, echocardiography reveals motion abnormalities of the ventricular walls in areas of fibrosis. Progressive and aggressive spreading of fibrosis mediates a gradual enlargement of the ventricle, thinning of the ventricular wall and consequently a loss of contractility and heart failure. More than 40 % of DMD patients also develop arrhythmias that may lead to a sudden death [4–6].

Further extension of survival and amelioration in the quality of life for DMD patients depends not only on improving skeletal muscle performance but also on the development of therapies that enhance cardiac function. This requires a mechanistic understanding of the nature ofthe cardiac defects. In this reviewarticle we discuss the current view of cellular and molecular pathomechanisms of the dystrophic cardiomyopathy that finally determine the clinical phenotype.