*1.2. Dilated Cardiomyopathy in Muscular Dystrophy: Prevalence, Clinical Manifestations*

Duchenne muscular dystrophy (DMD) is the most common and a severe form of muscular dystrophy. It affects approximately 1 in 5000 males [5]. DMD is an X-linked myopathy caused by a mutation in the dystrophin gene resulting in a complete loss of dystrophin protein in striated muscles. Absence of dystrophin leads to disruption of the dystrophin-associated glycoprotein complex (DGC), which connects the cytoskeleton to the extracellular matrix and contributes to force transmission. Dystrophin is essential for stabilization of the sarcolemma. In DMD, loss of dystrophin leads to a fragile sarcolemma susceptible to stress-induced damage, resulting in myocyte death and progressive muscle wasting [6]. Early signs of muscle weakness in children affected with DMD generally occur between the ages of three and five. Muscle weakness initially involves the proximal muscles (Gowers' sign), followed by distal skeletal muscle groups (limbs and trunk). DMD is progressive, and in the absence of appropriate treatment and care, affected individuals typically lose ambulation by age 10–12 [7].

Until more recently, early loss of mobility and respiratory complications in DMD patients obscured symptoms of cardiac involvement. Over the past two decades, clinical advancements in respiratory assistance [8,9], implementation of anti-inflammatory drugs, and emerging muscle-targeted therapies led to improvement of activity levels, extended ambulation, and increased longevity in the DMD population. This, in turn, revealed cardiomyopathy as a major cause of morbidity and mortality in DMD patients [10–12]. It is estimated that 25% of boys have cardiomyopathy at 6 years of age and 59% by 10 years of age [13]. Cardiac involvement becomes highly prominent as DMD boys advance in age, with more than 90% of young men over 18 years of age having evidence of significant cardiac dysfunction [13].

The development of dilated cardiomyopathy in DMD is a consequence of multiple mechanisms, and a complete understanding of the pathophysiology has not been elucidated. The elevation of plasma creatine kinase (CK) is a hallmark of DMD, indicating that there is increased permeability of the plasma membrane, allowing soluble enzymes to leak out of the muscle cell [14–16]. The absence of dystrophin disrupts force transmission and causes contraction-induced sarcolemma damage and membrane permeability that allows an influx of calcium, triggering death of the myocyte [14–16]. The mechanisms that lead to increased permeability of the plasma membrane are not fully understood; however, it is widely acknowledged that increased calcium influx and calcium overload contribute to the molecular progression of the disease [17–20]. In the earlier stages of disease, compensatory mechanisms have been noted. In particular, an increase in calcium transient amplitude, increased sarcoplasmic reticulum calcium load and leak, and a reduced cardiac reserve are reported in animal models [21,22]. In the later decompensated stage, DMD cardiomyopathy presents as DCM, characterized by enlarged ventricles, reduced systolic function, decreased calcium transients, reduced cardiac wall thickness, and cardiac arrhythmias [3,23].
