*5.2. Drugs and Small Molecules*

There is currently no cure for DMD, and established small molecule therapy is limited to reducing the symptoms and hindering the mechanisms of disease progression in the heart. One of the predominant small molecules that has been used as a treatment for DMD patients are corticosteroids. Corticosteroids ameliorate the skeletal muscle phenotype with marked improvement in muscle strength and function [134]. Other studies have demonstrated that the use of corticosteroids leads to the stabilization of pulmonary function, prolonged ambulation, and reduced prevalence of scoliosis [135]. Although corticosteroids exhibit more potent effects in skeletal muscle than cardiac muscle, studies show steroids to be protective in the dystrophic heart, with possible benefits including preserved ventricular function, reduction in fibrosis, and improved survival [136–139]. In addition, corticosteroids have been associated with delaying the onset of cardiomyopathy by 4% for each year of treatment [139]. As a result of these documented benefits to skeletal muscle, pulmonary, and cardiac function, a daily regimen with corticosteroids such as deflazacort and prednisone is currently the earliest and most widely used DMD therapy [140]. However, the prolonged use of this drug is not without controversy, with the primary side-effects including reduced bone density, increased adiposity, and increased muscle catabolism [141]. In addition, some concerns stem from preclinical studies providing evidence that steroids may worsen the progression of DMD in the mouse heart [142,143]. Nevertheless, DMD clinical studies are largely in agreement that steroids are likely to be protective in the dystrophic heart, with possible benefits including improved survival, preserved ventricular function, and reductions in fibrosis.

Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) constitute another class of small molecules that have been used as a treatment for DMD patients [144]. Angiotensin II (AngII) and the AngII type 1 receptor (AT1R) exhibit many fundamental effects on the heart, including promoting fibrosis, ROS production, remodeling, and cardiomyocyte death [145–147]. ACE inhibitors are generally implemented when LV systolic dysfunction declines. These inhibitors prevent the conversion of angiotensin-I to angiotensin-II (Ang-II), thereby reducing circulating levels of Ang-II. When angiotensin-II is activated, it stimulates the adrenal cortex to secrete aldosterone, promoting fluid and sodium retention. Both angiotensin-II and aldosterone contribute to the formation of fibrosis and overgrowth of connective tissue in the heart and further complicate the myocardial fibrosis resulting from dystrophin deficiency in DMD patients [148]. Therefore, the use of ACE inhibitors, aldosterone antagonists, and angiotensin receptor blockers (ARBs) has become a significant therapeutic approach for dystrophic cardiomyopathy. ACE inhibitors are a drug class that is often used as the first line of therapy for general heart failure, and was the first drug to be used in trials to demonstrate improved cardiac function and survival among DMD patients [149]. ARBs are equally effective when compared directly to ACEIs and better tolerated by patients, but they are usually utilized as an alternative in cases of poor ACEI tolerance [150].

Beta-blockers are another class of small molecules that are regularly used for the treatment of acquired heart failure, where they are often combined with ACEIs to improve survival and reduce hospitalization rates [151]. Beta-blockers have been considered a candidate for cardiac-directed therapy in DMD aiming to limit β-AR effects. Beta-blockers act by interfering with beta-receptor binding by catecholamines, which leads to a reduction of sympathetic nervous system activity. They are therefore prescribed for arrhythmic patients and those with symptomatic but stable systolic dysfunction. It is

known that combination therapy with ACE and β-adrenergic blocker agents improves the survival of patients with left ventricular dysfunction [152].

A retrospective study demonstrated that DMD patients have improvement in echocardiographic parameters, such as fractional shortening, sphericity index, and left ventricular ejection, after the administration of either ACE inhibitors alone or the combination of both ACE inhibitors and beta-blockers [153]. In a study conducted by Kajimoto and coworkers, patients with different types of muscular dystrophies were assigned to receive either an ACE inhibitor plus a beta-blocker (carvedilol) for at least 2 years or an ACE inhibitor alone (cilazapril or enalapril) for at least 3 years. They observed that the ACE inhibitor treatment alone maintained fractional shortening whereas the combination therapy provided a significant improvement in left ventricular fractional shortening [154]. Studies have also demonstrated that the use of ACE inhibitors in combination with beta -blockers in DMD patients reversed congestive heart failure signs and symptoms, delayed the progression of left ventricular dysfunction, and also improved systolic function [144]. Although some DMD patient studies indicate that beta-blockers have additive effects on cardiac function and survival compared with ACEIs alone, some studies using beta-blockers in DMD cardiomyopathy have shown little effect, making it unclear as to whether these drugs deliver a significant benefit [155,156].

Mineralocorticoid receptor antagonists, such as eplerenone and spironolactone are another class of small molecules that have been used for managing heart failure with low ejection fraction, and are often incorporated into treatment for DMD cardiomyopathy [11]. In a pre-clinical study of DMD cardiomyopathy, the combination of spironolactone and ACEI therapy showed protective effects in both skeletal and cardiac muscle [143]. A recent clinical trial demonstrated that DMD patients with preserved ejection fraction already receiving treatment with an ACEI or ARB showed modest but significant improvements in myocardial strain, ejection fraction, and chamber dilation with eplerenone treatment, compared to those without eplerenone [157].
