*6.2. DCM with Mid-Range Reduction of LVEF*

Few studies have been addressed for DMD patients with mid-range systolic LV dysfunction.

Current indication endorses the use of traditional HF treatment to treat the progression of the disease. In detail, for mid-range ventricular dysfunction, some studies have shown some beneficial effect to preserve ventricular function. Among ACE inhibitors, lisinopril and losartan have been used for comparative analysis in established DCM. Allen 2013 [51] compared the effects of lisinopril (an ACEi) 0.07 mg/kg (5 mg/day) with losartan (an ARB) 0.7 mg/kg (25 mg/day) in a randomized, double-blind, controlled trial of 22 DMD patients. Interestingly, if the LVEF decreased by 5 to 10% the initial dose was doubled. This trial showed no significant difference between lisinopril and losartan in preserving or improving ventricular function.

Cardioprotective effect of adding eplerenone to an ACE inhibitor or ARB was evaluated by MRI after 12 months in 42 DMD patients. This multicenter, randomized, placebo-controlled trial, Raman et al. [35] showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain and LVEF at 12 months, when compared to the placebo group.

Raman et al. showed that also spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk [52].

Therefore, at the early stage of the disease, before any clinical overt DCM, the prophylactic use of perindopril for cardioprotection is entered widely in the clinical practice and endorsed by current indication although biological effects are still unclear. When the DCM is detectable even in case of mild reduction of ejection fraction (>45% LVEF), fosinopril or losartan with the combination of mineralocorticoid receptor antagonists (i.e., eplerenone) might improve ventricular function.

In addition, beta blockers (BB) have been tested. Carvedilol was administered in 22 patients and was progressively uptitrated over 8 weeks. This therapy modestly improved cardiac MRI-derived measured ejection fraction (41% +/− 8.3% to 43% +/− 8%; *p* < 0.02), as well as the mean rate of pressure rise (dP/dt) during isovolumetric contraction (804 +/− 216 to 951 +/− 282 mmHg/s; *p* < 0.05) and the myocardial performance index (0.55 +/− 0.18 to 0.42 +/− 0.15; *p* < 0.01) [53].

#### *6.3. Patients with Severe Ventricular Dysfunction*

While in recent years, many studies have focused on the early identification of myocardial damage and the early start of cardiac therapy capable of slowing cardiac remodeling has been emphasized in DMD, the therapeutic strategy for patients with established DCM has been studied less deeply [3,16,54]. Current indication recommends all drugs used for HF treatment.

Although in adult HF, the use of betablockers is mandatory when ventricular function declines, the same evidence in children is lacking. In recent years, some retrospective and non-randomized prospective studies have demonstrated the beneficial effect of BB therapy in patients with DMD/DCM [52,55–58], while in some others this positive effect was not observed [59,60]. Although most of the studies are retrospective including various ages, BB in adjunct to ACEi showed to improve 5-year and 7-year survival rates [58], and also improving ventricular function [56]. These conflicting results have contributed to variable and often delayed initiation of BB use in DMD. However, BBs are usually added to ACEi/ARB when a sufficient improvement in cardiac function is not achieved with the initial therapy.

Furthermore, in DMD DCM, this therapy is often indicated for the presence of autonomic dysfunction and the consequent predisposition to arrhythmias [61].

In the current literature the drugs most frequently used are Carvedilol (0.01–0.02 mg/kg administered twice daily and slowly increased to a dose of 0.5–1 mg/kg) [53,55–57,59], Bisoprolol (3–4 mg per day) [58], and Metoprolol (1 to 2 mg/kg/day) [55,60].

In many studies the combination therapy with ACEi and BBs has been proved to be superior to ACEi alone in the improvement of LV function, [53,56] in the prevention of major cardiac events (death, deterioration of HF, and severe arrhythmias) [57] and in long-term survival [58].

It was noted that in patients treated with BBs the improvement of LVEF was correlated with the reduction of mean heart rate (HR) [57].

#### *6.4. End Stage of DCM DMD*

Our group has recently demonstrated the utility of the HR reduction (HRR) strategy obtained with BBs and Ivabradine (2.5 mg twice daily increasing until 15 mg daily every two weeks when HR was still above 70 bpm and LVEF < 40%) in the reduction of the long-term incidence of acute adverse events in DMD patients with advanced cardiac involvement [62]. Previously, ivabradine had been proven to be effective in reducing HR and in improving LVEF in a multicenter, randomized, placebo-controlled trial in children with DCM and symptoms of HF. Unfortunately in this trial DMD patients were excluded and a follow-up of only six months was considered [63].

According to European and American Guidelines for the management of HF in adults, MRAs, spironolactone, and eplerenone, are recommended in all symptomatic patients (despite treatment with an ACEI and BB) with HF and LVEF ≤ 35%, to reduce mortality and HF hospitalization [49,64].

In the near future a new MRA called vamorolone, able to mirror the anti-inflammatory effect of glucocorticoids, probably could be a valid alternative to both "old MRAs" and "simple glucocorticoids" in the DMD therapy scenario [65]. To date there are no studies about the use of MRAs in advanced phase of DCM in DMD patients. Despite this, eplerenone or spironolactone are currently used in these patients, at the discretion of the cardiologist, in addition to therapy with ACEi and BB, as long as they do not have renal insufficiency and hyperkalemia.

Sacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that in the past decade has changed the treatment of adult HF, has recently been approved by the Food and Drugs Administration (FDA) for the treatment of pediatric patients (aged 1 to 18 years) with symptomatic HF and systemic LV systolic dysfunction. This approval was based on the major reduction in the value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) that was observed in sacubitril/valsartan arm compared to enalapril one after 12 weeks of therapy from the ongoing 52-week PANORAMA-HF trial [66]. Of note, DMD patients are included in the trial.

#### *6.5. Symptomatic Drugs*

Furosemide is the most common loop diuretic used to reduce systemic and pulmonary congestion and the correlated symptoms in the advanced stage of disease. For chronic use, 1 to 6 mg/kg of frusemide in partitioned doses are used. The addition of metolazone (0.1 mg/kg dose bis-in-die up to max 20 mg/day) may be useful in patients who are unresponsive to loop diuretic agents alone [67].

It is important to remark that loop diuretics are symptomatic medications and there is no evidence of their effectiveness in improving long-term prognosis [68].

Digoxin has been a pivotal drug in the treatment of HF in children and also reported as standard therapy for treatment of DCM DMD [5]. Today its use has decreased significantly in favor of more effective and safe drugs such ACEi and BBs [67,69].

In patients with severe LV dysfunction an antithrombotic therapy should be considered in the primary prevention of thromboembolic events, although not routinely recommended [70].

#### **7. Advanced Cardiac Therapies**
