enalapril and Muscular-Dystrophy--Duchenne

X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function.. Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting.. DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events.. From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed.. Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size.. DRKS-number 00000115, EudraCT-number 2009-009871-36.

Topics: Adolescent; Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Child; Double-Blind Method; Enalapril; Female; Humans; Kaplan-Meier Estimate; Male; Metoprolol; Muscular Dystrophy, Duchenne; Treatment Outcome; Ventricular Dysfunction, Left

Inhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5 mg/kg enalapril i.p. for 4-8 weeks have been compared with those of 1 mg/kg α-methyl-prednisolone (PDN), as positive control. Enalapril caused a dose-dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5 mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-β1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest the ability of enalapril to blunt angiotensin-II dependent activation of pro-inflammatory and pro-oxidant pathways which may be earlier events with respect to the pro-fibrotic ones, and may in part account for both functional impairment and muscle necrosis. The PDN-like profile may corroborate the combined use of the two classes of drugs in DMD patients so to potentiate the beneficial effects at skeletal muscle level, while reducing both spontaneous and PDN-aggravated cardiomyopathy.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Humans; Male; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Oxidative Stress

So far, a beneficial effect of combined angiotensin-converting enzyme inhibitors (ACEI) and β-blocker therapy for systolic dysfunction in Duchenne muscular dystrophy (DMD) has been reported only in patients in whom DMD was due to deletions in the dystrophin gene.. In a 24-year-old male with DMD due to the point mutation c.4213C>T (p.Gln1405X) in exon 30 of the dystrophin gene, cardiologic examination at the age of 23 years revealed asymptomatic severely reduced systolic dysfunction with a fractional shortening of 14% in the absence of dilated cardiomyopathy. A combined therapy with enalapril (2.5 mg/day) and bisoprolol (1.25 mg/day) was initiated. After a slow increase in the dosage to 10 mg enalapril/day and 2.5 mg bisoprolol/day, systolic dysfunction resolved to a fractional shortening of 26% already after 7 months.. This case shows that asymptomatic reduced systolic function also in patients with DMD due to a point mutation responds favourably to a combination therapy with ACEI and β-blockers.

Topics: Adult; Antihypertensive Agents; Bisoprolol; Drug Therapy, Combination; Enalapril; Humans; Male; Muscular Dystrophy, Duchenne; Point Mutation; Systole; Treatment Outcome; Ventricular Dysfunction, Left

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Child; Enalapril; Humans; Muscular Dystrophy, Duchenne; Ventricular Dysfunction, Left; Ventricular Function, Left

The role of angiotensin-converting enzyme inhibitors in the management of cardiomyopathy related to Duchenne muscular dystrophy has not been completely defined. The purposes of this study were to describe the response to enalapril and its relation to dystrophin mutation type, ventricular size, or age at the onset of left ventricular (LV) systolic dysfunction. Serial clinical and echocardiographic data from 50 patients with Duchenne muscular dystrophy (aged 10 to 20 years) were retrospectively reviewed. Twenty-seven patients (46%) developed LV systolic dysfunction (mean age 13.2 +/- 2.4 years). Ten (43%) responded to enalapril with the normalization of function. Responders and nonresponders developed LV systolic dysfunction at similar ages (p = 0.91). At the onset of LV systolic dysfunction, only 2 patients (1 responder, 1 nonresponder) had dilated left ventricles. The positive response to enalapril was sustained in 7 patients (median follow-up 23 months, range 5 to 58). No specific mutation was associated with the response to enalapril (p = 0.66) or predictive of the development of LV systolic dysfunction (p = 0.8). In conclusion, 10 of 26 patients (43%) with Duchenne muscular dystrophy responded to the use of enalapril with normalization of the shortening fraction. Age at the onset of LV systolic dysfunction and the type of mutation were not predictors of response to enalapril.

Topics: Adolescent; Age of Onset; Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathies; Child; Dystrophin; Enalapril; Humans; Muscular Dystrophy, Duchenne; Mutation; Ventricular Dysfunction, Left; Ventricular Function, Left

This study was performed to determine whether I-123 metaiodobenzylguanidine (MIBG) scintigraphy can depict myocardial sympathetic nerve abnormalities in Becker muscular dystrophy.. A 34-year-old man with Becker muscular dystrophy underwent Tl-201 and I-123 MIBG scintigraphy sequentially before and 4 months after the beginning of oral administration of enalapril maleate, an angiotensin-converting enzyme inhibitor.. Before and during treatment, stress Tl-201 scintigraphy revealed nonreversible myocardial perfusion defects in the anterior, inferoposterior, and apical walls, and I-123 MIBG scintigraphy depicted a region with decreased sympathetic nerve function or innervation. Before treatment, the I-123 MIBG heart count- mediastinum count (H:M) ratio was 2.1 and the washout rate was 21% on delayed images obtained 4 hours after the injection of I-123 MIBG, indicating hyperactivity of the sympathetic nervous system in the myocardium. During treatment, the H:M ratio was 3.0 and the washout rate was 15%.. With I-123 MIBG scintigraphy it is possible to evaluate an abnormality of the myocardial sympathetic nervous system and the efficacy of administration of an angiotensin-converting enzyme inhibitor in this disease.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System Diseases; Enalapril; Exercise Test; Follow-Up Studies; Heart; Humans; Iodine Radioisotopes; Iodobenzenes; Male; Muscular Dystrophy, Duchenne; Radionuclide Imaging; Sensitivity and Specificity; Severity of Illness Index