cardiovascular-agents and Muscular-Dystrophy--Duchenne

The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further.. To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months.. On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies.. We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months.. Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria.. We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between. Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.

Topics: Adolescent; Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiovascular Agents; Child; Disease Progression; Eplerenone; Human Growth Hormone; Humans; Lisinopril; Losartan; Male; Muscular Dystrophy, Duchenne; Non-Randomized Controlled Trials as Topic; Perindopril; Placebos; Randomized Controlled Trials as Topic; Stroke Volume; Ubiquinone; Young Adult

Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (δ-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na

Topics: Animals; Calcium; Cardiomyopathies; Cardiovascular Agents; Disease Models, Animal; Heart Failure; Humans; Hydrogen-Ion Concentration; Ion Channels; Muscular Dystrophy, Duchenne; Myocardium; Signal Transduction; Sodium; Sodium-Hydrogen Exchanger 1

Mutations in either the nuclear or the mitochondrial genome can lead to structural and functional changes within the skeletal muscles. These genetic skeletal myopathies are rare, although not infrequent when their cumulative incidence is considered. Dystrophinopathies (Duchenne and Becker muscular dystrophies) and mitochondrial disease are some of the most frequent clinical entities, and those developing heart failure more frequently. Neurohormonal antagonism represents the cornerstone of heart failure management, even though its role in the prevention and treatment of heart failure in patients with dystrophinopathies or mitochondrial disorders remains undefined. In the present paper we will summarise current available evidence on this topic. Particular attention will be devoted to Duchenne muscular dystrophy, and to the approaches modulating neurohormonal function by targeting the skeletal muscle.

Topics: Cardiovascular Agents; Disease Management; Heart Failure; Humans; Mitochondrial Diseases; Muscle, Skeletal; Muscular Dystrophy, Duchenne

Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies. In addition to muscle disease, there nearly always is an associated cardiomyopathy in Duchenne or Becker muscular dystrophy. In these muscular dystrophies, the severity of cardiomyopathy and congestive heart failure may not parallel the severity of skeletal muscle disease. Loss of normal dystrophin function in the heart produces four-chamber dilation and reduction in left ventricular function that develop after the onset of muscle weakness. Arrhythmias affecting both atrial and ventricular rhythms occur and may be life threatening. The degree to which hypoventilation and pulmonary dysfunction are present also directly affect cardiac function in muscular dystrophy. Care guidelines recently were issued to outline surveillance and treatment strategies for the younger patient with Duchenne muscular dystrophy. Herein, we review those guidelines, and additionally, provide recommendations for monitoring and treating cardiac disease in the populations of advanced Duchenne and Becker muscular dystrophies.

Topics: Arrhythmias, Cardiac; Cardiac Resynchronization Therapy; Cardiomyopathy, Dilated; Cardiovascular Agents; Defibrillators, Implantable; Disease Progression; Dystrophin; Genes, X-Linked; Heart Transplantation; Humans; Male; Monitoring, Physiologic; Muscular Dystrophy, Duchenne; Myocardium

End-stage dilated cardiomyopathy (DCM) is the leading cause of morbidity and mortality in patients with Duchenne Muscular Dystrophy (DMD). No studies are available on the effect of ivabradine on long-term outcomes in end-stage DMD/DCM.. We prospectively enrolled a cohort of end-stage DMD/DCM patients with LV ejection fraction <40%, on chronic HF treatment with an ACE inhibitor referred consecutively from 2012 to 2017 to Bambino Gesù Children's Hospital. In each patient, before starting HRR strategy and after 1 year, we collected medical records comprehensive of clinical, demographic and imaging parameters, BNP levels, neurological and respiratory assessment.. Twenty male patients with DMD/DCM with a mean age of 15.0 ± 3.5 (13-19 IQR) years were enrolled and divided into 2 groups according to ivabradine therapy. This group showed a higher incidence of MACEs compared to others in treatment with ivabradine (87.5% vs 12.5%, p = 0.025). At Kaplan Meier survival analysis curves, the rate free from MACEs was higher in patients treated with ivabradine (log rank p = 0.017). At multivariate Cox regression analysis, ivabradine therapy was an independent predictor of freedom from MACEs (H.R. 0.078, 95% CI 0.007-0.877, p = 0.039).. HRR strategy, whether achieved by beta blockers alone or in combination with ivabradine, seemed to be effective in reducing the incidence of acute adverse events, reaching optimal target heart rate and improving left ventricular function in DMD/DCM patients.

Topics: Adolescent; Adult; Cardiomyopathies; Cardiovascular Agents; Cohort Studies; Follow-Up Studies; Heart Rate; Humans; Ivabradine; Magnetic Resonance Imaging, Cine; Male; Muscular Dystrophy, Duchenne; Pilot Projects; Prospective Studies; Young Adult

The majority of patients with Duchenne muscular dystrophy (DMD) have electrocardiographic abnormalities, but the clinical significance of conduction disturbances remains unclear. This study aimed to evaluate age-dependent cardiac conduction disturbances by electrocardiogram (ECG) to identify risks of complete atrioventricular (AV) block in this patient population.In total, 47 patients with DMD (age, ≥20 ys) who recorded ECGs at our hospital from July 2015 to June 2016 were included in this study. The PR interval and QRS duration in their previous ECGs were analyzed retrospectively. Associations between ECG findings and left ventricular (LV) systolic function obtained from the latest echocardiography were examined.The mean age of patients was 27.6 ± 6.0 years, and the mean observation period was 9.8 ± 3.7 years. The PR interval gradually increased with age, but no ECGs showed an abnormally prolonged PR interval. On the other hand, the QRS duration tended to increase progressively with age, and some patients had an abnormally prolonged QRS duration. The QRS duration was not correlated with LV systolic function (P = 0.867). One patient who developed a complete AV block had a drastically prolonged QRS duration before the onset of the disorder.The QRS duration tended to increase progressively with age, irrespective of LV systolic function in patients with DMD. Attention should be paid to the QRS duration as an indicator of risk for complete AV block in older patients.

Topics: Adult; Age Factors; Arrhythmias, Cardiac; Cardiovascular Agents; Disease Progression; Echocardiography; Electrocardiography; Humans; Male; Muscular Dystrophy, Duchenne; Retrospective Studies; Risk Factors; Ventricular Function, Left; Young Adult

Topics: Animals; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiovascular Agents; Claudin-5; Disease Progression; Double-Blind Method; Drug Evaluation, Preclinical; Dystrophin; Gene Expression Regulation; Genetic Therapy; Heart Failure; Humans; Mice; Mice, Inbred mdx; Mineralocorticoid Receptor Antagonists; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Randomized Controlled Trials as Topic; Translational Research, Biomedical; Utrophin

Topics: Adult; Benzazepines; Cardiomyopathy, Dilated; Cardiovascular Agents; Disease Progression; Heart Failure; Humans; Ivabradine; Male; Muscular Dystrophy, Duchenne; Treatment Outcome

Topics: Benzazepines; Blood Gas Analysis; Cardiovascular Agents; Electrocardiography; Heart Failure; Humans; Ivabradine; Male; Muscular Dystrophy, Duchenne

Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.. Three month old female mdx mice were exposed to the β(1) receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.. BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.. This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.

Topics: Adrenergic beta-Agonists; Analysis of Variance; Animals; Aortic Valve; Blood Pressure; Body Weight; Cardiomyopathies; Cardiovascular Agents; Collagen; Disease Models, Animal; Drug Administration Schedule; Dystrophin; Female; Fibrosis; Heart Rate; Injections, Intraperitoneal; Isoproterenol; Mice; Mice, Inbred mdx; Muscle Strength; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Myocardial Contraction; Myocardium; Poloxamer; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Pressure