Lucia I. Comi

The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy

To assess the incidence, nature and evolution of cardiac disease in Duchenne muscular dystrophy, 328 patients were studied between 1976 and 1987 for periods varying from 3 to 11 years. Patients underwent regular clinical examination, electrocardiography, echocardiography and radiological assessment. Pre-clinical cardiac involvement was found in 25% of patients under 6 years old increasing to 59% between the ages of 6 and 10 years and then declining in incidence with age. Clinically apparent cardiomyopathy is first evident after 10 years of age and increases in incidence with age, being present in all patients over 18 years of age. Its clinical impact is discussed.

Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols.

We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy. Thirty-seven boys were treated with protocol-N using deflazacort at a dose of 0.6 mg/kg per day for the first 20 days of the month and no deflazacort for the remainder of the month. Boys with osteoporosis received daily vitamin D and calcium. Deflazacort treatment started between 4 and 8 years of age. Thirty-two were treated with protocol-T using deflazacort at a dose of 0.9 mg/kg per day, plus daily vitamin D and calcium. Treatment started between 6 and 8 years of age. All boys were monitored every 4-6 months. The results were compared with age-matched controls in the two groups (19 for protocol-N and 30 for protocol-T). For the boys treated with protocol-N, 97% were ambulatory at 9 years (control, 22%), 35% at 12 years (control, 0%), 25% at 15 years (control, 0%). For the 32 boys treated with protocol-T, 100% were ambulatory at 9 years (control, 48%), 83% at 12 years (control, 0%) and 77% at 15 years (control, 0%). No aids or leg braces were used for ambulation. In boys 13 years and older, a scoliosis of >20 degrees developed in 30% of the boys on protocol-N, 16% on protocol-T and 90% of controls. For protocol-N, no cataracts were observed while in protocol-T, 30% of boys had asymptomatic cataracts that required no treatment. Fractures occurred in 19% (control 16%) of boys on protocol-N and 16% (control, 20%) of boys on protocol-T. This report illustrates: (a) the importance of collaborative studies in developing treatment protocols in Duchenne muscular dystrophy and (b) the long-term beneficial effects of deflazacort treatment in both protocols. However, the protocol-T seems to be more effective and frequently is associated with asymptomatic cataracts.

Mutation of dystrophin gene and cardiomyopathy

The correlations between the type of gene mutation and the cardiac clinical picture were examined in 284 patients with dystrophinopathy (200 Duchenne and 84 Becker). The subjects with normal heart showed deletions including exons 48-49 in 21.4% DMD and in 25% BMD, and other deletions in 35.7% DMD and 25% BMD; vice versa the cases with severe cardiac involvement showed deletions including 48-49 in 38.8% DMD and 37.5% BMD and other deletions in 32.9% DMD and 20% BMD. The age of death was 18 years in DMD patients with deletions including 48-49 whereas the age was about 22 in the cases with other deletions. The differences were statistically significant.

A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies

AIM Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement. METHODS AND RESULTS Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period. CONCLUSIONS The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

Autonomic nervous system imbalance and left ventricular systolic dysfunction as potential candidates for arrhythmogenesis in Becker muscular dystrophy

We evaluated the arrhythmic profile in a population of 20 Becker muscular dystrophy (BMD) patients searching for possible correlations between the severity of the arrhythmic events, the cardiac autonomic balance (assessed by heart rate variability analysis in the time domain) and the degree of left ventricular systolic impairment. A population of 14 male healthy individuals served as the control group. BMD subjects exhibited lower values of SDNN (P=0.013), SDANN index (P=0.008) and 24-h mean heart rate (P=0.002). The total number of premature ventricular beats (totPVB) and the number of PVB out of 1000 heartbeats (PVB/1000) appeared also higher in BMD subjects (P=0.05 and P=0.046, respectively). No difference was found in terms of 24-h mean QTc and 24-h longest QT among the two groups. TotPVB and PVB/1000 were inversely related to both the ejection fraction (r= -0.620, P=0.004 and r= -0.517, P=0.019) and to the shortening fraction (r= -0.568, P=0.009 and r= -0.469, P=0.037). Twenty-four-h mean QTc was also inversely related to both the ejection fraction (r= -0.520, P=0.019) and the fractional shortening (r= -0.491, P=0.028). These data suggest that in BMD there is cardiac autonomic imbalance characterized by sympathetic predominance and an increased susceptibility to ventricular arrhythmias, even in the absence of overt cardiomyopathy. Furthermore, the severity of the arrhythmic profile in BMD appears closely related to the degree of left ventricular systolic dysfunction.

Is the value of QT dispersion a valid method to foresee the risk of sudden death? A study in Becker patients

Sudden cardiac death is a dramatic, undesirable event that can often result from cardiomyopathies. To investigate the validity of the QTdispersion (QTd) in revealing regional heterogeneity of repolarisation, with consequent possibility of sudden death,1 we evaluated ECGs of patients affected by Becker muscular dystrophy (BMD). This is an X linked recessive muscular dystrophy caused by dystrophin anomalies in striated muscles with myocardial involvement2–4 and consequent dilated cardiomyopathy, ventricular arrhythmias and, in 30% of cases, sudden cardiac death.5,6 The study was retrospective using the clinically validated database of ECGs and echocardiograms (echo recorded together with the ECG) from 30 BMD patients (mean (SD) age 25 (10) years) with variable stages of myocardial involvement, and 26 healthy, age matched controls. All subjects underwent a physical examination, blood analyses, and M mode and two dimensional echocardiography. The diagnosis of the type of muscular dystrophy in Becker patients was confirmed by DNA analysis (polymerase chain reaction) and by reduced dystrophin labelling from the immunohistochemical examination of biopsy samples. We excluded the ECGs from subjects with ST-T anomalies on the 12 lead ECG, and with sustained ventricular arrhythmias at 24 hour Holter monitoring, electrolyte …

The cardiomyopathy of Duchenne/Becker consultands

Clinical, electrocardiographic, echocardiographic and other instrumental examinations were performed on 233 persons primarily seeking genetic advice about the Duchenne/Becker gene in order to reveal the incidence of dystrophic cardiomyopathy in a population of females with a close relationship with patients suffering from Duchenne or Becker muscular dystrophy. Among these consultands, 210 were Duchenne and 23 Becker. Eight five (40.4%) Duchenne and 8 (34.8%) Becker consultands showed a normal cardiac status; 35 (16.6%) Duchenne and 6 (26.1%) Becker had clinically evident cardiomyopathy; 90 (43%) Duchenne and 9 (39.1%) Becker showed minor signs of myocardial involvement. The link between myocardial involvement and the Duchenne/Becker carrier condition was demonstrated through the observation that the percentage of cases showing pre-clinical or clinically evident cardiomyopathy was higher in the consultands with pathological values of serum creatine kinase activity (obligatory carriers) and/or an estimated genetic risk higher than 70% than in the consultands showing a normal value of serum creatine kinase activity (less than 80 U/l) and/or a genetic risk lower than 70%.

Skeletal muscle cytochrome c in X-linked muscle dystrophies

Recent research on X-linked muscular dystrophies [l-4] allowed Hoffman to claim (Zagreb, 1990) that ‘the molecular basis of Duchenne and Becker dystrophies is now understood at both biochemical and genetics levels’. Duchenne dystrophy is accompanied by a deficiency of dystrophin, while in Becker dystrophy dystrophin is present but abnormal in amount and/or in molecular structure: both disorders result from mutations of the gene encoding dystrophin. However, the link between abnormalities in dystrophin and the mechanism of the severe skeletal muscle and myocardial damage is not understood. While several authors [5-91 have described an accumulation of calcium in muscle mitochondria from dystrophic hamsters and from patients affected by Duchenne dystrophy even at an early stage of the disease, others It0-121 have described focal lesions in the plasma membrane of the sarcolemma and changes in its lipid composition. It is clear that a fuller knowledge of the pathogenesis of X-linked muscular dystrophies can be reached only when the linkage is discovered between the abnormality of dystrophin and the changes in calcium and sarcolemma of dystrophic muscular cells. We have hypothesized that the occurrence of multiple microscopic infarcts of muscle described by many authors [13-151 could be the consequence of an impairment of oxidative phosphorylation, which could in turn be the cause of the abnormal accumulation of calcium, and of the sarcolemmal damage, with consequent leakage of enzymes in dystrophic muscle.