Ultrasound tissue characterization does not differentiate genotype, but indexes ejection fraction deterioration in becker muscular dystrophy.

The aims of the study were, first, to assess whether myocardial ultrasound tissue characterization (UTC) in Becker muscular dystrophy (BMD) can be used to differentiate between patients with deletions and those without deletions; and second, to determine whether UTC is helpful in diagnosing the evolution of left ventricular dysfunction, a precursor of dilated cardiomyopathy. Both cyclic variation of integrated backscatter and calibrated integrated backscatter (cIBS) were assessed in 87 patients with BMD and 70 controls. The average follow-up in BMD patients was 48 ± 12 mo. UTC analysis was repeated only in a subgroup of 40 BMD patients randomly selected from the larger overall group (15 with and 25 without left ventricular dysfunction). Discrimination between BMD patients with and without dystrophin gene deletion was not possible on the basis of UTC data: average cvIBS was 5.2 ± 1.2 and 5.5 ± 1.4 dB, and average cIBS was 29.9 ± 4.7 and 29.6 ± 5.8, respectively, significantly different (p < 0.001) only from controls (8.6 ± 0.5 and 24.6 ± 1.2 dB). In patients developing left ventricular dysfunction during follow-up, cIBS increased to 31.3 ± 5.4 dB, but not significantly (p = 0.08). The highest cIBS values (34.6 ± 5.3 dB, p < 0.09 vs. baseline, p < 0.01 vs BMD patients without left ventricular dysfunction) were seen in the presence of severe left ventricular dysfunction. Multivariate statistics indicated that an absolute change of 6 dB in cIBS is associated with a high probability of left ventricular dysfunction. UTC analysis does not differentiate BMD patients with or without dystrophin gene deletion, but may be useful in indexing left ventricular dysfunction during follow-up.

Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers.

BACKGROUND: This study was designed to assess whether cardiovascular magnetic resonance imaging (CMR) in Duchenne muscular dystrophy carriers (DMDc) may index any cell milieu elements of LV dysfunction and whether this cardiac phenotype may be related to genotype. The null hypothesis was that myocardial fibrosis, assessed by late gadolinium enhancement (LGE), might be similarly accounted for in DMDc and gender and age-matched controls. METHODS: Thirty DMDc patients had CMR and genotyping with 37 gender and age-matched controls. Systolic and diastolic LV function was assessed by 2D-echocardiography. RESULTS: Absolute and percent LGE were higher in muscular symptomatic (sym) than asymptomatic (asy) DMDc (1.77 ± 0.27 vs 0.76 ± 0.17 ml; F = 19.6, p < 0.0001 and 1.86 ± 0.26% vs 0.68 ± 0.17%, F = 22.1, p < 0.0001, respectively). There was no correlation between LGE and age. LGE was seen most frequently in segments 5 and 6; segment 5 was involved in all asy-DMDc. Subepicardial LGE predominated, compared to the mid-myocardial one (11 out of 14 DMDc). LGE was absent in the subendocardium. No correlations were seen between genotyping (type of mutation, gene region and protein domain), confined to the exon's study, and cardiac phenotype. CONCLUSIONS: A typical myocardial LGE-pattern location (LV segments 5 and 6) was a common finding in DMDc. LGE was more frequently subepicardial plus midmyocardial in sym-DMDc, with normal LV systolic and diastolic function. No genotype-phenothype correlation was found.

New phenotype and pathology features in MYH7-related distal myopathy.

Laing distal myopathy is an autosomal dominant disease due to mutations in the gene encoding for the human slow-ß myosin heavy chain, MYH7. Most reports describe it as a mild, early onset myopathy with involvement usually restricted to foot extensors, hand finger extensors and neck flexors, and unspecific findings on muscle biopsy. We identified the first two Italian families with Laing distal myopathy, harboring two novel mutations in the MYH7 gene and performed clinical, neurophysiological, pathological, muscle MRI and cardiological investigations on affected members from the two families. Subjects from one family presented a moderate-severe phenotype, with proximal together with distal involvement and even loss of ambulation at advanced age. One patient displayed atypical muscle biopsy findings including cytoplasmic bodies and myofibrillar myopathy-like features. Affected members from the second family shared a very mild phenotype, with weakness largely limited to long toe and foot extensors and/or late onset. No patient showed any sign of heart involvement. Our study significantly broadens the clinical and pathological spectrum of Laing distal myopathy. We suggest that MYH7 screening should be considered in undiagnosed late-onset distal myopathy or cytoplasmic body myopathy patients.

Ultrasound tissue characterization of the myocardium in patients after Kawasaki disease.

We sought to determine if changes in myocardial physical properties, detected by ultrasound tissue characterization (UTC), are present in asymptomatic children years after an acute episode of Kawasaki disease (KD) and if such changes are related to coronary artery aneurysms (CAs). Myocardial UTC analysis was performed 4.8 + or - 3.4 years after acute KD in 22 patients, mean age 6.6 + or - 3.4 years, with or without CA, who had a normal ECG and normal left ventricular (LV) systolic and diastolic function by echocardiography. Twenty-two age-matched subjects were studied as controls. Cyclic variation of integrated backscatter (cvIBS) and calibrated integrated backscatter (cIBS) were assessed in 16 LV myocardial segments in each patient and control. We found large differences in the UTC data between patients and controls: cvIBS, 7.8 + or - 0.8 vs 8.9 + or - 0.6 dB; cIBS, 28.6 + or - 3.2 vs 25.2 + or - 1.0 dB (P\10-3 for both). The average values of cIBS and cvIBS did not differ significantly between KD patients with and patients without CA or stenosis. In conclusion, UTC analysis demonstrated significant differences in myocardial tissue properties between KD patients and controls, despite similar measures of LV function, independent of coronary artery abnormalities. UTC analysis might improve risk stratification for KD patients.

Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression.

Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMP-are progressively induced or repressed in the natural history of DMD.

Widespread electroanatomic alterations of right cardiac chambers in patients with myotonic dystrophy type 1.

INTRODUCTION: Conduction disturbances and arrhythmias characterize the cardiac feature of myotonic dystrophy type 1 (MD1); a myocardial involvement has been suggested as part of the cardiac disease. The aim of our study was to investigate the underlying myocardial alterations using electroanatomic mapping (CARTO) and their possible correlation with genetic and neurological findings. METHODS AND RESULTS: Right atrial and ventricular CARTO maps were obtained in 13 MD1 patients. Thirteen age-matched patients with paroxysmal supraventricular tachycardia and normal heart served as controls. Unipolar voltage (UNI-v), bipolar voltage (BI-v) amplitudes, bipolar potential duration (Bi-dur), and atrial propagation time (A-pt) were measured. UNI-v and BI-v in interatrial septum, anterolateral atrial wall, and right ventricle outflow tract were lower in MD1 patients than controls (P < 0.001). Bi-dur and A-pt were longer in MD1 patients than controls (P < 0.001, P = 0.046, respectively). A significant relationship was documented between CTG triplets and the percentage of Bi-v <0.5 mV in the atrial anteroseptal region (r = 0.6, P = 0.02). CONCLUSIONS: Altered electroanatomic patterns are present in the right cardiac chambers in MD1 patients. Widespread myocardial alterations, not necessarily limited to the conduction system, may support the presence of a cardiac myopathy as part of the disease.

Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations.

AIMS: Retrospective studies have identified a mutation in the lamin A/C (LMNA) gene in patients selected on the basis of a phenotype characterized by dilated cardiomyopathy, atrioventricular conduction disturbances and sudden death. However, the features of cardiac abnormalities in patients with an initial diagnosis of Emery-Dreifuss muscular dystrophy (EDMD) are poorly known. Aim of the present study was to investigate the spectrum of cardiac disease in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene. METHODS AND RESULTS: Ten consecutive patients with EDMD and a LMNA gene mutation were evaluated with structured medical interview, physical examination, ECG, echocardiogram and 24-h Holter monitoring. Electrophysiological testing and cardiac catheterization were performed if a class 1 or 2 American Heart Association guidelines indication was present. Cardiac disease was found in eight of 10 patients and consisted in the variable combination of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated cardiomyopathy, non-dilated cardiomyopathy, restrictive cardiomyopathy and sudden death despite pacemaker implant. CONCLUSIONS: Cardiac disease is common in patients with an initial diagnosis of EDMD caused by a mutation in the LMNA gene and consists of arrhythmias, disorders of atrioventricular conduction, cardiomyopathies and sudden death despite pacemaker implant.

Ultrasound tissue characterization detects preclinical myocardial structural changes in children affected by Duchenne muscular dystrophy.

Our goal was to identify early changes in myocardial physical properties in children with Duchenne muscular dystrophy (DMDch). Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, which triggers complex molecular and biological events in skeletal and cardiac muscle tissues. Although about 30% of patients display overt signs of cardiomyopathy in the late stage of the disease, it is unknown whether changes in myocardial physical properties can be detected in the early (preclinical) stages of the disease. We performed an ultrasonic tissue characterization (UTC) analysis of myocardium in DMDch with normal systolic myocardial function and no signs of cardiomyopathy. Both the cyclic variation of integrated backscatter (cvIBS) and the calibrated integrated backscatter (cIBS) were assessed in 8 myocardial regions of 20 DMDch, age 7 +/- 2 years (range 4 to 10 years), and in 20 age-matched healthy controls. We found large differences in the UTC data between DMDch and controls; the mean value of cvIBS was 4.4 +/- 1.5 dB versus 8.8 +/- 0.8 dB, whereas the mean value of cIBS was 36.4 +/- 7.1 dB versus 26.9 +/- 2.0 dB (p < 10(-6) for both). In DMDch, all eight sampled segments showed cIBS mean values to be significantly higher and cvIBS mean values to be significantly lower than those in the controls. Finally, interindividual differences were greater in DMDch than in controls for both parameters.The myocardium in DMDch displays UTC features different from those in healthy controls. These results show that lack of dystrophin is commonly associated with changes in myocardial features well before the onset of changes of systolic function and overt cardiomyopathy.