Denis Duboc

Brugada syndrome and abnormal splicing of SCN5A in myotonic dystrophy type 1

BACKGROUNDnIn patients with myotonic dystrophy type 1 (DM1), the mechanisms underlying sudden cardiac death, which occurs in up to 1/3 of patients, are unclear.nnnAIMSnTo study the potential role of Brugada syndrome in ventricular tachyarrhythmias and sudden death in DM1 patients.nnnMETHODSnWe screened 914 adult patients included in the DM1 Heart Registry during 2000-2009 for the presence of type 1 Brugada pattern on electrocardiogram (ECG). We also performed direct sequencing of SCN5A in patients with Brugada pattern. Further, we analysed SCN5A splicing on ventricular myocardial specimens harvested during cardiac transplantation in a 45-year-old patient with DM1 and three controls with inherited dilated cardiomyopathy.nnnRESULTSnA type 1 Brugada pattern was present on the ECG of seven of 914 patients (0.8%), including five with a history of sustained ventricular tachyarrhythmia or sudden death, who fulfilled the criteria for Brugada syndrome. SCN5A sequencing was normal in all patients. Ventricular myocardial specimen analysis displayed abnormal splicing of SCN5A exon 6, characterized by over-expression of the neonatal isoform, called exon 6A, in the patient with DM1, but not from the controls.nnnCONCLUSIONnOur findings suggest a potential implication of Brugada syndrome in sudden death in DM1, which may be related to missplicing of SCN5A. Our findings provide a new insight into the pathophysiology of heart disease in DM1.

Cardiac Findings in Congenital Muscular Dystrophies

Cardiac involvement (CI) in congenital muscular dystrophies (CMDs) has been only rarely investigated so far. By means of a systematic literature search we reviewed the literature about CI in CMD and found that CI is apparently absent in Ullrich CMD or CMD with integrin deficiency and only mild in Bethlem CMD. CI in merosin deficiency includes dilated cardiomyopathy and systolic dysfunction. CI in dystroglycanopathies seems most prevalent among all CMDs and includes dilated cardiomyopathy, systolic dysfunction, and myocardial fibrosis in Fukuyama CMD. Among the nonspecified dystroglycanopathies, CI manifests as dilated cardiomyopathy, hypertrophic cardiomyopathy (CMP) or systolic dysfunction. With CMD type 1C, as well as with limb-girdle muscular dystrophy 2I, up to half of the patients develop dilated cardiomyopathy. In rigid-spine syndrome, predominantly the right heart is affected secondary to thoracic deformity. In patients who carry LMNA mutations, CI may manifest as dilated cardiomyopathy, hypertrophic cardiomyopathy, or fatal ventricular arrhythmias. Overall, CI in patients with CMD varies considerably between the different CMD types from absent or mild CI to severe cardiac disease, particularly in merosin deficiency, dystroglycanopathies, and laminopathies. Patients with CMD with CI require regular cardiologic surveillance so that severe, treatable cardiac disease is not overlooked.

Impaired myocardial deformation detected by speckle-tracking echocardiography in patients with myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most frequent neuromuscular disease in adults [1]. This autosomal-dominant hereditary disease, caused by the excessive repetition of a CTG codon in the dystrophia myotonica-protein kinase (DMPK) gene, [2] is frequently complicated by conduction disorders, supraventricular and ventricular rhythm disorders, and left ventricular (LV) dysfunction [3]. Screening for subclinical myocardial abnormalities could lead to earlier treatment initiation for patients at risk of developing cardiac insufficiency and better stratification of rhythm risk. Our objective was to determine whether speckle tracking echocardiography (STE) could identify LV contractility abnormalities in DM1 patients with normal LVEF. 2D echocardiography and STE were used to evaluate DM1 patients managed in the Department of Neuromuscular Consultations at the Institut de Myologie (Paris, France). Inclusion criteria were DM1 patients, 18–50 years old, with LVEF N55%, whose mutation comprised N50 CTG repeats and normal 2D echocardiography. Included patients underwent a standard protocol consisting of neurological and cardiac clinical evaluations, with Walton score assessment of muscle function, [4] ECG, 2D echocardiography and strain-rate imaging based on STE. Each DM1 patient was age(±5 years) and sex-matched to a control volunteer,whohadundergone an echocardiographic evaluation with a similar protocol. This study was conducted in accordance with Declaration of Helsinki, was approved by the local Ethics Committee and the patients gave their informed consent to participate. Global longitudinal strains were measured automatically with a program that integrated themeasurements derived from the analysis of 6 segments detected in the apical 4(4C) and 2-chamber (2C) views, and the 4 segments detected in the 3-chamber (3C) view. Mean circumferential and radial strains were determined by manually calculating the mean of the measurements obtained from the 6 segments identified in short-axis parasternal angle. Values are expressed as means±standard deviation (SD), or counts and percentages as appropriate. The existence of any correlation between STE and any clinical or other echocardiographic variable was investigated using Spearman correlation. Patients values were compared to those of an ageand sex-matched control group using Student t-test for continuous variables and chi-square or Fisher exact test for difference in frequencies, as appropriate. All statistical analyses were performed using STATA Version 10.1 (StataCorp LP, College Station, TX) and a p-value of less than .05 was considered statistically significant. The main demographic, genetic, muscle and cardiac characteristics of DM1 patients are summarized in Table 1. The 2 groups were comparable for the main parameters measured with 2D echocardiography (LV mass, left atrium area, LV filling pressures and systolic pulmonary artery pressure), except for the diastolic interventricular thickness and systolic LV diameter. Of note, LVEF was comparable in both groups. The global longitudinal strain was significantly lower in 4C and 2C views for DM1 patients, compared to controls, with no significant differences between-group in 3C-view. The mean circumferential strain was significantly higher in DM1 patients but mean radial strain values were comparable in the 2 groups (Table 2). Only the apical 4C global longitudinal strain was significantly correlated with the PR interval (r=.396, P=.013), among the parameters assessed, including the Walton muscle-function score and the size of the DMPK-gene mutation. The 3 main findings of this study were the diminished apical 4C global longitudinal strain in DM1 patients with LVEF N55%, suggesting altered myocardial contractility, increased mean circumferential International Journal of Cardiology 152 (2011) 375–418

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most common neuromuscular disorder and is associated with cardiac conduction defects. However, the mechanisms of cardiac arrhythmias in DM1 are unknown. We tested the hypothesis that abnormalities in the cardiac sodium current (INa) are involved, and used a transgenic mouse model reproducing the expression of triplet expansion observed in DM1 (DMSXL mouse). The injection of the class-I antiarrhythmic agent flecainide induced prominent conduction abnormalities and significantly lowered the radial tissular velocities and strain rate in DMSXL mice compared to WT. These abnormalities were more pronounced in 8-month-old mice than in 3-month-old mice. Ventricular action potentials recorded by standard glass microelectrode technique exhibited a lower maximum upstroke velocity [dV/dt](max) in DMSXL. This decreased [dV/dt](max) was associated with a 1.7 fold faster inactivation of INa in DMSXL myocytes measured by the whole-cell patch-clamp technique. Finally in the DMSXL mouse, no mutation in the Scn5a gene was detected and neither cardiac fibrosis nor abnormalities of expression of the sodium channel protein were observed. Therefore, alterations in the sodium current markedly contributed to electrical conduction block in DM1. This result should guide pharmaceutical and clinical research toward better therapy for the cardiac arrhythmias associated with DM1.

0315: Cardiovascular protection of statins could be mediated by an increase of total bile acids concentration in sera? A pilot study

Introduction in animal models of atheroma (ApoE-/- and LDL -/- mice), bile acids (BAs) exerts an anti-atherosclerotic effect through the anti-inflammatory action of their receptors, TGR5 and FXR, decreasing dramatically the surface of the atheroma plaque. BAs are cholesterol derivatives synthetized by the liver. In a previous study, we found that a decrease in BAs (lithocholic acid) is an independent risk factor of coronary disease in human. Aim Statins are known to reduce cardiovascular events in atherosclerotic patients. Given the experimental protective effect of BAs against atherosclerosis, the aim of this preliminary study was to dertermine the total BAs concentration in sera after statins administration. Methods Between January 2015 and April 2015, patients hospitalized for a coronary angiogram and starting a statins treatment for coronary atheroma were included. Exclusion criteria were post cardiac arrest, non-fasting status, hepatic disease, antibiotics and corticosteroids. The total BAs concentration was measured before and 1 month after the initiation of statin therapy by liquid chromarography mass spectrometry. Wilcoxon test was used for statistical analysis. Results On a cohort of 360 patients, 37 were eligible and 17, aged of 54±9.6 years old have been retrospectively included. 95% were prescribed with atorvastatin (68% with atorvastatin 40mg). The mean concentration of the total BAs before statin was 0.68µmol/L (SEM 0.08µmol/L) and 1.37µmol/L after (SEM 0.21µmol/L) (p=0.013, figure 1). Conclusion statins administration is associated with a doubling of circulating BAs after one month of treatment. This raises a question about statins increasing BAs synthesis by the liver: the deflection of the cholesterol synthesis by the liver into BAs instead, could participate to the efficacy of statins. This could theoretically be beneficial by slowing down the atheroma development through anti-inflammatory effects of BAs on the macrophage of the plaque. Download : Download high-res image (70KB) Download : Download full-size image Abstract 0315 – Figure