Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families. The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons. Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2. One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years. Despite the different mutations, there is little phenotypic variation of CPVT for the CASQ2 mutations. Of the 16 heterozygous carriers of these various mutations, 14 were devoid of clinical symptoms or ECG anomalies, whereas 2 of them had ventricular arrhythmias at ECG on exercise tests. In line with this, the diagnosis of the probands was difficult because of the absence of a positive family history. In conclusion, these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT. The full text of this article is available at http://www.circresaha.org.

Functional consequences of an LMNA mutation associated with a new cardiac and non-cardiac phenotype.

Heritable dilated cardiomyopathy is a genetically highly heterogeneous disease. To date 17 different chromosomal loci have been described for autosomal dominant forms of dilated cardiomyopathy with or without additional clinical manifestations. Among the 10 mutated genes associated with dilated cardiomyopathy, the lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy. For the first time, we report here a French family affected with a new phenotype composed of an autosomal dominant severe dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias, and a specific quadriceps muscle myopathy. In all previously reported cases with both cardiac and neuromuscular involvement, neuromuscular disorders preceded cardiac abnormalities. The screening of the coding sequence of the LMNA gene on all family members was performed and we identified a missense mutation (R377H) in the lamin A/C gene that cosegregated with the disease in the family. Cell transfection experiments showed that the R377H mutation leads to mislocalization of both lamin and emerin. These results were obtained in both muscular (C2C12) and non-muscular cells (COS-7). This new phenotype points out the wide spectrum of neuromuscular and cardiac manifestations associated with lamin A/C mutations, with the functional consequence of this mutation seemingly associated with a disorganization of the lamina.

Mutational analysis of the beta- and delta-sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one-third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the beta- and delta-sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron-exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single-strand conformation polymorphism for the beta-sarcoglycan gene and by direct sequencing for the delta-sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of delta-sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.

Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model.

Although previous findings have suggested that some adult stem cells are pluripotent and could differentiate in an appropriate microenvironment, the fate conversion of adult stem cells is currently being debated. Here, we studied the ability of mobilized stem cells to repair cardiac tissue injury in a nonhuman primate model of acute myocardial infarction. Mobilization was carried out with stem cell factor, 25 mcg/Kg/d (D), and granulocyte-colony-stimulating factor, 100 mcg/Kg/D administered 5 days before (D - 5 group; n = 3) or 4 hours after (H + 4 group; n = 4) circumflex coronary artery ligation; no growth factor was administered to 3 baboons of the control group. No adverse effect relating to growth factor administration was observed. Flk-1 and transcription factors of cardiac lineages could be detected in peripheral blood only by reverse transcriptase-polymerase chain reaction. When comparing positron emission tomography (PET) with [11C]-acetate between examinations from D2 and D30, a relative increase (perfusion ratio between infarct and noninfarct regions) of 26% (P =.01) in myocardial blood flow was found in the H + 4 group; the relative rate of oxidative metabolism remained unaltered in the 3 groups. No change was observed in the echographic indices of the left ventricular enlargement or systolic function in the 3 animal groups during the 2-month follow-up. The PET findings concurred with the immunohistochemistry analysis of left ventricular myocardial sections with evidence of endothelial cells but no myocyte differentiation; few cycling cells were observed at this time. Thus, the present data suggest that, in nonhuman primates submitted to coronary artery ligation, mobilization by hematopoietic growth factors could promote angiogenesis in the infarcted myocardium, without detectable myocardial repair.