Abstract-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT , and 5 RyR R4496C pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR R4496C mice but none of the WT developed VT (Pϭ0.02); 4/5 RyR R4496C mice pretreated with propranolol developed VT (Pϭ0.56 nonsignificant versus RyR R4496C mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias. (Circ Res. 2005;96:e77-e82.) Key Words: arrhythmias Ⅲ genetics Ⅲ ion channels Ⅲ transgenic mice Ⅲ calcium Ⅲ catecholamine C atecholaminergic polymorphic ventricular tachycardia (CPVT; OMIM: 604772) is a highly malignant cardiac disease manifesting in childhood and adolescence. It is characterized by adrenergically-mediated bidirectional or polymorphic ventricular tachycardia leading to syncope and/or sudden cardiac death. 1,2 Based on previously reported linkage data that had mapped the disease to chromosome 1q42-43, 3 we reported that the gene for the autosomal dominant variant of CPVT was RyR2; ie, the gene encoding for the cardiac isoform of the ryanodine receptor. 4 The first family in which a RyR2 mutation was identified was affected by a highly malignant form of the disease that was resistant to beta blockers; the mutation present in the family (R4497C) is a hot spot that we subsequently identified in other CPVT patients unrelated to the first kindred. The R4497C mutation has been extensively investigated in different in vitro models that demonstrated that it enhances the release of calcium from the sarcoplasmic reticulum. [5][6][7][8] It has therefore been inferred that arrhythmias may develop as a consequence of abnormal calcium release from intracellular stores. However, experimental evidence linking this mutation to the development of life-threatening arrhythmias is still lacking. Here we report on a conditional knock-in mouse-model carrier of the R4496C mutation that is the mouse equivalent of the human mutation R4497C. The objectives of the present study were to evaluate if the R449...

Abstract-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca 2ϩ -signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2 R33Q in adult rat myocytes led to an increase in excitationcontraction coupling gain and to more frequent occurrences of spontaneous propagating (

Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system (CNS) that leads to severe neurological disability. There is an interest in potential biomarkers that could provide information predicting disease activity and progression. Long non-coding RNAs (lncRNAs) have been reported to be involved in the pathogenesis of various human disorders, such as oncologic, cardiovascular, and neurodegenerative diseases. No studies have so far explored a potential link between lncRNAs and MS pathology. We screened 84 lncRNAs, involved in autoimmunity and human inflammatory response, in the serum of relapsing-remitting MS (RR-MS) patients (n = 12), age-matched controls (n = 12), and in patients with idiopathic inflammatory myopathy (IIM) (n = 12). We used the following criteria for lncRNAs analysis: fold change >2 and p < 0.05. According to these criteria, by real-time PCR, we identified three lncRNAs up-regulated in RR-MS patients respectively to controls: nuclear paraspeckle assembly transcript 1 (NEAT1), taurine up-regulated 1 (TUG1), and 7SK small nuclear (RN7SK RNA). Literature data showed that NEAT1, TUG1, and RN7SK RNA play an important role in neurodegenerative processes. Our results indicate that these lncRNAs may be involved in MS pathogenesis. Additional experimental data are needed to clarify the molecular mechanisms through which lncRNAs up-regulation may have a role in MS.