Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca 2+ release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.CPVT is an inherited arrhythmia syndrome characterized by a normal baseline electrocardiogram (ECG), polymorphic ventricular tachycardia induced by adrenergic stress in the absence of structural heart disease, and a high mortality rate in young individuals1. Treatment with β-adrenergic blockers reduces arrhythmia burden and mortality but is not completely effective1, and implantable cardioverter defibrillators (ICDs) are used for the prevention of sudden death. However, painful appropriate or inappropriate defibrillation shocks can trigger further adrenergic stress and arrhythmias, and deaths have occurred despite appropriate ICD shocks2 , 3. In such instances, stellate ganglionectomy4 or even cardiac transplantation5 have been considered. Two CPVT disease-related genes have been identified: RYR2, encoding the cardiac ryanodine receptor Ca 2+ release channel (RyR2), and CASQ2, encoding cardiac calsequestrin 6,7 . Mutations in these genes destabilize the RyR2 Ca 2+ release complex 8,9 . In mice with CPVT-linked mutations, catecholamines cause spontaneous sarcoplasmic reticulum Ca 2+ release resulting in delayed after depolarizations (DADs), and they produce triggered activity in myocytes and polymorphic ventricular tachycardia in ©2009 Nature America, Inc. All rights reserved NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript vivo 10, 11. Here we identify a therapy that directly targets the underlying arrhythmia mechanisms: we found that flecainide, an approved antiarrhythmic drug known to block sodium channels, showed remarkable efficacy in suppressing spontaneous sarcoplasmic reticulum Ca 2+ release by inhibiting RyR2. Flecainide treatment completely prevented adrenergic stress-induced arrhythmias in a mouse model of CPVT and in humans with CASQ2 or RYR2 mutations that are refractory to standard drug treatment.The local anesthetic tetracaine has been used to inhibit RyR2 and suppress spontaneous sarcoplasmic reticulum Ca 2+ release in isolated myocytes 12 . However, tetracaine causes a rebound increase in sarcoplasmic reticulum Ca 2+ release events during prolonged exposure 13 , effective inhibitory concentrations 14 are too high for clinical use, and systemic administration is contraindicated in humans. We searched among clinically available antiarrhythmic drugs for a more useful RyR2 inhibitor and found that flecainide inhibited RyR2 more potently than tetracaine and by a different mechanism. Whereas tetrac...

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel α subunit Na V 1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel β1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, β1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when Na V 1.5 was coexpressed with mutant β1 or β1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.

Treatment with gefitinib alone for chemotherapy-naïve NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity. To assess the proper timing of gefitinib in such patients, a subsequent randomized trial comparing gefitinib with standard chemotherapy is warranted.