Background-The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite ␤-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. Methods and Results-We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543Ϯ65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with ␤-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (PϽ0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc Ͻ500 ms predicted very low risk. The percentage of patients with Ͼ5 CEs declined from 55% to 8% (PϽ0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (Pϭ0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. Conclusions-LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite ␤-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell–cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.

Background Brugada syndrome (BrS) primarily associates with loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (AC; or arrhythmogenic right ventricular cardiomyopathy, ARVC). Experimental models showed correlation between loss of expression of desmosomal protein plakophilin-2 (PKP2), and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features. Methods and Results We searched for PKP2 variants in genomic DNA of 200 patients with BrS diagnosis, no signs of AC, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at site of cell contact. These deficits were restored by transfection of wild-type PKP2 (PKP2-WT), but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) from a patient with PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of WT, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to reduced number of channels at the intercalated disc, and increased separation of microtubules from the cell-end. Conclusions This is the first systematic retrospective analysis of a patient group to define the co-existence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

Abstract-Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca 2ϩ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2 R4496C ) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 R4496C and in 9% of 11 wild-type (Pϭ0.03) littermates perfused with Ca 2ϩ and isoproterenol; 66% of 12 RyR2/RyR2 R4496C and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (Pϭ0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2 R4496C mice. Under current clamp, single Purkinje cells from RyR2/RyR2 R4496C mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT. 604772) is an inherited disease leading to arrhythmias and sudden cardiac death. 1 The autosomal dominant form has been linked to ryanodine receptor gene (RyR2) mutations, leading to increased spontaneous Ca 2ϩ release from the sarcoplasmic reticulum. 2 Typical arrhythmias are bidirectional ventricular tachycardia (BVT) and polymorphic ventricular tachycardia (PVT) that can degenerate into ventricular fibrillation (VF) and thus sudden cardiac death. 3 BVT is infrequent, characterized by beat-to-beat 180°alternation of the QRS of the ECG and occurs in CPVT, as well as in digitalis toxicity; thus, it has been inferred that arrhythmogenesis in CPVT is mediated by delayed afterdepolarization (DAD)-induced triggered activity (TA).Mice heterozygous for the R4496C mutation (RyR2/ RyR2 R4496C ) recapitulate the human phenotype of CPVT by developing BVT, PVT, and/or VF under adrenergic stimulation. 4 Recently, Liu et al 5 have demonstrated DADs in RyR2/RyR2 R4496C mouse ventricular myocytes both in control and in the presence of isoproterenol. However, it remains to be demonstrated whether the arrhythmia origin...