Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

This study highlights the potential of hiPSCs for studying inherited arrhythmogenic syndromes, in general, and CPVT specifically. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies.

Background-The hyperpolarization-activated nucleotide-gated channel-HCN4 plays a major role in the diastolic depolarization of sinus atrial node cells. Mutant HCN4 channels have been found to be associated with inherited sinus bradycardia. Methods and Results-Sixteen members of a family with sinus bradycardia were evaluated. Evaluation included a clinical questionnaire, 12-lead ECGs, Holter monitoring, echocardiography, and treadmill exercise testing. Eight family members (5 males) were classified as affected. All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Segregation analysis suggested autosomal-dominant inheritance. Direct sequencing of the exons encoding HCN4 revealed a missense mutation, G480R, in the ion channel pore domain in all affected family members. Function analysis, including expression of HCN4 wild-type and G480R in Xenopus oocytes and human embryonic kidney 293 cells, revealed that mutant channels were activated at more negative voltages compared with wild-type channels. Synthesis and expression of the wild-type and mutant HCN4 channel on the plasma membrane tested in human embryonic kidney 293 cells using biotinylation and Western blot analysis demonstrated a reduction in synthesis and a trafficking defect in mutant compared with wild-type channels. Conclusions-We describe an inherited, autosomal-dominant form of sinus node dysfunction caused by a missense mutation in the HCN4 ion channel pore. Despite its critical location, this mutation carries a favorable prognosis without the need for pacemaker implantation during long-term follow-up.

Multiple LVP configurations were clinically useful in a significant number of patients undergoing CRT system implantation by helping to overcome high LVP thresholds and PNS, and by providing more flexibility in placing the LV lead.

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BackgroundAcute end points of catheter ablation for ventricular tachycardia (VT) remain incompletely defined. The aim of this study is to identify causes for failure in patients with structural heart disease and to assess the relation of this acute outcome to longer‐term management and outcomes.Methods and ResultsFrom 2002 to 2010, 518 consecutive patients (84% male, 62±14 years) with structural heart disease underwent a first ablation procedure for sustained VT at our institution. Acute ablation failure was defined as persistent inducibility of a clinical VT. Acute ablation failure was seen in 52 (10%) patients. Causes for failure were: intramural free wall VT in 13 (25%), deep septal VT in 9 (17%), decision not to ablate due to proximity to the bundle of His, left phrenic nerve, or a coronary artery in 3 (6%), and endocardial ablation failure with inability or decision not to attempt to access the epicardium in 27 (52%) patients. In multivariable analysis, ablation failure was an independent predictor of mortality (hazard ratio 2.010, 95% CI 1.147 to 3.239, P=0.004) and VT recurrence (hazard ratio 2.385, 95% CI 1.642 to 3.466, P<0.001).ConclusionsWith endocardial or epicardial ablation, or both, acute ablation failure was seen in 10% of patients, largely due to anatomic factors. Persistence of a clinical VT is associated with recurrence and comparatively higher mortality.

Absence of LA contraction and LA volume index ≥33 ml/m(2) result in a significant increase in the risk for thromboembolic stroke after the Maze procedure for patients in sinus rhythm.

Objectives-To conduct a clinical, genetic and functional analysis of three unrelated families with familial sinus bradycardia (FSB).Background-Mutations in the hyperpolarization-activated nucleotide-gated channel (HCN4) are known to be associated with FSB.