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Background— Mutations in LMNA ( lamin A/C ), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored. Methods and Results— The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction ( Conclusions— The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA -related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.

Introduction: Mutations in LMNA, which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance (CCD), atrial fibrillation, and malignant ventricular arrhythmias (MVAs). Although the type of LMNA mutations have been reported to be associated with susceptibility to MVAs, the gene-based risk stratification for cardiac complications remains unexplored. Hypothesis: We hypothesized that truncation mutations might be associated with poor prognosis in LMNA mutation carriers, due to CCD, MVAs, and heart failure. Methods: The multicenter cohort included 77 LMNA mutation carriers (49 male, mean age: 45+/-17 yrs old) in 45 families from 7 institutions in Japan. All cause mortality and cardiac disorders were retrospectively analyzed. Results: Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families, in which 71 (92%) were phenotypically affected, and showed CCD (81%), lower left ventricular ejection fraction (LVEF Conclusions: The truncation mutations were associated with earlier manifestation of cardiac phenotypes in LMNA -related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification in LMNA mutation carriers.

Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P, Circulation: Arrhythmia and Electrophysiology, 7(3), pp.511-517; 2014

Background— Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. Methods and Results— We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP . Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. Conclusions— The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.

Background: Calmodulin ( CALM ) is a ubiquitous Ca2+-sensor molecule, and it modulates various proteins including several ion channels, ryanodine receptor 2, and Ca 2+ /calmodulin-dependent protein kinase. Recently, several studies reported that CALM mutations are associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism remains unknown. Purpose: The present study aims to establish the in-vitro disease model of CALM -related LQTS and elucidate the pathophysiological mechanism using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods: The hiPSC clones were generated from a 12-year-old boy with LQTS carrying a missense CALM2 mutation (c.293A>G, p.N98S), and differentiated into cardiomyocytes via embryoid body (EB) formation. The electrophysiological characteristics of CALM2 -N98S hiPSC-CMs, including action potential (AP) and L-type Ca 2+ channel (LTCC) currents, were analyzed by patch-clamp technique, and compared with those of hiPSC-CMs derived from healthy control. Results: The beating rate of CALM2 -N98S EBs was significantly lower than that of control (23.8 ± 1.6 bpm vs 47.3 ± 1.7 bpm, p < 0.01). The corrected AP duration at 90% repolarization (cAPD90) of CALM2 -N98S hiPSC-CMs was significantly prolonged compared to that of control (480.9 ± 59.4 ms vs 201.5 ± 19.5 ms, p < 0.01, Figure). At 1 Hz pacing, CALM2 -N98S hiPSC-CMs exhibited significantly longer APD90 than control (495.5 ± 47.7 ms vs 227.8 ± 21.6 ms, p < 0.01). The time constants of LTCC inactivation tau fast of CALM2 -N98S hiPSC-CMs were significantly larger than those of control at 0, +10, and +20 mV test potentials (Figure). Conclusion: The hiPSC-CMs model of CALM2 -related LQTS successfully recapitulated the disease phenotypes, and elucidated the pathophysiological mechanism: impaired inactivation of LTCC currents. This model might be useful for drug discovery in CALM2 -related LQTS.

We appreciated hearing from Casado-Arroyo et al regarding our recently published article, “Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization,” showing that SCN5A is a novel causative gene of early repolarization syndrome.1 In this study, we identified 3 SCN5A mutations in 3 unrelated patients with idiopathic ventricular fibrillation associated with early repolarization (or early repolarization syndrome). Because all of the patients had J-point elevation in the right precordial lead(s) in addition to J-point elevation in the inferior/lateral leads, Casado-Arroyo et al suggested that all of our patients have Brugada syndrome based on their recent findings that the risk of arrhythmia events is similar between patients with the Type 1 Brugada electrocardiographic pattern in 1 of the right precordial leads and patients with the Type 1 electrocardiographic pattern in >1 lead.2 However, we respectfully disagree because our patients never met the diagnostic criteria for Brugada syndrome.3 The diagnosis of Brugada syndrome is made when patients have a Type 1 Brugada electrocardiographic pattern, which is characterized by a prominent coved ST-segment elevation displaying a J-wave amplitude or ST-segment elevation ≥0.2 mV followed by a negative T-wave in ≥2 of the right precordial leads in the absence or presence of sodium channel blockers.3 Although the J-point elevation was ≥0.2 mV in 1 (Patients 2 and 3) or 2 (Patient 1) of the right …