Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Clinical characterization of type 1 long QT syndrome caused by C-terminus Kv7.1 variants.

BACKGROUND: Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K+ channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated. OBJECTIVE: We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants. METHODS: The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated. RESULTS: We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect. CONCLUSION: The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis.

Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy.

Sudden death, or unexpected natural death of a healthy individual, is a serious problem in all nations. Sudden cardiac death (SCD) mainly due to ischemic heart diseases is the top cause of sudden death. However, there are pathophysiological conditions, referred to as sudden arrhythmic death syndrome, in which no apparent lesion can be identified even after complete conventional or ordinary autopsy. While postmortem genetic analyses have accumulated evidence about underlying genetic abnormality in such cases, the precise relationships between genetic background and the phenotype have been largely elusive. In this study, a retrospective investigation of 17 autopsy cases in which lethal arrhythmia was suspected to be the cause of death was carried out. Genetic analysis focusing on 72 genes reported to be associated with cardiac dysfunctions was performed, in combination with detailed histopathological and postmortem imaging examination, and a family study. As a result, in two cases of suspected arrhythmogenic cardiomyopathy (ACM), we found a nonsense variant in PKP2 and frameshift variant in TRPM4 gene. In contrast, the other 15 cases showed no morphological changes in the heart despite the presence of a frameshift variant and several missense variants, leaving the clinical significance of these variants obscure. The findings of the present study suggest that nonsense and frameshift variants could be involved in the morphological abnormality in cases of SCD due to ACM, while missense variants alone rarely contribute to massive structural changes in the heart.

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Targeted deep sequencing analyses of long QT syndrome in a Japanese population.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

Novel CACNA1C R511Q mutation, located in domain â -â ¡ linker, causes non-syndromic type-8 long QT syndrome.

BACKGROUND: Gain-of-function mutations in CACNA1C encoding Cav1.2 cause syndromic or non-syndromic type-8 long QT syndrome (LQTS) (sLQT8 or nsLQT8). The cytoplasmic domain (D)Ⅰ-Ⅱ linker in Cav1.2 plays a pivotal role in calcium channel inactivation, and mutations in this site have been associated with sLQT8 (such as Timothy syndrome) but not nsLQT8. OBJECTIVE: Since we identified a novel CACNA1C mutation, located in the DⅠ-Ⅱ linker, associated with nsLQTS, we sought to reveal its biophysical defects. METHODS: Target panel sequencing was employed in 24 genotype-negative nsLQTS probands (after Sanger sequencing) and three family members. Wild-type (WT) or R511Q Cav1.2 was transiently expressed in tsA201 cells, then whole-cell Ca2+ or Ba2+ currents (ICa or IBa) were recorded using whole-cell patch-clamp techniques. RESULTS: We identified two CACNA1C mutations, a previously reported R858H mutation and a novel R511Q mutation located in the DⅠ-Ⅱ linker. Four members of one nsLQTS family harbored the CACNA1C R511Q mutation. The current density and steady-state activation were comparable to those of WT-ICa. However, persistent currents in R511Q-ICa were significantly larger than those of WT-ICa (WT at +20 mV: 3.3±0.3%, R511Q: 10.8±0.8%, P<0.01). The steady-state inactivation of R511Q-ICa was weak in comparison to that of WT-ICa at higher prepulse potentials, resulting in increased window currents in R511Q-ICa. Slow component of inactivation of R511Q-ICa was significantly delayed compared to that of WT-ICa (WT-tau at +20 mV: 81.3±3.3 ms, R511Q-tau: 125.1±5.0 ms, P<0.01). Inactivation of R511Q-IBa was still slower than that of WT-IBa, indicating that voltage-dependent inactivation (VDI) of R511Q-ICa was predominantly delayed. CONCLUSIONS: Delayed VDI, increased persistent currents, and increased window currents of R511Q-ICa cause nsLQT8. Our data provide novel insights into the structure-function relationships of Cav1.2 and the pathophysiological roles of the DⅠ-Ⅱ linker in phenotypic manifestations.

Discrimination of atypical atrioventricular nodal reentrant tachycardia from atrial tachycardia by the V-A-A-V response.

INTRODUCTION: The electrophysiological discrimination between fast-slow (F/S-) atrioventricular (AV) nodal reentrant tachycardia (NRT) and atrial tachycardia (AT) originating from the interatrial septum remains challenging. While a V-A-A-V response may occur immediately after ventricular induction or entrainment of either tachycardia, the electrophysiological dissimilarities in that response between the two tachycardias remain unclear. The purpose of this study was to identify a diagnostic indicator discriminating F/S-AVNRT from AT by examining the difference in the V-A-A-V response between the two tachycardias. METHODS: This retrospective study included 17 patients with F/S-AVNRT [seven with common-form F/S-AVNRT using a typical slow pathway (SP) and 10 with superior type F/S-AVNRT using a superior SP] and 10 patients with reentrant AT. All 27 patients presented with long RP supraventricular tachycardia and an initial V-A-A-V response upon ventricular induction or entrainment. The V-A-A-V response in patients with F/S-AVNRT was due to dual atrial responses. We measured the interval between the first (A1) and second atrial electrogram (A2) of V-A-A-V and calculated ΔAA by subtracting A1-A2 from the tachycardia cycle length. RESULTS: V-A-A-V responses were observed most often upon ventricular induction of F/S-AVNRT (6 ± 5 times) as well as AT (6 ± 6 times; p = .87). The V-A-A-V response upon ventricular entrainment was observed in a single patient with F/S-AVNRT versus 10 all patients with AT (p < .001). ΔAA ranged between -80 and 228 ms in F/S-AVNRT and between -184 and 26 ms in AT. A ΔAA > 26 ms predicted a diagnosis of F/S-AVNRT with a 76% sensitivity and 100% specificity, while a ΔAA <-80 ms predicted a diagnosis of AT with a 50% sensitivity and 100% specificity. CONCLUSIONS: ΔAA is a useful, confirmatory, diagnostic indicator of F/S-AVNRT versus AT associated with the V-A-A-V response.

Therapeutic Potential of Vortioxetine for Anhedonia-Like Symptoms in Depression: A Post Hoc Analysis of Data from a Clinical Trial Conducted in Japan.

AIM: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder. METHODS: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0-17 or ≥18). RESULTS: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was -1.34 for vortioxetine 10 mg (P = 0.0300) and -1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was -3.11 (10 mg dose) and -3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥18), and -2.08 (10 mg) and -2.61 (20 mg) for patients with a lower baseline score (0-17). CONCLUSION: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.

Impact of Depression Onset and Treatment on the Trend of Annual Medical Costs in Japan: An Exploratory, Descriptive Analysis of Employer-Based Health Insurance Claims Data.

INTRODUCTION: We aimed to clarify medical expenses in Japanese individuals before and after major depressive disorder (MDD) diagnosis, and to determine whether MDD treatment also reduces medical costs for comorbid physical conditions. METHODS: This was an exploratory, descriptive, retrospective analysis of insurance claims data from JMDC Inc. Cohort A included individuals aged 18-64 years between January 2015 and December 2019. Cohorts B and C included Cohort A individuals with diabetes/hypertension ('chronic disease'), and sleep/anxiety disorders ('high depression risk'), respectively. Individuals in Cohorts A-C with an MDD diagnosis were analyzed by year of MDD onset (Cohorts A-CMDD2015-2019). Diagnoses and median medical costs were derived from International Classification of Diseases 10 codes. RESULTS: Total medical and non-neuropsychiatric drug costs in MDD onset years were 170,390-182,120 and 8480-9586 yen higher, respectively, for Cohorts AMDD2015-2019 than for Cohort A. In Cohort AMDD2019, total medical and non-neuropsychiatric drug costs increased incrementally from 2015 to 2019 (total changes: + 165,130 and + 7365 yen, respectively), to a greater degree than in Cohort A (+ 10,510 and + 1246 yen, respectively). Neuropsychiatric drug costs increased in the year of MDD onset only and decreased thereafter. After MDD onset, decreases in total medical and non-neuropsychiatric drug costs were observed (Cohorts AMDD2015-2019). Non-neuropsychiatric drug costs also decreased after MDD onset in the chronic disease groups (Cohorts CMDD2015-2019), but not in patients with MDD recurrence. CONCLUSION: Treating MDD reduces medical costs for comorbid physical conditions and may be a useful strategy for improving healthcare efficiency in Japan.

Early Improvement with Vortioxetine Predicts Response and Remission: A Post Hoc Analysis of Data from a Clinical Trial Conducted in Japan.

AIM: Several weeks of treatment with an antidepressive agent may be required before efficacy is demonstrated in patients with major depressive disorder. This study investigated the predictive value of early partial improvement with vortioxetine for treatment response and remission. METHODS: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20-75 years with recurrent major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 26. The key outcomes were the predictive value of early partial improvement (reduction in MADRS total score of ≥20% from baseline to week 2) with vortioxetine for MADRS response (≥50% decrease in score from baseline) and remission (decrease in score to ≤10) at week 8. RESULTS: Relevant data were available for 478 patients; 62/158 patients receiving placebo, 71/162 receiving vortioxetine 10 mg, and 66/158 receiving vortioxetine 20 mg were early improvers. Early improvers receiving vortioxetine (10 mg or 20 mg) were more likely than non-early improvers to achieve a week 8 response (71.2-73.2% vs 29.7-38.0%) or remission (50.7-51.5% vs 17.4-18.7%). Positive predictive values for response and remission with vortioxetine were ~70% and ~50%, respectively; negative predictive values were ~70% and ~80%, respectively. CONCLUSION: Improvement with vortioxetine may be predicted by early partial improvement in MADRS score. Some patients may benefit from longer-term treatment even without early improvement, another finding that may aid clinical decision-making. ClinicalTrials.gov registration for primary study: NCT02389816.

[Current Clinical Practice Pattern for Castration-Resistant Prostate Cancer(CRPC)in Japan].

Although various agents are reported against castration-resistant prostate cancer(CRPC), little is known about their actual clinical use in Japan. In this study, 484 patients diagnosed with CRPC during androgen-deprivation therapy were selected from Japan's leading multicenter collaborative research real-world database. The treatment details and prognosis were analyzed. It was observed that the castration treatment represented by the use of LH-RH agonists and antagonists was continued in almost all cases even after CRPC diagnosis. First-line non-castration agents for the CRPC treatment including certain novel agents approved from 2010 onwards and conventional agents used before that were selected for use in 76.5% and 23.5% of cases, respectively, with the 1-year continuation rates being 57.7%, and 52.4%, respectively. The 1.5-year overall survival rate from CRPC was 63.7%(90.0% in the conventional agents' group and 58.8% in the novel agents' group). Previously, conventional agents were sometimes selected for the CRPC treatment; hence, they still seemed to play a role in clinical practice in Japan.

Pacing site- and rate-dependent shortening of retrograde conduction time over the slow pathway after atrial entrainment of fast-slow atrioventricular nodal reentrant tachycardia.

INTRODUCTION: We tested our hypothesis that atrial entrainment pacing (EP) of a) the common-type (com-) fast-slow (F/S-) atypical atrioventricular nodal reentrant tachycardia (AVNRT) using a typical slow pathway (SP), or b) the superior-type (sup-) F/S-AVNRT using a superior SP, both modify the retrograde conduction time across the SP immediately after termination of EP (retro-SP-time). METHODS: We measured the difference in the His-atrial interval (HA difference) immediately after cessation of EP, performed at 2 ± 2 rates from the high right atrium (HA[1]-HRA) versus from the proximal coronary sinus (HA[1]-CS) in 17 patients with com-F/S-AVNRT and 11 patients with sup-F/S-AVNRT. We also measured the atrial-His and HA intervals of the first and second cycles immediately after cessation of EP and during stable tachycardia. RESULTS: Unequal responses, defined as a ≥ 20-ms HA difference at ≥1 EP rates, were observed in 16 patients (57%), including 7 with com- and 9 with sup-F/S-AVNRT. Irrespective of the EP rate, all unequal responses of com-F/S-AVNRT were due to a shorter HA[1]-CS than HA[1]-HRA, with a mean 34 ± 11 ms HA difference, whereas all unequal responses of sup-F/S-AVNRT were due to a longer HA[1]-CS than HA[1]-HRA, with a mean 49 ± 25 ms HA difference. The unequal responses resolved within two cycles after the cessation of EP. CONCLUSIONS: We have identified a little-known pacing site- and pacing rate-dependent shortening of the retro-SP-time.

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

AIMS: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. METHODS AND RESULTS: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. CONCLUSION: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

A Claims-Based Cohort Study on the Treatment Patterns of Japanese Patients with Type 2 Diabetes Mellitus and the Association of Early First Physician Visit with Time to Prescription of Oral Hypoglycemic Agents.

INTRODUCTION: This study aimed to investigate the relationships between timing of the first physician visit after detection of an abnormal glycated hemoglobin (HbA1c) value at routine annual check and the time to antidiabetic treatment prescription; and understand treatment patterns in patients newly diagnosed with type 2 diabetes mellitus (T2DM). METHODS: This retrospective, longitudinal, observational cohort study examined data from JMDC Inc., an administrative claims database. Patients with HbA1c value of at least 6.5% at routine annual check, aged 20 years or older, and prescribed at least one antidiabetic drug were included. This cohort was classified into early physician visit and delayed physician visit groups based on the timing of the first physician visit relative to the median. Patients were monitored from the date of first HbA1c checkup of at least 6.5% to the date of first physician visit with an HbA1c test, and from the date of the first physician visit to the date of prescription of first-line and second-line T2DM treatments. The time to first prescription of antidiabetic treatment for the two groups was then compared. RESULTS: Of 4798 eligible patients, 54.8% were prescribed first-line T2DM therapy less than 2 months from the first physician visit for T2DM diagnosis. A lower percentage of the early group compared with the delayed group required T2DM pharmacological therapy in less than 2 months (46.1% vs. 63.4%). The early group had a longer median time to prescription of first-line therapy [92 days vs. 15 days, p < 0.0001; hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.24, 1.39] and second-line therapy (1599 days vs. 1315 days, p < 0.0001; HR 1.22, 95% CI 1.11, 1.34) compared with the delayed group. CONCLUSION: In Japanese patients with T2DM, early physician visit after abnormal HbA1c detection at routine annual check is associated with a longer period before T2DM medication requirement, and may improve disease course.

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of ß-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

Multiple arrhythmic and cardiomyopathic phenotypes associated with an SCN5A A735E mutation.

BACKGROUND: SCN5A mutations are associated with multiple arrhythmic and cardiomyopathic phenotypes including Brugada syndrome (BrS), sinus node dysfunction (SND), atrioventricular block, supraventricular tachyarrhythmias (SVTs), long QT syndrome (LQTS), dilated cardiomyopathy and left ventricular noncompaction. Several single SCN5A mutations have been associated with overlap of some of these phenotypes, but never with overlap of all the phenotypes. OBJECTIVE: We encountered two pedigrees with multiple arrhythmic phenotypes with or without cardiomyopathic phenotypes, and sought to identify a responsible mutation and reveal its functional abnormalities. METHODS: Target panel sequencing of 72 genes, including inherited arrhythmia syndromes- and cardiomyopathies-related genes, was employed in two probands. Cascade screening was performed by Saner sequencing. Wild-type or identified mutant SCN5A were expressed in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp techniques. RESULTS: We identified an SCN5A A735E mutation in these probands, but did not identify any other mutations. All eight mutation carriers exhibited at least one of the arrhythmic phenotypes. Two patients exhibited multiple arrhythmic phenotypes: one (15-year-old girl) exhibited BrS, SND, and exercise and epinephrine-induced QT prolongation, the other (4-year-old boy) exhibited BrS, SND, and SVTs. Another one (30-year-old male) exhibited all arrhythmic and cardiomyopathic phenotypes, except for LQTS. One male suddenly died at age 22. Functional analysis revealed that the mutant did not produce functional INa. CONCLUSIONS: A non-functional SCN5A A735E mutation could be associated with multiple arrhythmic and cardiomyopathic phenotypes, although there remains a possibility that other unidentified factors may be involved in the phenotypic variability of the mutation carriers.

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome.

BACKGROUND: SCN5A-related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX). OBJECTIVE: We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects. METHODS: Target panel sequencing was performed. Wild-type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24-36 hr, whole-cell sodium currents (INa ) were recorded using patch-clamp techniques. RESULTS: The proband was 29-year-old male who experienced cardiopulmonary arrest. Later, his 36-year-old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G-INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p < .01), and steady-state activation (SSA) was shifted to depolarizing potentials compared with WT-INa (V1/2 -WT: -39.1 ± 0.8 mV, W374G: -30.9 ± 1.1 mV, p < .01). Incubation of W374G-transfected cells with MEX (W374G-MEX) increased INa density, but it was still reduced compared with WT-INa (W374G-MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G-MEX-INa was comparable to W374G-INa (V1/2 -W374G-MEX: -31.6 ± 0.7 mV, P = NS). CONCLUSIONS: Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.