Background
Telethonin (TCAP) is a Z‐disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. TCAP is shown to modulate α‐subunit of the human cardiac ...sodium channel (hNav1.5) by direct interactions. Several TCAP variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes.
Methods
Mutational analyses for TCAP were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J‐wave pattern ECG. Using patch‐clamp techniques, electrophysiological characteristics of hNav1.5 were studied in HEK‐293 cells stably expressing hNav1.5 and transiently transfected with wild‐type (WT) or variant TCAP.
Results
We identified two TCAP variants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J‐wave pattern ECG. No patient had variant hNav1.5. Patch‐clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT‐TCAP (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward‐shifted by 5 mV in cells expressing p.E49K compared with WT‐TCAP. Voltage dependency of activation was not leftward‐shifted by p.R153H, while voltage dependency of steady‐state inactivation was leftward‐shifted by p.E49K.
Conclusions
We found two TCAP variants in the patients with BrS, J‐wave pattern ECG, and ARVC that can cause loss‐of‐function of the hNav1.5 in heterologous expression systems. Our observation suggests that these variants might impair INa and be associated with the patients’ electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.
Background:A hyperdynamic state of the basal left ventricle sometimes results in obstruction of the left ventricular outflow tract (LVOT). However, the prevalence, clinical presentation, and ...prognostic effect of LVOT obstruction in takotsubo cardiomyopathy (TC) have not been fully evaluated.Methods and Results:Among 933 consecutive patients who underwent emergency coronary angiography for suspected acute coronary syndrome, 35 patients (3.8%) were diagnosed as TC. The cumulative 3-year incidence of all-cause death, cardiac death, hospitalization for congestive heart failure (CHF), and recurrent TC was 24.2%, 0.0%, 6.5%, and 12.2%, respectively. Among 27 patients with information of a LVOT pressure gradient, LVOT obstruction was present in 9 (33%). The prevalence of moderate to severe mitral regurgitation (67% vs. 11%, P=0.003), CHF (78% vs. 28%, P=0.02), and hypotension (56% vs. 5.6%, P=0.008) was significantly higher in patients with LVOT obstruction than in those without. Nevertheless, the cumulative 3-year incidence of all-cause death was not significantly different between the 2 groups (49.2% vs. 23.0%, P=0.22) with no cardiac deaths in either group. Hospitalization for CHF and recurrent TC were significantly more frequent in patients with LVOT obstruction (25.0% vs. 0.0%, P=0.04, and 25.0% vs. 6.7%, P=0.02).Conclusions:In 35 consecutive patients with TC, those with significant LVOT obstruction (33%) had a more serious clinical presentation such as CHF and hypotension, but had similar 3-year mortality rate as compared with those without. (Circ J 2015; 79: 839–846)
Premature cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), probably due to different expression patterns of membrane ionic ...currents. We developed a method for determining expression patterns of functional channels in terms of whole-cell ionic conductance (G
) using individual spontaneous AP configurations. It has been suggested that apparently identical AP configurations can be obtained using different sets of ionic currents in mathematical models of cardiac membrane excitation. If so, the inverse problem of G
estimation might not be solved. We computationally tested the feasibility of the gradient-based optimization method. For a realistic examination, conventional 'cell-specific models' were prepared by superimposing the model output of AP on each experimental AP recorded by conventional manual adjustment of G
s of the baseline model. G
s of 4-6 major ionic currents of the 'cell-specific models' were randomized within a range of ± 5-15% and used as an initial parameter set for the gradient-based automatic G
s recovery by decreasing the mean square error (MSE) between the target and model output. Plotting all data points of the MSE-G
relationship during optimization revealed progressive convergence of the randomized population of G
s to the original value of the cell-specific model with decreasing MSE. The absence of any other local minimum in the global search space was confirmed by mapping the MSE by randomizing G
s over a range of 0.1-10 times the control. No additional local minimum MSE was obvious in the whole parameter space, in addition to the global minimum of MSE at the default model parameter.
Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease. While desmosomal gene mutations are considered major causes of ARVC, LMNA mutations have ...been reported to be possible causes of ARVC. In this study, we performed extensive genetic screening for LMNA mutations in our Japanese ARVC cohort to assess the prevalence and characteristics of LMNA mutation-positive ARVC cases. Methods Our study cohort consisted of 57 ARVC probands. Genetic analyses were performed by using direct sequencing and targeted sequencing of LMNA and four desmosomal genes. We compared clinical features of probands with desmosomal gene mutations to those of probands with LMNA mutations. Results Among 57 clinically diagnosed ARVC probands, we identified desmosomal gene mutations in 26 probands (45.6%) and two LMNA mutations in two probands. The first LMNA mutation p.M1K was detected in a 62-year-old male proband, while the second mutation p.W514X was found in a 70-year-old male proband. Compared to the 26 probands with desmosomal gene mutations, in the two probands with LMNA mutations, the mean age at diagnosis was significantly higher, and their heart rate at the diagnosis was significantly slower. While both probands with LMNA mutations underwent pacemaker implantation, only one proband with desmosomal mutations received this treatment (2/2 vs. 1/26). Conclusion Genetic screening for LMNA gene is important for ARVC patients, particularly in patients with bradycardia.
Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel ...(hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias.
To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome.
Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study. Genetic screening using direct sequencing identified a novel SCN5A variant, p.V1328M. Electrophysiological parameters of WT and p.V1328M and their effects on drug pharmacokinetics were studied using the patch-clamp method.
Whole-cell sodium current densities were similar for WT and p.V1328M channels. While p.V1328M mutation did not affect the voltage-dependence of the activation kinetics, it caused a positive shift of voltage-dependent steady-state inactivation by 7 mV. The tonic block in the presence of pilsicainide was similar in WT and p.V1328M, when sodium currents were induced by a low frequency pulse protocol (q15s). On the contrary, p.V1328M mutation enhanced pilsicainide induced use-dependent block at 2 Hz. (Ki: WT, 35.8 μM; V1328M, 19.3 μM).
Our study suggests that a subclinical SCN5A mutation, p.V1328M, might predispose individuals harboring it to drug-induced Brugada Syndrome.
School-based routine screenings of electrocardiograms (ECGs) have been performed upon admission to primary school (PS), junior high school (JHS), and high school (HS) in Japan. Though ECGs with ...prolonged QT intervals are occasionally found, the role of regular ECG screening tests in identifying long QT syndrome (LQTS) remains to be determined. We investigated the usefulness of the ECG screenings by comparing the results of genetic tests between students who showed QT-prolongation in the screenings and patients with LQTS.
We genetically screened 341 students (106 PS, 173 JHS, and 62 HS). Of these, 230 subjects showed QT-prolongation during regular screenings (S-S group), and the other 111 patients were clinically consulted with suspected LQTS by paediatricians (C-C group). Genotype-phenotype relationships were compared between the two groups. The positive rates in the genetic tests were comparable among the two groups; however, symptomatic subjects were significantly fewer in the S-S group than the C-C group (3% vs. 70%). Compared to the genotype-negative subjects, the positive subjects showed significantly longer QTc (P < 0.0001) and more frequently presented LQTS risk scores with ≥3.5 points (P < 0.0001). Lethal arrhythmic events (LAE) occurred only in the C-C group; 18 subjects experienced LAE and 83% of them were found to carry variant(s) in the LQTS-related genes.
The school-based ECG screenings are effective in identifying young patients with LQTS who require genetic analysis. If individuals are screened at a younger age, we can identify patients at risk earlier and provide preventative treatments.
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.
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.
Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and ...encodes an auxiliary β-subunit for K channels. KCNE5 has been shown to modify the transient outward current (I(to)), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF).
In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.D92E;E93X in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, I(to) was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns.
KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.
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