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.

Two-Dimensional SERS Sensor Array for Identifying and Visualizing the Gas Spatial Distributions of Two Distinct Odor Sources.

The spatial distribution of gas emitted from an odor source provides valuable information regarding the composition, size, and localization of the odor source. Surface-enhanced Raman scattering (SERS) gas sensors exhibit ultra-high sensitivity, molecular specificity, rapid response, and large-area detection. In this paper, a SERS gas sensor array was developed for visualizing the spatial distribution of gas evaporated from benzaldehyde and 4-ethylbenzaldehyde odor sources. The SERS spectra of the gas were collected by scanning the sensor array using an automatic detection system. The non-negative matrix factorization algorithm was employed to extract feature and concentration information at each spot on the sensor array. A heatmap image was generated for visualizing the gas spatial distribution using concentration information. Gaussian fitting was applied to process the image for localizing the odor source. The size of the odor source was estimated using the processed image. Moreover, the spectra of benzaldehyde, 4-ethylbenzaldehyde, and their gas mixture were simultaneously detected using one SERS sensor array. The feature information was recognized using a convolutional neural network with an accuracy of 98.21%. As a result, the benzaldehyde and 4-ethylbenzaldehyde odor sources were identified and visualized. Our research findings have various potential applications, including odor source localization, environmental monitoring, and healthcare.

The utility of zebrafish cardiac arrhythmia model to predict the pathogenicity of KCNQ1 variants.

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.

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.

Hypertrophic Cardiomyopathy Predicts Thromboembolism and Heart Failure in Patients With Nonvalvular Atrial Fibrillation　- A Prospective Analysis From the Hokuriku-Plus AF Registry.

BACKGROUND: The prognostic effect of concomitant hypertrophic cardiomyopathy (HCM) on adverse events in patients with atrial fibrillation (AF) has not been evaluated in a multicenter prospective cohort study in Japan.Methods and Results: Using the Hokuriku-Plus AF Registry, 1,396 patients with nonvalvular AF (1,018 men, 72.3±9.7 years old) were assessed prospectively; 72 (5.2%) had concomitant HCM. During a median follow-up of 5.0 years (interquartile range 3.5-5.3 years), 79 cases of thromboembolism (1.3 per 100 person-years) and 192 of heart failure (HF) (3.2 per 100 person-years) occurred. Kaplan-Meier analysis revealed that the HCM group had a significantly greater incidence of thromboembolism (P=0.002 by log-rank test) and HF (P<0.0001 by a log-rank test) than the non-HCM group. The Cox proportional hazards model demonstrated that persistent AF (adjusted hazard ratio 2.98, 95% confidence interval 1.56-6.21), the CHA2DS2-VASc score (1.35, 1.18-1.54), and concomitant HCM (2.48, 1.16-4.79) were significantly associated with thromboembolism. Conversely, concomitant HCM (2.81, 1.72-4.43), older age (1.07, 1.05-1.10), lower body mass index (0.95, 0.91-0.99), a history of HF (2.49, 1.77-3.52), and lower left ventricular ejection fraction (0.98, 0.97-0.99) were significantly associated with the development of HF. CONCLUSIONS: Concomitant HCM predicts the incidence of thromboembolism and HF in AF patients.

Effect of Catheter Ablation for Atrial Fibrillation in Heart Failure With Mid-Range or Preserved Ejection Fraction　- Pooled Analysis of the AF Frontier Ablation Registry and Hokuriku-Plus AF Registry.

BACKGROUND: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear.Methods and Results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group. CONCLUSIONS: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Ablation index-guided high-power vs. moderate-power cavotricuspid isthmus ablation.

Ablation index (AI)-guided ablation is useful for pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. However, the impact of radiofrequency (RF) application power on CTI ablation with a fixed target AI remains unclear. One-hundred-thirty drug-refractory atrial fibrillation and/or atrial flutter patients who underwent AI-guided CTI ablation with or without PVI between July 2020 and August 2021 were randomly assigned to high-power (45 W) and moderate-power (35 W) groups. We performed CTI ablation with the same target AI value in both groups: 500 for the anterior 1/3 segments and 450 for the posterior 2/3 segments. In total, first-pass conduction block of the CTI was obtained in 111 patients (85.4%), with 7 patients (5.4%) showing CTI reconnection. The rate of first-pass conduction block was significantly higher in the 45 W group (61/65, 93.8%) than in the 35 W group (50/65, 76.9%, P = 0.01). CTI ablation and CTI fluoroscopy time were significantly shorter in the 45 W group than in the 35 W group (CTI ablation time: 192.3 ± 84.8 vs. 319.8 ± 171.4 s, P < 0.0001; CTI fluoroscopy time: 125.2 ± 122.4 vs. 171.2 ± 124.0 s, P = 0.039). Although there was no significant difference, steam pops were identified in two patients from the 45 W group at the anterior segment of the CTI. The 45 W ablation strategy was faster and provided a higher probability of first-pass conduction block than the 35 W ablation strategy for CTI ablation with a fixed AI target.

Characterization of baseline clinical factors associated with incident worsening kidney function in patients with non-valvular atrial fibrillation: the Hokuriku-Plus AF Registry.

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0-79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7-3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible.

Prediction of atrioventricular conduction disturbance after ablation of persistent atrial fibrillation.

The prevalence of atrioventricular conduction disturbance (AVCD) in patients with persistent atrial fibrillation (AF) has not yet been fully investigated. We sought to identify the predictors of AVCD in patients with AF by analyzing the relationship between pre-ablation heart rate during AF and the PR interval in sinus rhythm after ablation. We analyzed pre-ablation 24-h Holter electrocardiogram (ECG) and 12 lead ECG 12 months after ablation of 121 consecutive patients with persistent AF who underwent their first ablation procedure and maintained sinus rhythm at 12 months. AVCD was defined as a first-degree atrioventricular block (AVB), second-degree AVB, high-degree AVB, or third-degree AVB observed on ECG at 12 months after ablation. Seventeen out of 121 patients (14.0%) had AVCD at 12 months. In the group with AVCD, total heartbeat (THB) and maximum heart rate (Max HR) were significantly lower, and the prevalence of concomitant Cavo-tricuspid isthmus-dependent atrial flutter before ablation and the appearance of macro reentrant atrial tachycardia (AT) during the procedure were significantly higher than those in the group without AVCD. Multiple regression analysis revealed that maximum HR and macro reentrant AT were significant predictors of AVCD. Receiver operating characteristic curve analysis revealed that Max HR of <165.0 bpm predicts AVCD with a sensitivity of 76.47% and a specificity of 74.00%. In patients with persistent AF, low Max HR and the presence of macro reentrant AT during the ablation procedure were predictors of AVCD.

An Odor Trace Visualization System Using a Two-Dimensional Backside Scattering Localized Surface Plasmon Resonance Gas Sensor.

Odor information fills every corner of our lives yet obtaining its spatiotemporal distribution is a difficult challenge. Localized surface plasmon resonance has shown good sensitivity and a high response/recovery speed in odor sensing and converts chemical information such as odor information into optical information, which can be captured by charge-coupled device cameras. This suggests that the utilization of localized surface plasmon resonance has great potential in two-dimensional odor trace visualization. In this study, we developed a two-dimensional imaging system based on backside scattering from a localized surface plasmon resonance substrate to visualize odor traces, providing an intuitive representation of the spatiotemporal distribution of odor, and evaluated the performance of the system. In comparative experiments, we observed distinct differences between odor traces and disturbances caused by environmental factors in differential images. In addition, we noted changes in intensity at positions corresponding to the odor traces. Furthermore, for indoor experiments, we developed a method of finding the optimal capture time by comparing changes in differential images relative to the shape of the original odor trace. This method is expected to assist in the collection of spatial information of unknown odor traces in future research.

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.

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.

Identification of discriminating chemical compounds in banana species and their odor characterization using GC-MS, statistical, and clustering analysis.

The study aims identification of discriminating chemical constituents in the banana odor grown in Philippines and Ecuador using GC-MS characterization. Ester is recognized as a major chemical class in selected banana odor. Odors discriminating compounds like, 2-hexenal, ethyl acetate, and hexanoic acid, ethyl ester, etc. have been identified. Besides, other odors generating chemical compounds (alcohols, esters, aldehydes, and ketones) have been recognized. Furthermore, principal component analysis (PCA) and hierarchical cluster analysis were implemented to differentiate banana odors. PCA achieved 100% discrimination of selected bananas odors using the peak area information about recognizing chemical compounds. Odor identity and discrimination of selected bananas have been achieved successfully. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-021-05298-9.

Personalized medicine for cardiovascular diseases.

Personalized medicine is an emerging concept involving managing the health of patients based on their individual characteristics, including particular genotypes. Cardiovascular diseases are heritable traits, and family history information is useful for risk prediction. As such, determining genetic information (germline genetic mutations) may also be applied to risk prediction. Furthermore, accumulating evidence suggests that genetic background can provide guidance for selecting effective treatments and preventive strategies in individuals with particular genotypes. These concepts may be applicable both to rare Mendelian diseases and to common complex traits. In this review, we define the concept and provide examples of personalized medicine based on human genetics for cardiovascular diseases, including coronary artery disease, arrhythmia, and cardiomyopathies. We also provide a particular focus on Mendelian randomization studies, especially those examining loss-of function genetic variations, for identifying high-risk individuals, as well as signaling pathways that may be useful targets for improving healthy living without cardiovascular events.

Association of Lower Urinary Tract Symptoms Based on the International Prostate Symptom Score and Cardiovascular Disease.

BACKGROUND: Because it is unclear whether lower urinary tract symptoms (LUTS) are associated with cardiovascular disease (CVD) in the Japanese population, we explored the association in general Japanese men aged 55-75 years.Methods and Results:The cross-sectional study included male participants who had both national health checkup data and the International Prostate Symptom Score (IPSS) in the same calendar year between 2009 and 2017. LUTS severity was evaluated by IPSS. A robust Poisson regression model was used to assess the association between LUTS severity and the composite CVD outcome [coronary artery disease (CAD), stroke, or atrial fibrillation (AF)] and each component of the composite outcome. Prevalence ratio (PR) was adjusted for conventional cardiovascular risk factors. Of 16,781 male participants (mean age, 67±5 years), mild LUTS were observed in 9,243 (55.1%); moderate, 6,445 (38.4%); and severe, 1,093 (6.5%). Compared with the mild LUTS group, moderate LUTS [PR 1.18, 95% confidence interval (CI) 1.10-1.25, P<0.001] and severe LUTS (PR 1.38, 95% CI 1.24-1.53, P<0.001) were significantly associated with a higher prevalence of CVD. LUTS severity was associated with higher prevalence of CAD and stroke, but not AF. CONCLUSIONS: The severity of LUTS was associated with a higher prevalence of CVD, especially CAD and stroke, independent of conventional CVD risk factors.

A Novel Risk Stratification System for Ischemic Stroke in Japanese Patients With Non-Valvular Atrial Fibrillation.

BACKGROUND: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry.Methods and Results:The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m2(L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E2S2score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS2(0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA2DS2-VASc scores (0.641; 95% CI=0.608-0.673, P=0.008). CONCLUSIONS: The HELT-E2S2score may be useful for identifying Japanese NVAF patients at risk of ischemic stroke.

First-degree atrioventricular block is significantly associated with incident atrial fibrillation in the population predominantly including participants aged ≥ 60 years.

Some previous studies demonstrated that first-degree atrioventricular block (f-AVB) was associated with incident atrial fibrillation (AF), while evidence is scarce regarding the association between f-AVB and incident AF in older populations. Therefore, we sought to investigate the association of f-AVB with incident AF in the population predominantly including participants aged ≥ 60 years. Eligible participants were residents in Kanazawa City, Japan aged ≥ 40 years who underwent 12-lead ECG at the National Japanese Health Check-up in 2013. Participants with AF detected at the baseline exam and those without adequate follow-up were excluded. f-AVB was defined as PR interval ≥ 220 ms based on the Minnesota code (6-3). The cumulative incidence of AF was estimated by the Kaplan-Meier curve analysis, and statistical significance was evaluated by the Log-rank test. Unadjusted and adjusted hazard ratios (HRs) were computed by Cox proportional hazard models. HRs were adjusted for conventional risk factors for AF. 37,730 participants (mean age, 72.3 ± 9.6 years; male, 37%) were included. Baseline f-AVB was observed in 667 (1.8%) participants. During the median follow-up period of 5 years (interquartile range, 4.0-5.0 years), 691 cases of incident AF were observed. A 5-year cumulative incidence of AF was significantly higher in f-AVB (+) group compared with f-AVB (-) group (6.8% vs 2.1%, p < 0.01). In the fully adjusted model, f-AVB was significantly associated with incident AF (HR, 1.75; 95% confidence interval 1.25-2.45; p value < 0.01). f-AVB was independently associated with incident AF in the population predominantly including participants aged ≥ 60 years.

SERS Gas Sensors Based on Multiple Polymer Films with High Design Flexibility for Gas Recognition.

The Surface-Enhanced Raman Scattering (SERS) technique is utilized to fabricate sensors for gas detection due to its rapid detection speed and high sensitivity. However, gases with similar molecular structures are difficult to directly discriminate using SERS gas sensors because there are characteristic peak overlaps in the Raman spectra. Here, we proposed a multiple SERS gas sensor matrix via a spin-coating functional polymer to enhance the gas recognition capability. Poly (acrylic acid) (PAA), Poly (methyl methacrylate) (PMMA) and Polydimethylsiloxane (PDMS) were employed to fabricate the polymer film. The high design flexibility of the two-layer film was realized by the layer-by-layer method with 2 one-layer films. The SERS gas sensor coated by different polymer films showed a distinct affinity to target gases. The principle component analysis (PCA) algorithm was used for the further clustering of gas molecules. Three target gases, phenethyl alcohol, acetophenone and anethole, were perfectly discriminated, as the characteristic variables in the response matrix constructed by the combination of gas responses obtained 3 one-layer and 3 two-layer film-coated sensors. This research provides a new SERS sensing approach for recognizing gases with similar molecular structures.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.

Optimization of the hot balloon ablation strategy using real-time pulmonary vein potential monitoring.

INTRODUCTION: Optimal radiofrequency-generated thermal energy applications have not been established for hot balloon ablation (HBA) systems. We investigated the feasibility of real-time monitoring of pulmonary vein (PV) potentials and optimal time-to-isolation (TTI)-guided application strategies in HBAs. METHODS AND RESULTS: Real-time monitoring of PV potentials was performed using a four-electrode unidirectional catheter in 34 consecutive patients. Acute isolation was achieved when PV potentials disappeared during HBAs and were undetected by high-resolution mapping. The TTI, the difference between TTI and the time to reach target temperature (TTRT), and ablation time after isolation were examined for 177 applications in 136 PVs. Real-time monitoring of PV activity was obtained in 167 out of 177 applications (94.3%) and acute isolation was achieved in 97 out of 177 (54.8%) applications. TTI-TTRT was significantly shorter, and ablation times after isolation were significantly longer in the acute isolation group than in the other groups. TTI-TTRT <4.5 seconds and TTIs <33.5 seconds predicted acute isolation (sensitivity 74.2%, specificity 88.4%; sensitivity 76.3%, specificity 76.7%, respectively). Ablation time after isolation >148.5 seconds (sensitivity 93.6%, specificity 51.7%) and >120.5 seconds (sensitivity 84.0%, specificity 78.6%) predicted acute isolation in superior PVs and inferior PVs, respectively. CONCLUSIONS: Real-time assessment of PV isolation can be achieved during HBAs with single-shot techniques. (TTI-TTRT)s <4.5 seconds and TTIs <33.5 seconds predicted for acute isolation. Ablation time after isolation >148.5 seconds in superior PVs and >120.5 seconds in inferior PVs were effective application durations.