Impact of SGLT2 inhibitors on old age patients with heart failure and chronic kidney disease.

BACKGROUND: The heart failure (HF) "pandemic" is an ongoing critical issue related to the aging population. Among the new heart failure medications, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to provide clinical benefit in HF patients with chronic kidney disease (CKD). However, the efficacy and safety of SGLT2i in old age patients remains uncertain. METHODS: The OSHO-heart (Optimal Solution after Hospitalization in Onomichi for heart failure) is a prospective study of 213 patients aged ≥ 75 years-old hospitalized for acute decompensated HF with stage 3 to 4 CKD. The composite outcomes of HF rehospitalizations or cardiovascular death and the rate of decline in the estimated glomerular filtration rate (eGFR) were compared between the Loop (n = 76), tolvaptan (TLV) (n = 80) and SGLT2i (n = 57) groups, respectively. RESULTS: During follow-up (17.2 months, median), composite of HF rehospitalization or cardiovascular death events occurred in 30 (39.5%) in Loop, 19 (23.8%) in TLV and 8 (14%) in SGLT2i groups, respectively (Log-rank: P = 0.015). A multivariate analysis demonstrated that the continuation of SGLT2i (hazard ratio, 0.41; 95% CI, 0.19 to 0.78; P = 0.022) and an EF < 30% (hazard ratio, 2.19; 95% CI, 1.22 to 3.92; P = 0.009) were independently associated with the composite outcome. The rate of decline in the eGFR was significantly less in TLV and SGLT2i groups than Loop group (-1.64 vs. -1.28 vs. -5.41 ml/min/1.73 m2 per year, P = 0.007, respectively). CONCLUSIONS: SGLT2i therapy might reduce the combined risk of HF hospitalizations or cardiac death and preserve a worsening renal function in old age patients with HF and CKD.

Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs.

PURPOSE: Thromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their frequency across different direct oral anticoagulants (DOACs). We aimed to compare the intra-ablation blood coagulability and post-procedural hemoglobin fall as alternatives to those complications across 4 DOACs. METHODS: We enrolled AF patients younger than 65 years old in 3 cardiovascular centers who skipped a single dose of apixaban, dabigatran, edoxaban, and rivaroxaban, prior to the ablation. Endpoints included the activated clotting time (ACT), heparin requirement during the ablation, and drop in the hemoglobin level 24 h after the procedure. RESULTS: The time-course curves of the ACT differed significantly across the patients with apixaban (N = 113), dabigatran (N = 130), edoxaban (N = 144), and rivaroxaban (N = 81), with its highest level in the dabigatran group (P < 0.001). The average ACT was greater in the dabigatran group than in the other groups (312.3 ± 34, 334.4 ± 44, 308.1 ± 41, and 305.8 ± 34.7 s; P < 0.001). A significant difference was noted in total heparin requirement across the patient groups (3990.2 ± 1167.9, 3890.4 ± 955.3, 4423.8 ± 1051.6, and 3972 ± 978.7 U/m2/h; P < 0.001), with its greatest amount in the edoxaban group. The reduction in the hemoglobin level was similar (- 0.93 ± 0.92, - 0.88 ± 0.79, - 0.89 ± 0.97, - 0.95 ± 1.23 g/dL; P = 0.94). No inter-group difference was noted in the rate of major or minor bleedings (0.9%, 2.3%, 1.4%, and 3.7%; P = 0.51), and no thromboembolic events were encountered. CONCLUSION: A difference in DOACs may have an impact on intra-ablation anticoagulation; however, it may not be on the procedural blood loss in the setting of a single skip.

Remaining activity of temporary interrupted direct oral anticoagulants and its impact on intra-ablation heparinization in patients with atrial fibrillation: Comparisons across four drugs and two dose regimens.

BACKGROUND: Atrial fibrillation (AF) ablation with minimally interrupted direct oral anticoagulants (DOACs) may raise a concern about their remaining activity. We tested the residual activity of four different DOACs and its impact on intraprocedural heparinization in patients undergoing AF ablation. METHODS: We measured the anti-factor Χa activity for rivaroxaban, apixaban, and edoxaban, and serum DOAC concentration for rivaroxaban, apixaban, and dabigatran, 24 hours after the last intake in patients undergoing AF ablation treated with standard or reduced doses of DOACs. The heparin requirement during the procedure was also measured. RESULTS: We enrolled 34 patients with rivaroxaban, 35 with apixaban, 32 with edoxaban, and 31 with dabigatran, and among them, 30 were treated with reduced doses. The anti-factor Χa activity was the highest in the apixaban group among the patients with standard doses. The DOAC concentration was paradoxically lower in patients with standard doses than in those with reduced doses among the patients with rivaroxaban (34.3 ± 19.8 vs 56.6 ± 7.7 ng/mL; P = .01) and dabigatran (12.6 ± 10.6 vs 23.4 ± 14.7 ng/mL; P = .03). The total heparin requirement per body surface area had significant correlations with the anti-factor Χa activity (r = -.36) and DOAC concentration (r = -.32). Two different multiple linear regression models (adjusted R2 = 0.56 and 0.6, respectively) revealed that the anti-factor Χa activity (ß = -.28; P = .002) and DOAC concentration (ß = -.38; P < .001) were independent determinants of the total heparin requirement. CONCLUSIONS: Factors determining residual DOAC activity may include its type and dose regimen, and it may influence the heparin requirement during AF ablation.

Residual anticoagulation activity in atrial fibrillation patients with temporary interrupted direct oral anticoagulants: Comparisons across 4 drugs.

BACKGROUND: Atrial fibrillation (AF) ablation with minimally interrupted direct oral anticoagulants (DOACs) predominates, possibly raising concern about their remaining activity during the procedure. We aimed to examine residual activities of 4 different DOACs. METHODS: The serum DOAC concentration and anti-factor Χa activity were measured 3 and 24 h after the last intake in patients undergoing AF ablation who were treated with rivaroxaban, apixaban, edoxaban, or dabigatran. RESULTS: The reduction in the apixaban concentration between the 2 blood sampling time points (N = 32, mean ±â€¯SD, -67.7 ±â€¯14.8% [231.6 ±â€¯93.1 to 71.9 ±â€¯31.8 ng/mL]) was smaller than that for rivaroxaban (N = 28, -83.6 ±â€¯10.9% [234.2 ±â€¯96.6 to 34.3 ±â€¯19.8 ng/mL]; P < 0.001) and dabigatran (N = 20, -90.7 ±â€¯7.3% [135.3 ±â€¯68.3 to 12.6 ±â€¯10.6 ng/mL]; P < 0.001), with its greatest value measured 24 h after the last intake in the apixaban group. The decrease in the anti-factor Χa activity was also smaller in the patients with apixaban (-73.8 ±â€¯12.7%) than with rivaroxaban (-87.9 ±â€¯7.9%; P < 0.001) and edoxaban (N = 22, -81.9 ±â€¯15.2%; P = 0.049), and its remaining activity 24 h after the last dose was the highest in the apixaban group. A serum DOAC concentration measured 24 h after the last dose of >30 ng/mL was seen in 41 (51.3%) patients with rivaroxaban, apixaban, or dabigatran, and it was independently associated with apixaban versus rivaroxaban (odds ratio 5.0; P = 0.01) and apixaban versus dabigatran (odds ratio 74.0; P < 0.001). CONCLUSION: The pattern of drug elimination from blood may vary depending on DOACs, and their residual activity may not be negligible even 24 h after the last intake.

A mimic of tachycardia-bradycardia syndrome in a patient with long-standing persistent atrial fibrillation.

Pause following incessant tachycardia is often encountered in clinical practice. We encountered a rare arrhythmic condition mimicking tachycardia-bradycardia syndrome. We hereby describe the step-by-step diagnostic process.

Ser96Ala genetic variant of the human histidine-rich calcium-binding protein is a genetic predictor of recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA) still remains a serious issue. Ca2+ handling has a considerable effect on AF recurrence. The histidine-rich calcium-binding protein (HRC) genetic single nucleotide polymorphism (SNP), rs3745297 (T>G, Ser96Ala), is known to cause a sarcoplasmic reticulum Ca2+ leak. We investigated the association between HRC Ser96Ala and AF recurrence after RFCA in paroxysmal AF (PAF) patients. METHODS AND RESULTS: We enrolled PAF patients who underwent RFCA (N = 334 for screening and N = 245 for replication) and were genotyped for HRC SNP (rs3745297). The patient age was younger and rate of diabetes and hypertension lower in the PAF patients with Ser96Ala than in those without (TT/TG/GG, 179/120/35; 64±10/60±12/59±13 y, P = 0.001; 18.5/ 9.2/8.6%, P = 0.04 and 66.1/50.0/37.1%, P = 0.001, respectively). During a mean 19 month follow-up, 57 (17.1%) patients suffered from AF recurrences. The rate of an Ser96Ala was significantly higher in patients with AF recurrence than in those without in the screening set (allele frequency model: odds ratio [OR], 1.80; P = 0.006). We also confirmed this significant association in the replication set (OR 1.74; P = 0.03) and combination (P = 0.0008). A multivariate analysis revealed that the AF duration, sinus node dysfunction, and HRC Ser96Ala were independent predictors of an AF recurrence (hazard ratio [HR], 1.04, P = 0.037; HR 2.42, P = 0.018; and HR 2.66, P = 0.007, respectively). CONCLUSION: HRC SNP Ser96Ala is important as a new genetic marker of AF recurrence after RFCA.

Chromosome 4q25 Variant rs6817105 Bring Sinus Node Dysfunction and Left Atrial Enlargement.

Genome-wide association studies have reported a strong association of the single nucleotide polymorphism (SNP) rs6817105 (T > C) on chromosome 4q25 with atrial fibrillation (AF), but phenotype alterations conferred by this SNP have not been described. We genotyped SNP rs6817105 and examined the relationships among rs6817105 genotype, clinical characteristics, echocardiographic parameters, and electrophysiological parameters in 574 AF patients and 1,554 non-AF controls. Further, multiple microRNAs (miRNAs) are reported to be involved in atrial remodeling and AF pathogenesis, so we investigated relationships between rs6817105 genotype and serum concentrations of 2555 miRNAs. The rs6817105 minor allele frequency was significantly higher in AF patients than non-AF controls (66% vs. 47%, odds ratio 2.12, p = 4.9 × 10-26). Corrected sinus node recovery time (CSRT) was longer and left atrial volume index (LAVI) was larger in AF patients with the rs6817105 minor allele than patient non-carriers (CSRT: CC 557 ± 315 ms, CT 486 ± 273 ms, TT 447 ± 234 ms, p = 0.001; LAVI: CC 43.6 ± 12.1, CT 42.4 ± 13.6, TT 39.8 ± 11.6, p = 0.030). There were no significant differences between rs6817105 genotype and the serum concentrations of miRNAs. These findings strongly implicate rs6817105 minor allele in sinus node dysfunction and left atrial enlargement.

Maintenance of low inflammation level by the ZFHX3 SNP rs2106261 minor allele contributes to reduced atrial fibrillation recurrence after pulmonary vein isolation.

INTRODUCTION: The single nucleotide polymorphism (SNP) rs2106261 in the transcription factor gene ZFHX3 (16q22), a major regulator of inflammation, has been reported linking to atrial fibrillation (AF) by genome-wide association studies. Inflammation is known to be a strong predictor of atrial fibrillation recurrence after ablation, so we examined the association of the ZFHX3 SNP rs2106261 to inflammation marker expression and recurrence after AF ablation. METHODS: We genotyped ZFHX3 SNP rs2106261 and compared the minor (T) allele frequency between 362 paroxysmal AF (PAF) patients underwent pulmonary vein isolation (PVI) and 627 non-AF controls. We also analyzed associations between ZFHX3 SNP rs2106261 genotype and recurrence rate after pulmonary vein isolation and the inflammation markers. RESULTS: The minor (T) allele frequency of the ZFHX3 SNP rs2106261 was significantly higher in AF patients than non-AF controls (odds ratio 1.52, p = 2.2×10-5). Multivariable analysis revealed that the minor allele (T) decreased AF recurrence rate after pulmonary vein isolation (hazard ratio 0.53, p = 0.04). Further, neutrophil/lymphocyte (N/L) ratio, C-reactive protein (CRP), and interleukin-6 (IL-6) expression levels were lower in PAF patients with the ZFHX3 SNP rs2106261 minor allele (TT+TC) than in CC patients (N/L ratio: CC 2.22 ± 0.08, TT+TC 1.98 ± 0.06, p = 0.018; CRP: CC 0.103 ± 0.009 mg/dl, TT+TC 0.076 ±0.007 mg/dl, p = 0.016; IL-6: CC 60.3 ± 3.0 pg/ml, TT+TC 52.8 ± 2.3 pg/ml, p = 0.04). CONCLUSIONS: The ZFHX3 SNP rs2106261 minor allele is associated with lower AF recurrence rate after pulmonary vein isolation. Low baseline inflammation conferred by this allele may reduce AF recurrence risk.

HCN4 Gene Polymorphisms Are Associated With Occurrence of Tachycardia-Induced Cardiomyopathy in Patients With Atrial Fibrillation.

BACKGROUND: Tachycardia-induced cardiomyopathy (TIC) is a reversible cardiomyopathy induced by tachyarrhythmia, and the genetic background of the TIC is not well understood. The hyperpolarization-activated cyclic nucleotide-gated channel gene HCN4 is highly expressed in the conduction system where it is involved in heart rate control. We speculated that the HCN4 gene is associated with TIC. METHODS: We enrolled 930 Japanese patients with atrial fibrillation (AF) for screening, 350 Japanese patients with AF for replication, and 1635 non-AF controls. In the screening AF set, we compared HCN4 single-nucleotide polymorphism genotypes between AF subjects with TIC (TIC, n=73) and without TIC (non-TIC, n=857). Of 17 HCN4 gene-tag single-nucleotide polymorphisms, rs7172796, rs2680344, rs7164883, rs11631816, and rs12905211 were significantly associated with TIC. Among them, only rs7164883 was independently associated with TIC after conditional analysis (TIC versus non-TIC: minor allele frequency, 26.0% versus 9.7%; P=1.62×10-9; odds ratio=3.2). RESULTS: We confirmed this association of HCN4 single-nucleotide polymorphism rs7164883 with TIC in the replication set (TIC=41 and non-TIC=309; minor allele frequency, 28% versus 9.9%; P=1.94×10-6; odds ratio=3.6). The minor allele frequency of rs7164883 was similar in patients with AF and non-AF controls (11% versus 10.9%; P=0.908). CONCLUSIONS: The HCN4 gene single-nucleotide polymorphism rs7164883 may be a new genetic marker for TIC in patients with AF.

In Paroxysmal Atrial Fibrillation Patients, the Neutrophil-to-lymphocyte Ratio Is Related to Thrombogenesis and More Closely Associated with Left Atrial Appendage Contraction than with the Left Atrial Body Function.

Objective The neutrophil-to-lymphocyte ratio (NLR) is an inflammation marker that can be used to detect atrial inflammatory changes, which may contribute to a reduced left atrial (LA) function and thrombosis. Our study aimed to determine whether or not the association of NLR with the LA appendage (LAA) function in relation to thrombogenesis differs from the association with the LA body function in paroxysmal atrial fibrillation (PAF) patients. Methods A total of 183 PAF patients were studied. The LA volume index, mitral flow velocity (A), and mitral annular motion velocity (A') were examined using transthoracic echocardiography. The LAA area, LAA wall motion velocity, and presence of spontaneous echo contrast (SEC) were examined using transesophageal echocardiography. Results The NLR of patients with cerebral embolism was significantly greater than in patients without the disorder. A cut-off point of 2.5 for the NLR had a sensitivity of 71% and a specificity of 74% in predicting cerebral embolism. The patients with an NLR ≥2.5 had a higher CHADS2 score and greater LA volume index or LAA area than those with an NLR <2.5. The NLR was an independent risk factor for SEC and was significantly correlated with the LAA wall motion velocity (r=-0.409) in 153 patients without SEC and with the LAA wall motion velocity and LAA area (r=-0.583, r=0.654, respectively) in 30 patients with SEC, but not with the LA volume index, A, or A' in either group. Conclusion In PAF patients, a high NLR indicates thrombogenesis with a high degree of certainty and is associated with reduced LAA contraction rather than with the LA body function.

H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters.

BACKGROUND: A common SCN5A polymorphism H558R (c.1673 A > G, rs1805124) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS. METHODS AND RESULTS: We genotyped H558R in 100 BrS (mean age 45 ± 14 years; 91 men) and 1875 controls (mean age 54 ± 18 years; 1546 men). We compared clinical parameters in BrS with and without H558R (H558R+ vs. H558R- group, N = 9 vs. 91). We also obtained right atrial sections from 30 patients during aortic aneurysm operations and compared SCN5A expression and methylation with or without H558R. H558R was less frequent in BrS than controls (9.0% vs. 19.2%, P = 0.028). The VF occurrence ratio was significantly lower (0% vs. 29.7%, P = 0.03) and spontaneous type 1 ECG was less observed in H558R+ than H558R- group (33.3% vs. 74.7%, P = 0.01). The SCN5A expression level was significantly higher and the methylation rate was significantly lower in sections with H558R (N = 10) than those without (0.98 ± 0.14 vs. 0.83 ± 0.19, P = 0.04; 0.7 ± 0.2% vs. 1.6 ± 0.1%, P = 0.004, respectively). In BrS with heterozygous H558R, the A allele mRNA expression was 1.38 fold higher than G allele expression. CONCLUSION: The SCN5A polymorphism H558R may be a modifier that protects against VF occurrence in BrS. The H558R decreased the SCN5A promoter methylation and increased the expression level in cardiac tissue. An allelic expression imbalance in BrS with a heterozygous H558R may also contribute to the protective effects in heterozygous mutations.

Radiofrequency catheter ablation is effective for atrial fibrillation patients with hypertrophic cardiomyopathy by decreasing left atrial pressure.

BACKGROUND: Radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) refractory to medical therapy remains controversial in patients with hypertrophic cardiomyopathy (HCM); the acute effects on the direct left atrial (LA) pressure are not completely understood. METHODS: We consecutively studied patients with HCM (n=15) and without HCM (NHCM, n=106) who underwent extensive encircling pulmonary vein isolation for drug-refractory AF. We compared clinical parameters, echocardiographic parameters, electrophysiological parameters, LA pressures using hemodynamic catheterization and recurrence rate in both groups. RESULTS: The LA volume index was significantly higher (51.9±13.6 mL/m2 vs. 41.6±12.7 mL/m2, p=0.02) in the HCM group than the NHCM group. The pre-ablation mean LA pressure was significantly higher in the HCM group than the NHCM group. Among the AF patients, the mean LA pressure decreased more significantly in the HCM group than the NHCM group (post-ablation minus pre-ablation pressures: 4.2±3.7 mmHg vs. 0.9±4.1 mmHg, p=0.03). The early recurrence rate (within 30 days after ablation) tended to be higher in the HCM group than the NHCM group (20% vs. 5.7%, p=0.08), but the rates of late recurrences (>30 days after ablation) were similar (13.3% vs. 7.6%, p=0.83). Discontinuation of antiarrhythmic drugs occurred at rates of 13% and 62% in the HCM and NHCM groups, respectively (p<0.001). CONCLUSIONS: The LA pressure in the HCM group decreased immediately after AF RFCA. Patients with HCM and drug-refractory AF may benefit from RFCA.

Genetic variations of aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B are associated with the etiology of atrial fibrillation in Japanese.

BACKGROUND: Alcohol consumption and oxidative stress are well-known risk factors for developing atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes encoding enzymes of alcohol and reactive aldehyde metabolism, respectively, are prevalent among East Asians. Here, we examined whether these SNPs were associated with AF in Japanese patients. METHODS AND RESULTS: Five hundred seventy-seven Japanese patients with AF undergoing catheter ablation and 1935 controls at Hiroshima University Hospital were studied. Alcohol consumption habits, medical history, electrocardiogram (EKG), electrophysiology and cardiac echocardiography were reviewed. Patients were also genotyped for ALDH2 (rs671) and ADH1B (rs1229984). A significant linear correlation was found between ALDH2 genotype and mean alcohol intake (P = 1.7 × 10-6). Further, ALDH2 (rs671) was associated with AF (P = 7.6 × 10-4, odds ratio [OR] = 0.6). Frequency of the ALDH2 SNP allele A which limits acetaldehyde metabolism was lower in patients with AF (18.8%) than in controls (23.5%). In contrast, we found that the frequencies of the ADH1B SNP genotypes were similar in patients with AF and in controls. Subset analysis among the 182 patients with lone AF and 914 controls (control II) (<60 years of age and without hypertension), both ALDH2 and ADH1B SNPs were significantly associated with AF (P = 0.013, OR = 0.7; P = 0.0007, OR = 1.4, respectively). The frequency of the dysfunctional allele A of ALDH2 was significantly lower and the dysfunctional allele G of ADH1B was significantly higher in patients with lone AF than in control II (ALDH2 A allele frequency = 0.176 vs 0.235, OR = 1.3, P = 0.013, ADH1B SNP G allele frequency = 0.286 vs 0.220, OR = 1.4, P = 0.0007). CONCLUSIONS: When considering all patients enrolled, the dysfunctional ALDH2 allele was negatively associated with AF. When examining a subset of patients with lone AF, the dysfunctional ALDH2 allele was negatively associated with AF and the slower metabolizing ADH1B allele was positively associated with AF. Hence, prolonged metabolic conversion of alcohol to acetaldehyde may be associated with the occurrence of AF in the Japanese and other East Asian populations.

Dexmedetomidine Depresses Sinoatrial and Atrioventricular Nodal Function Without Any Change in Atrial Fibrillation Inducibility.

It has been reported that dexmedetomidine (dex) has an impact on the cardiac conduction system and even has potential antiarrhythmic actions. We examined the influence of dex on the cardiac electrophysiological properties and atrial fibrillation (AF) inducibility. Adult paroxysmal AF patients were randomly assigned to receive (N = 107) or not receive (N = 108) dex during cardiac electrophysiological studies. The corrected sinus node recovery time (558 ± 331 vs. 459 ± 260 milliseconds; P = 0.02), Wenckebach cycle length (P < 0.001), atrioventricular nodal effective refractory period (317 ± 76 vs. 252 ± 54 milliseconds; P < 0.001), and atrio-His interval (P < 0.001) were longer in patients with dex than in those without. We tested the induction of repetitive atrial firing (RFA) defined as the occurrence of ≥2 successive atrial activities induced by single premature atrial stimuli to determine the AF inducibility. RFA was seen with a similar proportion (41.1% vs. 44.4%), yet it was evoked at a longer stimulus coupling interval in the dex patients, which was potentially attributed to the longer atrial effective refractory period (237 ± 36 vs. 213 ± 27 milliseconds; P < 0.001) and more prolonged atrial conduction delay seen in the dex group. In conclusion, dex may depress the sinus and atrioventricular nodal function, however, it may not reduce the AF inducibility.

Risk stratification of ventricular fibrillation in Brugada syndrome using noninvasive scoring methods.

BACKGROUND: Risk stratification for ventricular fibrillation (VF) in patients with Brugada syndrome (BrS) remains controversial. OBJECTIVE: The purpose of this study was to construct a novel prediction model for VF risk in BrS patients using noninvasive parameters. METHODS: A total of 143 Japanese BrS patients with VF (n = 35) and without VF (n = 108) were retrospectively enrolled. We built a logistic regression model predicting VF occurrence and evaluated it by cross-validation. RESULTS: Frequencies of history of syncope and spontaneous type 1 ECG, r-J interval in V1, QRS duration in V6, and LAS40, Tpeak-Tend dispersion, and max T-wave alternans were significantly associated with VF occurrence in univariate analyses. The history of syncope, r-J interval in V1, QRS duration in V6, and Tpeak-Tend dispersion were identified as independent predictors by multivariate logistic regression analysis. The predictive model was constructed using all these parameters with good discrimination of VF occurrence (area under the curve 0.869 with 97.1% sensitivity and 65.7% specificity). The area under the curve based on leave-one-out cross-validation was 0.845, with 97.1% sensitivity and 63.0% specificity suggesting good performance of the model. Retrospective survival analysis revealed that the cumulative VF event rate was significantly higher in patients at high risk than in those with low risk using the log rank test (P = 2.97 × 10(-8)). Notably, no BrS patient below the cutoff value developed a subsequent VF event. CONCLUSION: This novel prediction method may effectively assesses VF risk in BrS patients, especially when determining implantable cardioverter-defibrillator placement for asymptomatic BrS patients.

Electrical Remodeling of the Atrioventricular Node Caused by Persistent Atrial Fibrillation in Humans.

BACKGROUND: An animal experiment showed that long-term atrial pacing or persistent atrial fibrillation (AF) caused electrical remodeling of the atrioventricular (AV) node. We aimed to test the hypothesis that persistent AF decreases the AV conductivity in human hearts. METHODS AND RESULTS: We retrospectively compared the cardiac electrophysiological properties between patients with paroxysmal AF who underwent catheter ablation (PXAF, N = 254) and those with persistent or longstanding persistent AF (PSAF, N = 213). The PSAF patients were more likely than PXAF patients to have longer atrial-His (AH) (96.3 ± 25.7 vs. 91.3 ± 20.4 milliseconds; P = 0.02) and His-ventricle (HV) (43.1 ± 9.4 vs. 41.2 ± 8.6 milliseconds; P = 0.02) intervals. The AV nodal effective refractory period (ERP) (299.1 ± 74.6 vs. 276.2 ± 58.9 milliseconds; P < 0.001) and Wenckebach cycle length (420.9 ± 80.3 vs. 386 ± 58.6 milliseconds; P < 0.001) were also more prolonged in the PSAF patients. We found a dual AV nodal physiology with a similar frequency in both groups. The AH interval, fast pathway ERP, and Wenckebach cycle length in the PSAF patients were more likely than in the PXAF patients to be prolonged among the patients without dual pathways, while those intergroup differences were never seen among the patients with dual pathways. In subgroup analyses including only PSAF patients, there was no difference in the AV conductivity between the patients with persistent AF and those with longstanding persistent AF. CONCLUSIONS: Persistent AF may cause a mild decrease in the AV nodal function in human hearts. Electrical remodeling may be uncommon if dual AV nodal pathways are present, and its extent may not depend on the duration of persistent AF.

Increased left atrial pressure in non-heart failure patients with subclinical hypothyroidism and atrial fibrillation.

BACKGROUND: The impact of subclinical hypothyroidism on the cardiovascular risk is still debated. We aimed to measure the relationship between subclinical hypothyroidism and the left atrial (LA) pressure. METHODS: The LA pressures and thyroid function were measured in consecutive patients undergoing atrial fibrillation (AF) ablation, who did not have any known heart failure, structural heart disease, or overt thyroid disease. RESULTS: Subclinical hypothyroidism (4.5≤ thyroid-stimulating hormone <19.9 mIU/L) was present in 61 (13.0%) of the 471 patients included. More subclinical hypothyroidism patients than euthyroid patients (55.7% vs 40.2%; P=0.04).'euthyroid patients had persistent or long-standing persistent AF (55.7% vs 40.2%; P = 0.04). The mean LA pressure (10.9 ± 4.7 vs 9.1 ± 4.3 mmHg; P = 0.002) and LA V-wave pressure (17.4 ± 6.5 vs 14.3 ± 5.9 mmHg; P < 0.001) were, respectively, higher in the patients with subclinical hypothyroidism than in the euthyroid patients. After an adjustment for potential confounders, the LA pressures remained significantly higher in the subclinical hypothyroidism patients. A multiple logistic regression model showed that subclinical hypothyroidism was independently associated with a mean LA pressure of >18 mmHg (odds ratio 3.94, 95% CI 1.28 11.2; P = 0.02). CONCLUSIONS: Subclinical hypothyroidism may increase the LA pressure in AF patients.

Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current.

BACKGROUND: Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of patients with BrS have no genetic explanation. We investigated relationships between genotypes of 3 single-nucleotide polymorphisms reported in a recent genome-wide association study and BrS phenotypes. METHODS AND RESULTS: SCN10A (rs10428132), SCN5A (rs11708996), and downstream from HEY2 (rs9388451) single-nucleotide polymorphisms were genotyped and compared between 95 Japanese patients with BrS and 1978 controls. Relationships between the single-nucleotide polymorphisms and clinical characteristics, 12-lead ECG findings, signal-averaged ECG findings, and electrophysiological parameters were also examined in patients with BrS. Both rs10428132 and rs9388451 were significantly associated with BrS (P=2.7×10(-14); odds ratio, 3.0; P=9.2×10(-4); odds ratio, 1.7, respectively). Interestingly, the HEY2 risk allele C was less frequent in BrS patients with ventricular fibrillation than in those without (59% versus 74%; P=4.1×10(-2); odds ratio, 0.5). A significant linear correlation was found between HEY2 genotypes and QTc interval (CC: 422±27 ms; CT: 408±21 ms; and TT: 381±27 ms; P= 4.0×10(-4)). The HEY2 mRNA expression level in the right ventricular specimens from patients with BrS (n=20) was significantly lower in patients with CC genotype than the other genotypes (P=0.04). Additionally, during 63±28 months follow-up periods after implantable cardioverter defibrillator implantation (n=90), Kaplan-Meier event-free survival curves revealed that the cumulative rate of ventricular fibrillation events was significantly lower in cases with HEY2 CC genotype (P=0.04). CONCLUSIONS: Our findings suggest that HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current.

Mechanical and substrate abnormalities of the left atrium assessed by 3-dimensional speckle-tracking echocardiography and electroanatomic mapping system in patients with paroxysmal atrial fibrillation.

BACKGROUND: Left atrial (LA) remodeling progresses to electrical remodeling, contractile remodeling, and subsequently structural remodeling. Little is known about the relationship between LA electrical and anatomical remodeling and LA mechanical function. OBJECTIVES: We aimed to clarify the relationship between LA mechanical function using 3-dimensional speckle-tracking echocardiography (3D-STE) and LA electrical remodeling using an electroanatomic mapping system (CARTO 3) and to estimate atrial fibrillation (AF) substrate in patients with paroxysmal AF (PAF). METHODS: A total of 52 patients with PAF (41 (79%) men; mean age 61 ± 11 years) undergoing their initial pulmonary vein isolation (PVI) were examined. The standard deviation of the time to peak strain in each LA segment (%SD-TPS) was analyzed as an index of LA dyssynchrony using 3D-STE before PVI. Contact LA bipolar voltage and activation maps were constructed during sinus rhythm before PVI using CARTO 3. The LA total activation time was measured and low-voltage zones (LVZs) were determined with a local bipolar electrogram amplitude of <0.5 mV. The patients were divided into those with an LVZ (LVZ group; n = 23) and those without an LVZ (non-LVZ group; n = 29). RESULTS: The %SD-TPS was significantly higher (14.1 ± 5.7 vs 8.0 ± 5.1; P=.0002) in the LVZ group than in the non-LVZ group and was an independent determinant of the LVZ (odds ratio 1.21; 95% confidence interval 1.04-1.49; P=.01). In addition, the LA total activation time was weakly correlated with the %SD-TPS. CONCLUSION: LA dyssynchrony and conduction delay exist in patients with PAF. The 3D-STE enabled noninvasive estimation of LA electrical remodeling and AF substrate.