Hiroya Matsumura

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.

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.

Role of transthoracic left atrial appendage wall motion velocity in patients with persistent atrial fibrillation and a low CHADS2 score

BACKGROUND AND PURPOSE Thromboembolic risk has been examined by semi-invasive transesophageal echocardiography. We assessed the risk of thrombogenesis in patients with persistent atrial fibrillation (AF) noninvasively by using transthoracic tissue Doppler echocardiography (TDE) in relation to a low CHADS2 score. METHODS Eighty patients with persistent AF underwent both transthoracic and transesophageal echocardiography. Peak left atrial appendage (LAA), wall motion velocity (WV) during LAA contraction was measured by transthoracic and transesophageal TDE. LAA flow velocity was also determined by transesophageal echocardiography. RESULTS Transthoracic LAAWV could be measured in 78 of the 80 patients, and the values were closely correlated with transesophageal TDE values (r=0.98) and with transesophageal LAA flow velocity (r=0.82). Transthoracic LAAWV was significantly lower with increasing spontaneous echo contrast (SEC) severity (severe SEC, mild SEC, no SEC: 5.7±2.4, 10.2±3.3, and 14.5±5.5cm/s, respectively). Severe SEC was noted in 31 of 61 patients with a CHADS2 score ≤2, in 19 of 46 patients with a CHADS2 score ≤1 and in 6 of 21 patients with a CHADS2 score=0. For diagnosing severe SEC, a transthoracic LAAWV <10cm/s had a sensitivity of 81% and specificity of 92% in the patients with a CHADS2 score ≤2, a sensitivity of 74% and specificity of 91% in the patients with a CHADS2 score ≤1 and a sensitivity of 44% and specificity of 83% in the patients with a CHADS2 score=0. CONCLUSIONS A transthoracic LAAWV <10cm/s in persistent AF patients with a low CHADS2 score may be a very specific diagnostic tool for evaluating severe SEC, one of the high risk factors for thromboembolism.

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.

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.

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

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.

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.

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.

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.