Yoshikazu Watanabe

A Nonsynonymous Polymorphism in Semaphorin 3A as a Risk Factor for Human Unexplained Cardiac Arrest with Documented Ventricular Fibrillation

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67–5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A I334V, VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A I334V (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A I334V. Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A I334V genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A I334V in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

Presentations of acute coronary syndrome related to coronary lesion morphologies as assessed by intravascular ultrasound and optical coherence tomography

BACKGROUND Pathologically, the lesions responsible for acute coronary syndrome (ACS) are ruptures of vulnerable plaques (and occasionally fibrous-cap erosions or calcified nodules) with a superimposed thrombosis. We aimed to clarify the clinical presentations related to the morphologies of coronary lesions of ACS using intravascular ultrasound (IVUS) and optical coherence tomography (OCT). METHODS AND RESULTS Seventy-five culprit lesions of ACS patients were clearly assessed with IVUS and OCT. Patients were classified into two groups based on the presence or absence of a rupture of a culprit plaque as identified by OCT. Clinical characteristics and lesion morphologies were compared between the two groups. Waist circumference was significantly greater (p<0.02) and prevalence of the metabolic syndrome (MS) higher (p=0.0011) in the rupture group. The prevalence of prodromal angina was higher in patients without plaque ruptures (p<0.0001). Using multivariate analysis, the MS and prodromal angina were independent predictors of rupture of a culprit coronary plaque (odds ratio (OR): 27.30, p<0.003 and OR: 0.04, p=0.0004, respectively). Among the components of the MS, the prevalence of abdominal obesity was a significant independent predictor of rupture of a culprit plaque (OR: 4.24, p<0.02). CONCLUSIONS There are two presentations related to the coronary lesion morphologies of ACS: we should understand these aspects of ACS.

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.

Deterioration of the circadian variation of heart rate variability in Brugada syndrome may contribute to the pathogenesis of ventricular fibrillation

AIMS Abnormal sympathetic innervation triggers ventricular fibrillation (VF). We examined the circadian variation of autonomic nervous system and its relevance to risk stratification of VF in patients with Brugada syndrome (Brs). METHODS We enrolled 12 male Brs patients with documented VF (Brs-S; mean age, 42±4 years), 17 without documented VF (Brs-N; mean age 48±4 years), and 16 age- and gender-matched controls. The clinical data, 12-lead electrocardiography (ECG), signal-averaged ECG, electrophysiological study (EPS), and heart rate variability from 24h Holter ECG were compared between the groups. RESULTS The low frequency components (LF) in Brs-S and Brs-N and high frequency components (HF) in Brs-S patients were significantly lower than in the controls (409.8±128.6ms(2), 329.5±108ms(2) vs. 945.3±111.3ms(2); 135.1±73.8ms(2) vs. 391.8±63.9ms(2), respectively). The circadian variation of the LF and LF/HF decreased in the Brs patients, the standard deviation (SD) of LF/HF (<2.5) and SD of LF (<400ms(2)) had sufficiently high sensitivity (96.6%) and specificity (92.9%) for the diagnosis of Brs. Most of the Brs-S patients (83.3%) were located under the line formed by the SD/mean of HF=SD/mean of LF in the scatter plots. CONCLUSION Lack of the circadian variation of autonomic function occurs in Brs, and this may contribute to the pathogenesis of VF.

Clinical impact of dyslipidemia for coronary plaque vulnerability in acute coronary syndrome without metabolic syndrome.

BACKGROUND Although the metabolic syndrome is associated with incident cardiovascular disease, low-density lipoprotein (LDL) cholesterol is a well-known risk factor for coronary atherosclerosis. The aim of this study was to clarify the clinical markers for coronary plaque vulnerability in acute coronary syndrome (ACS) patients (men) without the metabolic syndrome. METHODS Consecutive Japanese men with ACS (n=264) underwent emergent coronary angiography and B-mode carotid ultrasonography. Common carotid intima-media thickening and vascular dilatation were considered to indicate carotid artery remodeling. Patients were divided into two groups based on the number of complex plaques identified by coronary angiography. RESULTS Abdominal obesity and low high-density lipoprotein cholesterol levels were frequently observed in overall patients with multiple complex coronary lesions. Although the metabolic syndrome was a significant independent predictor of multiple complex coronary lesions in overall ACS patients, a high LDL cholesterol level was an independent predictor in ACS patients without the metabolic syndrome. Carotid artery remodeling was an independent predictor of multiple complex coronary lesions in both overall patients and patients without the metabolic syndrome. CONCLUSION In ACS patients without the metabolic syndrome, high LDL cholesterol levels and carotid artery remodeling are important indicators for assessing the efficacy of aggressive treatments for secondary prevention of ACS.

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.

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.