To prevent atrial fibrillation (AF), it is essential to reduce its risk factors and extend healthy life expectancy as a result. There are few reviews on the AF risk factors. We discuss them and approach the prevention of AF. We briefly review traditional risk factors for incident AF, especially focusing on high blood pressure, overweight/obesity, dyslipidemia, diabetes, tobacco smoking, and excessive drinking. When trying to prevent AF by modifying lifestyle, it is important to comprehensively utilize the risk factors for AF to predict the 10-year as an AF risk score. However, there are only 2 risk scores of AF just for the US population. There are few studies of the AF risk factors in non-Western populations. A risk score for incident AF in non-Westerners is awaited because different race and lifestyles may have different contributions as AF risk factors. An AF risk score in accordance with race could be useful for identifying persons with a high risk of AF in order to encourage them to consult a doctor and encourage lifestyle modifications before the onset of AF. (Circ J 2016; 80: 2415–2422)
Background:Mutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.
Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0–61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias.
Conclusions:VariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing “ankyrin-B” syndrome. (Circ J 2016; 80: 2435–2442)
Background:Long QT syndrome 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). Most of its mutations give rise to unstable hERG proteins degraded by the proteasome. Recently, carbachol was reported to stabilize the wild-type hERG-FLAG via activation of the muscarinic type 3 receptor (M3-mAChR). Its action on mutant hERG-FLAG, however, remains uninvestigated.
Methods and Results:A novel mutant hERG-FLAG carried 2 mutations: an amino acid substitution G572S and an in-frame insertion D1037_V1038insGD. When expressed in HEK293 cells, this mutant hERG-FLAG was degraded by the proteasome and failed to be transported to the cell surface. Carbachol restored stability of the mutant hERG-FLAG and facilitated cell-surface expression. Carbachol activated PKC, augmented phosphorylation of heat shock factor 1 (HSF1) and enhanced expression of heat shock proteins (hsps), hsp70 and hsp90. Both a M3-mAChR antagonist, 4-DAMP, and a PKC inhibitor, bisindolylmaleimide, abolished carbachol-induced stabilization of the mutant hERG-FLAG.
Conclusions:M3-mAChR activation leads to enhancement of hsp expression via PKC-dependent phosphorylation of HSF1, thereby stabilizing the mutant hERG-FLAG protein. Thus, M3-mAChR activators may have a therapeutic value for patients with LQT2. (Circ J 2016; 80: 2443–2452)
Background:The association between serum uric acid (UA) levels and atrial fibrillation (AF) in the general population in Japan is not well known.
Methods and Results:In total, 285,882 consecutive subjects (men, 130,897; women, 154,985; age, 58±15 years) not receiving treatment for hyperuricemia who underwent health checkups were enrolled. Subjects were stratified into deciles according to age, body mass index, estimated glomerular filtration rate, systolic blood pressure, and UA level. AF prevalence was calculated for each decile. The odds ratio that defined the decile with the lowest AF prevalence as reference was calculated in each sex. In men, the mean UA was 6.0±1.4 mg/dl; AF prevalence was 1.8% and was lowest in the decile with UA 4.4–4.9 mg/dl. Deciles with both high and low UA (5.4–5.6 mg/dl to >7.8 mg/dl and <4.3 mg/dl) were associated with significantly higher AF prevalence. In women, the mean UA was 4.5±1.1 mg/dl; AF prevalence was 0.7% and was lowest in the decile with UA 3.6–3.8 mg/dl. Deciles with highest UA (5.0–5.2 mg/dl to >5.9 mg/dl) were associated with significantly higher AF prevalence. The analysis adjusted for other clinical covariates demonstrated an independent association between UA and AF in both sexes.
Conclusions:In a representative Japanese general population, UA level was significantly associated with AF, independently of other cardiovascular risk factors. (Circ J 2016; 80: 2453–2459)
Background:There are few data on the long-term prognosis and chronological changes in left ventricular (LV) function after aortic valve replacement (AVR) in patients with severe chronic aortic regurgitation (AR) among the Japanese population.
Methods and Results:We retrospectively investigated the long-term prognosis in 80 consecutive patients with severe chronic AR who underwent AVR. Additionally, 65 patients with follow-up echocardiography at 1 year after AVR were investigated to evaluate chronological changes in LV function. The mean follow-up period was 8.9±5.2 years. Freedom from all-cause death and cardiac death at 10 years after AVR was 76% and 91%, respectively. The preoperative ejection fraction (EF) and estimated glomerular filtration rate were independent predictors of all-cause death. Preoperative EF, LV end-systolic diameter, and diabetes might be useful predictors of cardiac death. Among the 65 patients with follow-up echocardiographic data, LV function had normalized at 1 year after AVR in all patients, except for 2 who died of cardiac causes in the long-term after AVR. LV end-diastolic diameter, LV end-systolic diameter, and EF at 1 year after AVR might be useful predictors of long-term cardiac death.
Conclusions:In patients with severe chronic AR, preoperative LV dysfunction is remarkably improved at 1 year after AVR. Pre- and postoperative echocardiographic data are important for predicting long-term outcome after AVR. (Circ J 2016; 80: 2460–2467)
Background:Because increased age is a strong independent predictor of mortality and morbidity, surgery for octogenarians with Stanford type A aortic dissection (AAD) may be avoided.
Methods and Results:From 2005 to 2015, 158 patients underwent surgical repair for AAD via a median sternotomy. We compared 24 (15.2%) octogenarians (83±3 years) with 134 (84.8%) patients aged ≤79 years (62±13 years), based on retrospectively collected clinical data. Octogenarians were predominantly female (79.2% vs. 44.8%, P=0.0033). Ascending aortic replacement was more frequently performed in the octogenarians (95.8% vs. 65.7%, P=0.0015) and total arch replacement in the younger patients (4.2% vs. 26.9%, P=0.0165). There were 14 hospital deaths among the younger patients, none among the octogenarians (0% vs. 10.4%, P=0.1303), and major morbidity rates were comparable. There were 3 late deaths among the octogenarians and 9 deaths among the younger patients. The respective 1-, 3-, and 5-year survival rates were 94.4%, 81.5%, and 81.5% in the octogenarians and 86.9%, 85.6%, and 83.9% in the younger patients, with no significant differences.
Conclusions:Surgical repair for AAD in octogenarians showed favorable results when compared with a younger patient cohort, with low hospital mortality rate and excellent late outcomes. Therefore, this technique should not be disregarded just because the patient is an octogenarian. (Circ J 2016; 80: 2468–2472)
Background:Systolic blood pressure (SBP) is an important prognostic indicator for patients with acute heart failure (AHF). However, its changes and the effects in the different phases of the acute management process are not well known.
Methods and Results:The Tokyo CCU Network prospectively collects on-site information about AHF from emergency medical services (EMS) and the emergency room (ER). The association between in-hospital death and SBP at 2 different time points (on-site SBP [measured by EMS] and in-hospital SBP [measured at the ER; ER-SBP]) was analyzed. From 2010 to 2012, a total of 5,669 patients were registered and stratified into groups according to both their on-site SBP and ER-SBP: >160 mmHg; 100–160 mmHg; and <100 mmHg. In-hospital mortality rates increased when both on-site SBP and ER-SBP were low. After multivariate adjustment, both SBPs were inversely associated with in-hospital death. Notably, the risk for patients with ER-SBP of 100–160 mmHg (intermediate risk) differed according to their on-site SBP; those with on-site SBP <100 or 100–160 mmHg were at higher risk (OR, 7.39; 95% CI, 4.00–13.6 and OR, 2.73; 95% CI, 1.83–4.08, respectively [P<0.001 for both]) than patients with on-site SBP >160 mmHg.
Conclusions:Monitoring changes in SBP assisted risk stratification of AHF patients, particularly patients with intermediate ER-SBP measurements. (Circ J 2016; 80: 2473–2481)
Background:The aim of this study was to determine the prevalence of depression assessed by the 9-item test from the Patient Health Questionnaire (PHQ-9) and the effect of depression on adverse cardiovascular outcomes in Japanese outpatients with cardiovascular disease (CVD).
Methods and Results:This prospective observational study enrolled 1,453 outpatients with CVD (mean age 67±13 years; 31.3% female; 32.6% ischemic heart disease). Depression was defined as a PHQ-9 score ≥10. The main composite outcome was the time to death from any cause or a cardiovascular event. 81 patients (5.6%) were diagnosed with depression (PHQ-9 ≥10). NYHA class III, living alone, and unemployment were independently associated with depression. During an average follow-up of 584±80 days, the main outcome occurred in 85 patients (5.8%). There was a higher incidence of the main outcome in patients with depression than in those without depression (P<0.001). Depression was an independent predictor of the primary outcome (hazard ratio 4.64, 95% confidence interval 2.24–9.09, P<0.001).
Conclusions:Depression assessed by the PHQ-9 was found in 5.6% of Japanese outpatients with CVD and was an important risk factor for adverse outcomes. (UMIN-CTR No. UMIN 000023514) (Circ J 2016; 80: 2482–2488)
Background:Although obesity is a well-known risk factor for cardiovascular disease, the cutoff of body mass index (BMI) for elevated cardiovascular risk is still controversial in Asian. Thus, this study was conducted to investigate the functional and structural changes of the left ventricle (LV) according to the degree of obesity in a general Korean population.
Methods and Results:A total of 31,334 apparently healthy Korean adults who underwent echocardiography were enrolled. The study population was stratified into 5 groups according to the degree of obesity classified by the Asian-Pacific obesity guideline. The odd ratios (ORs) with 95% confidence interval (CI) of impaired LV diastolic function, LV remodeling, and hypertrophy were compared among the 5 groups using multivariable logistic regression analysis. When the normal group was set as the reference, the adjusted ORs (95% CI) for impaired LV diastolic function showed a proportional relationship with BMI [OR; 0.86 (95% CI 0.59–1.22) in underweight, 1.81 (95% CI 1.63–2.00) in overweight, 2.75 (95% CI 2.49–3.03) in obese, and 4.34 (95% CI 3.65–5.16) in severe obese]. Adjusted ORs for LV remodeling and hypertrophy significantly increased proportional to BMI.
Conclusions:Even with strict classification of obesity by the Asian-Pacific guideline, BMI of more than overweight (≥23 kg/m2) was significantly associated with impaired LV diastolic function, remodeling, and hypertrophy. (Circ J 2016; 80: 2489–2495)
Background:In heart failure patients, chronic hyperactivation of sympathetic signaling is known to exacerbate cardiac dysfunction. In this study, the cardioprotective effect of vidarabine, an anti-herpes virus agent, which we identified as a cardiac adenylyl cyclase inhibitor, in dogs with pacing-induced dilated cardiomyopathy (DCM) was evaluated. In addition, the adverse effects of vidarabine on basal cardiac function was compared to those of the β-blocker, carvedilol.
Methods and Results:Vidarabine and carvedilol attenuated the development of pacing-induced systolic dysfunction significantly and with equal effectiveness. Both agents also inhibited the development of cardiac apoptosis and fibrosis and reduced the Na+-Ca2+exchanger-1 protein level in the heart. Importantly, carvedilol significantly enlarged the left ventricle and atrium; vidarabine, in contrast, did not. Vidarabine-treated dogs maintained cardiac response to β-AR stimulation better than carvedilol-treated dogs did.
Conclusions:Vidarabine may protect against pacing-induced DCM with less suppression of basal cardiac function than carvedilol in a dog model. (Circ J 2016; 80: 2496–2505)
Background:Single-phase myocardial computed tomography perfusion (CTP) is useful for detecting myocardial ischemia, but determining the optimal scan time is difficult. The present study evaluated this by analyzing dynamic CTP data.
Methods and Results:We retrospectively selected 32 patients, all of whom had undergone stress dynamic CTP and magnetic resonance myocardial perfusion imaging (MR-MPI). Myocardial ischemia was assessed by MR-MPI using the 16-segment model. Whole-heart dynamic CTP data were acquired for 30 consecutive heartbeats without spatial or temporal gaps using a wide-detector CT, and redistributed into 11 series of single-phase CTP acquired from –2 s to 8 s from the time of maximal enhancement (Tmax) in the ascending aorta. Single-phase CTP images were visually assessed at the segment level, and diagnostic performance of single-phase CTP images for detecting myocardial ischemia was compared with dynamic CTP. Of 512 segments, 177 segments (35%) were diagnosed as ischemic by MR-MPI. The diagnostic accuracy of single-phase CTP acquired at 2–6 s from Tmax in the ascending aorta (median 86%, range 84–87%) was comparable to that of dynamic CTP.
Conclusions:The optimal scan time for detecting myocardial ischemia with single-phase CTP was at 2–6 s from Tmax in the ascending aorta. (Circ J 2016; 80: 2506–2512)
Background:Coronary revascularization has been shown to induce left ventricular (LV) reverse remodeling (RR). The serial morphologic changes in enhanced necrotic tissue during RR on cardiac magnetic resonance imaging (CMR) have not been investigated.
Methods and Results:This retrospective study included 26 patients with severe LV systolic dysfunction (ejection fraction [EF], <35% on echocardiography) who underwent CMR before and >6 months after surgical revascularization. Of 26 patients, 20 had a reduction of ≥10% in end-diastolic and end-systolic volumes (classified as RR group). The RR group had improvement in EF after revascularization (28.8±6.6% vs. 40.6±7.8%, P<0.0001), and no change in absolute infarct mass (17.3±10.9 g vs. 17.5±10.4 g, P=0.8), but an increase in relative infarct mass (21.0±13.7% vs. 26.5±19.4%, P=0.01) due to reduction of myocardial mass after revascularization. Significant increase in regional transmural extent (30.3±21.6 vs. 42.6±22.8, P<0.0001) and in thickness of enhanced tissue (4.2±1.5 mm vs. 5.9±1.8 mm, P<0.0001) was found in the RR group. No significant differences were observed in any of the variables in the non-RR group.
Conclusions:In patients with chronic myocardial ischemic dysfunction, significant volume reduction after revascularization led to significant increase in regional transmural extent of the enhanced area without a change in absolute infarct mass, on CMR. (Circ J 2016; 80: 2513–2519)
Background:Few studies have compared the platelet reactivity of prasugrel and clopidogrel in the acute phase of ST-segment elevation myocardial infarction (STEMI).
Methods and Results:Primary percutaneous coronary intervention (PCI) was performed in 78 patients with STEMI within 12 h of onset. Patients were randomly assigned to receive a Japanese standard loading dose of prasugrel 20 mg or clopidogrel 300 mg. Platelet reactivity was serially assessed using the VerifyNow-P2Y12 assay, the results of which were expressed as P2Y12-reaction-units (PRU). PRU values were significantly lower in the prasugrel group (n=38) than in the clopidogrel group (n=40) at 3 h, 24 h, and 14 days after loading (191±101 vs. 271±50, 147±80 vs. 261±57, and 171±67 vs. 221±70, respectively, P<0.05), although the PRU levels at baseline (231±57 vs. 237±58, P=0.65) and 1 h after loading (282±65 vs. 291±62, P=0.54) were similar. As compared with the baseline values, the PRU levels at 1, 3 and 24 h after clopidogrel loading were significantly higher (respectively, P<0.05), whereas only the PRU at 1 h after prasugrel was elevated (P<0.001).
Conclusions:In Japanese patients with STEMI who undergo primary PCI, prasugrel provides stronger platelet inhibition than clopidogrel from 3 h after loading, whereas platelet reactivity remained elevated within 24 h after clopidogrel loading. (Circ J 2016; 80: 2520–2527)
Background:Hyogo Prefecture is the 2nd prefecture in Japan, after Kanagawa, to enact a ban with penal code on smoking in public places, although the restriction is partial.
Methods and Results:This study included consecutive patients with acute coronary syndrome (ACS) who were admitted to 33 major hospitals in the Hyogo District during the 12 months before implementation of the legislation and during the 24 months thereafter. Consecutive patients with ACS from Gifu Prefecture who were admitted to 20 major hospitals were enrolled as geographical controls. The number of ACS admissions did not change from the years 2012–2015 in both Hyogo District (1,774 in the pre-year, 1,784 in the 1st year, and 1,720 in the 2nd year) and Gifu Prefecture (1,226 in the pre-year, 1,174 in the 1st year, and 1,206 in the 2nd year). However, a clear reduction was observed in the subanalysis for Kobe City (895 in the preceding year, 830 (−7.3%) in the 1st year, and 792 (−11.5%) in the 2nd year), where adherence to the smoking ban was higher than in other Hyogo districts.
Conclusions:The primary endpoint did not show a significant change. However, the subanalysis showed a significant decrease in ACS admissions in Kobe City. These results suggest that ACS reduction may depend on the degree of adherence to a smoking ban. (Circ J 2016; 80: 2528–2532)
Background:Segmental and global mitral valve prolapse (MVP) comprise 2 representative phenotypes in this syndrome. While mitral regurgitation (MR) severity is a major factor causing left atrial (LA) remodeling in MVP, prominent mitral valve (MV) annulus dilatation in global MVP may specifically cause inferiorly predominant LA remodeling. We compared MV annulus and LA geometry in patients with segmental and global MVP.
Methods and Results:LA volume as well as inferior, middle, and superior LA cross-sectional areas (CSA) were measured on 3-D echocardiography in 20 controls, in 40 patients with segmental MVP, and in 18 with global MVP. On multivariate analysis, MR severity was primarily associated with LA dilatation in segmental MVP (P<0.001), while MV annular dilatation was primarily associated with LA dilatation in global MVP (P<0.001). Although there was no regional predominance in LA dilatation in segmental MVP, inferior predominance of LA dilatation was significant in global MVP (increase in inferior, middle, and superior LA-CSA relative to mean of the controls: +220±70% vs. +171±55% vs. +137±37%, P<0.001).
Conclusions:LA remodeling in segmental and global MVP is considerably different regarding its association with MR volume or MV annular dilatation and its regional predominance. While MR volume may mainly contribute to LA remodeling in segmental MVP, MV annular dilatation seems to have an important role in LA remodeling in global MVP. (Circ J 2016; 80: 2533–2540)
Background:Modified low-density lipoprotein (LDL) binding to scavenger receptors has been implicated in atherosclerosis. It is hypothesized that a third molecule may affect modified LDL binding, therefore, this study focuses on the soluble endogenous protein, developmental endothelial locus-1 (Del-1), as an inhibitor of oxidized LDL (oxLDL) interactions.
Methods and Results:Del-1 preferentially bound oxLDL over native LDL in a cell-free binding assay. Del-1 also inhibited DiI-labeled oxLDL uptake by scavenger receptors irrespective of the receptor type (LOX-1, SR-AI, CD36, or SR-BI) expressed in COS-7 cells, and independent of cell type (human coronary artery endothelial cells (HCAECs) or THP-1-derived macrophages). Furthermore, Del-1 suppressed oxLDL-inducedMCP-1andICAM-1expression and endothelin-1 secretion in HCAECs. Then, male Del-1 transgenic (Del-1Tg) and wild-type mice (WT) mice were established and fed a Paigen diet for 20 weeks from the age of 24 weeks. While plasma lipid concentrations did not differ between WT and Del-1Tg mice, plasma LOX-1-ligand activity was significantly lower in Del-1Tg than in WT mice. Moreover, lipid accumulation in aortic roots was significantly less in the Del-1Tg mice, evaluated with Oil red-O. Taken together, Del-1 appears to block the activity of oxLDL pharmacologically by direct binding in vitro, and attenuates atherogenesis in vivo, although its role in physiological settings are yet to be resolved.
Conclusions:Del-1 intercepted oxLDL before its receptor binding to reduce atherogenesis. (Circ J 2016; 80: 2541–2549)
Background:It remains to be elucidated whether cardiac sympathetic nervous activity is impaired in patients with Anderson-Fabry disease (AFD).
Methods and Results:We performed 123I-meta-iodobenzylguanidine (MIBG) scintigraphy and gadolinium-enhanced cardiovascular magnetic resonance (CMR) in 5 AFD patients. MIBG uptake in the inferolateral wall, where wall thinning and delayed enhancement were noted on CMR, was significantly lower compared with the anteroseptal wall. The localized reduction in MIBG uptake was also noted in 2 patients with no obvious abnormal findings on CMR.
Conclusions:Cardiac sympathetic nervous activity is impaired in AFD before development of structural myocardial abnormalities. (Circ J 2016; 80: 2550–2551)
Background:Since August 2015, the pediatric ventricular assist device (VAD), Berlin Heart EXCOR®, has been accepted for use in Japan.
Methods and Results:Between August 2015 and July 2016, 4 pediatric patients with endstage heart failure underwent LVAD implantation with the EXCOR®device. The median age and body weight at operation were 8 months and 4.8 kg. During a median follow-up of 7.3 months (range, 5.0–10.3), all patients survived. Two patients went on to heart transplantation and the remaining 2 are on a waiting list with stable hemodynamics.
Conclusions:The early outcomes of the Berlin Heart EXCOR®pediatric VAD were satisfactory. (Circ J 2016; 80: 2552–2554)