Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH2-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events. (Circ J 2016; 80: 2259–2268)
Cardiac fibrosis remains an important health concern, but the study of fibroblast biology has been hindered by a lack of effective means for identifying and tracking fibroblasts. Recent advances in fibroblast-specific lineage tags and reporters have permitted a better understanding of these cells. After injury, multiple cell types have been implicated as the source for extracellular matrix-producing cells, but emerging studies suggest that resident cardiac fibroblasts contribute substantially to the remodeling process. In this review, we discuss recent findings regarding cardiac fibroblast origin and identity. Our understanding of cardiac fibroblast biology and fibrosis is still developing and will expand profoundly in the next few years, with many of the recent findings regarding fibroblast gene expression and behavior laying down the groundwork for interpreting the purpose and utility of these cells before and after injury. (Circ J 2016; 80: 2269–2276)
Primarily, the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of the proximal tubules to the blood, and excrete glucose into the urine. Therefore, glucose and caloric balances become negative, reducing both the blood glucose level and insulin secretion. On the other hand, the proximal tubular fluid, constituted with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. Under low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, similar to when loop diuretics are given. Subanalysis data on heart failure (HF) from the EMPA-REG OUTCOME trials are discussed, assuming that SGLT2 inhibitors are loop diuretics. Renin-angiotensin system inhibitors and β-blockers contribute to prognostic improvements of HF, independent of SGLT2 inhibitors, and therefore, both regimens are essential for the treatment of HF. On the other hand, the prognostic improvements by SGLT2 inhibitors are not significant under treatment including conventional diuretics such as loop diuretics and aldosterone antagonists, suggesting that the prognostic improvement in HF by SGLT2 inhibitors is mostly through their diuretic action. (Circ J 2016; 80: 2277–2281)
From August 27th to 31st, the 2016 Annual Congress of the European Society of Cardiology (ESC 2016) was held in Fiera di Roma, Italy. Despite the socially unstable situation, more than 32,000 attendees, including clinical physicians, basic researchers, medical students, and paramedical personnel, as well as 5,000 exhibitors from 106 countries gathered in this historical city to share the latest findings and to discuss the present issues in cardiovascular medicine. There were scientific sessions, including 28 Hot Lines, 26 clinical trial updates, 24 registry studies, and 5 clinical practice guideline sessions. Japan had 1,170 attendees, with 1,743 submitted and 670 accepted abstracts, including the NIPPON trial presented in the hotline session. From 2011 to 2016, Japan has been the first abstract submitter and has had the most abstracts accepted, which indicates the great contribution of Japanese cardiologists and the Japanese Circulation Society. This report briefly introduces the key presentations and highlights from the ESC 2016 Scientific Sessions. (Circ J 2016; 80: 2282–2286)
Background:Catheter ablation (CA) is a common treatment for atrial fibrillation (AF). Although rivaroxaban is increasingly used as a substitute for warfarin, its safety and efficacy during CA have not been established in Japanese patients. In the present study we explored the efficacy/safety of rivaroxaban during the CA perioperative period.
Methods and Results:We prospectively enrolled Japanese AF patients scheduled for CA who had received either rivaroxaban (rivaroxaban cohort, JACRE-R) or warfarin (warfarin cohort, JACRE-W) during the perioperative period. Primary outcome was a composite of thromboembolism and major bleeding within 30 days after CA. In JACRE-R and JACRE-W, 1,118 (median age, 65 years) and 204 patients (median, 69 years) were enrolled from 42 and 22 institutions, respectively. In JACRE-R, the primary outcome occurred in 7 patients (0.6%), comprising thromboembolism in 2 and major bleeding in 5. Non-major bleeding occurred in 27 patients (2.4%), and the incidence was significantly lower in patients without heparin bridging (n=572) than in those with heparin bridging (n=546). In JACRE-W, the primary outcome occurred in 3 patients (1.5%), all of which were major bleeding. After adjustment for patients’ characteristics, no signiﬁcant difference was observed between the JACRE-R and JACRE-W cohorts for the primary outcome.
Conclusions:The rates of thromboembolism and major bleeding events during the AF ablation perioperative period in Japanese patients treated with rivaroxaban was as low as in those treated with warfarin. (Circ J 2016; 80: 2295–2301)
Background:Whether pacing from the right ventricular (RV) septum improves prognosis is unclear. Furthermore, the clinical characteristics of patients who develop atrial fibrillation (AF) and cardiovascular events during long-term RV septal pacing have not been described.
Methods and Results:We retrospectively evaluated the incidence of AF and cardiovascular events, including cardiac death, heart failure requiring hospitalization, or stroke, for a median of 4.0 years in 123 recipients of dual-chamber pacemakers implanted for atrioventricular block with preserved left ventricular function, who were free from AF before device implantation. AF developed in 30 patients (24%), and multivariable analysis suggested that the cumulative percentage of RV pacing was the only independent predictor of newly developed AF (hazard ratio: 1.19 for each 10% increment; 95% confidence interval: 1.04–1.41; P=0.01). Furthermore, older age, newly developed AF and a paced QRS duration ≥155 ms at pacemaker implantation were significant predictors of cardiovascular events.
Conclusions:RV septum pacing may induce AF in up to one-quarter of patients paced for atrioventricular block, according to the frequency of pacing. More importantly, in such patients, AF induced by RV pacing and a paced QRS duration ≥155 ms at pacemaker implantation are significantly associated with poor prognosis. Therefore, we recommend pacing from sites producing a paced QRS duration <155 ms and avoiding unnecessary RV pacing. (Circ J 2016; 80: 2302–2309)
Background:Ventricular fibrillation (VF) is a life-threatening disease that can be remedied by prompt defibrillation. However, data regarding such risk in a general population remain limited. This general population study was to explore the epidemiological profile of VF.
Methods and Results:We investigated patients with VF younger than 60 years (average population, 19,725,031) using a national database spanning the period 2000–2010. We identified 3,971 (68.4% male) patients with VF (crude incidence rate: 1.83/100,000). Incidence rates were low in patients younger than 10 years and increased steadily after adolescence. Comorbidities were noted in 2,766 (69.7%) patients, with 2,431 (61%) having cardiac diseases. Over half of the adolescent and young adult patients did not have comorbidities. Among the 838 deaths (mortality rate 21.1%), approximately half (381/838, 45.5%) occurred after arrival at emergency services (ES). The proportion of deaths after arrival at ES relative to total deaths increased sharply to a peak in the 15–19-years age group and thereafter remained stationary.
Conclusions:VF patients, with a male dominance, increased after adolescence and were likely to die at presentation to ES. Approximately half of young adults, with high mortality, did not have comorbidities, suggesting underdiagnosis of underlying primary electrical diseases and the need for implementing automated external defibrillator programs. (Circ J 2016; 80: 2310–2316)
Background:The optimal implantation technique for the bioresorbable scaffold (Absorb, Abbott Vascular) is still a matter of debate. The purpose of the present study was to evaluate the effect of implantation technique on strut embedment and scaffold expansion.
Methods and Results:Strut embedment depth and scaffold expansion index assessed by optical coherence tomography (OCT) (minimum scaffold area/reference vessel area) were evaluated in the ABSORB Japan trial (OCT subgroup: 87 lesions) with respect to implantation technique using either quantitative coronary angiography (QCA) or OCT. Strut embedment was assessed at the strut level (n=667), while scaffold expansion was assessed at the lesion level (n=81). The mean embedment depth was 63±59 µm. Balloon sizing and inflation pressure had no direct effect on strut embedment. Plaque morphology affected strut embedment [nonatherosclerotic (58.9±54.3 µm), fibroatheroma (73.3±59.6 µm), fibrous plaque (59.7±51.1 µm), and fibrocalcific plaque (–3.1±61.6 µm, negative value means malapposition), P <0.001]. The balloon-artery ratio positively correlated with the expansion index. This relationship was stronger when the OCT-derived reference vessel diameter (RVD) was used as a reference for balloon selection rather than the QCA-derived one [predilatation (Pearson correlation r: QCA: 0.167 vs. OCT: 0.552), postdilatation (QCA: 0.316 vs. OCT: 0.717)].
Conclusions:Underlying plaque morphology influenced strut embedment, whereas implantation technique had no direct effect on it. Optimal balloon sizing based on OCT-derived RVD might be recommended. However, the safety of such a strategy should be investigated in a prospective trial. (Circ J 2016; 80: 2317–2326)
Background:Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.
Methods and Results:The JROAD-DPC database included 704,593 health records’ data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range [IQR], 76.9–88.0%), there were wide variations in the proportions of patients prescribed β-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6–55.7%; ACEI/ARB, 52.0%, IQR 40.3–62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8–47.6%; ACEI/ARB, 41.0%, IQR 31.7–49.1%).
Conclusions:A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327–2335)
Background:Some disagreements surround the effects of calcium-channel blockers (CCBs) on the risk of dementia. The purpose of this study was to investigate the protective effects of CCBs on dementia among elderly hypertensive Koreans.
Methods and Results:We conducted a large population-based cohort study using the senior cohort database of the Korean National Health Insurance Service (2002–2013). Subjects were elderly hypertensive Koreans older than 60 years of age. A total of 18,423 patients (CCB user group: 13,692 patients; non-CCB antihypertensive user group: 4,731 patients) were statistically analyzed using the Cox proportional hazard regression model to estimate the adjusted hazard ratio (aHR) and confidence intervals (CIs) of dementia associated with CCB use. There were 2,881 cases (21.0%) of dementia in the CCB user group and 1,124 cases (23.8%) in the non-user group. CCB use significantly reduced the risk of total dementia (aHR 0.81, 95% CI 0.75–0.87, P<0.0001), Alzheimer’s dementia (aHR 0.80, 95% CI 0.72–0.88, P<0.0001), and vascular dementia (aHR 0.81, 95% CI 0.70–0.94, P=0.0067).
Conclusions:CCB use had a protective effect on the risk of dementia among elderly hypertensive Koreans. (Circ J 2016; 80: 2336–2342)
Background:The aim of this study was to examine whether the burden of diabetes on cardiovascular disease (CVD) in Japan has increased in recent years.
Methods and Results:Three cohorts were established, consisting of Japanese residents aged 40–69 years, in 1992–1995 (n=8,744), 1996–1999 (n=7,996), and 2000–2003 (n=7,273). All participants had follow-up for a median of 10 years. Diabetes was defined according to the following criteria: (1) fasting serum glucose ≥7.0 mmol/L; (2) non-fasting serum glucose ≥11.1 mmol/L; or (3) anti-diabetic treatment at baseline. During follow-up, the number of CVD incidents was 277 in the first, 214 in the second, and 190 in the third cohorts. The prevalence of diabetes increased slightly over time. Adjusting for traditional cardiovascular risk factors, multivariable HR (95% CI) for diabetes as a cardiovascular risk factor were 1.40 (0.91–2.14) in the first, 1.93 (1.25–3.00) in the second, and 2.59 (1.77–3.81) in the third cohorts. The population attributable fraction of CVD due to diabetes was 2.8%, 5.6%, and 12.4%, respectively.
Conclusions:This is the first study in middle-aged Japanese people to clarify an increased burden of CVD due to diabetes since the early 1990 s. Further efforts are needed to prevent and control diabetes through lifestyle modification and treatment. (Circ J 2016; 80: 2343–2348)
Background:The incidence of coronary artery disease (CAD) varies depending on ethnicity, but the precise differences remain to be firmly established. This study therefore evaluated the disparity in coronary artery calcification (CAC), as a marker of CAD, in asymptomatic US and Korean adults.
Methods and Results:CAC score was compared between asymptomatic Korean (n=15,128) and US (n=7,533) adults. Propensity score matching was performed according to age, gender, hypertension, diabetes, dyslipidemia, and current smoking, which generated 2 cohorts of 5,427 matched pairs. Both cohorts were categorized according to age group: 45–54, 55–64, and 65–74 years. Overall, the prevalence of CAC score >0, >100, and >400 in Korean adults was lower than in US adults (P<0.001, all). According to increasing age groups, the likelihood of CAC was most often lower in Korean adults, especially in Korean women. The odds of having CAC >400 in Korean adults aged 65–74 years was 0.66 (95% CI: 0.48–0.91) overall, 0.78 (95% CI: 0.52–1.19) in men, and 0.50 (95% CI: 0.29–0.86) in women, compared with US counterparts.
Conclusions:Korean adults have a lower prevalence and severity of atherosclerotic burden as assessed on CAC, compared with US adults, but the disparity in CAC according to ethnicity may decline with older age. (Circ J 2016; 80: 2349–2355)
Background:The aim of this study was to examine whether zero coronary artery calcium (CAC) score is associated with favorable prognosis of all-cause mortality (ACM) according to a panel of conventional risk factors (RF) in asymptomatic Korean adults.
Methods and Results:A total of 48,215 individuals were stratified according to presence/absence of CAC, and the following RF were examined: hypertension, diabetes, current smoking, high low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol. The RF were summed on composite score as 0, 1–2, or ≥3 RF present. The warranty period was defined as the time to cumulative mortality rate >1%. Across a median follow-up of 4.4 years (IQR, 2.7–6.6), 415 (0.9%) deaths occurred. Incidence per 1,000 person-years for ACM was consistently higher in subjects with any CAC, irrespective of number of RF. The warranty period was substantially longer (eg, 9 vs. 5 years) for CAC=0 compared with CAC >0. The latter observation did not change materially according to pre-specified RF, but difference in warranty period according to presence/absence of CAC reduced somewhat when RF burden increased.
Conclusions:In asymptomatic Korean adults, the absence of CAC evoked a strong protective effect against ACM as reflected by longer warranty period, when no other RF were present. The usefulness of zero CAC score and its warranty period requires further validation in the presence of multiple RF. (Circ J 2016; 80: 2356–2361)
Background:The 1st nationwide survey by the Japanese Society of Pediatric Cardiology and Cardiac Surgery of acute or fulminant myocarditis (AMC/FMC) in children revealed that the survival rate of FMC was only 51.6%. The 2nd nationwide survey was performed to evaluate the recent outcomes of pediatric myocarditis.
Methods and Results:Questionnaires regarding patients aged ≤18 years with AMC/FMC during the period from January 2006 to December 2011 were mailed. A total of 221 cases (age 6.5±5.3 years, 116 boys and 105 girls) were reported. There were 145 (65.6%) and 74 cases (33.5%) of AMC/FMC, respectively; the type of myocarditis was not reported in the remaining 2 cases (0.9%). Viruses were identified in 56 cases (25.3%), including coxsackie B in 9 and influenza A in 8. Histopathology by either endomyocardial biopsy or autopsy was obtained in 38 cases (19.2%). Intravenous immunoglobulin was effective in 49 (34.3%) of 143 cases. Steroid therapy was effective in 20 (32.8%) of 61 cases. Mechanical circulatory support was given in 54 cases (24.4%) and 94.2% of them were patients with FMC. The survival rates for the whole study population, acute myocarditis, and FMC were 75.6%, 91.0%, and 48.6%, respectively.
Conclusions:The survival rate of children with myocarditis was almost identical to that of 10 years ago. (Circ J 2016; 80: 2362–2368)
Background:The characteristics of aortic elasticity are unclear in children with connective tissue disorders (CTDs) such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), especially in those with a non-dilated aortic root (AoR). This study evaluated the aortic elasticity properties of pediatric MFS and LDS patients with either dilated or non-dilated AoR.
Methods and Results:The 31 children with MFS or LDS were classified into dilated (Z score of AoR diameter ≥2.5; n=17) or non-dilated (Z score of AoR diameter <2.5; n=14) AoR groups and compared with controls. Using transthoracic echocardiography, we analyzed the aortic elasticity parameters of distensibility, strain, and stiffness index at the levels of the AoR, sinotubular junction, ascending aorta, and descending aorta. Aortic distensibility and strain were significantly lower in both test groups than in controls at the AoR level. The Z score of AoR diameter significantly correlated with aortic distensibility (R=–0.63, P<0.001), strain (R=–0.54, P=0.002), and stiffness index (R=0.52, P=0.002) in the patients’ groups. Multivariate analysis revealed that aortic distensibility and the type of CTD were independently associated with AoR dilatation.
Conclusions:Aortic elasticity at the level of the AoR may be decreased in children with MFS or LDS even before AoR dilatation progresses. Less aortic distensibility and CTD type are considered important parameters in estimating AoR dilatation in these patients. (Circ J 2016; 80: 2369–2375)
Background:Tenascin-C (TN-C) is an extracellular matrix glycoprotein that is heavily upregulated at sites of inflammation. We conducted a retrospective study to assess the utility of TN-C as a novel biomarker to predict the risk of developing coronary artery lesions (CAL) and resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD).
Methods and Results:We collected blood samples of 111 KD patients (IVIG-responder: 89, IVIG-resistant: 22; CAL: 8) and 23 healthy controls, and measured the serum levels of TN-C. TN-C levels on admission were significantly higher in patients than in healthy controls and in patients during convalescence after IVIG administration (69.6 vs. 20.4 vs. 39.7 ng/ml, respectively; P<0.001), and correlated positively with C-reactive protein (P<0.001), neutrophil (percentage; P=0.005), and ALT (P<0.001), and negatively with platelet count (P=0.023) and sodium level (P=0.025). On admission, TN-C levels in patients who later developed CAL were significantly higher than in those without CAL (P=0.010), and significantly higher in IVIG-resistant subjects than in IVIG-responders (P=0.003). The accuracy of TN-C testing for the prediction of IVIG resistance was comparable to that of the Kobayashi score.
Conclusions:Serum TN-C could be a biomarker for predicting the risk of developing CAL and IVIG resistance during the acute phase of KD. (Circ J 2016; 80: 2376–2381)
Background:Distal bypass is the first-line treatment for patients with critical limb ischemia (CLI). In Japanese high-volume centers, approximately half of these patients are on hemodialysis (HD). We have treated such patients first with bypass using a multidisciplinary perioperative strategy. We reveal the recent characteristics of patients who underwent distal bypass and the surgical outcomes in Japan, especially focusing on the foot conditions by using the wound, ischemia, and foot infection (WIfI) classification.
Methods and Results:The 152 patients underwent distal bypass in a tertiary center hospital, and we compared patients on HD (HD group) to those not on HD (non-HD group). There were significant differences between the 2 groups in the overall survival, major adverse cardiac event-free survival and amputation-free survival (AFS) rates (P<0.0001). The procedural outcomes were analyzed via primary and secondary patency, and there was no difference. In the subanalysis of limb status using WIfI stage, the AFS rate of the HD group was significantly worse than that of the non-HD group for WIfI stage 4 patients.
Conclusions:The life and limb prognoses of patients with CLI and HD were worse than those of non-HD patients. There was no difference in surgical outcomes suggested by the graft patency rates between the 2 groups. AFS in WIfI stage 4 was significantly worse in the HD group, which indicated the importance of preoperative limb status. (Circ J 2016; 80: 2382–2387)
Background:Extremely preterm infants frequently have patent ductus arteriosus (PDA). Recent recommendations include immediately beginning amino acid supplementation in extremely preterm infants. However, the effect of amino acids on closure of the ductus arteriosus (DA) remains unknown.
Methods and Results:Aminogram results in human neonates at day 2 revealed that the plasma glutamate concentration was significantly lower in extremely preterm infants (<28 weeks’ gestation) with PDA than in those without PDA and relatively mature preterm infants (28–29 weeks gestation). To investigate the effect of glutamate on DA closure, glutamate receptor expression in fetal rats was examined and it was found that the glutamate inotropic receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type subunit 1 (GluR1), mRNA was highly expressed in the DA compared to the aorta on gestational day 19 (preterm) and gestational day 21 (term). GluR1 proteins were co-localized with tyrosine hydroxylase-positive autonomic nerve terminals in the rat and human DA. Intraperitoneal administration of glutamate increased noradrenaline production in the rat DA. A whole-body freezing method demonstrated that glutamate administration induced DA contraction in both preterm (gestational day 20) and term rat fetuses. Glutamate-induced DA contraction was attenuated by the calcium-sensitive GluR receptor antagonist, NASPM, or the adrenergic receptor α1 blocker, prazosin.
Conclusions:These data suggest that glutamate induces DA contraction through GluR-mediated noradrenaline production. Supplementation of glutamate might help to prevent PDA in extremely preterm infants. (Circ J 2016; 80: 2388–2396)
Background:Previous research has demonstrated that ClC-3 is responsible for volume-regulated Cl–current (ICl.vol) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofICl.vol.
Methods and Results:Volume-regulated chloride current (ICl.vol) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction. Live cell imaging was used to observe ClC-3 transporting. The results showed that an overexpression of endophilin A2 could increaseICl.vol, while endophilin A2 knockdown decreasedICl.vol. In addition, the SH3 domain of endophilin A2 mediated its interaction with ClC-3 and promotes ClC-3 transportation from the cytoplasm to cell membranes. The regulation of ClC-3 channel activity was also verified in basilar arterial smooth muscle cells (BASMCs) isolated from endophilin A2 transgenic mice. Moreover, endophilin A2 increase VSMCs proliferation induced by endothelin-1 or hypo-osmolarity.
Conclusions:The present study identified endophilin A2 as a ClC-3 channel partner, which serves as a new ClC-3 trafficking insight in regulatingICl.volin VSMCs. This study provides a new mechanism by which endophilin A2 regulates ClC-3 channel activity, and sheds light on how ClC-3 is transported to cell membranes to play its critical role as a chloride channel in VSMCs function, which may be involved in cardiovascular diseases. (Circ J 2016; 80: 2397–2406)