Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491–1498)

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In the central nervous system endothelial nitric oxide (NO) is an essential molecule responsible for the preservation of the functional integrity of the neurovascular unit. NO causes vasodilatation and is an important inhibitor of platelet aggregation, smooth muscle cell proliferation, and white blood cell adhesion. In addition, endothelium-derived NO exerts anti-inflammatory and pro-angiogenic effects. More recently, it has been recognized that endothelial NO modulates the expression and processing of amyloid precursor protein in cerebrovascular endothelium and neuronal tissue. Studies in endothelial NO synthase (eNOS) knockout mice indicate that endothelial NO functions as a neurovascular protective molecule during aging. Indeed, genetic inactivation of eNOS exacerbates the detrimental effects of aging on cerebrovascular, microglial, and neuronal functions as well as on cognition. These findings suggest that the preservation of healthy endothelium and normal function of eNOS might be important therapeutic targets. Because the beneficial effects of NO are mostly mediated by the activation of guanylate cyclase/cyclic GMP signaling, inhibitors of phosphodiesterase isoforms, or activation of this signaling with exercise, may offer therapeutic opportunities in the prevention and treatment of aging-induced cognitive decline and Alzheimer’s disease. Most recent advances in understanding the molecular mechanisms linking loss of endothelial NO with cognitive decline will be discussed in this review. (Circ J 2016; 80: 1499–1503)

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Initially identified inDrosophila melanogaster, the Hippo signaling pathway regulates organ size through modulation of cell proliferation, survival and differentiation. This pathway is evolutionarily conserved and canonical signaling involves a kinase cascade that phosphorylates and inhibits the downstream effector Yes-associated protein (YAP). Recent research has demonstrated a fundamental role of Hippo signaling in cardiac development, homeostasis, injury and regeneration, and remains the subject of intense investigation. However, 2 prominent members of this pathway, RASSF1A and Mst1, have been shown to influence heart function and stress responses through YAP-independent mechanisms. This review summarizes non-canonical targets of RASSF1A and Mst1 and discusses their role in the context of cardiac hypertrophy, autophagy, apoptosis and function. (Circ J 2016; 80: 1504–1510)

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Stress in the heart causes loss of cardiomyocytes (CMs), the accumulation of which leads to heart failure, a major cause of clinical mortality. The improvement of CM survival and facilitation of CM regeneration are major goals in treatment for heart failure. The Hippo pathway is an evolutionarily conserved signaling mechanism that regulates organ size by controlling both apoptosis and cell proliferation. The main components of the Hippo pathway, including Mst1/2, Lats1/2 and Yes-associated protein (Yap), are present in the mammalian heart and play an important role in regulating the growth and death of CMs. Recent research in the cardiac field has demonstrated that Yap, a key downstream transcriptional cofactor in the Hippo signaling pathway, plays a crucial role in regulating survival and proliferation/hypertrophy of CMs. Increasing lines of evidence suggest that Yap promotes regeneration of the heart after myocardial infarction. In this review, we summarize the current knowledge regarding the roles and functions of the Hippo pathway in the heart, with a particular emphasis on the role of Yap in regulating growth and death of CMs. (Circ J 2016; 80: 1511–1519)

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Background:The aim of this study was to investigate the prognostic impact of acute-phase ventricular tachycardia and fibrillation (VT/VF) on ST-segment elevation myocardial infarction (STEMI) patients in the percutaneous coronary intervention (PCI) era.Methods and Results:Using the database of the Osaka Acute Coronary Insufficiency Study (OACIS), we studied 4,283 consecutive patients with STEMI who were hospitalized within 12 h of STEMI onset and underwent emergency PCI. Acute-phase VT/VF, defined as ≥3 consecutive ventricular premature complexes and/or VF within the 1st week of hospitalization, occurred in 997 (23.3%) patients. In-hospital mortality risk was significantly higher in patients with acute-phase VT/VF than inthose without (14.6% vs. 4.3%, adjusted hazard ratio (HR) 1.83, P=0.0013). Among patients discharged alive, 5-year mortality rates were comparable between patients with and without acute-phase VT/VF. Subgroup analysis showed that acute-phase VT/VF was associated with increased 5-year mortality after discharge in high-risk patients (GRACE Risk Score ≥115; adjusted HR 1.60, P=0.043), but not in intermediate- or low-risk patients.Conclusions:Even in the PCI era, acute-phase VT/VF was associated with higher in-hospital deaths of STEMI patients. However, the 5-year prognostic impact of acute-phase VT/VF was limited to high-risk patients. (Circ J 2016; 80: 1539–1547)

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Background:The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF).Methods and Results:In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS₂score, were detected among the regions. The highest mean CHADS₂score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism.Conclusions:Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548–1555)

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Background:In order to begin to precisely clarify the impact of renal denervation on the blood pressure, atrial fibrillation and ventricular tachyarrhythmias, in addition to proarrhythmic potential, its cardiovascular effects were assessed by using the chronic complete atrioventricular block dogs.Methods and Results:Cardiohemodynamic and electrophysiological effects, together with neurohumoral factors and/or electrolytes, were assessed before and 4 weeks after either renal denervation (n=5) or amiodarone treatment (n=6). Amiodarone hydrochloride was given orally to the animals every day in a dose of 200 mg/day for the first 7 days followed by 100 mg/day for the following 21 days. The renal denervation decreased the systolic pressure, idioventricular rate, prolonged ventricular effective refractory period, and slightly suppressed the adrenergic tone and the renin-angiotensin-aldosterone system, but hardly affected the atrial effective refractory period and terminal repolarization period. Amiodarone prolonged the atrial effective refractory period, whereas no significant change was detected in the other variables.Conclusions:Surgically performed renal denervation may possess the anti-ventricular tachyarrhythmic rather than anti-atrial fibrillatory potentials, and it also modestly decreased the blood pressure. Thus, currently obtained information may be used as guidance for better understanding the utility and limitation of renal denervation against various types of cardiovascular diseases. (Circ J 2016; 80: 1556–1563)

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Background:Characteristics and outcomes of emergency patients with bath-related sudden cardiac arrest in prehospital settings have not been sufficiently investigated.Methods and Results:From a prospective population-based registry, which covers all out-of-hospital cardiac arrests (OHCAs) in Osaka City, a total of 642 patients who had a bath-related OHCA from 2012 to 2014 were enrolled in the analyses. The characteristics and outcomes of OHCA were compared by three locations of arrest: home baths (n=512), public baths (n=102), and baths in other public institutions (n=28). Overall, bath-related OHCAs mainly occurred in winter (December–February, 48.9%, 314/642). The proportion of OHCAs that were witnessed by bystanders was 6.4% (33/512) in home baths, 17.6% (18/102) in public baths, and 25.0% (7/28) in baths in other public institutions. The proportion of public-access automated external defibrillator pad application was 0.8% (4/512) in home baths, 6.9% (7/102) in public baths, and 50.0% (14/28) in baths in other public institutions. Only 1 survivor with a favorable neurologic outcome was observed in a home bath, whereas there were no patients who survived with favorable neurologic outcomes in public baths and baths in other public institutions.Conclusions:Bath-related OHCAs mainly occurred in winter, and the outcome of victims was exceedingly poor, irrespective of location of arrest. The establishment of preventive measures as well as earlier recognition of cardiac arrest by bystanders are needed. (Circ J 2016; 80: 1564–1570)

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Background:Insomnia is associated with incident heart failure (HF), but the clinical significance and impact of insomnia on HF remain unclear.Methods and Results:Consecutive 1,011 patients admitted for HF were divided into 2 groups according to the presence of insomnia: HF with insomnia (insomnia group, n=519) and HF without insomnia (non-insomnia group, n=492). We compared (1) cardiac event rates including cardiac death and worsening HF; and (2) underlying clinical background including laboratory data, echocardiographic data, and cardiopulmonary exercise test between the 2 groups. On Kaplan-Meier analysis, cardiac event rate was significantly higher in the insomnia group than in the non-insomnia group (39.1 vs. 23.4%, P<0.001). The insomnia group, as compared with the non-insomnia group, had (1) higher plasma renin activity (P=0.042), renin concentration (P=0.007), and aldosterone (P=0.047); (2) lower peak V̇O₂(14.9 vs. 16.3 ml/kg/min, P=0.002) and higher V̇E/V̇CO₂slope (36.0 vs. 33.5, P=0.001); and (3) similar B-type natriuretic peptide and left ventricular ejection fraction. Importantly, on multivariate Cox proportional hazard analysis after adjusting for potential confounding factors, insomnia was an independent predictor of cardiac events in HF patients (hazard ratio, 1.899; P<0.001).Conclusions:Insomnia is an independent predictor of cardiac events in HF patients. HF patients with insomnia have activated renin-angiotensin-aldosterone system and lower exercise capacity. (Circ J 2016; 80: 1571–1577)

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Background:This study aimed to validate the Korean Genome Epidemiology Study (KoGES) risk score to predict the 4-year risk of hypertension (HT) in a large nationwide sample, and compare its discrimination and calibration with the Framingham and blood pressure (BP)-only models.Methods and Results:This study analyzed 69,918 subjects without HT at baseline from the National Sample Cohort in the National Health Insurance Service database. We compared the Framingham, KoGES, and BP-only models for discrimination using area under the receiver-operating characteristic curves (AROC), calibration using goodness-of-fit tests, and reclassification ability using the continuous net reclassification improvement (NRI) and integrated discrimination improvement. Of 69,918 subjects, 18.6% developed HT during the follow-up. AROC was significantly higher for the KoGES (0.733) than for the Framingham (0.729) or BP-only (0.707) model. Recalibrated Framingham model underestimated HT incidence in all deciles (P<0.001). BP-only model overestimated risk in the lower deciles (P<0.001). KoGES model accurately predicted risk in all except the highest decile (χ²=14.85, P=0.062). The KoGES model led to a significant improvement in risk reclassification compared with the Framingham and BP-only models (NRI, 0.354; 95% confidence interval [CI], 0.343–0.365 and 0.542; 95% CI, 0.523–0.561, respectively).Conclusions:In this validation study, the KoGES model demonstrated better discrimination, calibration, and reclassification ability than either the Framingham or BP-only model. The KoGES model may help identify Korean individuals at high risk for HT. (Circ J 2016; 80: 1578–1582)

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Background:The functional significance of an intermediate coronary lesion is crucial for determining the treatment strategy, but age-related changes in cardiovascular function could affect the functional significance of an epicardial stenosis. The aim of this study was therefore to investigate the impact of age on fractional flow reserve (FFR) measurements in patients with intermediate coronary artery disease (CAD).Methods and Results:Intracoronary pressure measurements and intravascular ultrasound (IVUS) were performed in 178 left anterior descending coronary arteries with intermediate stenosis. The morphological characteristics and FFR of 91 lesions in patients <65 years old were compared with those of 87 patients ≥65 years old. There was no difference in lesion location, diameter stenosis, minimum lumen area, plaque burden, or lesion length between the 2 age groups. Elderly patients had higher FFR (0.81±0.06 vs. 0.79±0.06, P=0.004) and lower ∆FFR, defined as the difference between resting Pd/Pa and FFR (0.13±0.05 vs. 0.15±0.05, P=0.014). Age, along with the location and degree of stenosis, was independently associated with FFR and ∆FFR (β=0.162, P=0.008; β=−0.131, P=0.043, respectively).Conclusions:Elderly patients with intermediate CAD are more likely to have higher FFR and lower ∆FFR, despite a similar degree of epicardial stenosis, compared with younger patients. (Circ J 2016; 80: 1583–1589)

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Background:The “smoker’s paradox” is an otherwise unexplained phenomenon in which the mortality of smokers after acute myocardial infarction is reduced, contrary to expectations. It has been suggested that an association with antiplatelet agents exists, but the true mechanism remains largely unidentified.Methods and Results:The analysis included 6,195 consecutive patients who underwent percutaneous coronary intervention (PCI) for acute coronary syndrome, registered in the Japanese multicenter PCI registry. Smokers were significantly younger and had less comorbidity than non-smokers. Unadjusted in-hospital mortality rate, general complication rate, and bleeding complication rate were lower in smokers than in non-smokers. After adjustment, the trend persisted and smoking was not associated with overall mortality (odds ratio [OR], 0.90; 95% confidence interval [CI]: 0.61–1.34; P=0.62), and was associated with lower overall (P=0.032) and bleeding complication events (P=0.040). Clopidogrel effectively reduced the occurrence of in-hospital complications and major adverse cardiac events in smokers compared with non-smokers (OR, 0.55; 95% CI: 0.53–0.98 vs. OR, 1.20; 95% CI: 0.87–1.67; and OR, 0.37; 95% CI: 0.20–0.70 vs. OR, 1.48; 95% CI: 0.90–2.43, respectively).Conclusions:The smoker’s paradox was largely explained by confounding factors related to the lower risk profile of smokers, and they benefited from a positive modification of the efficacy of clopidogrel. (Circ J 2016; 80: 1590–1599)

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Background:Because approximately 10% of patients with no-ST-segment elevation acute coronary syndrome (NSTE-ACS) show no obstructive coronary artery disease (NOCAD) on angiography, we assessed the spectrum of diagnoses and the predictors of outcome of these patients.Methods and Results:We studied 178 patients admitted to a coronary care unit with an initial diagnosis of NSTE-ACS, based on clinical, ECG and laboratory data, but found to have NOCAD. The final diagnosis in these patients was heterogeneous; true NSTE-ACS (ie, coronary thrombosis on an unstable plaque) was ascertained in 1 patient (0.6%), whereas diagnosis at discharge was microvascular NSTE-ACS in 56.2% of patients, variant angina in 10.1%, myocarditis in 8.9%, takotsubo disease in 7.9%, tachyarrhythmia-related chest pain in 6.7%, and non-cardiac pain in 9.6%. At 24.5-month follow-up, 21 deaths (11.8%) had occurred, 9 (5.1%) from cardiovascular causes, including 2 (1.12%) coronary deaths. By multivariable Cox analysis, age only predicted global (hazard ratio [HR] 1.07 [1.02–1.12]; P=0.006) and cardiovascular (HR 1.08 [1.01–1.16]; P=0.04) mortality; non-coronary vascular disease was the main predictor of cardiovascular death or readmission for cardiovascular disease (HR 3.28 [1.75–6.14]; P<0.001) and coronary death or readmission for angina (HR 3.20 [1.26–8.14]; P=0.014).Conclusions:Patients with an initial diagnosis of NSTE-ACS constitute a heterogeneous population with different final diagnoses. Patients have a rather high rate of fatal events, most of which, however, are not related to coronary causes. (Circ J 2016; 80: 1600–1606)

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Background:Optimal medical therapy (OMT) and the management of coronary risk factors are necessary for secondary prevention of major adverse cardiac and cerebrovascular events (MACCE) in post-acute coronary syndrome (ACS) patients. However, the effect of post-discharge patient adherence has not been investigated in Japanese patients.Methods and Results:The Prevention of AtherothrombotiC Incidents Following Ischemic Coronary Attack (PACIFIC) registry was a multicenter, prospective observational study of 3,597 patients with ACS. Death or MACCE occurred in 229 patients between hospitalization and up to 1 year after discharge. Among 2,587 patients, the association between OMT adherence and risk factor control at 1 year and MACCE occurring between 1 and 2 years after discharge was assessed. OMT was defined as the use of antiplatelet agents, angiotensin-converting enzyme inhibitors, β-blockers, and statins. Risk factor targets were: low-density lipoprotein-cholesterol <100 mg/dl, HbA1c <7.0%, non-smoking status, blood pressure <130/80 mmHg, and 18.5≤body mass index≤24.9 kg/m². The incidence of MACCE was 1.8% and associated with female sex (P=0.020), age ≥75 years (P=0.004), HbA1c ≥7.0% (P=0.004), LV ejection fraction <35% (P<0.001), estimated glomerular filtration rate <60 ml/min (P=0.008), and history of cerebral infarction (P=0.003). In multivariate analysis, lower post-discharge HbA1c was strongly associated with a lower risk of MACCE after ACS (P=0.004).Conclusions:Hyperglycemia after discharge is a crucial target for the prevention of MACCE in post-ACS patients. (Circ J 2016; 80: 1607–1614)

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Background:Atrial fibrillation (AF) is considered to be associated with poor clinical outcomes in patients with acute myocardial infarction (AMI). However, it remains uncertain whether transient new-onset AF (NOAF) during AMI has a subsequent increased risk of poor clinical outcomes.Methods and Results:Transient NOAF was defined as AF that developed during AMI without a prior history and not documented for 1 month after discharge. The primary endpoints were major adverse cardiac events (MACE) and all-cause death. We enrolled 2,105 consecutive AMI patients. Overall, AF was observed in 209 (9.9%) and transient NOAF occurred in 102 (4.8%) among 150 patients (7.1%) with NOAF. The transient NOAF group showed higher 1-month (21.8 vs. 7.0%, P<0.001), 2-year (37.8 vs. 20.7%, P<0.001), and 5-year MACE rates (51.8 vs. 28.0%, P<0.001) than the group without AF. In-hospital (16.7 vs. 5.2%, P<0.001), 1-month (17.9 vs. 5.7%, P<0.001), 2-year (30.0 vs. 11.6%, P<0.001), and 5-year mortality rates (36.9 vs. 14.0%, P<0.001) were also higher in patients with transient NOAF. Transient NOAF was a significant independent predictor of both MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.10–2.18, P=0.013) and death (HR 1.87, 95% CI 1.22–2.85, P=0.004).Conclusions:Transient NOAF was associated with the poorer clinical outcomes and was an important independent predictor of MACE and death in AMI patients. (Circ J 2016; 80: 1615–1623)

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Background:Prehospital ECG improves survival following ST-segment elevation myocardial infarction (STEMI). Although a new International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations placed new emphasis on the role of prehospital ECG, this technology is not widely used in Japan. We developed a mobile telemedicine system (MTS) that continuously transmits real-time 12-lead ECG from ambulances in a prehospital setting. This study was designed to compare reperfusion delay between STEMI patients with different prehospital transfer pathways.Methods and Results:Between 2008 and 2012, 393 consecutive STEMI patients were transferred by ambulance to hospital (PCI-capable center); 301 patients who underwent primary percutaneous coronary intervention (PCI) were enrolled prospectively. We compared time to reperfusion between patients transferred to PCI-capable hospital using the MTS (MTS group, n=37), patients directly transferred from the field to PCI-capable hospital without the MTS (field transfer group, n=125) and patients referred from a PCI-incapable hospital (interhospital transfer group, n=139). Times to reperfusion in the MTS group were significantly shorter than in the other groups, yielding substantial benefits in patients who arrived at a PCI-capable hospital within 6 h after symptom onset. On multivariate analysis, MTS use was an independent predictor of <90-min door-to-device interval (OR, 4.61; P=0.005).Conclusions:Reperfusion delay was shorter in patients using MTS than in patients without it. (Circ J 2016; 80: 1624–1633)

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Background:There is no information on differences in the effects of moderate- and low-intensity statins on coronary plaque in patients with acute coronary syndrome (ACS). The aim of this study was to compare the effects of 4 different statins in patients with ACS, using intravascular ultrasound (IVUS).Methods and Results:A total of 118 patients with ACS who underwent IVUS before percutaneous coronary intervention and who were found to have mild to moderate non-culprit coronary plaques were randomly assigned to receive either 20 mg/day atorvastatin or 4 mg/day pitavastatin (moderate-intensity statin therapy), or 10 mg/day pravastatin or 30 mg/day fluvastatin (low-intensity statin therapy). IVUS at baseline and at end of 10-month treatment was available in 102 patients. Mean percentage change in plaque volume (PV) was –11.1±12.8%, –8.1±16.9%, 0.4±16.0%, and 3.1±20.0% in the atorvastatin, pitavastatin, pravastatin, and fluvastatin groups, respectively (P=0.007, ANOVA). Moderate-intensity statin therapy induced regression of PV, whereas low-intensity statin therapy produced insignificant progression (–9.6% vs. 1.8%, P<0.001). On multivariate linear regression analysis, moderate-intensity statin therapy (P=0.02) and uric acid at baseline (P=0.02) were significant determinants of large percent PV reduction. LDL-C at follow-up did not correlate with percent PV change.Conclusions:Moderate-intensity statin therapy induced regression of coronary PV, whereas low-intensity statin therapy resulted in slight progression of coronary PV in patients with ACS. (Circ J 2016; 80: 1634–1643)

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Background:Presence of systemic inflammation in chronic kidney disease (CKD) is associated with advanced coronary artery calcification (CAC). The prognostic significance of this association, however, is unknown. We evaluated the associations between CAC, estimated glomerular filtration rate (eGFR) and all-cause mortality, to determine whether the associations differ according to the presence of systemic inflammation.Methods and Results:We followed 30,703 consecutive individuals who underwent CAC measurement for a median of 79 months (IQR, 65–96 months). Patients were categorized according to baseline CAC score (0, 1–99, 100–399 and ≥400), eGFR (<45, 45–59, 60–74, 75–89, 90–104, and ≥105 ml/min/1.73 m²) and high-sensitivity C-reactive protein (hsCRP; <2.0, and ≥2.0 mg/L). Prevalence and extent of CAC were greater in those with lower eGFR and higher hsCRP accordingly, even after adjustment. Lower eGFR was strongly associated with higher CAC score (≥400), and the association was more significant in patients with higher hsCRP. The greater CAC burden was associated with worse outcome in the CKD patients (eGFR <60 ml/min/1.73 m²) only in those with higher hsCRP.Conclusions:Patients with low eGFR and more extensive CAC had greater risk of mortality, and associations differed according to the presence of systemic inflammation. Among the CKD patients, coronary evaluation may be considered for those with elevated hsCRP. (Circ J 2016; 80: 1644–1652)

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Background:Recent studies have suggested that coronary perivascular adipose tissue (PVAT) impairs coronary vasomotion, so we examined whether PVAT is increased at the spastic coronary segment in patients with vasospastic angina (VSA).Methods and Results:PVAT volume in the left anterior descending (LAD) coronary arteries on CT coronary angiography was significantly increased in 48 VSA patients with LAD spasm compared with 18 controls (30.7±2.0 vs. 21.0±3.2 cm³, P=0.01), whereas that of total epicardial adipose tissue was comparable between the 2 groups.Conclusions:The results suggested an important role of PVAT in the pathogenesis of coronary spasm. (Circ J 2016; 80: 1653–1656)

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