Cardiovascular disease (CVD) is the leading cause of death in the world and half of the cases of CVD are estimated to occur in Asia. Compared with Western countries, most Asian countries, except for Japan, South Korea, Singapore and Thailand, have higher age-adjusted mortality from CVD. In Japan, the mortality from CVD, especially stroke, has declined continuously from the 1960s to the 2000s, which has contributed to making Japan into the top-ranking country for longevity in the world. Hypertension and smoking are the most notable risk factors for stroke and coronary artery disease, whereas dyslipidemia and diabetes mellitus are risk factors for ischemic heart disease and ischemic stroke. The nationwide approach to hypertension prevention and control has contributed to a substantial decline in stroke mortality in Japan. Recent antismoking campaigns have contributed to a decline in the smoking rate among men. Conversely, the prevalence of dyslipidemia and diabetes mellitus increased from the 1980s to the 2000s and, therefore, the population-attributable risks of CVD for dyslipidemia and diabetes mellitus have increased moderately. To prevent future CVD in Asia, the intensive prevention programs for hypertension and smoking should be continued and that for emerging metabolic risk factors should be intensified in Japan. The successful intervention programs in Japan can be applied to other Asian countries.  (Circ J 2013; 77: 1646–1652)

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Cardiac troponins (cTns) T and I are exclusively expressed at high concentrations in cardiac muscle and have emerged as the preferred biomarker in the universal definition of myocardial infarction (MI). With the recent introduction of high-sensitivity (hs) assays, diagnostic sensitivity for earlier detection of MI has substantially improved. However, lowering the diagnostic cut-off has increased the detection of myocardial injuries in various non-acute coronary syndrome (ACS) conditions, which are not related to myocardial ischemia, leading to rising difficulties in diagnosing MI in clinical situations. Several approaches, such as serial sampling and incorporation of relative or absolute δ-changes, have been proposed to overcome the limitation of decreased sensitivity for MI diagnosis with hs-cTn assays. Current consensus for rapid rule-in proposes a 20% increase within 3 or 6h when baseline cTn levels are elevated. In the case of negative baseline values, relative increases ≥50% above the 99^th percentile were found to be adequate to improve accuracy of MI diagnosis. Besides improved diagnostic accuracy for myocardial injury, even minor cTn elevations provide important prognostic information, and increased levels of cTn are associated with adverse outcomes in both the ACS and non-ACS condition, irrespective of whether the underlying cause is an acute or chronic illness. Thus, it is highly likely that lowering the diagnostic cut-off with even more sensitive assays might improve risk stratification in both conditions.  (Circ J 2013; 77: 1653–1661)

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Myocardial perfusion imaging (MPI) has played an important role in the diagnosis and risk assessment of coronary artery disease (CAD) since the early 1970s. Positron emission tomography (PET) MPI has high diagnostic accuracy and prognostic value. PET MPI can also be used to quantitatively evaluate regional myocardial blood flow (MBF) through a mathematical model. PET MBF measurements can be used in evaluating early-stage atherosclerosis with endothelial dysfunction right through to diagnosing CAD. PET/computed tomography scanners are now found in many facilities across North America, Europe, and Asia, and PET MBF quantification is expected to move from strictly research to more clinical applications. Nuclear cardiology has been a leader in quantification approaches that can be applied to other new imaging modalities. Therefore, it would be valuable to understand the basic aspects of quantification approaches. This review will address the basic aspects of MBF quantification and the additional value of quantification approaches in the clinical setting.  (Circ J 2013; 77: 1662–1671)

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Transthoracic epicardial catheter ablation is a useful supplemental or even preferred strategy to eliminate cardiac arrhythmias in the electrophysiology laboratory. The indication for this technique has extended to a diverse range of cardiac arrhythmias, including scar-related ventricular tachycardia (VT), idiopathic VTs, accessory pathways, atrial tachycardias, inappropriate sinus tachycardia, and atrial fibrillation, as the epicardial substrates of these tachyarrhythmias have become increasingly recognized. When endocardial ablation and epicardial ablation through the cardiac veins are unsuccessful, transthoracic epicardial ablation should be the next option. Intrapericardial access is usually obtained through a subxiphoidal pericardial puncture. This approach might not be possible in patients with pericardial adhesions caused by prior cardiac surgery or pericarditis. In such cases, a hybrid procedure involving surgical access with a subxiphoid pericardial window and limited anterior or lateral thoracotomy might be a feasible and safe method of performing epicardial catheter ablation in the electrophysiology laboratory. Potential complications associated with this technique include bleeding and collateral damage to the coronary artery and phrenic nerve. Although the risk of these complications is low, electrophysiologists who attempt epicardial catheter ablation should know the complications associated with this technique, how to minimize their occurrence, and how to rapidly recognize and treat the complications that they encounter. This review discusses the indications, techniques, and complications of transthoracic epicardial catheter ablation.  (Circ J 2013; 77: 1672–1680)

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Background: The long-term effects of catheter ablation (CA) on the left atrium and left atrial appendage (LAA) are unknown in persistent atrial fibrillation (AF). This study investigated left atrial (LA) reverse remodeling and evolution of LA/LAA function after successful CA for persistent AF and identified predictors for maintenance of sinus rhythm (SR) and LA reverse remodeling. Methods and Results: CA was performed in 123 patients with persistent AF. LA volumes, LA strain and LAA wall velocity were assessed both at baseline and at 12 months after ablation. Patients who maintained SR were divided into 2 groups according to whether LA volume decreased by ≥15% at follow-up (responders) or not (non-responders). During a follow-up period of 18±2 months, AF recurred in 45 patients (37%). Of the remaining 78 patients (63%) without recurrent AF, 62 patients (79%) were classified as responders. LA/LAA function significantly improved and the prevalence of spontaneous echo contrast decreased only in responders at follow-up. LA systolic strain and LAA wall velocity were independent predictors of both maintenance of SR (odds ratio [OR], 2.57; P=0.003; OR, 3.02; P=0.002, respectively) and LA reverse remodeling (OR, 4.44; P=0.007; OR, 3.52; P=0.01, respectively). Conclusions: Successful CA is associated with LA reverse remodeling and LA/LAA functional recovery in patients with persistent AF. LA systolic strain and LAA wall velocity at baseline predicted both maintenance of SR and LA reverse remodeling.  (Circ J 2013; 77: 1695–1704)

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Background: The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. Methods and Results: In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of β-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. Conclusions: Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.  (Circ J 2013; 77: 1705–1713)

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Background: Global medical devices have become more popular, but investment money for medical device development is not easily available in the market. Worldwide health-care budget constraints mean that efficient medical device development has become essential. To achieve efficient development, globalization is a key to success. Spending large amounts of money in different regions for medical device development is no longer feasible. Methods and Results: In order to streamline processes of global medical device development, an academic, governmental, and industrial consortium, called the Harmonization by Doing program, has been set up. The program has been operating between Japan and the USA since 2003. The program has 4 working groups: (1) Global Cardiovascular Device Trials; (2) Study on Post-Market Registry; (3) Clinical Trials; and (4) Infrastructure and Methodology Regulatory Convergence and Communication. Each working group has as its goals the achievement of speedy and efficient medical device development in Japan and the USA. The program has held multiple international meetings to deal with obstacles against efficient medical device development. Conclusions: This kind of program is very important to deliver novel medical devices. Involvement of physicians in this type of activity is also very helpful to achieve these goals.  (Circ J 2013; 77: 1714–1718)

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Background: Bleeding is a potentially catastrophic complication after primary percutaneous coronary intervention (PPCI). It occurs most frequently within the first 30 days following the intervention. The aim of this study was to generate a simple and accurate risk model for the prediction of bleeding after PPCI. Methods and Results: The training set included 2,096 patients enrolled in the RISK-PCI trial. The model was validated using a database of 961 patients enrolled in the ART-PCI trial. Bleeding was defined as type ≥3a bleeding according to the Bleeding Academic Research Consortium definition. Multivariate logistic regression was used to evaluate the predictors of outcome. A sum of weighted points for specific predictors was calculated to determine the final score. The model included 5 independent predictors of 30-day bleeding: gender (female); history of peptic ulcer; creatinine clearance at admission (<60ml/min); hemoglobin at presentation (<125g/dl); and Killip class >1 heart failure at admission. The model showed good discrimination and calibration for the prediction of bleeding in the derivation set (C-statistic, 0.79; goodness of fit, P=0.12) and in the validation set (C-statistic, 0.76; goodness of fit, P=0.37). Patients were classified into 3 risk classes and the observed incidence of 30-day bleeding of 1.0%, 3.5% and 10.7% corresponded to the low-, intermediate- and high-risk classes, respectively. Conclusions: A simple risk model was developed that has a reasonably good capacity for the prediction of 30-day bleeding after PPCI.  (Circ J 2013; 77: 1719–1727)

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Background: The association between endothelial progenitor cells (EPCs) at the time of percutaneous coronary intervention (PCI) and the subsequent long-term clinical outcome remains undefined. To address this issue, a pre-specified analysis of the PROgenitor Cells role in Restenosis and progression of coronary ATherosclerosis after percutaneous coronary intervention (PROCREATION) study was done. Methods and Results: A total of 155 patients with stable angina treated with PCI had flow cytometry before PCI. Patients had a 5-year follow-up. Primary outcome was the composite of major adverse cardiac or cerebrovascular events (MACCE), that is, death, stroke, myocardial infarction, and revascularization. During follow-up, MACCE occurred in 65 of 155 patients (42%). There were no significant differences in clinical and angiographic variables between patients with or without MACCE, apart from a different extent of coronary atherosclerosis. The incidence of MACCE increased significantly over tertiles of CD34+/KDR+/CD45– cells and CD133+/KDR+/CD45– cells, with rates of 25%, 39%, and 69% (P=0.0001), and 26%, 44%, and 59% (P=0.003), respectively. On multivariate analysis it was estimated that the increase in CD34+/KDR+/CD45– cells was associated with a 35% higher risk for MACCE (hazard ratio [HR], 1.75; 95% confidence interval [CI]: 1.07–1.99; P=0.001), and the increase in CD133+/KDR+/CD45– cells was associated with a 25% higher risk for MACCE (HR, 1.35; 95% CI: 1.01–1.74; P=0.03). Conclusions: Assessment of subpopulations of circulating EPCs in patients with stable angina treated with PCI can improve characterization of long-term prognosis (ClinicalTrials.gov: NCT01575431).  (Circ J 2013; 77: 1728–1735)

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Background: The DuraHeart left ventricular assist device (LVAD) is the world’s first approved magnetically levitated implantable centrifugal pump. We report our initial experience with the DuraHeart as a bridge to heart transplantation. Methods and Results: Between 2008 and 2011, 23 patients (17 males; mean age 35 years, range 16–53 years) with endstage heart failure underwent implantation with the DuraHeart LVAD at Osaka University Hospital. Of those, 7 underwent conversion surgery from a Nipro paracorporeal LVAD to the DuraHeart. There were no deaths during the mean support period of 559±241 days (176–999 days). In total, 17 patients (74%) remain with the LVAD and 5 (22%) underwent heart transplantation after 580±302 days (176–982 days) of support. Major adverse events included 8 (34%) driveline/pocket infections, 4 (17%) cerebrovascular accidents, 4 (17%) right heart failures requiring mechanical support, and 3 (13%) mechanical device failures (magnetic levitation failure caused by driveline fracture). Of the 5 patients who developed pump pocket infection, 3 underwent previous conversion surgery from the Nipro LVAD. Conclusions: Our initial experience with the DuraHeart LVAD in Japan demonstrated excellent long-term survival with acceptable rates of adverse events. With refinement of the system, including mechanical durability, this pump will further enhance the quality of life for patients who require long-term mechanical circulatory support.  (Circ J 2013; 77: 1736–1741)

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Background: The aim of this study was to investigate whether the extent of late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging reflecting myocardial fibrosis correlates with left ventricular (LV) longitudinal function during exercise in hypertrophic cardiomyopathy (HCM). Methods and Results: Mitral annular velocities (E’ and S’) were measured on echocardiography at rest and during graded bicycle exercise (25W, 3-min increments) in 46 HCM patients (mean age, 53 years; 32 men). LV longitudinal diastolic and systolic functional reserve indices were calculated as ΔE’×E’_base and ΔS’×S’_base, where ΔE’ and ΔS’ are the changes in E’ and S’ from baseline to 50W of exercise, respectively. The patients were divided into 2 groups according to the extent of LGE (as “percentage of LV mass containing LGE”: %LV with LGE; range, 0–37%; median, 6%): group 1 (n=23), %LV with LGE <6%, and group 2, %LV with LGE ≥6%. Baseline echocardiographic parameters were similar between the 2 groups, but changes in E’ and S’ during exercise were smaller in group 2 (ΔE’: 2.8±1.8cm/s vs.1.5±1.0cm/s, P=0.007; ΔS’: 2.2±1.2cm/s vs. 0.9±0.8cm/s, P<0.0001). LV functional reserve indices were also significantly lower in group 2 (ΔE’×E’_base: 12.8±7.7 vs. 5.5±3.4, P=0.001; ΔS’×S’_base: 12.6±7.4 vs. 4.7±4.5, P<0.0001). Conclusions: LV longitudinal function during exercise is influenced by the extent of LGE in HCM. Myocardial fibrosis may represent a pathologic substrate that determines LV functional reserve in patients with HCM.  (Circ J 2013; 77: 1742–1749)

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Background: Left ventricular (LV) dyssynchrony is not a stable phenomenon, but rather, changes dynamically. Given that the prognostic impact of dynamic dyssynchrony has not yet been elucidated, the objective was to investigate the clinical impact of dynamic dyssynchrony on patients with dilated cardiomyopathy (DCM). Methods and Results: Seventy DCM patients with ejection fraction 32±9% were retrospectively recruited, and 3-dimensional speckle-tracking area strain was used to measure both contractile reserve and changes in dyssynchrony during dobutamine stress. The standard deviation of time-to-peak area strain was adopted as the systolic dyssynchrony index. Event-free survival was then tracked over a 13-month period. A ≥7.55% increase in systolic dyssynchrony index during dobutamine stress (Δsystolic dyssynchrony index) was the best predictor of cardiovascular events with 77% sensitivity and 88% specificity. Multivariate Cox analysis indicated that not only the absence of contractile reserve (Δglobal area strain ≤21.1%: hazard ratio [HR], 15.29; P=0.01), but the presence of dynamic dyssynchrony (ΔLV dyssynchrony ≥7.55%: HR: 7.591; P=0.003) was an independent predictor of cardiovascular events. Importantly, absence of dynamic dyssynchrony and presence of contractile reserve were associated with the most favorable outcome (98%), whereas the reverse condition was associated with the worst outcome (20%, P<0.001). Conclusions: Dynamic dyssynchrony is a potential predictor of cardiovascular events in patients with DCM, while assessment of dynamic dyssynchrony in combination with contractile reserve may further improve prognostic risk stratification.  (Circ J 2013; 77: 1750–1759)

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Background: The aim of this study was to carry out 3-dimensional speckle tracking imaging (3DSTI) of the right ventricle (RV) and evaluate RV regional wall deformation. Methods and Results: 3DSTI of the RV was performed in 35 normal subjects, 8 patients with arrhythmogenic right ventricular cardiomyopathy, and 8 patients with pulmonary arterial hypertension. Peak systolic area change ratio and regional contraction timing relative to global systolic time (time to peak strain/time to end-systole×100) were measured in each segment. Good-quality images were acquired of the inflow segment in 87%, apex in 87%, outflow in 57%, and septum in 94% of the 35 normal subjects. In normal subjects, peak systolic area change ratio of the inflow anterior wall was –41±14%; inflow inferior wall, –35±9%; apical anterior wall, –41±10%; apical inferior wall, –31±11%; outflow, –31±9%; and septum wall, –36±11%. Contraction timing of the apical anterior wall and septum wall were earlier than those of other segments. In patients with RV dysfunction, 3DSTI indicated low peak systolic area change ratio in the damaged area. Conclusions: RV 3DSTI indicated segmental heterogeneity in magnitude and timing of RV contraction. 3DSTI may be a promising modality for providing precise quantitative information on complex RV wall motion.  (Circ J 2013; 77: 1760–1768)

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Background: The relationship between the functional significance of epicardial coronary artery stenosis and microvascular resistance remains to be determined. Furthermore, little is known regarding the determinants of microvascular resistance in patients with intermediate coronary lesions. Methods and Results: Using a pressure-temperature sensor-tipped guidewire, thermodilution-derived index of microcirculatory resistance (IMR) was measured, along with fractional flow reserve (FFR), in 131 coronary arteries of 104 patients with intermediate stenosis, in order to determine the relationship between IMR and clinical data. IMR varied widely (median, 20.8; range, 6.3–65.2), and no significant relationship was observed between IMR and FFR after IMR was corrected for coronary wedge pressure in the territories with functionally significant stenoses. There was no significant relationship between IMR and Framingham risk score, systematic coronary risk evaluation (SCORE), ACC/AHA lesion classification, or SYNTAX score. Right coronary artery (RCA) lesion location and history of hypertension were significantly associated with increased IMR. Multivariate analysis showed that RCA lesion location (odds ratio [OR], 4.52; 95% confidence interval [CI]: 1.84–11.11, P=0.001) and hypertension (OR, 3.03; 95% CI: 1.15–7.96, P=0.025) were independent predictors of increased IMR. Conclusions: Functional significance of intermediate coronary stenosis was not correlated with microvascular resistance of the perfusion territory. Intermediate coronary lesions may result in increased microcirculatory resistance irrespective of functional significance of the stenosis, with significant regional difference in microvascular resistance.  (Circ J 2013; 77: 1769–1776)

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Background: Circulating endothelial progenitor cells (EPCs) might limit endothelial dysfunction in patients with microvascular angina (MVA). Endothelial colony-forming cells (ECFCs; displaying the CD34+/KDR+/CD45– phenotype) are currently regarded as true EPCs. The aim of this study was to evaluate exercise-induced ECFC mobilization and platelet reactivity in patients with MVA or with obstructive coronary artery disease (CAD). Methods and Results: Exercise stress test (EST) was performed in 20 MVA patients, 20 CAD patients and 20 controls. Platelet reactivity was assessed before and after EST as formation of monocyte-platelet aggregates (MPAs) and CD41 platelet expression, without and with adenosine diphosphate (ADP) stimulation. ECFC number was measured before and 24h after EST. At rest, MPAs and CD41 platelet expression increased more with ADP in MVA patients (+71±11.0% and +37±7.5%, respectively), than in CAD patients (+37±8.6% and +19±4.5%, respectively) and controls (+29±3.5% and +21±3.1%, respectively; P<0.001 for both). At rest, ECFCs tended to be lower in CAD patients, compared to MVA patients and controls (4.1±5.0%, 7.2±6.0% and 7.3±7.0% cells/10⁵, respectively; P=0.056). After EST, ECFCs increased less in MVA patients (+2.8±11) compared to CAD patients (+3.3±15; P<0.05) and controls (+7.4±24; P<0.01). Conclusions: In MVA patients, EST is able to blunt the peculiar increase of platelet reactivity to ADP present at rest; in contrast, no potential protective response of ECFCs to exercise was seen in these patients.  (Circ J 2013; 77: 1777–1782)

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Background: Electrophysiological information as well as anatomic information are important for the detection of coronary artery lesions. The aim of this study was to assess the efficacy of resting magnetocardiography (MCG) in stable coronary artery disease (CAD) and cardiac allograft vasculopathy (CAV). Methods and Results: MCG and coronary angiography were performed within 1 month in 75 patients with suspected CAD and in 26 subjects after orthotopic heart transplantation (OHT). Plaque volumes were additionally measured on intravascular ultrasound in OHT recipients. The spatially distributed QT_c interval maps were constructed with 64-channel MCG. A T-wave propagation map and QT_c heterogeneity index including QT_c dispersion and smoothness index of QT_c (SI-QT_c) were derived for ischemia detection and localization. CAD patients had higher QT_c dispersion and SI-QT_c. Receiver operating characteristic curve analysis identified SI-QT_c ≥9ms, QT_c dispersion ≥79ms as the optimal cut-off for detecting CAD (diagnostic accuracy, 0.7953, 0.7819), better than T-wave propagation (0.6594, P<0.05). There was no significant difference of QT_c dispersion between CAD and OHT subjects. In OHT recipients, QT_c dispersion positively correlated with plaque volume, and SI-QT_c progressively increased after transplantation. Using T-wave propagation mapping, regionally increased dispersion could be demonstrated in CAD patients, but increased dispersion was noted in fewer OHT recipients. Conclusions: MCG is clinically feasible as a non-invasive tool for diagnosis of CAD, and could be used as a surrogate marker of CAV.  (Circ J 2013; 77: 1783–1790)

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Background: The aim of this study was to compare the effect on endothelial function of increasing statin dose to add-on ezetimibe in patients with coronary artery disease (CAD) already treated with statin. Methods and Results: Two-hundred and forty-three patients with CAD and low-density lipoprotein cholesterol (LDL-C) ≥70mg/dl even after treatment with atorvastatin (10mg) were prospectively randomized to the ezetimibe addition (10mg) group (A10E10; n=117) or to the double atorvastatin dose (to 20mg; A20; n=133) group for 12 weeks. Primary endpoint was change in endothelial function measured by logarithmic-scale reactive hyperemia index (L_RHI). After treatment, high-sensitivity C-reactive protein (hs-CRP) and all lipids except triglyceride and high-density lipoprotein cholesterol were significantly reduced in both groups. The mean percent changes in LDL-C for the A10E10 and A20 groups were –25.8% and –9.1%, respectively (P<0.001). L_RHI increased from 0.47 to 0.62 in the A20 group (P<0.001), but not in the A10E10 group (from 0.45 to 0.48, P=0.399). Absolute change in L_RHI was significantly higher in the A20 than A10E10 group (0.02±0.29 vs. 0.16±0.27, P<0.001). Conclusions: Statin and ezetimibe have different effects on endothelial function independent from LDL-C-lowering effects.  (Circ J 2013; 77: 1791–1798)

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Background: Mutations in genes encoding the L-type cardiac calcium channel (LTCC) are associated with various types of inherited arrhythmias, including Brugada syndrome (BrS). However, the frequency in Asian populations remains unknown. This study aimed to elucidate disease-causing mutations in LTCC-related genes in Japanese patients diagnosed as BrS or idiopathic ventricular fibrillation (IVF), early repolarization syndrome, short QT syndrome, and compare them with those carrying SCN5A mutations. Methods and Results: We screened CACNA1C and CACNB2b in 312 probands and compared the clinical characteristics between probands with gene mutations in CACNA1C or SCN5A. In results, we identified 6 CACNA1C mutations in 7 unrelated probands and SCN5A mutations in 20 probands. There were no CACNB2b mutation carriers. In topology, half of the mutations were located in the C-terminus. Among 7 CACNA1C mutation carriers, 2 were female and 3 were symptomatic; 2 patients were resuscitated from ventricular fibrillation, and 1 patient had syncope. Compared with SCN5A mutation carriers, there were no significant differences in the ECG characteristics. 2 of 3 symptomatic CACNA1C patients were female, but all female SCN5A mutation carriers remained asymptomatic. Conclusions: We identified 6 CACNA1C mutations in BrS and IVF patients and their phenotypes were varied. Although mutation frequency was not high, screening of LTCC channel genes may be clinically important to prevent unexpected sudden death.  (Circ J 2013; 77: 1799–1806)

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Background: It has been reported that 20-hydroxyeicosatetraenoic acid (20-HETE) aggravates myocardial ischemia/reperfusion (I/R) injury, but the exact mechanism of action is still unclear. Methods and Results: Experiments were performed in isolated rat hearts subjected to 35min of ischemia followed by 40min of reperfusion in Langendorff preparations. Perfusion with HET0016, an inhibitor of 20-HETE production, significantly improved I/R-induced reduction in cardiac contractility, myocardial infarction, and myocardial apoptosis. In contrast, administration of 20-HETE aggravated I/R-induced myocardial injury and enhanced apoptosis. I/R significantly increased production of reactive oxygen species (ROS) and oxidative stress, both of which were significantly inhibited by HET0016 and enhanced by 20-HETE administration. Apocynin, an inhibitor of NADPH oxidase, blocked 20-HETE-induced ROS production in the I/R hearts. 20-HETE increased the expression of gp91^phox and p22^phox, the subunits of NADPH oxidase; and stimulated NADPH oxidase activity. In addition, GF-109203 significantly attenuated the 20-HETE-induced increases in the NADPH oxidase expression and activity. Finally, in the Langendorff I/R preparation, both apocynin and tempol, ROS scavengers, significantly blocked 20-HETE-induced myocardial dysfunction. Conclusions: All of the results demonstrated that in isolated rat hearts 20-HETE stimulates NADPH oxidase-derived superoxide production, which aggravates I/R-induced myocardial injury via a PKC-dependent mechanism.  (Circ J 2013; 77: 1807–1816)

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Background: Reperfusion of ischemic myocardium may contribute to substantial cardiac tissue damage, but the addition of iron chelators, zinc or zinc complexes has been shown to prevent heart from reperfusion injury. We investigated the possible beneficial effects of an iron-chelating and zinc-complexing agent, Q50, in rat models of ischemia/reperfusion (I/R)-induced myocardial infarction and on global reversible myocardial I/R injury after heart transplantation. Methods and Results: Rats underwent 45-min myocardial ischemia by left anterior descending coronary artery ligation followed by 24h reperfusion. Vehicle or Q50 (10mg/kg, IV) were given 5min before reperfusion. In a heart transplantation model, donor rats received vehicle or Q50 (30mg/kg, IV) 1h before the onset of ischemia. In myocardial infarcted rats, increased left ventricular end-systolic and end-diastolic volumes were significantly decreased by Q50 post treatment as compared with the sham group. Moreover, in I/R rat hearts, the decreased dP/dt_max and load-independent contractility parameters were significantly increased after Q50. However, Q50 treatment did not reduce infarct size or have any effect on increased plasma cardiac troponin-T-levels. In the rat model of heart transplantation, 1h after reperfusion, decreased left ventricular systolic pressure, dP/dt_max, dP/dt_min and myocardial ATP content were significantly increased and myocardial protein expression of superoxide dismutase-1 was upregulated after Q50 treatment. Conclusions: In 2 experimental models of I/R, administration of Q50 improved myocardial function. Its mechanisms of action implicate in part the restoration of myocardial high-energy phosphates and upregulation of antioxidant enzymes.  (Circ J 2013; 77: 1817–1826)

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Background: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san’o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model. Methods and Results: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113. Conclusions: These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.  (Circ J 2013; 77: 1827–1837)

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Background: Although durable clinical outcomes have been reported, arterial repair after paclitaxel-coated nitinol drug-eluting stent (Zilver PTX) implantation in the superficial femoral artery (SFA) remains unclear. Methods and Results: Angioscopic evaluation was performed in SFA intra-stent surfaces 80±29 (range, 49–135) days or 84±18 (range, 52–112) days following Zilver PTX (20 stents in 10 patients; mean age, 72±8 years; 40% men) or bare metal stent (BMS; 14 stents in 9 patients; mean age, 70±7 years; 67% men) implantation, respectively. Neointimal coverage (NIC) was graded as 0, stent struts exposed; grade 1, struts bulging into the lumen, but still transparently visible although covered; grade 2, struts embedded in the neointima, but translucent; grade 3, struts fully embedded and invisible. NIC was defined as heterogeneous when the NIC grade variation was ≥1. Presence of yellow plaque and thrombus were investigated. Dominant NIC was significantly different between Zilver PTX (grade 0, 35%; grade 1, 20%; grade 2, 25%; grade 3, 20%) and BMS (grade 0, 7%; grade 1, 0%; grade 2, 14%; grade 3, 79%; P=0.001). NIC heterogeneity was less frequently observed in Zilver PTX (40% vs. 86%, P=0.009). Prevalence of yellow plaque or thrombus (75% vs. 79%, P=0.57) or thrombus (75% vs. 79%, P=0.57) were similar between Zilver PTX and BMS. Conclusions: Early phase arterial repair was different between Zilver PTX and BMS.  (Circ J 2013; 77: 1838–1843)

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Background: Differences in regulating factors and the clinical implications of body temperature variability (BTV) between subjects with and without diabetes have not been clarified to date. Methods and Results: In 66 subjects with ischemic heart disease (33 with diabetes and 33 without diabetes), BTV, the difference between the highest and lowest temperature measurements, and body temperature standard deviation (BT SD) were measured from axillary body temperature (ABT) records of 3 consecutive days and followed for 16.4±8.4 months. In subjects without diabetes BTV and BT SD were closely associated with endothelial function as evaluated on flow-mediated dilation (BTV, R=0.33, P=0.026; BT SD, R=0.41, P=0.029), whereas there was a poor association in subjects with diabetes. In the absence of an interrelationship between vascular function and thermoregulation, the contribution of inflammation to BTV was increased in subjects with diabetes (BTV, 0.59±0.21°C for C-reactive protein [CRP] <0.08mg/dl vs. 0.79±0.28°C for CRP >0.08mg/dl, P=0.014). Event-free survival analysis showed that in subjects with diabetes higher BT SD was associated with shorter event-free survival (log-rank P=0.012), but this relationship was not found in subjects without diabetes. Conclusions: In subjects with diabetes, the interrelationship between thermoregulation and vascular function was disrupted and the effect of inflammation on thermoregulation was enhanced, so that BTV had a sufficient predictive value for cardiovascular events in diabetic subjects.  (Circ J 2013; 77: 1844–1853)

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Background: Cold temperature has been reported to contribute to cardiovascular mortality, but it is not clear which people are more susceptible to cold temperature. Methods and Results: The relationship between ambient temperature and mortality was examined in 3,593 subjects from the Ibaraki Prefectural Health Study who died of cardiovascular disease during a mean follow-up period of 9.7±4.0 years. Daily values of meteorological variables were obtained from the Japan Meteorological Agency. Time-stratified case cross-over analysis was used. The multivariate odds ratios (ORs; 95% confidence interval) per 1°C decrease in daily maximum temperature over the day of death and the 2 days prior to this day adjusted for relative humidity were 1.018 (1.003–1.034) for all cardiovascular deaths and 1.025 (1.003–1.048) for stroke deaths. Risk-stratified analysis showed that younger subjects aged <80 years and those with hyperglycemia were more susceptible to cold temperature. The OR of all cardiovascular deaths related to cold temperature was 1.034 (1.012–1.056) for subjects aged <80 years, and that of stroke deaths was 1.076 (1.023–1.131) for those with hyperglycemia. Conclusions: Exposure to cold temperature triggers cardiovascular deaths. Additionally, younger age and hyperglycemia could enhance susceptibility to cold temperature.  (Circ J 2013; 77: 1854–1861)

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Background: Atopic dermatitis (AD) is a common skin condition in which Staphylococcus (S.) aureus can cause native valve destruction in patients with infective endocarditis (IE). The aim of this study was to determine the early and late outcomes of IE and AD. Methods and Results: The medical records of patients with IE and AD who presented between January 1997 and September 2010 were analyzed retrospectively. IE and AD patients were compared with those with IE without AD. The mean follow-up period was 5.5±3.4 years. The incidence of AD among IE patients was 6.7% and they were significantly younger than those without AD (28.4 years vs. 53.7 years; P<0.0001). Methicillin-sensitive S. aureus and Streptococcus species were more prevalent in IE with AD (P<0.0001) and without AD (P=0.0259), respectively. One developed postoperative mediastinitis caused by methicillin-resistant S. aureus despite preoperative skin care. None of the patients died in hospital or had IE recurrence. Freedom from recurrent IE or prosthetic valve endocarditis at 5 years was 100±0.0%. Conclusions: Patients with IE must be checked for AD and history of AD because AD patients have a high incidence of staphylococcal colonization in their skin lesion.  (Circ J 2013; 77: 1862–1866)

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Background: Bradykinin (BK) is a key mediator regulating coronary blood flow. It is degraded by angiotensin-converting enzyme (ACE), but what is unknown is whether enhanced tissue ACE activity interferes with BK-induced coronary vasodilation in obesity. Methods and Results: Coronary arterioles (∼100μm) were isolated from rats on a normal or high-fat diet (HFD) and from lean or obese patients undergoing heart surgery (n=74). We found that BK-induced dilation was diminished in the coronary arterioles of HFD rats, when compared with controls. When administered in vitro, the ACE inhibitor, captopril, restored the coronary dilation response to BK in HFD rats, but did not affect control responses. Abundant ACE expression was detected in coronary endothelium, which was associated with increased ACE activity in HFD arterioles, as measured by increased response to the ACE substrate, angiotensin I. Moreover, we found that in the coronary arterioles of obese patients, BK-induced dilation was augmented by in vitro captopril administration. Correspondingly, ACE activity was increased in the coronary arterioles of obese patients when compared with the non-obese. Logistic regression analysis revealed that obese patients taking ACE inhibitors prior to surgery exhibited an enhanced dilation response to BK. Conclusions: We demonstrated augmented tissue ACE activity in the coronary arterioles of obese subjects, which leads to reduced coronary dilation response to BK. We provide a rationale for ACE inhibitor therapy in obese patients to improve dilatation of coronary microvessels.  (Circ J 2013; 77: 1867–1876)

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