Heart failure (HF) is a highly prevalent disease that leads to significant morbidity and mortality. There is increasing evidence that the symptoms of HF are exacerbated by its deleterious effects on lung function. HF appears to cause airway obstruction acutely and leads to impaired gas diffusing capacity and pulmonary hypertension in the longer term. It is postulated that this is the result of recurrent episodes of elevated pulmonary capillary pressure leading to pulmonary oedema and pulmonary capillary stress fracture, which produces lung fibrosis. It is likely that impaired lung function impairs the functional status of HF patients and makes them more prone to central sleep apnoea. (Circ J 2010; 74: 2507-2516)

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Over the past decade, the ability to culture and differentiate human embryonic stem cells (ESCs) has offered researchers a novel therapeutic that may, for the first time, repair regions of the damaged heart. Studies of cardiac development in lower organisms have led to identification of the transforming growth factor-β superfamily (eg, activin A and bone morphogenic protein 4) and the Wnt/β-catenin pathway as key inducers of mesoderm and cardiovascular differentiation. These factors act in a context-specific manner (eg, Wnt/β-catenin is required initially to form mesoderm but must be antagonized thereafter to make cardiac muscle). Different lines of ESCs produce different levels of agonists and antagonists for these pathways, but with careful optimization, highly enriched populations of immature cardiomyocytes can be generated. These cardiomyocytes survive transplantation to infarcted hearts of experimental animals, where they create new human myocardial tissue and improve heart function. The grafts generated by cell transplantation have been small, however, leading to an exploration of tissue engineering as an alternate strategy. Engineered tissue generated from preparations of human cardiomyocytes survives poorly after transplantation, most likely because of ischemia. Creation of pre-organized vascular networks in the tissue markedly enhances survival, with human capillaries anastomosed to the host coronary circulation. Thus, pathways controlling formation of the human cardiovascular system are emerging, yielding the building blocks for tissue regeneration that may address the root causes of heart failure. (Circ J 2010; 74: 2517-2526)

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Epidemiological studies have shown that age is the chief risk factor for lifestyle-related diseases such as cardiovascular disease and diabetes, but the molecular mechanisms that underlie the increase in the risk of such diseases conferred by aging remain unclear. Recently, genetic analyses using various animal models have identified molecules that are crucial for aging. These include components of the DNA repair system, the tumor suppressor pathway, the telomere maintenance system, the insulin/Akt pathway, and other metabolic pathways. Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a causative link between cellular senescence and aging. This review examines the hypothesis that cellular senescence might contribute to lifestyle-related disease. (Circ J 2010; 74: 2527-2533)

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Background: Atrioventricular block (AVB) sometimes complicates QT prolongation and torsades de pointes (TdP). Methods and Results: The clinical and genetic background of 14 AVB patients (57±21 years, 13 females) who developed QT prolongation and TdP was analyzed. Electrophysiological characteristics of mutations were analyzed using heterologous expression in Chinese hamster ovary cells, together with computer simulation models. Every patient received a pacemaker or implantable cardioverter defibrillator; 3 patients had recurrence of TdP during follow-up because of pacing failure. Among the ECG parameters, QTc interval was prolonged to 561±76ms in the presence of AVB, but shortened to 495±42ms in the absence of AVB. Genetic screening for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 revealed four heterozygous missense mutations of KCNQ1 or KCNH2 in 4 patients (28.6%). Functional analyses showed that all mutations had loss of functions and various gating dysfunctions of I_Ks or I_Kr. Finally, action potential simulation based on the Luo-Rudy model demonstrated that most mutant channels induced bradycardia-related early afterdepolarizations. Conclusions: Incidental AVB, as a trigger of TdP, can manifest as clinical phenotypes of long QT syndrome (LQTS), and that some patients with AVB-induced TdP share a genetic background with those with congenital LQTS. (Circ J 2010; 74: 2562-2571)

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Background: Mutations in SCN5A are reportedly linked to Brugada syndrome (BS), but recent observations suggest that they are not necessarily associated with ventricular fibrillation (VF) in BS patients. Therefore, the clinical importance of SCN5A mutations in BS patients was examined in the present study. Methods and Results: The 108 BS patients were examined for SCN5A mutations and various parameters were compared between patients with and without mutations. An implantable cardioverter defibrillator (ICD) was implanted in 49 patients and a predictor of appropriate ICD shock was investigated. The existence of a SCN5A mutation was not associated with initial VF episodes (21.7% vs 20.0%, P=0.373). In the secondary prevention group, appropriate shock-free survival rate was significantly lower in patients with spontaneous type 1 ECG than in those without (41.1% vs 85.7% at 2 years, P=0.014). The appropriate shock-free survival rate was also significantly lower in patients with SCN5A mutations than in those without (28.6% vs 83.3% at 1 year, P=0.040). Appropriate shock was more frequent in patients with SCN5A mutations than in those without (6.6±6.2 vs 1.7±3.0, P=0.007). Conclusions: SCN5A mutations are associated with early and frequent VF recurrence, but not with initial VF episodes. This is the first report on the genotype-phenotype interaction and clinical significance of this mutation. (Circ J 2010; 74: 2572-2578)

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Background: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca²⁺ leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2^R2474S/+ knock-in (KI) mouse model was investigated. Methods and Results: ECG was monitored in KI mice (n=6) and wild-type (WT) mice (n=6), before and after an injection of epinephrine (1.0mg/kg) or on exercise using a treadmill. In all KI (but not WT) mice, bi-directional ventricular tachycardia (VT) was induced after an injection of epinephrine or on exercise. Pre-treatment with dantrolene (for 7-10 days) significantly inhibited the inducible VT (P<0.01). In KI cardiomyocytes, Ca²⁺ spark frequency (SpF; s^-1·100μm^-1: 5.8±0.3, P<0.01) was much more increased after the addition of isoproterenol than in WT cardiomyocytes (SpF: 3.6±0.2). The increase in SpF seen in KI cardiomyocytes was attenuated by 1.0μmol/L dantrolene (SpF: 3.6±0.5, P<0.01). Conclusions: Dantrolene prevents CPVT, presumably by inhibiting Ca²⁺ leak through the RyR2. (Circ J 2010; 74: 2579 . 2584).

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Background: Recent studies have shown that monocytes in human peripheral blood are heterogeneous. The clinical significance of 2 distinct monocyte subsets as a marker of late in-stent restenosis (ISR) following implantation of bare-metal stents (BMSs) in patients with acute myocardial infarction (AMI) was examined. Methods and Results: Seventy-one consecutive patients with AMI who underwent BMS implantation were enrolled in the study. Peripheral blood was collected 12 days after AMI onset. Two distinct monocyte subsets (CD14⁺CD16^-CCR2⁺ and CD14⁺CD16⁺CX3CR1⁺) were measured by flow cytometry. All patients underwent angiography at a scheduled follow up after 9 months. CD14⁺CD16⁺CX3CR1⁺ monocyte subset counts were significantly higher in patients with restenosis than in patients without restenosis, whereas neither the total monocytes nor the CD14⁺CD16^-CCR2⁺ subset counts differed significantly between the 2 groups of patients. There was also a significant positive correlation between the CD14⁺CD16⁺CX3CR1⁺ monocyte counts and angiographic late lumen loss. In multivariate analysis, the CD14⁺CD16⁺CX3CR1⁺ monocyte count was an independent predictor for in-stent late lumen loss. Conclusions: CD14⁺CD16⁺CX3CR1⁺ monocytes might have a role in ISR following coronary BMS implantation in patients with AMI. (Circ J 2010; 74: 2585-2591)

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Background: Long-term clinical outcomes of diabetes mellitus (DM) patients who underwent drug-eluting stent deployment has not well investigated. Methods and Results: A total of 2,050 cases were enrolled consecutively from 50 sites in Japan into the Cypher stent Japan Post-Marketing Surveillance (Cypher J-PMS) registry, and the 3-year outcomes of DM patients were analyzed. Subjects were divided into 2 groups based on the treatment of DM (insulin-treated diabetes (IT) group, n=207; and non insulin-treated diabetes (NIT) group, n=682). Major adverse cardiac event (MACE) rates in the IT group and the NIT group were 26.0% and 14.5% at 3 years, respectively (P<0.001). There were no significant differences in stent thrombosis rates (definite and probable by Academic Research Consortium (ARC) definition) (0% and 1.08%, respectively). Multivariate analysis suggested that hemodialysis and insulin-treated DM were independent predictors for MACE, and insulin-treated DM, hemodialysis and long lesions were strong independent predictors for target-lesion revascularization (TLR). Conclusions: Hemodialysis and insulin-treated DM were strong independent predictors of mortality and TLR in DM patients. These results might suggest that special attention to patients with hemodialysis and insulin-treated DM is warranted in the setting of sirolimus-eluting stent deployment for DM patients. (Circ J 2010; 74: 2592-2597)

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Background:  Little is known about the influence of dynamic training on the hemodynamic and neurohormonal responses to static exercise and on inflammatory markers in optimally treated post-coronary artery bypass grafting (CABG) patients. Methods and Results:  One hundred and twenty male patients, aged 55±6 years, 3 months after receiving CABG, were randomized to either 6 weeks of aerobic training on a cycloergometer, 3 times a week, at a 70-80% of the maximum tolerated heart rate (HR) (training group, n=60) or to a control group (n=60). At baseline and at the end of the study, all patients underwent: (1) a cardiopulmonary test; (2) handgrip at 30% of maximal voluntary contraction for 3min in a sitting position during in which HR, blood pressure (BP), stroke volume (SV, by impedance cardiography), cardiac output (CO) and total peripheral resistance (TPR) were monitored; and (3) plasma level assessment of catecholamines, nitric oxide and inflammatory markers. During the final tests, handgrip-induced increases in HR, BP, and TPR (14% vs 27%, P<0.01) were lower, whereas SV and CO were higher (by 13% and 15%, respectively, P<0.05) in trained patients compared with controls. Moreover, a higher increase in nitric oxide level (46% vs 14%, P<0.01) and a lower increase in noradrenaline (11% vs 20%, P<0.05) were observed in trained patients compared with controls. Accordingly, training caused significant improvement in peak oxygen uptake per kilogram body weight (peak VO₂) and inflammatory markers. Conclusions:  Short-term dynamic training caused significant improvement of hemodynamic and neurohormonal responses to handgrip, cardiovascular fitness and inflammatory state. (Circ J 2010; 74: 2598-2604)

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Background: Obesity is a risk factor for cardiovascular disease (CVD) and is also associated with an increased risk of death in subjects without CVD. However, in heart failure (HF), elevated body mass index (BMI) has been shown to be associated with better prognosis, but it is unknown whether this is the case in unselected HF patients encountered in routine clinical practice in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed for 2.1 years. Study cohort (n=2,488) was classified into 3 groups according to baseline BMI: <20.3kg/m² (n=829), 20.3-23.49kg/m² (n=832), and ≥23.5kg/m² (n=827). The mean BMI was 22.3±4.1kg/m². Patients with higher BMI had lower rates of all-cause death, cardiac death, and rehospitalization because of worsening HF. After multivariable adjustment, the risk for all-cause death and cardiac death significantly increased with decreased BMI levels compared with patients with BMI ≥23.5kg/m². However, BMI levels were not associated with rehospitalization for worsening HF. Conclusions: Lower BMI was independently associated with increased long-term all-cause, as well as cardiac, mortality in patients with HF encountered in routine clinical practice in Japan. (Circ J 2010; 74: 2605-2611)

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Background: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities. Methods and Results: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan. First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non-ischemic CHF patients. Conclusions: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF. (Circ J 2010; 74: 2612-2621)

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Background: Experimental animal data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) might reduce enhanced sympathetic activity, a hallmark of hypertensive patients. This hypothesis was tested for the first time in patients with primary hypertension. Methods and Results: Using a prospective, randomized, placebo-controlled, double-blind, cross-over design, a proof-of-principle trial was performed in 13 patients with mild to moderate primary hypertension, who were randomly assigned to a regimen of atorvastatin (80mg/day) for 3 weeks, followed by placebo for 3 weeks or to a regimen of placebo for 3 weeks, followed by atorvastatin (80mg/day) for 3 weeks. Microneurography was used at the end of each treatment period to measure sympathetic nervous system activity (muscle sympathetic nerve activity: MSNA). Heart rate variability (HRV) and plasma norepinephrine concentrations were also measured. Additionally, effects on blood pressure (BP) and heart rate (HR) were assessed by 24-h ambulatory BP measurement. Atorvastatin reduced postganglionic MSNA (atorvastatin 35.0±2.0 vs placebo: 39.2±1.5 bursts/min, P=0.008) and heart frequency corrected MSNA (atorvastatin: 58.5±2.0 vs placebo: 64.7±3.0 bursts/100 beats, P=0.02). Atorvastatin had no significant effect on plasma norepinephrine levels, HRV, BP or HR. Conclusions: In patients with mild to moderate hypertension, atorvastatin reduces postganglionic MSNA, which supports the hypothesis that HMG-CoA reductase plays a role in sympathetic nervous system activity. (Circ J 2010; 74: 2622-2626)

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Background: Aging and westernization of lifestyle has accelerated the prevalence and severity of atherosclerotic cardiovascular diseases in the Japanese population. The aim of this study was to examine the prevalence of complex plaque formation in the descending thoracic aorta (DTA) as assessed by real-time 3-dimensional transesophageal echocardiography (3DTEE) and its relation to clinical factors. Methods and Results: A prospective analysis of atherosclerotic plaque in the DTA of 350 consecutive patients who were clinically indicated for real-time 3DTEE was performed. Systematic assessment of the DTA plaques was performed using a biplane mode from the aorta at the level of the stomach to the aortic arch. When a large plaque (>4mm) was identified, detailed 3-dimensional (D) observations were performed using a 3D zoom mode. Complex plaque was defined as either mobile or an ulcer-like pouch in the DTA. Complex plaques were detected in 51 patients (15%), who were more advanced in age and had a higher prevalence of chronic kidney disease. A multivariate analysis revealed that the presence of complex plaque was an independent predictor of renal impairment. Conclusions: The prevalence of complex plaque was not low in the this Japanese study population. A close association between complex plaque and renal dysfunction raises the possibility that complex plaque in the DTA is a potential cause of renal dysfunction. (Circ J 2010; 74: 2627-2632)

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Background: Few studies have compared the ability of cardiac magnetic resonance (CMR) with that of scintigraphy using 201-thallium (201-Tl) and 99m-technetium pyrophosphate (99m-Tc PYP) to evaluate microvascular obstructions (MOs). In the present study the relationship between the scintigraphic and CMR characteristics of MOs after acute myocardial infarction (MI) was examined. Methods and Results: The 14 patients (age 69±8 years, 11 males) underwent 201-Tl/99m-Tc PYP SPECT 7±3 days, initial CMR 16±12 days, and follow-up CMR 193±20 days after a reperfused first acute MI. Each image was analyzed using a 17-segment model. Segmental extent of delayed enhancement (DE), wall motion (WM) and degree of 201-Tl uptake were scored in 238 segments. Of 91 MI segments, MO was recognized in 22 (25%) segments on CMR. WM was significantly better in proportion to 201-Tl uptake (P=0.01) in MO segments. All 8 MO segments with WM improvement at follow-up had 99m-Tc PYP uptake, although only 3 (21%) of 14 MO segments that did not show WM improvement at follow-up had 99m-Tc PYP uptake (P=0.001). Conclusions: 99m-Tc PYP and 201-Tl scintigraphy have the potential to predict WM status and improvement of the MO region after reperfused acute MI. (Circ J 2010; 74: 2633-2640)

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Background: The purpose of this study was to develop a new online integrated backscatter intravascular ultrasound (IB-IVUS) system and to validate its ability to measure fibrous cap thickness by comparing IB-IVUS images with those from optical coherence tomography (OCT). Methods and Results: Images were acquired from 125 segments of 26 coronary arteries obtained at autopsy from 11 cadavers. In the training study (n=30), 242 regions-of-interest on color-coded maps were compared with histology. In the validation study, 95 cross-sections were diagnosed by IB-IVUS and histology. In 24 patients with stable angina, 28 arterial cross-sections were imaged by IB-IVUS and OCT in vivo. In the training study, cutoff values of 39 decibels (dB) and 17dB were the optimal predictors of lipid pool/fibrosis and fibrosis/calcification, respectively, with 38-MHz mode; 42dB and 20dB, respectively, with 43-MHz mode. In the validation study, IB classified the fibrous, lipid-rich and fibrocalcific components with an accuracy of 92%, 91% and 95%, respectively. Agreement between the histological and IB-IVUS diagnoses was excellent (Cohen's κ=0.83). There was a correlation between the fibrous cap thickness measured by IB-IVUS and OCT (r=0.74, P<0.001). Conclusions: The IB-IVUS system with improved resolution provides high diagnostic accuracy for the analysis of the tissue characteristics of coronary plaques, and enables estimation of the thickness of the fibrous cap in the clinical setting. (Circ J 2010; 74: 2641-2648)

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Background:  Precise evaluation of the aortic root geometry prior to transcatheter aortic valve implantation is important for procedural success in patients with aortic stenosis (AS). To determine the potential for 3-dimensional transesophageal echocardiography (3DTEE), the aims of the present study were: (1) to assess the accuracy of 3DTEE measurements of the aortic root using multidetector computed tomography (MDCT) as a reference, and (2) to examine whether aortic root geometry differs between patients with and without AS. Methods and Results:  3DTEE and contrast-enhanced MDCT were performed in 35 patients. Multiplanar reconstruction was used to measure the left ventricular outflow tract (LVOT) and aortic annulus diameter/area, aortic valve area (AVA), and distances between the annulus and coronary artery ostium. The same 3DTEE measurements were performed in patients with (n=71) and without AS (n=80). Aortic annular and LVOT areas measured by 3DTEE were slightly but significantly smaller compared with values obtained with MDCT. Both methods revealed that the aortic annulus and LVOT have an oval shape. Aortic annular and LVOT area, AVA and the distances between the aortic annulus and the coronary ostia correlated well between the 2 modalities. Only minor differences in aortic root geometry were observed between patients with AS and those without. Conclusions:  The geometry of the aortic annulus can be reliably evaluated using 3DTEE as an alternative to MDCT for the assessment of aortic root. (Circ J 2010; 74: 2649-2657)

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Background: Usefulness of diastolic dysfunction after adenosine stress for detecting coronary stenosis has not been defined. The diagnostic accuracy of a combination of myocardial perfusion and diastolic function, as defined by prolongation of time to peak-filling rate (TTPF)/R-R and myocardial perfusion alone for the detection of coronary restenosis, was evaluated. Methods and Results: We used rest ²⁰¹Tl/ adenosine stress ^99mTc-tetrofosmin myocardial perfusion singlephoton emission computed tomography (SPECT) in 70 patients. Patients were divided into the following 4 groups: 20 patients with normal SPECT without stent (Control group), 20 patients showing normal SPECT without coronary restenosis (Group 1), 16 patients showing significant coronary restenosis and myocardial ischemia (Group 2a) and 14 patients showing significant coronary restenosis without myocardial ischemia (Group 2b). The TTPF, which was calculated by quantitative gated SPECT (QGS)/R-R, was not different between after stress and at rest in Control group (0.18±0.02 vs 0.19±0.04, P=NS). The TTPF/R-R after stress was significantly lower than that at rest in Group 1 (0.17±0.02 vs 0.18±0.03, P<0.05), but TTPF/R-R after stress was significantly higher than that at rest in Groups 2a and 2b (0.22±0.03 vs 0.16±0.03, P<0.001 in Group 2a and 0.19±0.02 vs 0.16±0.02, P<0.001 in Group 2b, respectively). Diagnostic accuracy improved from 72% to 92% when prolongation of TTPF/R-R was taken into account (P<0.001). Conclusions: Diastolic dysfunction after stress was an accurate marker for detecting significant restenosis following stent implantation. (Circ J 2010; 74: 2658-2665)

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Background: Transient ischemic dilatation (TID) and post-stress dysfunction of the left ventricle (LV) are important markers of severe coronary artery disease (CAD). To clarify the effects of stressor type on TID and post-stress LV dysfunction, changes in LV measurements were compared between patients with exercise- or vasodilator-induced stress. Methods and Results: The 689 patients referred for technetium-99m tetrofosmin myocardial perfusion imaging were included. Patients were stressed with either a vasodilator (n=236) or exercise (n=453). LV measurements were obtained with ECG-gated SPECT. LV end-diastolic and end-systolic volume indexes (LVEDVI, LVESVI) increased and LV ejection fraction (LVEF) decreased after stress in the vasodilator-stress group. Vasodilator-stress and the summed difference score (SDS) were independent variables that decreased LVEF after stress. Even in patients without reversible defects, vasodilator-stress impaired LV function. There were no differences in the stress-to-rest ratios of LVEDVI (rEDV) and LVESVI (rESV) among patients with normal myocardial perfusion, fixed defects and reversible defects in the vasodilator-stress group, whereas in the exercise-stress group, rESV was significantly higher in the patients with reversible defects than in those without reversible defects. Within the vasodilator-stress group, neither rEDV nor rESV correlated with the SDS. Conclusions: Vasodilator-stress by itself decreases LVEF after stress. TID should be carefully interpreted when vasodilator-stress is used to detect severe CAD. (Circ J 2010; 74: 2666-2673)

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Background: Although the renin-angiotensin system (RAS) can affect the development of left ventricular (LV) hypertrophy, few data exist regarding the relationships between RAS polymorphisms and alteration of LV function. The effect of RAS polymorphisms on LV function in genotyped hypertrophic cardiomyopathy (HCM) was examined in the present study. Methods and Results: The study group comprised 126 carriers with sarcomere gene mutations from 49 HCM families (64 males, mean age 51±21 years). LV morphology and function were evaluated by echocardiography. In angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the D allele (n=81) exhibited significantly larger LV end-systolic dimension (LVDs) (32±11mm) and lower ejection fraction (56±15%) than those with the II genotype (28±7mm and 62±12%, respectively, P<0.05; n=45). Although angiotensin II type 1 receptor (AT₁-R) A/C¹¹⁶⁶ polymorphism did not affect echocardiographic parameters, the presence of the ACE D allele with the AT₁-R C¹¹⁶⁶ allele (n=9) was associated with larger LVDs (37±17mm) and lower ejection fraction (48±20%) compared with other genotypes (30±9mm and 58±14%, respectively, P<0.05; n=117). Under these conditions, severe LV hypertrophy was frequently associated with LV wall thinning. Conclusions: The presence of both the ACE D and AT₁-R C¹¹⁶⁶ allele is associated with LV dilation with systolic dysfunction in genotyped HCM. In addition to the severity of LV hypertrophy, screening for these RAS polymorphisms could contribute to further risk stratification of patients with HCM, although other genetic polymorphisms should be further examined. (Circ J 2010; 74: 2674-2680)

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Background: The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes. Methods and Results: Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS^-/-, iNOS^-/-, eNOS^-/-, and triply n/i/eNOS^-/- mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS^-/- mice and to a lesser extent in eNOS^-/- mice, but not in nNOS^-/- or iNOS^-/- mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS^-/- mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT₁) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS^-/- mice. Conclusions: These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT₁ receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. (Circ J 2010; 74: 2681-2692)

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Background: Immobilization (IMO) confers emotional stress in animals and humans. It was recently reported that IMO in rats induced translocation of connexin-43 (Cx43) to gap junctions (GJs) and attenuated arrhythmogenesis with GJ inhibition, and Cx43 translocation in the ischemic heart was also shown. Few reports show the contribution of adrenoceptors to Cx43 upregulation in cardiomyocytes, but the involvement of adrenoceptors and ischemia in Cx43 translocation in IMO remains elusive. Methods and Results: Male Sprague-Dawley rats underwent IMO and the ventricular distribution of Cx43 was examined by western blotting. IMO induced translocation of Cx43 to the GJ-enriched membrane fraction, with a peak at 60min. The IMO-induced Cx43 translocation was inhibited by pretreatment with the α₁-adrenoceptor blockers, prazosin (1mg/kg, PO) and bunazosin (4mg/kg, PO), but not with either the β₁-blocker, metoprolol (10mg/kg, IP), or the β₁₊₂-blocker, propranolol (1mg/kg, PO). The translocation was inhibited by the nitric oxide, donor isosorbide dinitrate (100μg·kg^-1·min^-1, IV), possibly through sympathetic inhibition. Hypoxia inducible factor-1α was not redistributed by IMO. The β-blockers, but not the α-blockers, inhibited the premature ventricular contractions (PVCs) induced by IMO. Conclusions: Translocation of Cx43 to the GJ-enriched fraction occurs via the α₁-adrenoceptor pathway, independently of ischemia. The β-adrenoceptor pathway contributes to the inducing of PVCs in IMO. (Circ J 2010; 74: 2693-2701)

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Background: Cardiomyopathy is a life-threatening condition in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (known as MELAS). However, no effective therapy has been available until now. In the present study cardiac energetics and acute effects of L-arginine (Arg) were evaluated in MELAS patients. Methods and Results: The 6 patients with MELAS (M-group) and 6 volunteers (C-group) underwent dynamic C-11 acetate positron emission tomography (PET) imaging. TCA-cycle metabolic rate (k_mono), myocardial efficiency (double product (DP)/k_mono), and myocardial blood flow (MBF) were determined before and after L-Arg administration. Baseline k_mono showed a lower value in the M-group than in the C-group (0.051±0.013 vs 0.070±0.019min^-1, P=0.055). On the other hand, baseline DP/k_mono was significantly greater in the M-group (1.69±5.9 vs 0.95±1.2×10⁵, P=0.004). After L-Arg administration, 4 patients showed significant elevation of k_mono. No relationship was observed between the distribution of k_mono elevation and the increase in MBF. Conclusions: The TCA cycle metabolic rate is markedly suppressed in MELAS patients, indicating a shift in energy production to the anaerobic pathway, leading to a paradoxical increase in myocardial efficiency. L-Arg can enhance TCA-cycle metabolism, regardless of its vasodilatation effect, and can be used as a treatment for patients with mitochondrial cardiomyopathy. (Circ J 2010; 74: 2702-2711)

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Background: It has been previously reported that the transgenic mouse expressing the dominant negative mutant of the neuron restrictive silencing factor (dnNRSF) in the heart died from lethal arrhythmia, so the present study aimed to clarify the electrophysiological alteration of the ventricular myocyte isolated from the dnNRSF mouse. Methods and Results: The action potential (AP) and membrane currents were recorded using the whole-cell patch-clamp method. Intracellular Ca²⁺ was measured with Indo-1AM. The AP of dnNRSF myocytes exhibited reduction of resting membrane potential, prolongation of AP duration, and frequent early afterdepolarization (EAD). The EAD was completely inhibited by SEA0400, a specific blocker of the Na⁺-Ca²⁺ exchanger (NCX). The most notable alteration of membrane current was a reduction in the inward rectifier K⁺ current (I_K1) density. In addition to re-expression of fetal type cardiac ion channels, a Na⁺-permeable, late inward current was observed in a small population of dnNRSF myocytes. The diastolic intracellular Ca²⁺ concentration was also raised in dnNRSF myocytes, and spontaneous Ca²⁺ oscillation was induced by β-adrenergic stimulation. Conclusions: In dnNRSF myocytes, the "repolarization reserve" of the AP was significantly reduced by specific alterations in membrane currents. Under these conditions, the amplitude of EAD generated by the inward NCX current might be enlarged, thereby increasing the cells' vulnerability to ventricular arrhythmia. (Circ J 2010; 74: 2712-2719)

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Background: Coronary sequelae that persist after Kawasaki disease (KD) have been associated with coronary vascular events in adolescents and young adults. The aim of this study was to investigate the relationship between coronary sequelae late after KD and circulating endothelial progenitor cells (EPCs), as a marker of vascular repair, or monocyte subsets as a marker of inflammation. Methods and Results: The 31 KD patients were divided into 3 groups according to the type of coronary artery lesion (CAL): group 1 consisted of 14 patients with persistent aneurysm; group 2 consisted of 9 patients with regressed aneurysms; group 3 included 8 KD patients with normal coronary arteries from disease onset. The control group (group 4) consisted of 10 healthy subjects. Flow cytometric analysis was used to quantify circulating EPCs defined as CD34⁺KDR⁺ cells and 2 distinct monocyte subsets (CD14⁺CD16⁺ and CD14⁺CD16^-). The number of EPCs in group 1 and group 2 was significantly decreased compared with group 4. In contrast, neither the number of CD14⁺CD16⁺ monocytes nor that of CD14⁺CD16^- monocytes was significantly different among the 4 groups. Finally, there were not any significant relationship between the numbers of EPCs and the 2 monocyte subsets. Conclusions: There are lower numbers of EPCs in the chronic phase of KD, irrespective of both CAL formation and monocyte subsets. (Circ J 2010; 74: 2720-2725)

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Background: The relationship between cytokine gene polymorphisms and susceptibility to Kawasaki diseases (KD) is still controversial, so the aim of the present study was to investigate the association of 14 various polymorphisms of 9 cytokine genes (interleukin (IL)-1A, IL-1B, IL-1RN, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-A and transforming growth factor-B) with KD risk. Methods and Results: A total of 211 KD children and 221 adult controls were recruited. All controls were frequency matched to KD patients on sex and ethnicity. PCR and TaqMan assays were used for genotyping. There were no significant differences between KD children and adult controls in the genotype or allelic type frequencies of the 14 polymorphisms. No significant associations were found between haplotypes, constructed by IL-1B, IL-4, IL-8, and IL-10 cytokine genes, and risk of KD. Additionally, a linear trend was observed when these single nucleotide polymorphisms were combined, as evidenced by an increasing risk of KD as the number of at-risk genotypes increased (P_{linear trend}=0.002). In the stratification analysis of age and sex, there was a linear trend of KD risk as the number of at-risk genotypes increased among those aged >12 months (P=0.014) or female (P=0.001), respectively. Conclusions: No associations between individual cytokine genetic polymorphisms and susceptibility of KD were observed, but a gene-dosage effect on the risk of KD was found, especially for older or female subjects. (Circ J 2010; 74: 2726-2733)

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Background: Fibroblast growth factor 23 (FGF-23) is a novel bone-derived phosphate-regulating hormone, and serum FGF-23 levels are associated with mortality among hemodialysis (HD) patients. However, the pathophysiological role of FGF-23 in those patients remains unclear, so the association between serum FGF-23 levels and known cardiac biomarkers or echocardiographic measurements were investigated in long-term HD patients without cardiac symptoms. Methods and Results: The 87 consecutive patients treated in a single HD center (51 males, 36 females; mean age 64 years, mean HD duration 5.8 years) were included in this study. Comprehensive echocardiography was performed after HD. Blood samples were obtained before HD. Serum FGF-23 levels in dialysis patients were 1,171±553pg/ml. In univariate analysis, serum phosphate (r=0.443, P<0.001) and calcium levels (r=0.256, P=0.04), left ventricular mass index (LVMI) (r=0.268, P=0.039) were significantly associated with FGF-23 levels. Neither the B-type natriuretic peptide (BNP) nor the cardiac troponin T level was correlated with FGF-23. In multivariate regression analysis, only LVMI (β=0.287, P=0.031, confidence interval (CI) 0.390-8.040) and phosphate levels (β=0.419, P=0.001, CI 57.12-207.7) and calcium levels (β=0.277, P=0.025, CI 24.95-360.1) remained significantly correlated with FGF-23. Conclusions: Beside BNP, FGF-23 was identified as a factor that is significantly associated with LVMI. FGF-23 could be a novel biomarker of left ventricular overload, which is closely associated with the increased risk of death in HD patients. (Circ J 2010; 74: 2734-2740)

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Background: This study aimed to apply a software to calculate myocardial infarction (MI) volume by single-photon emission computed tomography. Methods and Results: The cardioVol software has been developed to reconstruct 3D figures from sequential short axis images. We re-analyzed the data from the EPO/AMI-I Study. The MI volume at baseline correlated with maximum creatine kinase. The MI volume significantly decreased during the 6-month follow up in the erythropoietin (EPO) group, but not in the control group. The decrements of MI volume in the EPO group were significantly larger than those in the control group. Conclusions: The efficacy of EPO was further confirmed by the software. (Circ J 2010; 74: 2741-2743)

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This article reviews the treatment of patients with multivessel coronary artery disease (CAD). Percutaneous coronary intervention (PCI) has been challenging coronary artery bypass grafting (CABG) as the gold standard of care for patients with multivessel disease; however, the application of PCI to these patients has been mainly limited by restenosis. Up to the beginning of the 2000s, many large-scale, randomized trials addressed this issue by comparing CABG to PCI with balloon angioplasty or bare metal stents in not only Western countries but also in Asian countries. These studies demonstrated similar rates of all-cause death and myocardial infarction in both groups, although the need for revascularization remained significantly lower in the CABG group. PCI with drug-eluting stents (DES) is safe and may represent a viable alternative to CABG for selected patients with diabetes and multivessel CAD. Moreover, DES implantation under intravascular ultrasound guidance and with fractional flow reserve might have the potential to influence treatment strategy and reduce both DES thrombosis and repeat revascularization. The evolution of DES and advanced vascular imaging would mean that PCI continues to challenge CABG as treatment of choice for patients who need revascularization for a better prognosis. (Circ J 2010; 74: 2744-2749)

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Coronary artery bypass graft (CABG) surgery is still the best therapy for patients with multivessel and left main coronary artery disease. Recently, the introduction of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in these patients has improved the restenosis rate compared with bare metal stents. Furthermore, according to the results of the SYNTAX trial, no differences were found in the frequencies of mortality or myocardial infarction between CABG and PCI patients. PCI with DES is being increasingly performed for the treatment of patients with either left main trunk, diffuse, or multivessel lesions. In Japan, to avoid any side effects from cardiopulmonary bypass, off-pump coronary artery bypass (OPCAB) was performed in 66% of the total isolated CABG procedures in 2009, and is markedly different from the procedures performed in North America and Europe. However, the comparative effectiveness of PCI and OPCAB remains uncertain. In the present study, the current evidence from randomized trials, a meta-analysis and several observation studies are reviewed. (Circ J 2010; 74: 2750-2757)

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