Similarities between the inflammatory pathways in atherosclerosis and rheumatoid arthritis (RA) are striking. Chronic systemic inflammation in RA patients leads to cardiovascular (CV) events beyond traditional cardiac risk factors. Clinicians typically focus on treating the joint manifestations of RA while neglecting to eliminate systemic inflammation, which leaves RA patients vulnerable to adverse CV events. In this review we provide an understanding of how systemic inflammation in RA accelerates atherosclerosis. This knowledge should guide therapeutic targets to minimize CV risk in RA, and may lead to insights into the inflammatory mechanisms of atherosclerosis in general. (Circ J 2009; 73: 977-985)

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Nitric oxide (NO) is produced in almost all tissues and organs, exerting a variety of biological actions under both physiological and pathological conditions. NO is synthesized by 3 distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human cardiovascular system. The regulatory roles of NOSs in cardiovascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors. However, the specificity of the NOS inhibitors continues to be an issue of debate. To overcome this issue, genetically engineered animals have been used. All types of NOS gene-deficient (knockout: KO) animals, including singly, doubly, and triply NOS-KO mice, and various types of NOS gene-transgenic (TG) animals, including conditional and non-conditional TG mice bearing endothelium-specific or cardiomyocyte-specific overexpression of each NOS gene, have thus far been developed. The roles of individual NOS isoforms, as well as the entire NOS system, in the cardiovascular system have been extensively investigated in those mice, and the results provide pivotal insights into the pathophysiology of NOSs in human cardiovascular diseases. Based on studies with murine NOS genetic models, this review summarizes the latest knowledge of NOSs and cardiovascular diseases. (Circ J 2009; 73: 986-993)

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Atherosclerosis is an inflammatory disease in which a systemic inflammatory reaction is combined with an accumulation of immune cells, such as monocytes/macrophages, dendritic cells (DCs), and numerous lymphocytes, in atherosclerotic plaques. The immune system, comprising innate immunity and adaptive immunity, has been implicated in all stages of atherosclerosis, from initiation through progression and in atherothrombotic complications. It is clear that different subpopulations of leukocytes are involved in the pathogenesis of atherosclerosis and plaque instability. Recent studies have also demonstrated that each heterogeneity of immune-associated cells contributes to the atherogenic and atheroprotective axis. This review highlights recent advances in research and explores the role of the complex heterogeneity of leukocyte subsets, especially monocytes/macrophages (inflammatory monocytes, resident monocytes, M1, and M2), DCs (myeloid DCs, plasmacytoid DCs, pre DCs, conventional DCs, inflammatory DCs), and CD4⁺ cells (T-helper 1, T-helper 2, regulatory T, and T-helper 17 cells), in the initiation and development of atherosclerotic disease and its complications. (Circ J 2009; 73: 994-1001)

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Orthostatic hypertension, a measure of blood pressure (BP) variability, is a clinically important pathologic condition associated with the progression of target organ damage and subsequent cardiovascular risk. Orthostatic hypertension precedes hypertension and could be considered as prehypertension if a patient has seated clinic BP <140/90 mmHg. The simple examination of orthostatic BP changes using a self-measured home BP monitoring, through which abnormal pathological conditions can be detected with high reproducibility without the white-coat effect. Orthostatic hypertension is associated with morning hypertension and increased neurohumoral activation; however, the precise mechanism of orthostatic hypertension remains unclear, and accumulation of further clinical evidence is necessary. (Circ J 2009; 73: 1002-1007)

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Background: A multicenter, randomized, placebo-controlled, double-blind trial was conducted with patients with persistent atrial fibrillation (AF) to determine the dose-response effects and safety of bepridil, using every-day transtelephonic monitorings. Methods and Results: A total of 90 patients were randomized to receive placebo, 100 mg/day and 200 mg/day of bepridil treatment for 12 weeks. After the treatment, those patients who converted to sinus rhythm was 3.4% in placebo, 37.5% in those who received 100 mg/day and 69.0% in those who received 200 mg/day, thus demonstrating a linear dose-response relationship for AF conversion. The conversion rate gradually reached a maximal value at ~6 weeks after initiation of bepridil. However, the AF recurrence rate was high (91.7% in those receiving 100 mg/day and 75.0% in those receiving 200 mg/day). Adverse events, presumably related to the drug, were also frequent: ventricular tachycardia in 2, QT prolongation in 4 and sinus bradycardia in 2 patients. In those patients treated with 200 mg/day group, 1 patient died suddenly because of ventricular tachycardia. Conclusions: This study demonstrated the dose response-relationships of bepridil for AF conversion to sinus rhythm. However, the high rate of AF recurrence and substantial drug-related adverse effects, including sudden death, raised caution about using bepridil to treat persistent AF. The balance between benefits and risks of the drug should be individualized. (Circ J 2009; 73: 1020-1027)

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Background: Although high defibrillation threshold (DFT) is a major and unavoidable clinical problem after implantation of an implantable cardioverter defibrillator (ICD), little is known about the cause and management of a high DFT in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to assess the predictors of a high DFT in patients with HCM. Methods and Results: Twenty-three patients with non-dilated HCM who underwent ICD implantation were included. The DFT at the time of the device implantation was measured in all patients. The patients were divided into 2 groups, a high DFT group (DFT ≥15J, n=13) and a low DFT group (DFT <15J, n=10); and their baseline characteristics were compared. The QRS duration was longer in the high than in the low DFT group (128 ±31 vs 103 ±12 ms, respectively; P=0.02). QRS duration, left ventricular (LV) end-systolic diameter, and LV ejection fraction were significant predictors of DFT in univariate analysis. However, in multivariate analysis, the only factor significantly associated with DFT was QRS duration (P=0.002). Conclusions: QRS duration is the most consistent predictor of a high DFT in HCM patients undergoing ICD implantation. (Circ J 2009; 73: 1028-1032)

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Background: Sirolimus-eluting stents (SES) have incomplete neointimal coverage at 6-month follow up as determined with optical coherence tomography (OCT). The long-term detailed changes of neointima in SES remains to be clarified. Methods and Results: Serial changes in neointimal coverage of SES from 6 months to 12 months using OCT were examined. Of 21 SES in 13 patients, OCT was used to visualize 2,321 stent struts at 6 months and 2,285 stent struts at 12 months. The frequency of struts without neointimal coverage decreased from 6 months to 12 months (from 10.4 to 5.7%). The frequency of malapposed struts decreased from 6 months to 12 months (from 1.7 to 0.2%). The average thickness of the neointima increased (from 112 ±123 to 120 ±130 μm). The frequency of struts located at the side branch orifice without neointima decreased (from 4 out of 17 (24%) to 0 out of 17 (0%)). Complete coverage with neointima was observed in 14% (3 of 21 SES) at 6 months, and 24% (5 of 21 SES) at 12 months. Conclusions: Additional neointimal coverage was observed between 6 and 12 months, with a small increase in the neointimal thickness. The incidence of complete coverage, however, was still low at 12 months. These findings suggest delayed neointimalization on SES. (Circ J 2009; 73: 1033-1037)

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Background: Clinical data of sirolimus-eluting stent (SES) implantation are under investigation in Japan. Methods and Results: The CYPHER stent Japan Post-Marketing Surveillance Registry (J-PMS) was conducted at 50 medical centers to assess the results of SES in daily clinical practice exclusively under aspirin plus low dose ticlopidine (200 mg/day). A total of 2,459 lesions in 2,054 patients were treated with 3,285 SES. The mean age was 67.1 ±10.1 years, 75.6% were men and 43.3% were diabetics. Intravascular ultrasound was used in 77.2%. The 8-month angiographic and 1-year clinical follow-up data were available in 85.4% and 96.8%, respectively. Quantitative coronary angiography showed the reference vessel diameter and percentage diameter stenosis at baseline were 2.47 ±0.58 mm and 72.0 ±16.1%. The 8-month late loss was 0.20 ±0.50 mm. The major adverse cardiovascular events at 1 year was 7.3%; cardiac death: 1.1%, myocardial infarction (MI): 1.2%, and target lesion revascularization (TLR): 4.2%. The rates of definite and probable stent thrombosis at 1 year were 0.30% and 0.10%, respectively. Hemodialysis was the strongest predictor of death/MI or TLR. Conclusions: J-PMS showed the effectiveness of SES implantation under aspirin plus low dose ticlopidine administration at 1 year, although further studies are necessary to demonstrate the safety. (Circ J 2009; 73: 1038-1044)

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Background: The shortage of heart transplantation donors is a problem, but partial left ventriculectomy (PLV) and mitral valve replacement (MVR) are feasible at the optimal timing, even in young children. Methods and Results: From May 1998 to May 2008, 11 children under the age of 3 years were diagnosed with severe dilated cardiomyopathy (DCM). Indications and outcomes of non-transplant surgical strategies were evaluated and 8 procedures were performed in 6 children: 5 PLV and 3 MVR. Two of them underwent MVR after PLV because of deterioration of mitral regurgitation (MR). Age at surgery ranged from 8 months to 2 years 11 months. Four are alive, of whom 1 eventually underwent a heart transplant overseas. Two children died during the study period: 1 who underwent only MVR died of intracranial bleeding during thrombolytic therapy for a thrombus stack valve and the other child died of congestive heart failure because of progressive MR 2 months after PLV. Follow-up after PLV ranged from 2 months to 8 years, and after MVR ranged from 1 month to 4 years. Conclusions: PLV and MVR are feasible and effective and should be considered when heart failure resists conventional therapy. (Circ J 2009; 73: 1045-1048)

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Background: As an increasing number of aging patients are being referred for coronary artery bypass grafting (CABG), the radial artery (RA) has gained increasing popularity as a conduit. The aim of this study was to investigate the effectiveness of RA in CABG for the elderly with coronary heart disease. Methods and Results: Three hundred and twenty-six elderly patients underwent CABG with RA harvesting between January 2000 and June 2008. A total of 377 RA as grafts were collected. The mean number of distal anastomoses per patient was 3.1 while the mean for RA was 1.1. The operative mortality was 3.1%. Twenty patients developed atrial fibrillation, 7 experienced acute renal failure, 9 had neurological accidents, and 4 had myocardial infarction. There was no ischemic complication on hand. Paresthesia in the donor hand was found in 2 patients. A complete follow up was obtained in 77.2% of patients, with a mean time of 53.5 ±35.9 months. RA patency displayed by coronary angiography was 95.83% after a mean time of 74 months of follow up. Conclusions: It was proven to be safe and effective to use RA as a secondary arterial graft after the left internal mammary artery in the elderly patients. (Circ J 2009; 73: 1049-1054)

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Background: Many patients with heart disease continue to have cardiac events despite receiving optimal treatments for traditional risk factors. Consequently, non-traditional risk factors for heart disease, such as perceived stress, have attracted attention. Associations between perceived stress and plasma B-type natriuretic peptide (BNP) were explored, while controlling for traditional heart disease risk factors. Methods and Results: This cross-sectional study examined 360 male and 446 female (age, >40 years) residents of a rural Japanese community who received annual health checkups in 2006. A lifestyle questionnaire was used to obtain information regarding perceived stress and medical history, and routine anthropometric and blood pressure measurements and a laboratory assessment of cardiovascular risk factors, including plasma BNP concentrations and an electrocardiogram, were done. After adjusting for traditional heart disease risk factors, multiple regression analysis showed that perceived stress was associated with BNP concentrations, particularly in women (F=6.12, P=0.026). In addition, multiple tests using Bonferroni's procedure showed that BNP concentrations decreased with perceived stress level in men and women. Similar trends were observed in the sub-analyses of subjects with and without known heart disease. Conclusions: Perceived stress in our study was negatively associated with plasma BNP concentrations, independently of traditional heart disease risk factors. (Circ J 2009; 73: 1055-1061

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Background: Undiagnosed diabetes mellitus (DM) and impaired glucose tolerance (IGT) have important health consequences. Methods and Results: To examine the prevalence of undiagnosed glucose intolerance, oral glucose tolerance tests were administered to 1,142 consecutively enrolled middle-aged subjects (age range 40-55 years; 914 men, mean 50.7 years; 228 women, mean 49.4 years) who worked in a company and underwent a health check in 2006. No subject had a history of glucose intolerance. Fasting glucose levels increased with age in both men and women, with the levels being higher in men than women at every age. Glucose intolerance was more common in men compared with women (fasting glucose 100.1 ±19.7 vs 92.9 ±9.6, P<0.01; 1-h 170.7 ±52.1 vs 139.7 ±11.6, P<0.01; 2-h 136.0 ±50.1 vs 119.8 ±31.5 mg/dl, P<0.01). The prevalence of IGT and DM was also higher in men than in women (IGT: 24.1 vs 16.7, P<0.01; diabetes 10.7 vs 1.4%, P<0.01). Conclusions: Fasting glucose levels increased with age in both men and women, with levels being higher in men than in women at every age. The prevalences of undiagnosed IGT and type 2 DM were also higher in men than in women. (Circ J 2009; 73: 1062-1066)

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Background: Patients with a high plasma adiponectin have a poor prognosis in chronic heart failure (CHF). Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are reported to increase the plasma adiponectin concentration, but the effect of β-blockers on plasma adiponectin in patients with CHF remains unknown. Methods and Results: Blood samples were collected at before and 6 months after administration of carvedilol in 44 CHF patients. The hemodynamic parameters, echocardiography, plasma concentrations of brain natriuretic peptide (BNP), norepinephrine and adiponectin were measured. Six months after treatment, there were significantly decreased plasma concentrations of adiponectin (15.8 ±1.4 to 11.0 ±1.1 μg/ml, P<0.0001), BNP and norepinephrine and increased left ventricular ejection fraction (LVEF). On stepwise multivariable analyses, a higher plasma adiponectin concentration before treatment (rs=-0.561, P<0.0001) was a significant independent predictor of a greater decrease in adiponectin concentration and the decrease in plasma adiponectin concentration was significantly correlated with the improvement of LVEF (r=-0.561, P<0.0001). Conclusions: These findings indicate that carvedilol decreases plasma adiponectin concentration and that the decrease in plasma adiponectin is associated with the improvement of LVEF after treatment with carvedilol in CHF patients. (Circ J 2009; 73: 1067-1073)

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Background: Although cardiac output index (CI), stroke volume index (SVI), and total systemic vascular resistance (TSVR) are important hemodynamic parameters for the prognosis of chronic heart failure (CHF), they are difficult to measure in an outpatient setting. Whole body bioimpedance monitoring using a Non-Invasive Cardiac System (NICaS) allows for easy, non-invasive estimation of these parameters. Here, whether NICaS-derived hemodynamic parameters are clinically significant was investigated by relating them to other conventional cardiovascular functional indices, and by evaluating their predictive accuracy for CHF readmission. Methods and Results: Study subjects of 68 patients with CHF were enrolled in the study immediately upon discharge from the hospital. NICaS-derived CI, -SVI, and -TSVR values obtained at an outpatient clinic were significantly related with left ventricular ejection fraction (LVEF) measured by echocardiography, serum B-type natriuretic peptide (BNP), and exercise tolerance. During the 100 ±98 days follow-up, 15 patients were readmitted to our hospital for CHF recurrence. Multivariate analysis indicated that LVEF, NICaS-derived CI, NICaS-derived SVI, and plasma BNP were significant indicators (receiver operating characteristic curve cut-off point, LVEF: 37%, NICaS-derived CI: 2.49 L · min^-1 · m^-2, NICaS-derived SVI: 27.2 ml/m², plasma BNP: 344 pg/ml) for readmission. Conclusions: Hemodynamic parameters derived by NICaS are applicable for the non-invasive assessment of cardiac function in outpatient CHF follow up. (Circ J 2009; 73: 1074-1079)

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Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial compared the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The present study aimed to clarify the effect of cardiac complications on cardiovascular events in patients enrolled in CASE-J. Methods and Results: Cardiac complications were defined as left ventricular hypertrophy (LVH) and ischemic heart disease (IHD). The primary endpoint was a composite of sudden death, cerebrovascular, cardiac, renal and vascular events. The study group was divided into 2,030 and 2,673 patients with and without cardiac complications. During 3.2 follow-up years, cardiovascular events occurred for a rate of 13.6 per 1000 patient-years in patients without cardiac complications, and 23.1 per 1000 patient-years in patients with cardiac complications (adjusted hazard ratio (HR): 2.22; P<0.001). Furthermore, LVH was associated with the onset of cerebrovascular events (adjusted HR: 2.38; P<0.001), whereas IHD was associated with the onset of cardiovascular death (adjusted HR: 2.22; P<0.05), especially sudden death and other cardiac events. Conclusions: Cardiac complications are independent predictors for cardiovascular events in Japanese high-risk hypertensive patients. In particular, LVH is related to cerebrovascular events and IHD is related to cardiac death and other cardiac events. (Circ J 2009; 73: 1080-1085)

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Background: The precursor of plaque rupture is known as thin cap fibroatheroma (TCFA). In the present study, the feasibility and accuracy of optical coherence tomography (OCT) for detecting the frequency and spatial distribution of TCFA was investigated ex vivo, and a 3-vessel OCT analysis was conducted to assess the feasibility of this modality in vivo. Methods and Results: In the ex vivo study, 108 coronary arterial segments from 38 human cadavers were examined by OCT, intravascular ultrasound (IVUS) and histology. The 3-vessel IVUS and OCT examinations were performed in 11 patients with acute coronary syndrome. By histological examination, 30 of 77 fibroatheromas were diagnosed as TCFAs, which showed a clear pattern of clustering in the proximal part of each coronary vessel. OCT accurately detected TCFA (sensitivity 90%, specificity 79%). The in vivo OCT study showed that 64% patients with acute coronary syndrome had 1 or more TCFAs. Conclusions: TCFAs, clustering in the proximal segments of the 3 major epicardial coronary arteries, are a common finding in unselected autopsy subjects. OCT is a feasible and accurate modality for detecting TCFA both ex vivo and in vivo. (Circ J 2009; 73: 1086-1091)

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Background: A pocket-sized portable transthoracic echocardiographic (pTTE) imaging device is commercially available, but its feasibility and accuracy in the assessment of cardiac chamber size and function has not been fully compared with the results of standard TTE (sTTE) examination. Methods and Results: The target population comprised 125 unselected patients who underwent sTTE and pTTE examinations. The left ventricular (LV) diastolic and systolic dimensions, fractional shortening (FS), the thickness of the interventricular septum (IVS) and of the LV posterior wall (PWT), left atrial (LA) dimension, and ascending aorta diameter were measured. Echocardiographic measurements were completed for both pTTE and sTTE in all patients (feasibility 100%). LV dimensions, FS, IVS, PWT, LA dimension, and aorta diameter obtained by pTTE showed excellent correlation and agreement with sTTE (r=0.87-0.98, all P<0.001). Observer variabilities for these measurements were similar between pTTE and sTTE. Conclusions: In the present study, pTTE with the Acuson P10 was feasible and accurate for assessing cardiac chamber size and function. (Circ J 2009; 73: 1092-1096)

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Background: The relationships among the circulating levels of endothelial progenitor cells (EPC), stromal cell-derived factor (SDF)-1α, interleukin (IL)-10 and outcome were examined in patients with ST-segment elevation acute myocardial infarction (ST-se AMI) undergoing primary coronary angioplasty. Methods and Results: Circulating levels of IL-10, SDF-1α, and EPCs [defined by staining markers: CD31/CD34 (E₁) and KDR/CD34 (E₂)] were examined by ELISA and flow cytometry, respectively. The IL-10 level was higher, whereas the circulating level of EPCs (E_1-2) was lower (all P<0.05) in AMI patients than in normal subjects. Additionally, the SDF-1α level was significantly and independently predictive of an increased level of circulating EPCs (E_1-2) (P<0.0001). Furthermore, patients with a high SDF-1α level (>1,500 pg/ml) had lower left ventricular performance, higher Killip score (defined as ≥3), and increased 30-day mortality than those with low SDF-1α level (≤1,500 pg/ml) (all P<0.007). Moreover, high circulating levels of E₂ and IL-10 were the most significant independent predictors of increased 30-day major adverse clinical outcome (MACO) (defined as advanced Killip score ≥3 or 30-day mortality) (P<0.01). Conclusions: The serum SDF-1α level is independently predictive of an increased level of circulating EPCs (E_1-2). E₂ and IL-10 are major independent predictors of 30-day MACO in ST-se AMI patients undergoing primary coronary angioplasty. (Circ J 2009; 73: 1097-1104)

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Background: In patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), identification of left main and/or 3-vessel disease (LM/3VD) is crucial for deciding whether to initiate early treatment with clopidogrel, which can increase the risk of surgical bleeding. Methods and Results: On admission, the clinical factors of 501 patients with NSTE-ACS, who underwent coronary angiography, were evaluated. ST-segment shifts and the widest QRS duration were measured on an admission 12-lead electrocardiogram. Ninety-six patients had LM/3VD. Univariate analysis indicated that many factors were related to LM/3VD. On multivariate analysis, QRS duration (odds ratio (OR) 9.04, P<0.01), the degree of ST-segment elevation in lead aVR (OR 7.10, P<0.01), and positive-troponin T (OR 1.52, P<0.05) were independent predictors of LM/3VD. A QRS duration of >90 ms and a ST-segment elevation in lead aVR of ≥0.5 mm best identified LM/3VD. A QRS duration of >90 ms, a ST-segment elevation in lead aVR of ≥0.5 mm, and a positive-troponin T identified LM/3VD with sensitivities of 88%, 76%, and 54% (P<0.01), and specificities of 88%, 86%, and 71% (P<0.01), respectively. Conclusions: A prolonged QRS duration, ST-segment elevation in lead aVR, and a positive-troponin T on admission are useful predictors of LM/3VD in patients with NSTE-ACS. In particular, a maximal QRS duration of >90 ms was the most sensitive predictor of LM/3VD. (Circ J 2009; 73: 1105-1110)

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Background: The effect of atorvastatin 10 mg vs 40 mg in clopidogrel resistance and clinical events after coronary stenting was compared in patients with acute coronary syndrome (ACS). Methods and Results: Platelet aggregation was measured before clopidogrel administration and 4 h, 24 h, 5 days, and 8 months later in 130 ACS patients. Stented patients were randomly assigned to atorvastatin either 10 mg (n=65) or 40 mg (n=65), and received an oral loading dose of 300 mg of clopidogrel followed by 75 mg/day for 8 months. Measurement of platelet aggregation was done by the turbimetric method. The mean % changes in inhibition of platelet aggregation were 35.5 ±8.3, 50.9 ±10.1, 38.3 ±8.3, 40.0 ±6.8 in the Atorvastatin 10 mg Group and 31.0 ±7.6, 43.7 ±9.8, 45.0 ±10.3, 43.5 ±7.8 (4 h, 24 h, 5 days, and 8 months, respectively, after 300 mg of clopidogrel pretreatment) in the Atorvastatin 40 mg Group with no significant differences between the 2 groups. Cardiovascular events showed no significant differences during the follow-up. Conclusions: Atorvastatin 10 mg or 40 mg co-administered with clopidogrel for 8 months did not affect the antiplatelet potency of clopidogrel and showed no significant differences in the clinical events in ACS patients. (Circ J 2009; 73: 1111-1118)

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Background: Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels. Given the difference in allele frequencies and linkage disequilibrium patterns across the populations, a GWAS was conducted using the Illumina 550K in a Japanese population (n=900) in search of population-specific genetic variations associated with high-density lipoprotein (HDL)-cholesterol. Methods and Results: Among the 368,274 single nucleotide polymorphisms (SNPs) with a minor allele frequency of at least 0.1, 43 SNPs exceeded the arbitrary threshold of -log₁₀P >4.0. The most significant SNP was rs3764261, located 5'upstream of CETP, exhibiting a -log₁₀P value of 6.17. Increasing the sample size by genotyping in the additional Suita sample (n=1,810) further improved the level of significance, with each additional copy of the minor allele being associated with an increase in HDL-cholesterol by 6.2 mg/dl (P =3.4×10^-12). Interestingly, the minor allele was more prevalent in cases with myocardial infarction than in controls (0.221 vs 0.196, nominal P=0.02). Conclusions: The association between genetic variants at CETP and HDL-cholesterol was replicated in our sample. None of the genetic variants exerted a greater influence on HDL levels than those at CETP. Associations for the top-ranked SNPs need to be tested for further replication in an independent sample. (Circ J 2009; 73: 1119-1126)

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Background: We hypothesized that the transient receptor potential vanilloid type 1 (TRPV1), which is found in the sensory nerve fibers, could modulate the cardiac function, be impaired by diabetes and could contribute to further severe postischemic heart injury. Methods and Results: Diabetes was induced in ICR mice by an intraperitoneal injection of streptozotocin. The expression of both TRPV1 and calcitonin gene-related peptide (CGRP) in diabetes mellitus (DM) hearts was significantly lower, as determined by Western blot and radioimmunoassay, respectively. During the ischemia/reperfusion, the cardiac function was measured by a Medlab system and the lactate dehydrogenase (LDH) in the effluents was measured by an ELISA kit. Compared with the non-DM hearts, the DM hearts demonstrated increased left ventricular end-diastolic pressure and decreased left ventricular developed pressure, heart rate and coronary flow, and also released more LDH in the effluents. Pretreatment with capsaicin attenuated the postischemic injury significantly in non-DM hearts, but not in DM hearts. Pretreatment with CGRP in both non-DM and DM hearts protected hearts against ischemic injury. Conclusions: The alteration of TRPV1 caused by diabetes is related to the poor recovery of cardiac function after myocardial ischemia. (Circ J 2009; 73: 1127-1132)

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Background: An increase in cytosolic protein phosphatases (PPs) de-phosphorylates phospholamban, decreasing the Ca²⁺ uptake of the sarcoplasmic reticulum (SR). The effects of PP inhibitors on cellular Ca²⁺ handling were investigated. Methods and Results: Twitch Ca²⁺ transients (CaTs) and cell shortening were measured in intact rat cardiac myocytes, and caffeine-induced Ca²⁺ transients (CaffCaTs) and Ca²⁺ sparks were studied in saponin-permeabilized cells. Calyculin A augmented isoproterenol-induced increases in CaTs and cell shortening without altering the diastolic [Ca²⁺]_i and twitch [Ca²⁺]_i decay. The protein kinase A catalytic subunit (PKA_cat) increased the peak of CaffCaTs between 5 and 50 U/ml, and the addition of inhibitor-1 (I-1) augmented the increase. PKA_cat increased Ca²⁺ spark frequency and the addition of I-1 increased it further. PKA_cat at 50 U/ml amplified the peak and prolonged the duration of Ca²⁺ sparks, whereas the addition of I-1 did not alter them. An abrupt inhibition of SR Ca²⁺ uptake following exposure to PKA_cat caused a gradual decrease in Ca²⁺ spark frequency, but the addition of I-1 did not accelerate the decline of Ca²⁺ spark frequency or CaffCaTs. Conclusions: Inhibition of PPs augmented the inotropic effect of isoproterenol. Specific inhibition of PP1 could stimulate the Ca²⁺ uptake of the SR with less significant effects on the Ca²⁺ release. (Circ J 2009; 73: 1133-1140)

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Background: Disturbance of the coronary microcirculation and catecholamine intoxication, which may be responsible for the pathogenesis of takotsubo cardiomyopathy, could trigger an oxidative stress response in the heart. Methods and Results: Expression and localization of inducible heme oxygenase-1 (HO-1), which is an oxidative stress-related factor in the heart of immobilization stressed (IMO) rats, an animal model of takotsubo cardiomyopathy, were investigated by real-time reverse transcriptase-polymerase chain reaction and in situ hybridization histochemistry and immunohistochemistry. In response to IMO, the levels of HO-1 mRNA in the heart and in the aorta were slightly increased at 90 min, and increased 3-fold at 3 h compared with control levels. The signals for HO-1 mRNA were expressed on scatted cells in the myocardium and aortic adventitia. Double fluorescence immunohistochemistry showed that HO-1 immunoreactive cells were also ED1 and ED2 positive, indicating that they were macrophages. The numbers of ED1 and ED2 positive cells were constant, whereas the number of HO-1 positive cells was increased 5-fold at 6 h compared with control levels. Blocking of α- and β-adrenoceptors attenuated IMO-induced upregulation of HO-1 mRNA levels in the heart. Conclusions: Emotional stress and a surge of catecholamine upregulate HO-1 in the cardiac and aortic macrophages. (Circ J 2009; 73: 1141-1146)

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Background: The number of adults with congenital heart disease (CHD) is increasing rapidly, but care programs have not been fully established in Japan. Methods and Results: Questionnaires regarding current status and resources of outpatient and in-hospital services, and management of pregnancy in patients with adult CHD (ACHD) were sent to 1,033 training hospitals for board-certified cardiologists. Useful replies were obtained from 458 hospitals (44%). In 417 hospitals (91%), at least 1 patient was followed in the outpatient clinic; however, only 14 hospitals (3%) had specialized outpatient clinics; 354 hospitals (77%) had in-hospital patients, but only 6 hospitals (2%) admitted >50 patients per year. Surgery for ACHD was performed in 232 hospitals (51%), but in 135 of these (58%), the number of operations was <5 per year. Pregnant women with CHD were managed in 157 hospitals (34%), although only 3 hospitals (2%) managed >10 cases per year. Conclusions: In most hospitals in Japan, a limited number of ACHD patients have been followed up and specialized multi-disciplinary facilities for ACHD need to be established. (Circ J 2009; 73: 1147-1150)

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Background: Although the aortic augmentation index (AI) is an attractive tool as an index of the vascular system, the association between radial AI or brachial-ankle pulse wave velocity (PWV) and severity of atheroma or arterial stiffness of the morphological central artery is unclear. Methods and Results: Severity of atheroma and aortic stiffness of the descending thoracic aorta (DTA) by transesophageal echography in 96 patients with paroxysmal atrial fibrillation was assessed. The relationship between radial AI or brachial-ankle PWV and atherosclerotic lesions was also investigated. The DTA was divided into 3 equal longitudinal portions, and the atheromatous lesions of each portion of the DTA were scored according to their character and extension. Instantaneous dimensional changes in the DTA was measured, and the aortic stiffness index β was calculated. Radial AI was significantly correlated with age, plasma low-density lipoprotein-cholesterol concentrations, systolic blood pressure, pulse pressure, the mean atheromatous score and the mean aortic stiffness index. However, brachial-ankle PWV was not associated with central arterial stiffness. Multivariate logistic regression analysis showed that radial AI was most closely correlated with the mean atheromatous score. Conclusions: Radial AI might be a novel tool for determining the severity of central aortic atheromatous lesions. (Circ J 2009; 73: 1151-1156)

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A 35-year-old man was referred to the emergency department after having a short syncopal episode while waiting for a Doppler scan of the lower extremities for a 4-week history of a painful right leg. He had no significant past medical history and was a non-smoker. On presentation he had severe chest pain and dyspnea associated with diaphoresis, and was hemodynamically unstable. His initial electrocardiogram (ECG) showed ST segment elevations in leads V_1-4, mimicking an anteroseptal myocardial infarction. However, the angiography showed the coronary arteries were normal and the right main pulmonary artery was partially occluded by large pulmonary emboli. The ECG changes were recorded in detail which also pointed to the diagnosis of pulmonary embolism (PE). This case shows how a PE can mimic an anteroseptal myocardial infarction on ECG, and the physiopathology of the ST elevation in PE was discussed. (Circ J 2009; 73: 1157-1159)

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A 61-year-old man suffered from atrial tachycardia (AT) following pulmonary vein isolation (PVI) treatment of atrial fibrillation. During a re-do procedure, all pulmonary veins (PVs) were isolated from the left atrium (LA) and programmed stimulation could not induce any atrial arrhythmias. Adenosine triphosphate exposed dormant PV-LA conduction at the right superior PV. PV firing during the reconnection caused AT with the same P-wave morphology as clinical AT. For 6 months after the elimination of that dormant PV conduction, the patient has been free of any AT. Evaluation of dormant PV conduction was effective in curing the recurrent AT after PVI. (Circ J 2009; 73: 1160-1162)

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Congenital left main coronary artery (LMCA) atresia is a rare anomaly and surgical revascularization is recommended once the diagnosis is confirmed. In some cases, LMCA atresia will coexist with other cardiac anomalies, mostly in pediatric patients. A 32-year-old woman had congenital LMCA atresia associated with patent ductus arteriosus (PDA), aortic regurgitation (AR), and moderate pulmonary hypertension. The PDA and AR were repaired surgically and the patient's symptoms improved. Coronary revascularization was not performed because the LCA was supplied by 2 large conus arteries, as "naturally occurring" bypass arteries. The patient remained asymptomatic at the 2.5-year follow-up visit. Given the positive outcome in this patient, surgical repair of the associated cardiac defect without coronary revascularization may be a reasonable approach for patients with congenital LMCA atresia, in which the left coronary arterial tree is supplied by other "naturally occurring" bypass arteries. (Circ J 2009; 73: 1163-1166)

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Mechanical circulatory support has been used to treat graft failure after heart transplantation, but in patients who needed mechanical circulatory support because of chronic rejection, we have suffered from the treatment because its outcome was catastrophic. Multiple organ failure was often caused by the addition of or increase in immunosuppressive medications, and it is known as a cause of the poor outcomes. The CardioWest total artificial heart was implanted for a case of chronic heart transplant rejection to enable complete withdrawal of immunosuppressive medication. The patient underwent re-heart transplantation, with a good result. This is a new therapeutic technique for chronic graft rejection. (Circ J 2009; 73: 1167-1168)

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