Platelet activation and subsequent accumulation at sites of vascular injury are the first steps in hemostasis. Excessive platelet activation after atherosclerotic plaque rupture or endothelial cell erosion may also lead to the formation of occlusive thrombi, which are responsible for acute ischemic events. Multiple pathways are involved in platelet activation, including those activated by adenosine diphosphate (ADP), thromboxane A₂ (TXA₂), serotonin, collagen, and thrombin. Antiplatelet agents used for prevention of atherothrombosis have focused on blocking the formation of TXA₂ (eg, aspirin) and interfering with ADP stimulation mediated by the P2Y₁₂ receptor (eg, clopidogrel). These agents, used alone or in combination, significantly decrease the risk for atherothrombotic events, but a significant residual risk for recurrent ischemic events remains. This has been, in part, attributed to persistence of elevated platelet reactivity despite the use of these agents. Several novel antiplatelet agents are currently under clinical development, with the goal of achieving more efficacious platelet inhibition. These include agents that more efficiently block TXA₂-mediated effects, as well as more potent P2Y₁₂ receptor antagonists. In addition, inhibition of the protease-activated receptor-1 platelet activation pathway stimulated by thrombin has emerged as a rational target for clinical development. An overview of the basic principles of platelet biology is given and currently available antiplatelet agents, as well as those under clinical development, are reviewed. (Circ J 2010; 74: 597-607)

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Neuronal activity is communicated to the cerebral vasculature so that adequate perfusion of brain tissue is maintained at all levels of neuronal metabolism. An increase in neuronal activity is accompanied by vasodilation and an increase in local cerebral blood flow. This process, known as neurovascular coupling (NVC) or functional hyperemia, is essential for cerebral homeostasis and survival. Neuronal activity is encoded in astrocytic Ca²⁺ signals that travel to astrocytic processes (`endfeet') encasing parenchymal arterioles within the brain. Astrocytic Ca²⁺ signals cause the release of vasoactive substances to cause relaxation, and in some circumstances contraction, of the smooth muscle cells (SMCs) of parenchymal arterioles to modulate local cerebral blood flow. Activation of potassium channels in the SMCs has been proposed to mediate NVC. Here, the current state of knowledge of NVC and potassium channels in parenchymal arterioles is reviewed. (Circ J 2010; 74: 608-616)

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Waon therapy is a form of thermal treatment in a dry sauna maintained at a temperature of 60°C, which differs from the traditional sauna. Waon therapy reportedly improves the hemodynamics, cardiac function, ventricular arrhythmias, vascular endothelial function, neurohormonal factors, sympathetic nervous system function, and symptoms in patients with chronic heart failure (CHF). It has also been demonstrated that the molecular mechanism by which Waon therapy improves vascular flow and endothelial function involves increased expression of endothelial nitric oxide synthase (eNOS). Furthermore, in a mouse model of hindlimb ischemia, repeated Waon therapy increased eNOS protein expression, blood flow, and capillary density. Moreover, Waon therapy did not increase blood flow and capillary density in eNOS-deficient mice, indicating that eNOS is a critical regulator of the angiogenesis induced by this therapy. Moreover, repeated Waon therapy is effective for patients with severe peripheral arterial disease (PAD), as evidenced by substantial decrease in pain scores, increases in both ankle-brachial pressure index and blood flow assessed by laser Doppler perfusion imaging, and by formation of new collateral vessels on angiography. In addition, ischemic ulcers heal or improve markedly. In conclusion, Waon therapy is an innovative and highly promising strategy for treating CHF and PAD. (Circ J 2010; 74: 617-621)

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Background: Female sex hormones may have protective effects against arrhythmias, including reperfusion arrhythmias (RAs), but the mechanisms are still not completely known. Methods and Results: Serial changes in rat hearts (rhythm, apoptosis and the its infuencing factors; cardiac vinculin mRNA expression and connexin43 (Cx43) dephosphorylation) were examined during periods of ischemia-reperfusion with and without estrogen treatment. After reperfusion, although the incidence of arrhythmias became higher in both the vehicle-group and estrogen-group, compared with the ischemia period, estrogen prevented reperfusion-induced upregulation of the incidence of arrhythmias, especially ventricular premature beats (VPB) and ventricular tachycardia (VT). The duration of VT and fibrillation, and the number of VPB and VT, were all significantly decreased in the estrogen-group. The expression of cardiac vinculin mRNA decreased significantly in the vehicle-group but not in the estrogen-group. Cx43 dephosphorylation and myocyte apoptosis increased in both groups, but the values for the estrogen-group were all markedly lower than those for the vehicle-group. A selective estrogen receptor (ER) β agonist prevented reperfusion-induced upregulation of the incidence of both VPB and VT significantly; a selective ERα agonist had no significant influence. Conclusions: Estrogen can protect the heart against RAs, at least in part, mediated through gap junctions. Upregulation of ERβ but not ERα mediated most of the estrogen-induced cardioprotection against RA. (Circ J 2010; 74: 634-643)

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Background: Although open irrigation tip catheters (OITC) are effective in producing transmural radiofrequency (RF) lesions, they have the potential for fluid overload or excessive tissue damage. Methods and Results: The 203 patients with non-paroxysmal atrial fibrillation (NPAF; 85.2% males, 55.2±10.6 years old) who underwent RF catheter ablation (RFCA) were analyzed retrospectively. Clinical outcomes and complications were compared between RFCA using OITC (n=92) and that using conventional catheters (CONC; n=111). Both the total procedure time (P<0.01) and fluoroscopic time (P<0.001) were shorter in the OITC group than in the CONC group. Total fluid loading during RFCA with OITC was 3.2±0.9L, and the average body weight increase was 1.8±1.2 kg. Symptomatic pulmonary edema and/or pleural effusion occurred in 3.3% of patients who had a bigger left atrium (P=0.005), longer duration of ablation procedure (P=0.002), higher post-RFCA serum pro-ANP level (P<0.001), and longer hospitalization (P<0.01). Conclusions: RFCA for NPAF using OITC results in a shorter procedure time compared with CONC. However, patients with a large left atrium and a large amount of fluid (>4L) infused via the OITC need to be carefully monitored to prevent pulmonary edema or pleural effusion because of fluid overload. (Circ J 2010; 74: 644-649)

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Background: Clinical characteristics, including risk factors for thromboembolism, and medications differ between men and women with atrial fibrillation (AF) in Western countries. Whether such a difference exists for Japanese patients with AF is unclear, so data from J-TRACE were used to investigate this issue. Methods and Results: A total of 2,892 patients (2,028 men, 864 women; 70.3 years old) with AF were analyzed for the respective prevalences of risk factors and medications. CHADS2 score was calculated to determine thromboembolic risk level. Women were older (P<0.001), and more frequently had heart failure (P<0.001), and hypertension (P=0.051) than men. The proportion of subjects aged 75 years or older was higher among women than among men (P<0.001). CHADS2 score was therefore significantly higher in women than in men (2.05±1.29 vs 1.88±1.33, P<0.001). Sex-related differences were not observed for the prevalence of diabetes mellitus, myocardial infarction or ischemic stroke, nor did warfarin usage differ between men and women. Conclusions: Sex-related differences were observed in the risk factor profile and medications of Japanese patients with AF. CHADS2 score was higher in women than in men. (Circ J 2010; 74: 650-654)

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Background: Previous studies suggest that a short temporal excitable gap exists between the fibrillation waves during atrial fibrillation (AF). The aim of this study was to investigate the role of that gap in the development of sustained AF in goats. Methods and Results: Eight female goats were instrumented with left atrium (LA) electrodes, and sustained AF (>24 h) was induced by intermittent rapid atrial pacing for 9.3±4.6 days. In the process of sustained AF development, the atrial effective refractory period (AERP), refractory period during AF (RP_AF), mean AF cycle length (AFCL), temporal excitable gap during AF (EG_AF = AFCL - RP_AF) and degree of fractionation of fibrillation electrograms at LA were studied. When the induced AF lasted for 3-10 min, AFCL, RP_AF and EG_AF were 98.3±11.0 ms, 90.5±13.2 ms and 7.8±2.4 ms, respectively. During sustained AF, the values were 84.9±5.2 ms, 63.0±4.8 ms and 21.9±3.5 ms, respectively (P<0.05). Percentage of single potentials was 94.2±3.9% and 75.6±5.5%, respectively (P<0.05). Conclusions: In this model progressive shortening of atrial refractoriness and widening of the temporal excitable gap induced by electrical remodeling created an electrophysiologic substrate for the perpetuation of AF. (Circ J 2010; 74: 655-663)

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Background: Although patients with Brugada syndrome (BS) are at risk of ventricular fibrillation (VF) and ensuing death, the action potential duration (APD) restitution properties of the right ventricular outflow tract (RVOT) in patients with BS remain undetermined. Methods and Results: Endocardial monophasic action potentials (MAPs) were obtained from 16 patients with BS and 17 control patients. MAPs were recorded from the RVOT in all patients. The MAP duration at 90% repolarization (MAPD₉₀), effective refractory period (ERP), and maximum slope of the APD restitution curve were obtained. VF was induced with up to 3 extrastimuli from the RV apex or RVOT. There was no difference in MAPD₉₀ between the 2 groups, but the ERP was significantly shorter in patients with BS than in control patients (210.7±10.5 vs 223.8±13.4 ms, P=0.008). MAPD at the shortest diastolic interval was significantly shorter in patients with BS than in control patients (149.9±19.9 vs 179.8±13.7 ms, P<0.001). The maximum slope of the APD restitution curve was steeper in patients with BS than in control patients (2.90±1.29 vs 1.38±0.41, P<0.001). Conclusions: The shorter ERP, shorter MAPD at the shortest diastolic interval and steeply sloped APD restitution curve in the RVOT appear to be related to the inducibility of VF in patients with BS. (Circ J 2010; 74: 664-670)

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Background: There are few data to compare the long-term efficacy of sirolimus-eluting stent (SES) and off-pump coronary artery bypass grafting (OPCAB) for diabetic patients with multivessel disease (MVD). Methods and Results: In a single-center non-randomized registry, 208 diabetic patients with MVD were examined (SES group: n=92, OPCAB group: n=116). The occurrence of major adverse cardiac and cerebrovascular events (MACCE, defined as all-cause death, non-fatal myocardial infarction, cerebrovascular event, and repeat revascularization) was compared between the 2 groups. Fasting blood glucose level, type of diabetic treatment and the prevalence of diabetic major vascular complications were similar between groups. The SES group had a significantly higher prevalence of 2-vessel disease and a significantly lower prevalence of 3-vessel disease compared with the OPCAB group. During the follow-up period (mean: 42±8 months), the rate of revascularization was significantly higher in the SES group than the OPCAB group (21% vs 6.9%, P=0.003). On the other hand, there was a significant higher occurrence of cerebrovascular events in the OPCAB group. Finally, the cumulative MACCE was similar between the 2 groups (27% vs 23%, P=0.492). Conclusions: At the 3-year clinical follow-up, the prevalence of MACCE in diabetic patients with MVD was comparable between the SES and the OPCAB groups. (Circ J 2010; 74: 671-678)

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Background: Few studies have examined whether high-responsiveness to antiplatelet therapy is associated with an increased risk of bleeding in patients receiving dual antiplatelet therapy. MethodsandResults: Elective drug-eluting stent implantation was performed in 184 patients treated with aspirin and a thienopyridine (200 mg/day of ticlopidine or 75 mg/day of clopidogrel). The subjects were divided into 3 groups according to post-treatment platelet reactivity before stenting as measured by the response to adenosine diphosphate: the 1^st quartile group was defined as high-responders, the 4^th as low-responders, and the other 2 quartiles as middle-responders. Major bleeding occurred more frequently in high-responders than in middle- or low-responders during an average of 16 months' follow-up (15 vs 4, 2%, P=0.02). High-responsiveness was the independent predictor of major bleeding (odds ratio 4.26, P=0.03). Adverse cardiac events were less frequent in high- and middle-responders than in low-responders (24, 16 vs 37%, P=0.02). Middle-responders had better net clinical outcomes, defined as the sum of major bleeding and adverse cardiac events, than did high- or low-responders (21 vs 39, 39%, P=0.02). Conclusions: In the present study high-responsiveness to antiplatelet therapy was associated with an increased risk of bleeding with no reduction in adverse cardiac events. Measuring platelet reactivity may be useful for risk stratification according to bleeding complications, as well as adverse cardiac events, in patients treated with drug-eluting stents. (Circ J 2010; 74: 679-685)

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Background: In recent years, the radial artery (RA) has become an alternative vascular access site for percutaneous coronary procedures, and the ulnar artery (UA) is another possibility. The objective of this study was to investigate the anatomy of the forearm arteries with ultrasound (US) and to evaluate the effect of the anatomy of the right RA (RRA) on the outcomes of transradial coronary procedures. Methods and Results: The 638 patients undergoing transradial coronary procedures were examined with US for measurement of the diameters of the forearm arteries and determination of their anatomical abnormalities before the procedures. The next day the incidence of RA occlusion was recorded. The diameters of the radial and ulnar arteries were similar (P>0.05). The procedure time was longer in patients with anatomical abnormalities (P<0.05) and whose RRA had a diameter <2 mm (P<0.05). The incidence of procedure failure, and of RA occlusion one day after the procedure was also higher in patients with an anatomical abnormality of the RRA (P<0.01 and P<0.05, respectively) and whose RRA diameter was <2 mm (P<0.05 and P<0.05, respectively). Conclusions: The diameters of the forearm arteries of Chinese people are similar. The small diameter and anatomical abnormalities of the RRA could result in longer procedure time, more incidence of procedure failure and RA occlusion. (Circ J 2010; 74: 686-692)

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Background: There are few studies comparing the efficacy of different drug-eluting stents and their long-term clinical outcomes in percutaneous coronary intervention (PCI) of chronic total occlusive (CTO) lesions. Methods and Results: To compare the efficacy of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) for CTO, and to identify predictors of outcome after PCI, 200 patients with at least 1 successfully revascularized CTO were enrolled into either a SES (n=132) or PES (n=71) group. At 6-9-month angiographic follow-up, SES was superior to PES (late loss 0.27±0.60 vs 0.53±0.62 mm, P=0.04). During mean follow-up of 2 years, the SES group had a significantly lower cumulative target vessel failure (TVF) rate than the PES group (14.9% vs 28.4%, P=0.01), as a consequence of lower target vessel revascularization (9.7% vs 23.9%, P=0.01) and also a partially lower rate of myocardial infarction (MI: 3.1% vs 7.6%, P=0.04). SES was also superior to PES in both early (≤9 months) and late (>9 months) TVF (P=0.02 for log-rank test, respectively). Predictors for TVF were use of PES (hazard ratio (HR) 3.81, P<0.01), previous history of MI (HR 4.06, P<0.01), diabetes (HR 2.07, P=0.04) and chronic kidney disease (CKD; HR 3.56, P=0.05). Conclusions: CTO lesions treated with SES showed better angiographic and long-term clinical outcomes than those treated with PES. Factors such as stent type, infarct-related CTO, diabetes and CKD affect the outcome of CTO intervention. (Circ J 2010; 74: 693-700)

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Background: The optimal antithrombotic strategy for patients with atrial fibrillation (AF) undergoing drug-eluting stent (DES) implantation is unknown. Methods and Results: The 622 consecutive AF patients undergoing DES implantation were prospectively enrolled. Among them, 142 patients (TT group) continued triple antithrombotic therapy comprising aspirin, clopidogrel and warfarin after discharge; 355 patients (DT group) had dual antiplatelet therapy; 125 patients (WS group) were discharged with warfarin and a single antiplatelet agent. Target INR was set as 1.8-2.5 and was regularly monitored after discharge. The TT group had a significant reduction in stroke and major adverse cardiac and cerebral events (MACCE) (8.8% vs 20.1% vs 14.9%, P=0.010) as compared with either the DT or WS group. In the Cox regression analysis, administration with warfarin (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.31-0.77; P=0.002) and baseline CHADS₂ score ≥2 (HR 2.09; 95%CI 1.27-3.45; P=0.004) were independent predictors of MACCE. Importantly, the incidence of major bleeding was comparable among 3 groups (2.9% vs 1.8% vs 2.5%, P=0.725), although the overall bleeding rate was increased in the TT group. Kaplan-Meier analysis indicated that the TT group was associated with the best net clinical outcome. Conclusions: The cardiovascular benefits of triple antithrombotic therapy were confirmed by reducing the MACCE rate, and its major bleeding risk might be acceptable if the INR is closely monitored. (Circ J 2010; 74: 701-708)

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Background: Cardiac rehabilitation (CR) has numerous benefits, including reduction of mortality and cardiovascular events, in patients with coronary artery disease (CAD). However, the long-term effect of phase III CR in elderly patients with stable CAD is still unknown. Methods and Results: The 111 elderly male CAD patients (≥65 years), including 37 subjects participating in supervised CR for 6 months and 74 age-matched controls, were analyzed. The patients were followed for up to 3,500 days, until the occurrence of death or 1 of the following major adverse cardiovascular events (MACE): cardiovascular death, acute coronary syndrome, refractory angina requiring revascularization, admission for congestive heart failure, or stroke. All-cause mortality tended to be lower in the CR group than in the Control group (14% vs 28%, P=0.081). The MACE incidence was significantly lower in the CR group than in the Control group (30% vs 62%, P=0.001). Multivariate Cox proportional hazard analysis showed that the MACE incidence was significantly lower in the CR group than in the Control group [adjusted hazard ratio 0.43 (95% confidence interval 0.20-0.91), P=0.027]. Conclusions: Phase III CR has the beneficial effect of reducing cardiovascular events even in elderly patients with stable CAD. (Circ J 2010; 74: 709-714)

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Background: This study was designed to elucidate the key factors for successful long-term support with a left ventricular assist system (LVAS) in the situation where heart transplantation is rarely available. Methods and Results: From 1992 to 2008, 106 patients underwent 121 LVAS implantations at Osaka University Hospital (Toyobo: 77; Novacor: 18; HeartMate: 14; Jarvik2000: 8; EvaHeart: 2; DuraHeart: 2). Risk factors for infection were early on the former implanted period (odds ratio (OR) 3.30), Toyobo (OR 2.25), mechanical right heart support (OR 2.30) and cardiopulmonary bypass time (OR 1.01). Left atrium as the inflow site was the risk factor for cerebrovascular events (OR 2.84). Older age (OR 1.04) and mechanical right heart support (OR 4.70) were risk factors for mortality. Risk factors for requiring mechanical right heart support were preoperative extracorporeal membranous oxygenation support (OR 5.641), serum total bilirubin (OR 1.11) and serum creatinine (OR 2.46). On the basis of the risk analysis for mortality, patients were divided into 2 subgroups (low and high risk) and the respective cumulative survival at 1 year after LVAS implantation was 75.2% and 25.0%. Conclusions: Appropriate selection of device, patient and the timing of implantation and less invasive operation are important for successful long-term LVAS support. (Circ J 2010; 74: 715-722)

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Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multiple ligand receptor induced by oxidative stress. However, its role in chronic heart failure remains unknown. Methods and Results: The left ventricular (LV) expression of LOX-1 was examined in a salt-sensitive Dahl rat model of hypertension. Compared with controls, LOX-1 mRNA levels increased by 4.7-fold in the LV with hypertrophy, and by 32-fold in the LV with decreased systolic function. LV LOX-1 mRNA levels strongly correlated with the decrease in LV ejection fraction (EF) (r=-0.772), and with increases in the LV mRNA levels of B-type natriuretic peptide (r=0.814), monocyte chemoattractant protein-1 (r=0.943), transforming growth factor-β₁ (r=0.936), and a macrophage marker, F4/80 (r=0.560). Serum levels of soluble LOX-1 were significantly elevated in patients with LV systolic dysfunction and hypertrophy, and significantly correlated with the decrease in EF (r=-0.495). Conclusions: Marked increase in the LV expression of LOX-1 in failing hearts may contribute to increased serum levels, and might be involved in chronic inflammation during the development of heart failure. (Circ J 2010; 74: 723-729)

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Background: To explore the acute effects of submaximal exercise on blood rheology and sympathetic nerve activity. Methods and Results: The effects of exercise (20 or 80 Watts (W)) on blood rheology and sympathetic nerve activity were assessed in 10 healthy Japanese men. Blood sampling and heart rate variability (HRV) recording were performed during 20-min supine rest and standing ergometric exercise (20 W for 10 min, 80 W for 10 min) and recovery. Blood passage time across the microchannels (diameter, 7 μm) as a parameter of blood rheology, and the number of adhesive leukocytes on microchannel terraces as a parameter of leukocyte activation were measured. Sympathetic nerve activity was evaluated by plasma noradrenalin levels and the ratio of low-frequency (LF)/high-frequency (HF) by spectral analysis of HRV. Compared with values while supine at rest, significant increases in hematocrit, leukocyte count, noradrenalin level and blood passage time were seen after strenuous ergometer exercise at 80 W (P<0.01 each). The LF/HF ratio and nitric oxide metabolites tended to be increased with 80 W exercise. Conclusions: Strenuous exercise dynamically alters blood rheological parameters, probably by changes in hematocrit and sympathetic nerve activity. (Circ J 2010; 74: 730-734)

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Background: In the present study the effective dose and image quality at distal anastomoses were retrospectively compared between prospective electrocardiogram (ECG)-gated axial and retrospective ECG-gated helical techniques on 64-detector computed tomographic (CT) angiography following coronary artery bypass graft surgery. Methods and Results: Following bypass surgery, 52 patients with a heart rate <65 beats/min underwent CT angiography: 26 patients each with prospective and retrospective ECG gating techniques. The effective dose was compared between the 2 groups using a 4-point scale (4, excellent; 1, poor) to grade the quality of curved multiplanar reformation images at distal anastomoses. Patient characteristics of the 2 groups were well matched, and the same CT scan parameters were used for both, except for the interval between surgery and CT examination, tube current, and image noise index. Image quality scores did not differ significantly (3.26±0.95 vs 3.35±0.87; P=0.63), but the effective dose was significantly lower in the prospective (7.3±1.8 mSv) than in the retrospective gating group (23.6±4.5 mSv) (P<0.0001). Conclusions: Following bypass surgery, 64-detector CT angiography using prospective ECG gating is superior to retrospective gating in limiting the radiation dose and maintaining the image quality of distal anastomoses. (Circ J 2010; 74: 735-740)

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Background: S100A8/A9 complex (S100A8/A9) is expressed in activated human neutrophils and macrophages. Enhanced expression of S100A8/A9 in atherosclerotic plaque of patients with unstable angina pectoris (UAP) has been demonstrated, but its profile in acute myocardial infarction (AMI) has not been clarified. Methods and Results: Serum S100A8/A9 levels were serially measured in patients with AMI (n=55) and UAP (n=16) during the acute period. The expression of S100A8/A9 was examined immunohistochemically in the infarcted myocardium of 7 autopsied patients with AMI. Serum S100A8/A9 levels on the 1st day were 1,118±115 (SE) ng/ml in AMI patients as compared with 787±147 ng/ml in UAP patients. On days 3-5, serum S100A8/A9 levels in AMI patients reached a peak value and were significantly higher than the values in UAP patients (1,690±144 ng/ml vs 844±100 ng/ml; P<0.0001). In AMI patients, peak S100A8/A9 levels positively correlated with peak white blood cell and neutrophil counts, and peak creatine kinase-MB and peak C-reactive protein levels. Double immunostaining revealed that S100A8/A9 was specifically expressed in neutrophils and macrophages infiltrating the infarcted myocardium. Conclusions: S100A8/A9 is implicated in the pathophysiology of AMI and may be an additional biomarker of the local inflammatory response following AMI. (Circ J 2010; 74: 741-748)

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Background: Atherosclerosis is currently being investigated as a chronic inflammatory process and the role of infectious agents is unclear. The presence of mycotic DNA in the wall of the non-atherosclerotic aorta of patients with coronary artery disease (CAD) and its association with levels of soluble intercellular adhesion molecule (sICAM)-1 expression was examined in the present study. Methods and Results: In 40 patients with CAD and a comparative group of 20 patients with aortic valve stenosis (AS) without CAD, specimens of the aortic wall were obtained during cardiac surgery. Mycotic DNA was analyzed by polymerase chain reaction (PCR) using a fungus-specific universal primer pair, ITS3 and ITS4, to amplify a portion of the 5.8S rDNA region, the entire ITS2 region and a portion of the 28S rDNA region, and using a species-specific primer pair, CALB1 and CALB2, to specifically amplify Candida (C.) albicans. The nested PCR method was performed to amplify the intergenic transcribed spacer regions of the rRNAs of Candida species. Before surgery the serum level of sICAM-1 was estimated. Mycotic DNA was detected in 48% of the CAD patients and in 40% of the AS patients, with C. albicans DNA in 58% and 100%, respectively (P>0.05). In CAD patients with a high level of sICAM-1, C. albicans DNA was found more frequently than in patients without elevated levels of sICAM-1 (P<0.05). Conclusions: Mycotic DNA was found in the non-atherosclerotic aortic wall of CAD patients as well as in patients with AS. In the CAD patients C. albicans DNA was related to sICAM-1 expression. (Circ J 2010; 74: 749-753)

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Background: Tissue characterization of coronary plaques is feasible using integrated backscatter intravascular ultrasound (IB-IVUS), and higher lipid content has been found in the target lesions of acute coronary syndrome (ACS). The present study was performed to identify clinical and IVUS parameters that correlate with plaque composition assessed by IB-IVUS. Methods and Results: A total of 109 patients (age 60.0±9.7 years) were evaluated with IVUS and IB-IVUS prior to percutaneous coronary intervention. Patients with ACS had a larger vessel size and higher plaque burden in the target lesion than those with stable angina. Relative lipid content of the target lesion by IB-IVUS was also higher in ACS (43.6%±12.0% vs 29.9%±14.2%; P<0.001). The remodeling index (r=0.403, P<0.001), plaque burden (%) (r=0.495, P<0.001), and vessel size (r=0.572, P<0.001) significantly correlated with lipid content. In the multiple regression analysis, vessel size was the most important independent predictor of lipid content followed by presence of ACS and the remodeling index. Conclusions: ACS, positive remodeling, and larger plaque burden were associated with higher lipid content of coronary plaque. However, the lipid content on IB-IVUS was also significantly affected by vessel size. Therefore, qualitative, morphologic assessment of coronary plaque rather than simple quantitative analysis of tissue components seems to be more appropriate for the identification of vulnerable plaque using IB-IVUS. (Circ J 2010; 74: 754-759)

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Background: Although right ventricular hypertrophy (RVH) is an adaptive process to stresses such as outflow tract obstruction, uncorrected persistent RVH often results in failure of the right ventricle or even the left ventricle. Histone deacetylase (HDAC) inhibitors can effectively prevent or block left ventricular hypertrophy, so the present study compared the effects of sodium valproate, an HDAC inhibitor, with those of captopril, an angiotensin-converting enzyme inhibitor, on RVH. Methods and Results: RVH was induced in rats by pulmonary artery banding (PAB) or monocrotaline (MCT) injection, and then either sodium valproate or captopril was administered. PAB or MCT injection caused a marked increase in the size of RV after 2 weeks, which was documented by weighing it, by evaluating echocardiograms or electrocardiograms, or by examining cardiac hypertrophy-associated gene expression. Sodium valproate significantly reduced RVH induced by either PAB or MCT injection. Interestingly, however, captopril failed to do so. Conclusions: In the present study sodium valproate, but not captopril, was effective in blocking RVH induced by PAB or MCT injection, which suggests that HDAC inhibitors may be a novel therapy for RVH. (Circ J 2010; 74: 760-770)

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Background: It has been suggested that anti-smoking therapy gives encouraging results, but this has not been verified by well-randomized study protocols. The present study was a randomized controlled trial of varenicline vs nicotine patch in adult smokers for comparison of efficacy, safety and withdrawal symptoms. Methods and Results: The 32 adult smokers were randomly divided into a varenicline group (VG, n=16) and a nicotine patch group (NG, n=16). The primary endpoints were the 12- and 24-week smoking-abstinence rates, safety and withdrawal symptoms including stress. No significant difference in abstinence rates was observed between the 2 groups over weeks 9-12 (71.4% vs 78.6% in the VG and NG, respectively), and weeks 9-24 (64.3% vs 71.4%, respectively). The frequencies of inability to concentrate at 2, 4, and 8 weeks, and wakeful nights at 2 weeks were higher in the VG than in the NG. Adverse side-effects associated with a gastrointestinal disorder occurred in 14 cases and 1 case in the VG and NG, respectively, and skin allergy was seen in 0 and 9 cases, respectively. Conclusions: The selection of treatment depends on the balance of desired acuteness of cessation of smoking and side-effects, such as psychiatric and gastrointestinal problems or skin allergy. (Circ J 2010; 74: 771-778)

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Background: Randomized trials have established statins as an agent for prevention of coronary heart disease (CHD). The purpose of this study was to assess the hypothesis that standard-dose statin therapy has a beneficial effect in normocholesterolemic diabetic patients with CHD. Methods and Results: A prospective, randomized, open, blinded-endpoint trial was conducted from 2002 to 2004 at 55 hospitals in Japan to evaluate the effect of statins on subsequent cardiovascular events. A total number of 1,016 CHD patients (301 patients with type 2 diabetes mellitus [DM] and 715 non-DM patients) with serum total cholesterol levels of 180-240 mg/dl were randomly divided into non-statin and statin treatments. Clinical parameters were comparable between DM and non-DM groups. Serum low-density lipoprotein (LDL)-cholesterol levels were equally decreased after statin treatment in the 2 groups. Statin treatment improved prognosis in both the DM and non-DM groups; however, the number needed to treat (NNT) and relative risk reduction (RRR) were remarkable especially in the DM group (NNT=8, RRR=67%) compared with the non-DM group (NNT=30, RRR=24%). Conclusions: Standard-dose statin therapy provides incremental clinical benefits in DM patients with normal cholesterol levels compared with non-DM patients. The data suggest that DM patients may enjoy the pleiotropic effects of statins, independent of the LDL-cholesterol lowering effects of these agents. (Circ J 2010; 74: 779-785)

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Background: The relationship between renal dysfunction and the severity of coronary artery disease (CAD) was examined. Methods and Results: The severity of CAD in 572 patients was graded according to the number of stenotic coronary arteries, and the estimated glomerular filtration rate (eGFR) was monitored for 3 years. Patients were stratified into 3 eGFR groups: normal (>75 ml · min^-1 · 1.73 m^-2), mild reduction (60-75) and chronic kidney disease (CKD: <60). There were 161 patients in the CKD group. The average number of stenotic coronary arteries was larger in the CKD group than in the other groups (normal vs mild reduction vs CKD =1.35±0.07 (SE) vs 1.22±0.08 vs 1.69±0.08 vessel disease (VD), P<0.001). During the 3-year follow-up, the renal function of 13.8% of the patients worsened. Those who showed more deterioration of eGFR had more severe CAD than those who did not (1.20±0.06 vs 1.61±0.06 VD, P<0.001). Multivariate analysis revealed that the severity of CAD was independently and significantly associated with the deterioration of eGFR. Conclusions: Patients with CKD had more severe CAD, which may explain the high rate of cardiovascular events in these patients. Moreover, the prognosis of renal function was poor in patients with severe CAD, and CAD was found to be an independent risk factor for worsening of renal dysfunction. (Circ J 2010; 74: 786-791)

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Background: Plasma B-type natriuretic peptide (BNP) levels are confounded by renal dysfunction, so this study examined whether plasma BNP might be a reliable biomarker of the onset of cardiovascular (CV) events in a population-based cohort with impaired renal function. Methods and Results: Baseline data, including plasma BNP, serum creatinine, and urinary protein levels, were determined in participants from a community-based population. Estimated glomerular filtration rate (eGFR) was calculated, and chronic kidney disease (CKD) was defined as either: eGFR <60 ml·min^-1·1.73 m^-2 and/or proteinuria (CKD definition-1) or GFR <60 ml·min^-1·1.73 m^-2 (CKD definition-2). The CV endpoint was surveyed prospectively. The cohorts were followed for 5,275 person-years for CKD definition-1, and for 4,350 person-years for CKD definition-2. The CV event-free survival rate in the highest BNP quartile in either CKD definition was the lowest among the quartile groups (P<0.001). In multivariate Cox regression models adjusted by traditional CV risk factors and atrial fibrillation, relative risk (RR) for CV events was significantly higher in the highest BNP quartile compared with the lowest BNP quartile (CKD definition-1, RR 3.51, P<0.01: CKD definition-2, RR 4.67, both P<0.01). Conclusions: Plasma BNP level provides strong predictive information about the future onset of CV events in CKD subjects selected from the general population. (Circ J 2010; 74: 792-797)

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Background: The endothelium modulates vascular tone by synthesizing and releasing several vasodilating factors, including vasodilator prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In the present study, we examined whether an angiotensin-receptor blocker, a calcium-channel blocker or their combination improved EDHF-mediated responses in diabetic apolipoprotein E-deficient (ApoE^-/-) mice. Methods and Results: We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE^-/- mice. The diabetic ApoE^-/- mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mg·kg^-1·day^-1), azelnidipine (AZL, 10 mg·kg^-1·day^-1), their combination (OLM + AZL), or hydralazine (HYD 5 mg·kg^-1·day^-1) for 5 weeks. In the untreated group, systolic blood pressure was significantly higher and both EDHF-mediated relaxation and endothelium-dependent hyperpolarization were markedly reduced as compared with the control group. Although EDHF-mediated relaxation was not significantly improved in the HYD, OLM and AZL groups, it was significantly improved in the OLM + AZL group, as was also the case with phosphorylation of Akt and endothelial NO synthase (eNOS). In contrast, the endothelium-independent relaxation response to sodium nitroprusside or NS-1619 (a direct opener of K_Ca channels) was unaltered in any group. Conclusions: OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE^-/- mice, in which activation of the endothelial Akt - eNOS pathway may be involved. (Circ J 2010; 74: 798-806)

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