Over the past few decades, sleep apnea has emerged as an important potential etiologic factor in a broad range of cardiac and vascular diseases. These disease conditions include hypertension, coronary artery disease, myocardial infarction, heart failure, and stroke. Recognition of the role of sleep apnea in clinical cardiology is also increasing in Japan. Although sleep apnea has been strongly linked to obesity in Western populations, in Japanese and other Asian populations there is evidence to indicate that sleep apnea may be prevalent even at lower levels of obesity. In this review we address the epidemiology of sleep apnea. Since sleep apnea includes the combined stresses of hypoxemia, apnea, and disrupted sleep, we also review briefly the potential disease mechanisms that may be activated as a consequence of sleep apnea. We further examine the role of sleep apnea in the pathophysiology and management of specific cardiovascular conditions. Overall, while the evidence of sleep apnea as a causal mechanism in cardiovascular disease is strong and increasing, definitive evidence of the etiologic role of sleep apnea has yet to be obtained. The evidence is most clear in patients with hypertension. Also remaining to be established is whether the treatment of sleep apnea prevents cardiac and vascular events. With regard to this question, although the available data strongly suggest that continuous positive airway pressure treatment is beneficial, randomized control trials are needed in order to confirm this. (Circ J 2009; 73: 1363 - 1370)

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Drug-eluting stents (DES) represent a revolutionary technology in their unique ability to provide both mechanical and biological solutions simultaneously to the target lesion. As a result of biological effects from the pharmacological agents and interaction of DES components with the arterial wall, considerable differences exist between DES and conventional bare metal stents (BMS), yet some of the old lessons learned in the BMS era remain clinically significant. In this context, contrast angiography provides very little information about in vivo device properties and their biomechanical effects on the arterial wall. In contrast, current catheter-based imaging tools, such as intravascular ultrasound, optical coherence tomography, and intracoronary angioscopy can offer unique insights into DES through direct assessment of the device and treated vessel in the clinical setting. This article reviews these insights from current DES with particular focus on performance and safety characteristics as well as discussing an optimal deployment technique, based upon findings obtained through the use of the invasive imaging technologies. (Circ J 2009; 73: 1371 - 1380)

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The guidelines of the Joint National Committee 7 from the USA on hypertension have unified the normal and high-normal blood pressure categories into a single entity termed `prehypertension'. In contrast, The European Guidelines for the management of hypertension in 2007 considered `prehypertensive' to be divided into normal and high-normal blood pressure. These patients with high-normal blood pressure or prehypertension might progress to hypertension over time. Previous studies have shown that high-normal blood pressure is a risk factor for cardiovascular disease (CVD) in Western countries and Japan. The combination of high-normal blood pressure and other cardiovascular risk factors increases the risks of CVD. Recently, metabolic syndrome has also been shown to be a risk factor for CVD. In Japan, the association between metabolic syndrome and CVD was also found to be significant. The risks for CVD incidence were similar among participants who had the same number of components, regardless of the presence of abdominal obesity. In the Japanese guidelines for the management of hypertension published in 2009, patients are considered to be in a high-risk group if they have diabetes, chronic kidney disease, 3 or more risk factors, target organ damage or CVD, even if they have only high-normal blood pressure, and appropriate antihypertensive therapy should be initiated. (Circ J 2009; 73: 1381 - 1385)

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It has been generally believed that advanced congestive heart failure (HF) is progressive, but there is increasing evidence that mechanical unloading with the use of left ventricular assist system (LVAS) occasionally reverses the progress of HF and permits device explantation. This "bridge to recovery" strategy is attracting interest, not only for the treatment of severe HF, but also in the study of the pathophysiological mechanisms involved in remodeling and its regression, with the hope of establishing reliable indicators of sustained recovery and strategies to enhance this process. Tissue samples obtained at the time of LVAS implantation and at explantation enabled study of the effects of LV unloading at the cellular and gene levels. However, the problem with these analyses is the lack of correlation between clinical improvement and cellular or molecular changes. Clinically, there are still many questions about the application of this strategy. The evaluation of LV function while on LVAS and the prediction of sustained recovery after explantation of the device have been the major concerns. Pharmacological regimens to promote recovery have been proposed, but require validation by multicenter study. Further investigation of the underlying mechanisms may help to establish strategies to enhance the recovery process. (Circ J 2009; 73: 1386 - 1392)

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Background: Evaluation of plasma markers of thrombin activity (thrombin-antithrombin III complex: TAT), active fibrinolysis (plasmin-α 2-plasmin inhibitor complex: PIC), and platelet activity (platelet factor 4: PF4) is useful for identifying patients with various cardiovascular disorders who are at high risk of thromboembolism. In this study, these markers were investigated in the left atria (LA) of patients with paroxysmal atrial fibrillation (pAF) in the non-paroxysmal period. Methods and Results: Patients with pAF (n=10) and chronic AF (cAF) (n=10) were enrolled. TAT, PIC, and PF4 levels were determined in blood samples obtained from the LA of AF patients before radiofrequency catheter ablation. TAT levels were high in both pAF and cAF patients. PF4 levels were slightly elevated in both groups, but there was no significant difference between the groups. On the other hand, PIC levels in both groups were almost within normal limits, again with no significant difference between groups. Conclusions: Coagulation activity is elevated in the LA of patients with pAF, even in the non-paroxysmal period, so these patients are at high risk of thromboembolism and anticoagulant therapy is indicated. (Circ J 2009; 73: 1403 - 1407)

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Background: The relationship between the activation delay during programmed stimulation and the inducibility of ventricular fibrillation (VF) and filtered QRS duration on signal-averaged ECG (SAECG) were assessed in patients with Brugada syndrome (BS). Methods and Results: The activation delay was assessed using the interval between the stimulus and the QRS complex during programmed stimulation in 25 patients with BS and 10 with idiopathic ventricular tachycardia (controls). The mean increase of delay (MID) was used to characterize the conduction curves. The filtered QRS duration (fQRSd) in leads V₂ (RfQRSd) and V₅ (LfQRSd) were also evaluated using SAECG. Both MIDs at the right ventricular outflow tract (RVOT) were significantly greater in symptomatic and asymptomatic BS patients than in the control group (symptomatic, 7.1 ±2.7 ms vs control, 2.5 ±1.2 ms, P<0.001, asymptomatic, 7.3 ±3.3 ms vs control, P<0.001, respectively). The MID correlated with the His-ventricular interval; however, there were no significant correlations between the MID and RfQRSd or RfQRSd - LfQRSd. Conclusions: The MID, which indicates an increase of the St-QRS during premature stimulation, was much greater in patients with BS (regardless of clinical symptoms) than in the control group, especially in the RVOT, which might be related to the easy inducibility of VF from the RVOT. (Circ J 2009; 73: 1408 - 1415)

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Background: To clarify the appropriate application and therapeutic strategy for the percutaneous cardiopulmonary system (PCPS) in patients in cardiopulmonary arrest (CPA), the effects of the duration of cardiopulmonary resuscitation (CPR), diagnosis of underlying diseases, subsequent intervention and complications were retrospectively investigated for the correlation between discharge or death of patients. The patients were treated under an identical therapeutic PCPS protocol. Methods and Results: The 69 CPA patients [55 males (78.6%), 14 females; age, 55.0 ±15.3 years; age range 15-79 years, 50 in-hospital CPA (I-CPA) and 19 out-of-hospital CPA (O-CPA) patients] were treated with emergency PCPS. The mean duration of CPR was 43.6 ±37.4 min. Of 18 discharged patients (26.1%), 14 had I-CPA and 4 had O-CPA. Significant factors in the discharge of patients were confirmed diagnosis, subsequent treatment and prevention of complications associated with PCPS. Conclusions: Appropriate patient selection for PCPS in cases of O-CPA is likely to give a similar survival rate as for I-CPA. Patient selection and reversibility of the underlying disease and clinical state after starting PCPS affect the prognosis. Aggressive diagnosis and therapy for the underlying disease and prevention of complications associated with PCPS are essential factors in successful discharge of patients. Patients with an unknown etiology are not expected to fully recover, despite PCPS. (Circ J 2009; 73: 1416 - 1422)

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Background: Prospective data about the association between serum total homocysteine (Hcy) and vascular disease in Asia is limited because few investigations have evaluated the cutpoint of Hcy for predicting the risk of vascular disease and death. Methods and Results: A community-based prospective cohort study of 2,009 participants, who were free from stroke, coronary heart disease (CHD) and cancer at baseline in 1994 were followed up to 2007 (median 11.95 years); there were 114 documented cases of stroke, 95 of CHD and 380 deaths. Cox proportional hazard model was used to examine the association between Hcy and the incidence of stroke, CHD, and all-cause death. The receiver-operating characteristic curve was performed for determining the cutpoint of Hcy in risk prediction. Hcy levels remained significantly associated with cardiovascular events and death in fully adjusted models. Participants with Hcy >9.47 μmol/L (sensitivity 81.1%, specificity 54.3%) had a 2.3-fold risk for cardiovascular events (95% confidence interval (CI), 1.24-4.18, P=0.008), and participants with Hcy >11.84 μmol/L (sensitivity 49.7%, specificity 84.0%) had a 2.4-fold risk for death (95%CI, 1.76-3.32, P<0.0001). Conclusions: Hcy was significantly related to cardiovascular events and all-cause death, with the best cutpoint values as 9.47 and 11.84, respectively. (Circ J 2009; 73: 1423 - 1430)

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Background: Autonomic dysfunction is thought to be an important mechanism of metabolic syndrome (MetS), but there has not been a study on the direct association between MetS and heart rate (HR) in Japanese. Methods and Results: The association between MetS and HR was examined using medical check-up data from 1,880 men and 1,079 women. HR was significantly higher in MetS subjects than in non-MetS subjects in both men and women (P<0.0001 in men, P<0.001 in women). The prevalence of MetS increased linearly through the quartiles of HR in both men and women. HR was significantly correlated with MetS-related risk factors other than uric acid in men and other than uric acid, body mass index, waist circumference, and high-density lipoprotein cholesterol in women. Conclusions: The prevalence of MetS increased linearly with the increase in HR among Japanese men and women, and HR was significantly correlated with MetS-related risk factors. (Circ J 2009; 73: 1431 - 1436)

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Background: It is unclear whether and to what extent there is clustering of cardiovascular risk factors in the prehypertension phase among Mongolians in the rural and animal husbandry area of Inner Mongolia, China. Methods and Results: The 2,589 Mongolian people aged ≥20 years served as subjects. Demographic data, lifestyle factors and family history of hypertension, blood pressure measurements, physical examination and blood samples were obtained and analyzed for all individuals. The proportions of 2 and ≥3 risk factors clustering were higher in hypertensives than in prehypertensives, and higher in prehypertensives than in normotensives (both P<0.01). After adjustment for age, sex and family history of hypertension, both prehypertension and hypertension were associated with mutually clustering of 5 risk factors; odds ratio (OR) of prehypertension with 1, 2 and ≥3 factors was 1.30 (1.02, 1.65), 1.93 (1.40, 2.67) and 2.44 (1.62, 3.68), respectively, and for hypertension the OR were 1.75 (1.31, 2.35), 3.84 (2.68, 5.48) and 6.95 (5.04, 10.63), respectively. Conclusions: There is clustering of risk factors in the phase of prehypertension among Mongolian people, so intervention measures should be taken to prevent progression to hypertension and other cardiovascular diseases. (Circ J 2009; 73: 1437 - 1441)

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Background: Previous studies have demonstrated that renal dysfunction is common in patients with heart failure (HF), but it is not known whether chronic kidney disease (CKD) is associated with increased risks of long-term adverse outcomes in unselected HF patients encountered in current routine clinical practice in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied a broad sample of patients hospitalized with worsening HF and their outcomes with an average of 2.4 years of follow-up. The study cohort (n=2,013) were classified into 3 groups by estimated glomerular filtration rate (eGFR): ≥60 (n=579), 30-59 (n=1,025), and <30 ml · min^-1 · 1.73 m^-2 or patients with dialysis (n=409); 1,372 patients (70.3%) had an eGFR <60 ml · min^-1 · 1.73 m^-2 and 62 patients were treated with dialysis. The multivariable adjusted risk for all-cause death or rehospitalization increased with reduced eGFR; an adjusted hazard ratio (HR) 1.520 (95% confidence interval (CI) 1.186-1.949) for eGFR 30-59 ml · min^-1 · 1.73 m^-2 (P=0.001) and HR 2.566 (95%CI 1.885-3.492) for eGFR <30 ml · min^-1 · 1.73 m^-2 or patients with dialysis (P<0.001). Conclusions: CKD is common in HF and was independently associated with long-term adverse outcomes in a broad cohort of Japanese patients. (Circ J 2009; 73: 1442 - 1447)

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Background: Previous studies have shown a correlation between coronary artery cross-sectional diameter and left ventricular (LV) mass. However, no studies have examined the correlation between actual coronary artery volume (CAV) and LV mass. In the present study, measurements of CAV by 64-multislice computed tomography (MSCT) were validated and the relationship between CAV and LV mass was investigated. Methods and Results: First, coronary artery phantoms consisting of syringes filled with solutions of contrast medium moving at simulated heart rates were scanned by 64-MSCT. Display window settings permitting accurate calculation of small volumes were optimized by evaluating volume-rendered images of the segmented contrast medium at different window settings. Next, 61 patients without significant coronary artery stenosis were scanned by 64-MSCT with the same protocol as for the phantoms. Coronary arteries were segmented on a workstation and the same window settings were applied to the volume-rendered images to calculate total CAV. Significant correlations between total CAV and LV mass (r=0.660, P<0.0001) were found, whereas an inverse relation was present between total CAV per 100 g of LV mass and LV mass. Conclusions: The novel concept of "CAV" for the characterization of coronary arteries may prove useful for future research, particularly on the causes of LV hypertrophy. (Circ J 2009; 73: 1448 - 1453)

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Background: Metabolic syndrome (MetS) is a risk factor and prognosticator for ischemic heart disease, but its actual effect on long-term mortality after acute coronary syndrome (ACS) remains unknown. Methods and Results: All-cause death and cardiovascular death were investigated among patients with ACS upon admission who underwent complete revascularization by either percutaneous coronary intervention or bypass surgery between 1984 and 1992. MetS was defined according to the NCEP/ATPIII criteria modified for waist circumference. From among 1,836 patients who underwent complete revascularization during the study period, 384 (21.0%) with ACS were enrolled, of whom 163 (42.5%) had MetS. During a mean follow-up of 10.4 ±3.4 years, the total number of deaths was 83 (21.6%), of which 38 (9.9%) were from cardiovascular causes. Cox proportional hazard analysis revealed that MetS increased the risk of mortality by a ratio of 1.62 (95% confidence interval (CI) 1.01-2.59, P=0.046) and of cardiovascular death by 2.40 (95%CI 1.16-4.94, P=0.018) in patients with ACS. Conclusions: MetS is a powerful determinant of long-term all-cause and cardiovascular death after ACS. Furthermore, MetS and ACS might jointly exacerbate poor long-term outcomes. (Circ J 2009; 73: 1454 - 1458)

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Background: The prevalence of coronary artery disease (CAD) is increasing in young adults. Risk factor profiling will help to prevent heart attacks in young patients. This study aimed to analyze the risk factor profile and predictors of major cardiovascular events (MACE) in young CAD patients. Methods and Results: From the Coronary REvascularization Demonstrating Outcome study in the Kyoto (CREDO-Kyoto) registry of Japanese patients undergoing their first coronary revascularization, 6,320 patients with complete data for all variables for statistical analyses were divided into younger (≤55 years; n=898; 14.3%) and older (>55 years; n=5,422; 85.7%) patients. The risk factors that were more prevalent in the younger patients than in the older patients included: male sex, body mass index of >25 kg/m², current smoker, family history of CAD, dyslipidemia and metabolic syndrome-like risk factor accumulation. Multivariate analyses revealed that chronic kidney disease (CKD) was the only significant predictor of MACE, the composite of cardiovascular death, myocardial infarction and cerebrovascular accident, in the younger patients. Importance of CKD as a prognostic factor was consistently shown by a multivariate analysis in the older patients. Conclusions: Accumulation of multiple risk factors is prevalent and CKD is associated with MACE in young Japanese CAD patients. (Circ J 2009; 73: 1459 - 1465)

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Background: Virtual histology intravascular ultrasound (VH-IVUS) is used to diagnose coronary plaques and evaluate statin therapy. However, in most cases, quantitative changes in plaques have been evaluated in the chronic stage. We evaluated the quantitative and qualitative early effects of 2 statins on coronary lesions using VH-IVUS. Methods and Results: Patients with acute coronary syndrome who underwent emergency percutaneous coronary intervention (PCI) were randomly assigned to receive pitavastatin (n=80; 2 mg/day) or atorvastatin (n=80; 10 mg/day) immediately after PCI. All patients underwent a blood lipid test and VH-IVUS evaluation of non-PCI lesions at admission and after 2-3 weeks of statin administration. After treatment, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) showed significant decreases to similar levels in each group (P<0.001). In the pitavastatin group, the plaque volume index and fibrofatty volume index (FFVI) also decreased significantly. In patients from the pitavastatin group with a dense calcium ratio of ≤10% (n=61), the percentage changes in FFVI and LDL-C were correlated positively (r=0.305, P=0.017), whereas no significant changes were found after treatment in the atorvastatin group. Conclusions: Fibrofatty composition and plaque volume decreased significantly following treatment with pitavastatin, which suggests that pitavastatin might have a higher affinity for fibrofat compared with atorvastatin. (Circ J 2009; 73: 1466 - 1472)

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Background: Patients with acute myocardial infarction (AMI) whose culprit lesionlies in a branch of the 3 major coronary arteries have well-preserved cardiac function. A first MI with preserved cardiac function is a risk factor for left ventricular free wall rupture (LVFWR), so the aim of this study was to investigate the possible relationship between AMI with branch segment occlusion and LVFWR. Methods and Results: The 439 patients with AMI were retrospectively studied. They were divided into 2 groups: group B (n=70; segments 4 atrioventricular node artery, 4 posterior descending coronary artery, 8, 9, 10, 12, 14, or 15 according to the AHA classification), and group P (n=369; segments 1, 2, 3, 5, 6, 7, 11, or 13). Primary percutaneous coronary intervention (PCI) was more often performed in group P (75% vs 57%; P=0.0018). In-hospital mortality tended to be lower in group B (1.4% vs 6.2%; P=0.105). The incidence of LVFWR was significantly higher in group B (10.0% vs 1.6%; P=0.0002).By multivariate logistic regression analysis, 1-vessel disease, absence of primary PCI, branch segment occlusion, and age were identified as independent predictors of LVFWR. Conclusions: The incidence of LVFWR was higher in group B and branch segment occlusion was identified as an independent predictor of LVFWR. (Circ J 2009; 73: 1473 - 1478)

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Background: The differences between acute coronary syndrome (ACS) and stable angina pectoris (SAP) in Toll-like receptor (TLR) expression levels in coronary plaques are not well known. TLR gene expression levels were examined, not only in peripheral blood mononuclear cells (PBMCs), but also in coronary plaques in ACS and SAP patients. Methods and Results: TLR gene expression levels were examined in PBMCs using real-time RT-PCR in 27 ACS patients, 45 SAP patients and 28 control subjects. TLR2 and TLR4 expression levels in the PBMCs were significantly higher in the ACS group than in the SAP group. TLR9 expression levels were not significantly different among the 3 groups. TLR gene expression levels were also measured in directional coronary atherectomy (DCA) samples from 9 ACS and 14 SAP patients. The TLR2 expression levels in the DCA samples did not significantly differ between the 2 groups. The TLR4 expression levels were significantly higher in the ACS group than in the SAP group. Conclusions: The results suggest that TLR4 signaling could be more associated with plaque destabilization than with plaque progression. TLR4 expression control may be a novel target for ACS treatment. (Circ J 2009; 73: 1479 - 1484)

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Background: High sympathetic tone creates a significant risk for ventricular arrhythmias and sudden death, which can especially affect patients after a myocardial infarction (MI) when exercising in a hypoxic environment. Methods and Results: The 16 patients after MI and 10 normal volunteers (NV) underwent a 1-day trip from low altitude (540 m, Bern) to high altitude (3,564 m Jungfraujoch, Swiss Alps). Autonomic function under resting and mental stress conditions at low and high altitude was assessed. MI patients demonstrated a significantly lower stroke volume (P<0.05) at rest compared with the NV at low as well as high altitude. High altitude exposure was accompanied by higher low-frequency/high-frequency values in the MI patients compared with NV (P<0.01). Following mental stress, MI patients failed to show the normal return to resting values at high altitude, suggesting sustained sympathetic and diminished parasympathetic activation during post-stress recovery. Conclusions: Although all MI patients were either on β-blockers or AII inhibitors, they showed higher sympathetic activity during exposure to high altitude compared with NV. In addition, the respective parasympathetic tone was reduced, especially during recovery. This puts patients after MI at an increased risk for cardiac arrhythmias and they should be advised of this if going to high altitudes. (Circ J 2009; 73: 1485 - 1491)

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Background: MicroRNAs (miRNAs) regulate various biological processes through inhibiting the translation of RNA transcripts. Although miRNA-1 (miR-1) and miRNA-133 (miR-133) are abundantly expressed in the adult heart and involved in cardiac hypertrophy, the roles of these miRNAs in spontaneous myocardial differentiation are unknown. Methods and Results: The levels of miR-1 and miR-133 in mouse embryonic stem (ES) cells were increased during spontaneous differentiation by 2-dimensional culture, but reduced during forced myocardial differentiation by a histone deacetylase inhibitor, trichostatin A. The overexpression of miR-1 or miR-133 by lentiviral infection reduced the expression of a cardiac-specific gene, Nkx2.5, during differentiation of ES cells. In addition, miR-1 also inhibited α-myosin heavy chain expression. The results of luciferase assays revealed that miR-1 recognizes and targets the 3' untranslated region of cyclin-dependent kinase-9 (Cdk9) in ES cells. Overexpression of miR-1 decreased the protein amounts of Cdk9 without affecting the mRNA levels, indicating that miR-1 post-transcriptionally inhibits Cdk9 translation. Conclusions: miR-1 and miR-133 may play significant roles in the myocardial differentiation of mouse ES cells, and Cdk9 may be involved in this process as a target of miR-1. (Circ J 2009; 73: 1492 - 1497)

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Background: The P2Y₁₂ adenosine diphosphate (ADP) receptor blocker, clopidogrel, an essential drug for the prevention of stent thrombosis after percutaneous coronary intervention (PCI), is a prodrug that requires CYP2C19- and CYP3A4-mediating activation. CYP2C19*2 and *3 polymorphisms are known to lack enzymatic activity. CYP2C19 polymorphisms have been reported to exhibit weaker antiplatelet response to clopidogrel in healthy subjects. The effect of polymorphisms of CYP2C19, CYP3A4 and P2Y₁₂ on the antiplatelet effect of clopidogrel in clinical patients was examined in the present study. Methods and Results: Single nucleotide polymorphisms of CYP2C19*2, *3, CYP3A4 (IVS10 +12G>A) and P2Y₁₂ (T744C) were determined in 25 PCI-scheduled patients who had been systematically analyzed for the antiplatelet effect of clopidogrel in a previous study. On the basis of CYP2C19 genotype, 11 patients (44%) were classified as extensive metabolizers (EMs), 8 (32%) as intermediate metabolizers (IMs) and 6 (24%) as poor metabolizers (PMs). The rates of inhibition of 5 μmol/L ADP-induced platelet aggregation by clopidogrel intake at 48 h were 31.6 ±14.3% in EMs, 18.4 ±10.0% in IMs (P=0.04 vs EMs) and 16.0 ±13.0% in PMs (P=0.02 vs EMs). Conclusions: CYP2C19 polymorphisms are frequent in Japanese, and the antiplatelet effect of clopidogrel is strongly affected by them in the real-world clinical setting. (Circ J 2009; 73: 1498 - 1503)

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Background: The renin-angiotensin-aldosterone system affects cellular morphology and function in the heart under a variety of pathologic conditions. In the present study the effects of aldosterone on the expression of connexin (Cx) 43 gap junctions in cardiomyocytes were investigated. Methods and Results: Cultured rat ventricular myocytes were exposed to aldosterone for 24 h. The protein and mRNA expression of Cx43 was estimated. Propagation of excitation was visualized by a multiple electrode array system. Treatment of the myocytes with 10^-8 mol/L aldosterone resulted in a significant upregulation of Cx43 (by ~1.5-fold in protein and by ~1.2-fold in mRNA). The immunoreactive signal of Cx43 was also increased. Conduction velocity (CV) was increased by ~24%. Treatment of the myocytes with aldosterone at higher concentrations (10^-6-10^-4 mol/L) caused a significant downregulation of Cx43 protein (by ~0.3-fold) without affecting Cx43 mRNA levels, and decreased the CV by ~23%. The Cx43 upregulation and CV acceleration at 10^-8 mol/L aldosterone were prevented by pretreatment with eplerenone, but unaffected by mifepristone. Pretreatment of the myocytes with eplerenone or mifepristone did not prevent the Cx43 downregulation by aldosterone at 10^-6-10^-4 mol/L. Conclusions: Aldosterone may be involved in arrhythmogenic gap junction remodeling through its dual effects on the expression of Cx43. (Circ J 2009; 73: 1504 - 1512)

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Background: The aim of this study was to clarify the incidence and clinical predictors of deep vein thrombosis (DVT) in patients with congestive heart failure (CHF) in Japan. Methods and Results: Between January 2003 and January 2008, 161 patients were admitted to Mie University Hospital with a diagnosis of CHF and underwent venous compression ultrasonography. Of them, 18 patients (11.2%) were diagnosed with DVT. As defined by New York Heart Association (NYHA) functional class, class IV patients had a higher incidence rate of DVT than those in class II or III (class II: 3 patients (4.4%), class III: 2 patients (4.8%), class IV: 13 patients (25.5%), P<0.01). Multiple logistic regression analysis identified that NYHA functional class and poor collapsibility of the inferior vena cava on ultrasonography as independent predictors of DVT (odds ratios (OR) 3.74, 95% confidence interval (CI) 1.72-8.16, P<0.01 and OR 4.43, 95%CI 1.36-14.43, P<0.05, respectively). Therapy without anticoagulation also indicated a significant increase in DVT incidence in CHF patients (OR 3.71, 95%CI 1.13-12.18, P<0.05). Conclusions: Patients with CHF have a high risk for DVT and the risk increases according to NYHA functional class, poor IVC collapsibility or therapy without anticoagulation. (Circ J 2009; 73: 1513 - 1517)

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Background: Contrast-induced nephropathy (CIN) is the third leading cause of all hospital-acquired renal insufficiency, accounting for 10%, and is associated with increased long-term mortality. The incidence of and risk factors for CIN after cardiac catheterization in Japanese patients are, however, unknown at present. Methods and Results: The 1,157 consecutive patients who underwent cardiac catheterization at Kyoto University Hospital from January 2003 to December 2004 were retrospectively examined. The incidence of CIN defined as an absolute increase in serum creatinine (SCr) ≥0.5 mg/dl, a relative ≥25% increase in SCr, and either an absolute or relative increase after cardiac catheterization were 4.0%, 13.8%, and 13.9%, respectively. Multivariate logistic models revealed that preexisting renal insufficiency and the use of high-volume contrast were independently associated with an absolute increase in SCr ≥0.5 mg/dl. Female gender, underweight, and high-volume contrast usage were independently associated with a relative ≥25% increase and either an absolute or relative increase in SCr. Conclusions: Although the incidence of and risk factors for CIN after cardiac catheterization varied in the study population according to the definition of CIN, careful attention should be paid to patients who have risk factors identified by each definition of CIN. (Circ J 2009; 73: 1518 - 1522)

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Background: Because postprandial hypertriglyceridemia and hyperglycemia may promote atherosclerosis, the present study investigated the effects of a clinical dose of pitavastatin on endothelial function and blood rheology in patients with coronary artery disease (CAD) before and after eating a test meal. Methods and Results: The 16 patients with stable CAD and mild dyslipidemia and 6 age-matched healthy men as controls were recruited. In each group, forearm blood flow (FBF) was measured during postischemic reactive hyperemia and blood samples were taken before and 2 h after the test meal. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also measured. The patients were started on pitavastatin 2 mg/day. The tests were repeated after 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in CAD patients than in control subjects (P=0.040). Fasting and postprandial FBF during reactive hyperemia significantly improved after pitavastatin treatment (P<0.05 vs baseline data for each phase) associated with reduced urine 8-OHdG, increased plasma adiponectin and improved lipid profile. No significant differences in baseline rheological parameters were seen between controls and CAD patients. Conclusions: Pitavastatin significantly improved fasting and postprandial dyslipidemia and endothelial dysfunction in CAD patients, partly via reducing oxidative stress and increasing plasma adiponectin, although rheological parameters remained unchanged. (Circ J 2009; 73: 1523 - 1530)

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Background: Interleukin (IL)-β plays a central role in inflammation and atherosclerosis, but levels of IL-1β, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism would increase the understanding of atherosclerosis pathogenesis. Methods and Results: Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1β, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1β, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1β levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area. Conclusions: Activation of innate immunity changed the balance between IL-1β and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1β ratio, was associated with reduced coronary atherosclerosis. (Circ J 2009; 73: 1531 - 1536)

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Background: Exposure to active and passive smoking is associated with arterial stiffness and cotinine is an objective biochemical indicator to classify smoking state. The aim of the study was to survey participant smoking condition with cotinine in North China and discuss its destructive effect on arterial stiffness. Methods and Results: Nine hundred and six people were recruited in this study and were classified into non-smokers, passive smokers and active smokers according to the cotinine level. Brachial-ankle pulse wave velocity (baPWV) was measured using an automatic device. Active smokers vs non-smokers showed a significantly higher baPWV (P=0.023) after adjusting for covariates. Participants who smoked longer than 10 years had a higher baPWV than non-smokers (P=0.029) although no significant difference existed between those who had a smoking history of less than 10 years and those who had never smoked. In less developed areas, the active and passive smoking rates were higher than that in Beijing (P<0.001) while active smokers vs non-smokers had a higher baPWV (P=0.017). Conclusions: Active smokers, as confirmed by the cotinine level have worse arterial stiffness, and long-term smoking can cause marked arterial stiffness. Smoking exposure might bring about more serious effects on arterial function in patients from poor areas than in modernized cities. (Circ J 2009; 73: 1537 - 1542)

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A case is presented of initially unrecognized takotsubo cardiomyopathy with a dramatic clinical course after emergency catecholamine treatment for circulatory support during stress-induced cardiac syncope followed by complete recovery of cardiac function after catecholamine withdrawal and starting β-blocker therapy. Echocardiography including 2D-strain imaging suggested that the left ventricle (LV) wall motion abnormality was mainly the consequence of geometry-induced regional differences in wall stress (progressively amplified by catecholamines), which might be another possible pathophysiological mechanism involved in the development of LV dysfunction in tako-tsubo cardiomyopathy. This case also suggests that in emergency, before coronary angiography is possible, echocardiography can be helpful for initial therapeutic decisions, especially to avoid emergency inotropic therapy in such patients. (Circ J 2009; 73: 1543 - 1546)

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Primary sarcomas of the pulmonary vein are extremely rare. Although myxomas are the most common intracavitary tumor of the left atrium, some findings should alert the clinician to the probability of malignancy. A 28-year-old woman developed hemoptysis, night fever, generalized malaise, anorexia and weight loss for 2 months, with progressive dyspnea for 2 weeks. She was preoperatively diagnosed as left atrial myxoma with a concurrent right lower lung tumor. (Circ J 2009; 73: 1547 - 1549)

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Cardiac resynchronization therapy (CRT) assists patients with advanced heart failure (HF) by improving left ventricular (LV) dyssynchrony, but there are significant numbers of non-responders, 1 reason being that the QRS duration is used as the only surrogate determinant of mechanical dyssynchrony, so an effective indicator of LV dyssynchrony is required. The present patient, who had HF, underwent CRT and showed clinical improvement with marked LV reverse remodeling. The regional contraction timing in the LV was assessed with software developed in an application on ECG-gated SPECT myocardial perfusion imaging that depicts the time-volume relationship of the segmented ventricular myocardium and the dispersion of time to end-systole as an expression of dyssynchrony. It was reduced in this patient following CRT. Discordance of systole in regional myocardial segments may present as mechanical dyssynchrony in the LV and could be used as an alternative to QRS duration. Quantitative assessment of dyssynchrony may be possible using this novel method, but further evaluation of the methodology is required. (Circ J 2009; 73: 1550 - 1553)

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Carcinoid tumors usually originate in the gastrointestinal tract, but in rare instances they may arise in other organs. A patient with severe tricuspid and pulmonary regurgitation because of carcinoid syndrome successfully underwent double valve replacement using bioprostheses. The patient was finally diagnosed with carcinoid heart disease from an isolated ovarian carcinoid cancer. The diagnosis of carcinoid syndrome should be recognized as an etiology in patients with organic tricuspid and pulmonary regurgitation without left valvular disease. (Circ J 2009; 73: 1554-1556)

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