Background The Jervell and Lange-Nielsen (JLN) syndrome is a variant of long QT syndromes (LQTS) and is associated with congenital deafness. The syndrome is caused by homozygous or compound heterozygous mutations in genes KCNQ1 and KCNE1, which are responsible for encoding the delayed rectifier repolarizing current, I_Ks. Methods and Results A novel and homozygous KCNQ1 mutation in a 23-year-old deaf woman with a prolonged QT interval and recurrent syncope in a Japanese family was identified. Genetic analyses revealed that the proband harbored a KCNQ1 missense mutation (W248F) located in the intracellular S4-S5 linker on both alleles. The same mutation was identified in both maternal and paternal families in a heterozygous manner. However, the family members of both sides had no clinical evidence of LQTS or hearing defects. Functional assays using a heterologous expression system revealed that W248F KCNQ1 plus KCNE1 channels reconstitute hardly measurable I_Ks currents. In contrast, heterozygous wild-type/W248F KCNQ1 plus KCNE1 channels displayed biophysical properties similar to those of the wild-type KCNQ1 plus KCNE1 channels with a weak dominant-negative effect. Conclusion In this study, we present a family with JLN syndrome. The electrophysiological properties of the mutant I_Ks channels explain the pathophysiology underlying JLNS. (Circ J 2008; 72: 687 - 693)

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Background In the LQT2 form of long QT syndrome (LQTS), mutation sites are reported to correlate with clinical phenotypes in Caucasians, but the relationship in Asian patients remains unknown. The present study was designed to determine whether the location of KCNH2 mutations would influence the arrhythmic risk in LQT2 patients. Methods and Results In 118 genetically-confirmed LQT2 patients (69 families, 62 KCNH2 mutations), the ECG parameters, Schwartz scores, and the incidence of cardiac events, defined as syncope, aborted cardiac arrest, and sudden cardiac death, were evaluated. To examine the effect of mutation sites, the participants were divided accordingly: pore (n=56) and non-pore (n=62) groups. The corrected QT_end interval was significantly greater in the pore than in the non-pore group (QTc; 522±63 ms vs 490±49 ms, p=0.002). In this study, the clinical course of each of the probands did not differ according to the mutation sites, whereas non-probands carrying the pore site mutation experienced their first cardiac events at significantly younger age than those with the non-pore site mutation (log-rank, p=0.0005). Conclusions In a Japanese LQT2 cohort, family members with the pore site mutation were at higher arrhythmic risk than those with the non-pore site mutation. (Circ J 2008; 72: 694 - 699)

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Background Several preliminary studies have indicated that atrial pacing can prevent atrial tachyarrhythmias. The suggested mechanisms by which pacing may be effective include suppression of premature atrial beats. Methods and Results The Atrial Pacing Preference^TM (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. The preventive effects of APP on paroxysmal atrial fibrillation (AF) were studied in 51 patients (70±11 years). Nine patients did not complete the protocol. The pacemaker was programmed in random order to APP off and APP on at 3 different settings (ie, 8, 16 and 32 cycles) for 4 weeks each, using a cross-over design. Percentage atrial pacing was lower in APP off than at the other settings. Premature beat counts were greater in APP off than at the other settings. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818±15,356 vs 596±1,719; p<0.01). Conclusions The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. Optimizing the setting of the APP algorithm is an important issue in the prevention of AF. (Circ J 2008; 72: 700 - 704)

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Background Atrial fibrillation (AF) is a very common cardiac arrhythmia, and is associated with an increased mortality in patients with hypertension. Whether the best therapeutic approach for these patients is to restore sinus rhythm (SR) or to adequately control the ventricular rate is still controversial. The aim of this study is to compare both strategies in patients with hypertension. Methods and Results Two hundred and twenty-one patients with hypertension and AF of duration >48 h were randomly assigned to either the rhythm (n=155) or rate (n=66) control group. Exercise capacity was improved in the rhythm control group in the 1^st year of the study (p<0.0001). There were no statistically significant differences in the embolic event rate and the total mortality between the 2 groups at the end of the study (p=NS). Conclusions Although restoring and maintaining SR had a beneficial effect on exercise capacity in patients with hypertension and AF, no significant difference was found in terms of the total mortality and the embolic event rates. Thus, rate control is an acceptable primary strategy in patients with AF and hypertension. (Circ J 2008; 72: 705 -708)

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Background It has been reported that bepridil is as good as amiodarone in converting persistent atrial fibrillation (AF) to sinus rhythm (SR). The conversion effect of bepridil alone is not always satisfactory, however. The efficacy of pharmacological cardioversion by the combination of bepridil and a class Ic antiarrhythmic drug for persistent AF is studied. Methods and Results The participants comprised 37 consecutive patients in whom pharmacological cardioversion was conducted to treat persistent AF (duration 22.5±29.6 months). Each patient first received a class Ia or Ic antiarrhythmic drug, then bepridil alone, then a combined therapy of bepridil at 200 mg/day with a class Ic antiarrhythmic drug at a routine dose. Unaccompanied use of any of the antiarrhythmic drugs achieved pharmacological cardioversion in 14 (38%) of the 37 patients (single therapy group), whereas SR was restored by combination of bepridil and a class Ic antiarrhythmic drug in 22 (combined therapy group) of the remaining 23 patients. The duration of AF was significantly longer in the combined therapy group than in the single therapy group (28.3±31.0 vs 7.3±4.1 months). Conclusion Combined therapy of bepridil and a class Ic antiarrhythmic drug is efficient for pharmacological cardioversion of refractory long-lasting persistent AF. (Circ J 2008; 72: 709 - 715)

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Background The aim of the study was to identify clinical factors, angiographic findings, and procedural features that predict no-reflow phenomenon (Thrombolysis In Myocardial Infarction (TIMI) flow grade ≤2) in patients with acute myocardial infarction (AMI) who undergo primary percutaneous coronary intervention (PCI). Methods and Results A series of 382 consecutive patients with AMI underwent primary PCI within 12 h of symptom onset. Patients with ischemic symptoms continuing for more than 12 h were also included. Clinical, angiographic and procedural data were collected for each subject. Ninety-three (24.3%) of the patients developed no-reflow phenomenon, and their findings were compared with those of the reflow group. Univariate analysis showed that advanced age (>60 years), delayed reperfusion (≥4 h), low (≤1) TIMI flow prior to PCI, cut-off type total occlusion, high thrombus burden on baseline angiography, long target lesion (>13.5 mm) and large vessel diameter all correlated with no-reflow (p<0.05 for all). Multiple logistic regression analysis identified that advanced age (odds ratio (OR) 1.04, p=0.001), delayed reperfusion (OR 1.4, p=0.0004), low TIMI flow before primary PCI (OR 1.1, p=0.0002), target lesion length (OR 5.1, p=0.0003) and high thrombus burden (OR 1.6, p=0.03) on angiography as independent predictors of no-reflow phenomenon. Conclusion The occurrence of no-reflow phenomenon after primary PCI can be predicted using simple clinical, angiographic and procedural features. In this selected group of patients, adjunctive pharmacotherapy and/or distal protection device may be of value. (Circ J 2008; 72: 716 - 721)

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Background The present study was designed to test the hypothesis that fluvastatin might improve arterial stiffness, as assessed with pulse wave velocity (PWV), in patients with coronary artery disease (CAD) and hyperlipidemia over the long term. Methods and Results Ninety-three patients were randomly assigned to either fluvastatin (group A, n=50) or bezafibrate (group B, n=43) and followed for 5 years. There was no difference in the clinical findings between the 2 groups. In group A, there was a progressive reduction in the brachial-ankle PWV along with a decrease in serum low-density lipoprotein-cholesterol (LDL-C) and C-reactive protein (CRP) by 12 months after fluvastatin, and the improvement was maintained until 5 years after treatment. In group B, despite identical lowering of the serum lipid, PWV was progressively increased. In group A, the percentage change in PWV correlated significantly with that of the serum CRP (r=0.49, p<0.001), but not with that of the serum LDL-C after treatment. Conclusions The beneficial vascular effects of fluvastatin persisted for a long period in patients with CAD and hyperlipidemia. Its anti-inflammatory action might contribute to the favorable effects on arterial stiffness. (Circ J 2008; 72: 722 - 728)

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Background Restenosis after percutaneous coronary angioplasty remains an important limitation of this procedure. This study evaluates the association between plasma pregnancy-associated plasma protein A (PAPP-A) levels and restenosis after coronary angioplasty. Methods and Results Blood samples were collected from all patients at baseline, and their levels of PAPP-A, inflammation (high-sensitivity C-reactive protein (hsCRP)) and platelet activation (soluble CD40 ligand (sCD40L)) were determined. Those patients whose PCI was successful underwent a repeat angiography at a median of 6.4 months (interquartile range 6-9.8 months). Their baseline and follow-up angiograms were compared by quantitative coronary angiography to assess the incidence of restenosis. Endpoints were restenosis (≥50%) and a composite of major adverse cardiac events. Of the 184 patients, 162 patients underwent an angiographic follow up at 6 months. Patients with restenosis had significantly higher PAPP-A levels than those without (19.24±2.56 vs 11.95±2.32 mIu/L; p<0.001). The PAPP-A levels were significantly correlated to follow up diameter stenosis (r=0.54, p=0.01). Late lumen loss at follow-up was significantly smaller when PAPP-A levels were <12.51 mIu/L (0.55±0.61 vs 0.90±0.57 mm; p<0.001). The rates for restenosis (28.4 vs 50.6%; p<0.001) and major advent cardiac events (15.6 vs 51.1%, p<0.001) were significantly lower in patients with PAPP-A levels <12.51 mIu/L. Univariate analysis revealed that PAPP-A (p<0.001), hsCRP (p=0.009) and sCD40L (p=0.03) were significantly related to restenosis. However, only PAPP-A could predict restenosis (odds ratio 0.95; 95% confidence interval 0.84-1.13; p=0.02) in multivariate analysis. Conclusions The PAPP-A level is a strong independent predictor of restenosis in patients who have undergone coronary angioplasty. (Circ J 2008; 72: 729 - 733)

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Background Percutaneous peripheral intervention (PPI) for superficial femoral artery (SFA) stenosis is associated with a high restenosis rate. Whether PPI improves the long-term outcome of patients with SFA occlusive disease remains to be determined. Methods and Results A review was done of 107 patients with SFA occlusive disease. Fifty-five patients received PPI for SFA (ie, PPI group) and 52 patients received conservative medical therapy (ie, control group). Clinical records were searched for adverse events (eg, death, limb amputation, re-hospitalization, new onset of coronary artery disease and cerebrovascular disease) for an average of 30.6±17.7 months. At follow-up, only 5 patients (9.1%) in the PPI group experienced improved limb symptoms compared with baseline, and 6 patients (10.9%) showed ischemic skin ulcer or gangrene. In addition, 2 of these 6 patients were unsuccessful PPI cases complicated with distal embolization and perforation. In the control group, 3 patients (5.8%) presented with improved limb symptoms, and an equal number of patients had worsening of symptoms. Although 2 patients showed ischemic skin ulcers at follow-up, both patients had these lesions at baseline. Adverse events were observed more frequently in the PPI group than the control group (69.1% vs 46.2%, p<0.05). This was mainly due to a higher frequency of re-hospitalization in the PPI group than in controls (52.7% vs 15.4%, p<0.001). Conclusions The current study demonstrates that PPI for patients with SFA occlusive disease does not provide superior long-term benefits compared with conservative medical therapy, and that medical therapy will continue to remain the primary treatment strategy for this group of patients. (Circ J 2008; 72: 734 - 739)

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Background In patients with chronic heart failure (CHF), it remains unclear whether perindopril is more cardioprotective than enalapril. Methods and Results Forty-five stable CHF outpatients undergoing conventional therapy including enalapril therapy were randomized to 2 groups [group I (n=24): continuous enalapril treatment; group II (n=21): enalapril was changed to perindopril]. Cardiac sympathetic nerve activity was evaluated using cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, hemodynamic parameters and neurohumoral factors before and 6 months after treatment. There was no difference in baseline characteristics between the 2 groups. In group I, there were no changes in MIBG parameters, left ventricular ejection fraction (LVEF) or plasma level of brain natriuretic peptide (BNP). In contrast, in group II the delayed heart/mediastinum count ratio was significantly increased (2.0±0.07 vs 2.15±0.07, p=0.013) and the washout rate was significantly decreased (33.0±1.4 vs 30.5±1.2, p=0.030) after 6 months compared with the baseline value. In addition, LVEF was significantly increased and the plasma BNP level was significantly decreased. Conclusion These findings suggest that for the treatment of CHF, perindopril is superior to enalapril with respect of cardiac sympathetic nerve activity and BNP. (Circ J 2008; 72: 740 - 746)

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Background Right heart failure is a major problem of young adults with congenital heart disease (ACHD) that has been corrected by cardiac surgery. In left ventricular dysfunction (LVD), β-blocker therapy improved cytokine concentrations and clinical status. Thus, the effect of bisoprolol on clinical status and plasma cytokine concentrations in ACHD patients with right heart failure after surgical correction for Tetralogy of Fallot was investigated. Methods and Results A prospective, randomized, double-blind, placebo controlled study for a duration of 6 months was carried out. A total of 34 patients (30.9±9.5 years; New York Heart Association I or II) with brain natriuretic peptide plasma concentrations >100 pg/ml and peak oxygen uptake <25 ml · kg^-1 ·min^-1 were recruited. Bisoprolol did not reduce plasma concentrations of soluble tumor necrosis factor receptors (sTNF-R) and interleukin-6 (IL-6) in ACHD patients (before/after: sTNF-R1: 750±131/802±130; sTNF-R2: 3,693±1,043/4,166±840; IL-6: 12.94±26.03/13.69±16.58 pg/ml). Likewise, peak oxygen uptake, right and left ventricular parameters (determined by magnetic resonance imaging) were not improved by bisoprolol treatment. Conclusion In contrast to previously observed beneficial effect(s) of β-blockade in patients with LVD, there were no beneficial therapeutic effects or cytokine reduction in asymptomatic or minimal symptomatic ACHD patients. These data point to a different pathophysiological role of cytokines in ACHD patients with right ventricular dysfunction, as compared to patients with LVD. (Circ J 2008; 72: 747 - 752)

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Background Although pulmonary thromboembolism (PTE) has been considered relatively uncommon in Japan, its incidence has been on the increase in recent years. Methods and Results To verify the incidence of PTE in Japan, PTE cases of obstetrics and gynecology were investigated among 102 facilities throughout Japan between 1991 and 2000. A total of 254 cases were enrolled, showing a 6.5-fold increase over the past 10 years. PTE occurred in 0.02% of total births; 0.003% after vaginal deliveries and 0.06% after cesarean births (C/S), of which 14.5% resulting in fatality. The mortality rate was 2.5 per 100,000 deliveries. The incidences among gynecological cases were 0.08% of total operations; 0.03% in benign diseases and 0.42% in malignant diseases of which 13.5% resulting in fatality. The mortality rate was 10.8 per 100,000 operations. The risk was 22 times higher in C/S compared with vaginal deliveries, 16 times higher in malignant diseases compared with benign diseases. Conclusions As our present survey has shown, PTE has been on the rise in Japan in recent years. C/S and malignant diseases are strong risk factors in obstetrics and gynecology. (Circ J 2008; 72: 753 - 756)

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Background Epidemiological studies have demonstrated the association between low birth weight and increased adulthood risk for cardiovascular and metabolic diseases. However, the precise mechanism underlying the association remains poorly understood. We investigated the association between birth weight and adult white blood cell (WBC) count in a Japanese population. Methods and Results The subjects were 779 men and 209 women aged 35-64 years. The mean WBC count was 5,283 /μl (SD: 1,326). Birth weight was divided to 6 categories: <2,500, 2,500-<2,800, 2,800-<3,000, 3,000-<3,200, 3,200-<3,500, and >3,500 g. Estimated WBC counts were 5,729, 5,341, 5,301, 5,212, 5,013 and 5,372 for the subjects with birth weights of the above respective categories (p=0.015, trend p=0.016) by one-way analysis of covariance after adjustments for sex, age, height, body mass index (BMI), lifestyles, and chronic diseases. This association was pronounced among the subjects with a BMI <25.0 kg/m² rather than those with a higher BMI. Conclusions These findings support the idea that part of the association of low birth weight with elevated risk for vascular and metabolic diseases in later life could be mediated by an inflammatory pathway. (Circ J 2008; 72: 757 - 763)

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Background The aim of the study was to evaluate whether the combined treatment of calcium channel blocker, amlodipine and β-blocker, betaxolol, favorably affects cardiac autonomic nervous activity (CANA) and health-related quality of life (HRQL). Methods and Results A total of 65 patients with a poor blood pressure (BP) control with a low dose amlodipine therapy were randomly assigned to the amlodipine dose-up group (n=21) and betaxolol adding group (n=44). Before and after a 6-month treatment, BP, heart rate variability (HRV), HRQL and blood chemistries were evaluated. Low frequency (LF) spectra/high frequency (HF) spectra and HF/total power spectra (TP) were calculated as indexes of CANA, and HRQL was assessed by the questionnaire sheets. BP was well controlled in all patients of the present study. In the betaxolol adding group, LF/HF decreased (2.1±1.9 to 1.3±0.9, p<0.05) and HF/TP reciprocally increased (0.41±0.17 to 0.52±0.18, p<0.05), whereas the amlodipine dose-up group showed no significant changes in the HRV. HRQL was significantly improved in the betaxolol adding group, whereas it remained unchanged in the amlodipine dose-up group. Blood chemistries remained unchanged except for the slightly increased plasma brain natriuretic peptide concentrations in the betaxolol adding group (36±47 to 62±62 pg/ml, p<0.05). Conclusions Combined treatment of amlodipine and betaxolol appears to be more useful than amlodipine dose-up therapy, because combined treatment improves CANA and HRQL. (Circ J 2008; 72: 764 - 769)

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Background Recent studies suggest that B-type natriuretic peptide (BNP) is an important predictor of cardiac events in hypertensive patients. Methods and Results The relationship between the plasma BNP level and various clinical parameters was examined in 154 untreated hypertensive patients without heart failure or atrial fibrillation (mean age: 58.0±10.7; mean blood pressure: 164.5±15.2/99.1±9.7 mmHg; mean BNP: 32.7±36.7 pg/ml). First, the patients were divided into 2 groups based on BNP: normal (<18.5 pg/ml, mean 9.7±5.7, n=69); or elevated (>18.5 pg/ml, mean 51.4±40.4, n=85). The elevated BNP group had a significantly greater electrocardiographic voltage index (SV₁+RV₅; 3.7±1.2 vs 3.2±0.8 mV, p=0.0029), cardiothoracic ratio/chest radiography (CTR; 49.1 vs 46.9%, p=0.0037), left ventricular mass index (LVMI; 122.2±31.7 vs 103.1±26.4 g/m², p=0.0005) and deceleration time (DT; 241±39 vs 208±30 ms, p=0.0001), as well as a smaller E-wave to A-wave (E/A ratio) (0.80±0.22 vs 0.96±0.28, p=0.0003), compared with the normal BNP group. There were no significant differences in casual blood pressure, body mass index, serum creatinine and ejection fraction between the 2 groups. Next, the patients were divided into 3 groups based on BNP: normal (<18.5, n=69), moderate (18.5 to 40, mean 27.0±5.7, n=43) and high (40<, mean 76.3±45.3, n=42). In the high BNP group, most clinical parameters indicated the most severe organ damage compared with other groups, including SV₁+RV₅, DT and LVMI. In all patients, logarithmic BNP was positively correlated with the age, pulse pressure, SV₁+RV₅, CTR, ventricular wall thickness, DT, LVMI and negatively correlated with hemoglobin, renin and E/A ratio. Using multiple regression analysis, renin and DT were significantly associated with BNP. No gender differences in the relationship between BNP and clinical parameters were found. Conclusions Results suggest that BNP is a useful indicator for the initial assessment of the severity of essential hypertension, detecting both cardiac hypertrophy and diastolic dysfunction, and may also be valuable for risk stratification. (Circ J 2008; 72: 770 - 777)

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Background Coronary calcification has been correlated with the presence and extent of coronary artery disease (CAD), so in the present study the associations between coronary artery calcification score (CACS) and endothelial dysfunction, as well as the important inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and oxidized low-density lipoprotein (OxLDL), were studied in asymptomatic individuals at intermediate risk for CAD. Methods and Results The study group comprised 177 subjects (103 males) aged 50.6±5.9 years. CACS was measured by multidetector computed tomography using the Agatston method. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent nitroglycerin-mediated dilatation (NMD) were measured by high-resolution external brachial ultrasound. Coronary artery calcification (CAC) was detected in 82 subjects (52 males), and the median CACS was 143 [31-311.25] units. After adjusting for gender and body mass index, log (CACS +1) correlated positively with age (r=0.401, p<0.001) and IL-6 levels (r=0.442, p<0.001), and negatively with FMD (r=-0.511, p<0.001). The correlations of log (CACS +1) with CRP and OxLDL levels, and with NMD, were non-significant. In a multivariate-adjusted logistic regression model, age (odds ratio (OR) =1.083 [1.014-1.156]), serum IL-6 level (OR=3.837 [2.166-6.798]) and FMD (OR=0.851 [0.793-0.913]) were significantly and independently associated with CAC. Conclusions Peripheral endothelial function inversely correlated with CACS, whereas IL-6 level was associated with CACS. Testing for endothelial function and IL-6 level may improve cardiovascular risk assessment and help target the therapeutic strategies in asymptomatic patients at intermediate CAD risk. (Circ J 2008; 72: 778 - 785)

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Background The ¹¹C-acetate positron emission tomography can estimate myocardial oxidative metabolism, but previous studies have only evaluated small populations and the difference between ischemic (ICM) and idiopathic dilated cardiomyopathy (DCM) has not been fully investigated. The present aims were to evaluate global and regional myocardial oxidative metabolism in a well-characterized, large population with left ventricular (LV) dysfunction in order to clarify the metabolic differences between ICM and DCM. Methods and Results Seventy-eight patients with ejection fraction (EF) ≤50% (33 ICM; 45 DCM) were compared with 14 healthy controls. Myocardial oxidative metabolism was estimated with a clearance rate constant (K_mono) and the coefficient of variation (CV) of regional K_mono. Patients with LV dysfunction had reduced K_mono and higher CV (p<0.05). In the comparison of oxidative alterations with clinical variables there was a weak correlation between K_mono and LVEF (r=0.27). Although K_mono was reduced in both ICM and DCM, CV was more pronouncedly increased in ICM (p=0.001). In multivariate analysis, the presence of left bundle branch block (LBBB) was an independent predictor of heterogeneous oxidative metabolism in DCM (R²=0.30, p<0.0001). Conclusions Global reduction of myocardial oxidative metabolism occurred in both ICM and DCM. Heterogeneous oxidative metabolism was observed in these patients, especially those with ICM. Furthermore, LBBB was the independent predictor of heterogeneous oxidative metabolism in patients with DCM. (Circ J 2008; 72: 786 - 792)

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Background Experimental and clinical evidence have recently shown that pluripotent stem cells can be mobilized using granulocyte-colony stimulating factor (GCSF) and may enhance myocardial regeneration after acute myocardial infarction (MI). The present study investigated the pharmacological role of angiotensin-converting enzyme inhibition on cardiac regeneration after MI using a mouse model of heterotopic cardiac transplantation and coronary ligation. Methods and Results Isogenic heterotopic cardiac transplantations and simultaneous coronary ligations were performed in green fluorescent protein (GFP) mice to produce MI in the donor heart. Five mice in the ligation group were treated with oral perindopril (PE) after the operation. Three mice in the ligation group were treated with subcutaneous GCSF and 4 angiotensin II type1a receptor knockout (AT1aRKO) mice were used as well. At 60 days after the operation, the maximum GFP-positive cell counts in the GCSF group were significantly higher than in the other 4 groups. The maximum GFP-positive cell counts in both the AT1aRKO and ligation & PE groups were significantly higher than in the sham and ligation groups. Conclusions Pharmacological modification for cardiac regeneration may provide an alternative treatment for subsequent cardiac remodeling in the late phase of MI. (Circ J 2008; 72: 793 -799)

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Background Atherosclerosis is a progressing inflammatory response mediated by various signaling molecules among which nuclear factor κB (NF-κB) is thought to have a pivotal role. This study demonstrated the efficacy of antioxidant MCI-186 in preventing the progression of atherosclerosis by inhibiting signaling molecules such as NF-κB. Methods and Results Balloon injury of intima was performed in the right common carotid artery of Japanese male white rabbits, which were then fed a 1% high cholesterol diet for 4 weeks, after assigning them to either the control (n=7) or MCI-186 (0.5 mg ·kg^-1 · day^-1, n=7) group. Histological analysis revealed a reduction in neointimal thickness and lipid deposition in the subendothelial area of the MCI-186 group. Immunohistochemical analysis revealed attenuation of E-selectin expression, macrophage migration and proliferation of smooth muscle cells in the MCI-186 treated group. In in vitro studies, rabbit aorta smooth muscle cells were incubated with rIL-1βin either the presence or absence of MCI-186. MCI-186 significantly inhibited rIL-1β-induced proliferation of smooth muscle cells from rabbit aorta, as well as the activation of NF-κB. Moreover, western blot analysis showed the inhibitory action of MCI-186 on the nuclear translocation of NF-κB in human umbilical vein endothelial cells under rIL-1βstimulation. Conclusions MCI-186 could provide a novel therapeutic strategy for atherosclerosis by inhibiting the NF-κB pathway. (Circ J 2008; 72: 800 - 806)

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Background Bone morphogenetic protein-2 (BMP-2) plays a key role both in vascular development and pathophysiological processes. However, the effects of oxidized low-density lipoprotein (ox-LDL) combined with atorvastatin on BMP-2 expression are entirely unknown in human umbilical vein endothelial cells (HUVECs). The present study investigates the effects of ox-LDL on BMP-2 expression. Furthermore, the influence of atorvastatin on ox-LDL-induced BMP-2 expression is also examined. Methods and Results The HUVECs were treated by ox-LDL or combined with pyrrolidine dithiocarbamate (PDTC) or atorvastatin. The expression level of BMP-2 mRNA was examined by real-time PCR and RT-PCR analysis. The expression of BMP-2 protein was assayed by enzyme-linked immunosorbent assay. The malondialdehyde (MDA) and activities of total superoxide dismutase (SOD) were detected by routine methods. The activation of nuclear factor κB (NF-κB) in HUVECs was determined using an assay kit from active motif and western blot analysis. Ox-LDL treatment significantly increased BMP-2 expression, which is associated with NF-κB activation, but BMP-2 expression was suppressed by treatment with PDTC or atorvastatin. Furthermore, the increase in MDA levels and decrease in activities of total SOD caused by ox-LDL treatment were reversed by the treatment of PDTC or atorvastatin. Conclusions Ox-LDL-induced BMP-2 expression was suppressed by PDTC or atorvastatin treatment. The effects of atorvastatin might contribute to the mechanisms by inhibiting NF-κB activation. (Circ J 2008; 72: 807 - 812)

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Background T-helper (Th)1/Th2 cytokine balance plays an important role in the pathogenesis of myocarditis. Recently, some studies indicate that interleukin (IL)-17, known as a T cell (Th17)-derived proinflammatory cytokine, is the major mediator of tissue inflammation in inflammatory and autoimmune diseases. Experimental autoimmune myocarditis (EAM) is a T cell-mediated autoimmune disease; however, the pathogenic role of IL-17 in the development of rat EAM remains largely unknown. Methods and Results In the present study, alterations of IL-17-related protein expressions were investigated and then the effect of hydrodynamic-based delivery of plasmid DNA encoding the IL-10-Ig gene on rat EAM and the effect of IL-10-Ig on IL-17 was evaluated. The results showed that IL-17 was expressed more highly than IFN-γ expressed by Th1 cells in αβT cells and the peaks of IL-17 related protein expression in the heart were the early phase of EAM. Moreover, we observed that IL-10-Ig gene therapy was effective in controlling EAM and that IL-10-Ig significantly suppressed the expression of IL-17 as well as other proinflammatory cytokines, IL-1β and TNF-α, in IL-1-stimulated splenocytes cultured from EAM rats. Conclusions IL-17 is highly produced by αβT cells in the early phase of EAM hearts and IL-17 inhibition might be a possible mechanism of the amelioration of EAM by IL-10-Ig treatment. These data suggest that IL-17 produced by Th17 plays an important role in the pathogenesis of rat EAM. (Circ J 2008; 72: 813 - 819)

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Background The increase in inward current, primarily L-type Ca²⁺ current, facilitates torsades de pointes (TdP). Because human atrial natriuretic peptide (ANP) moderates the L-type Ca²⁺ current, in our study it was hypothesized that ANP counteracts TdP. Methods and Results We tested the effect of ANP, guanosine 3', 5'-cyclic monophosphate analogue (8-bromo cGMP) and hydralazine on the occurrence of TdP in a rabbit model. In control rabbits, administration of methoxamine and nifekalant almost invariably caused TdP (14/15). In contrast, ANP (10 μg · kg^-1 · min^-1) markedly abolished TdP (2/15), whereas hydralazine failed to show a comparable anti-arrhythmic action (10/15). TdP occurred only in 1 of 15 rabbits treated with 8-bromo cGMP. Presence of early afterdepolarization-like hump in the ventricular monophasic action potential was associated with the occurrence of TdP. Conclusion Results suggest that ANP affects TdP in the rabbit model, and that this anti-arrhythmic effect of ANP is not necessarily shared by other vasodilating agents. (Circ J 2008; 72: 820 - 824)

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Background Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by a proliferation of vascular endothelial and smooth muscle cells, resulting in occlusion of the lumen of small pulmonary arteries. Cilostazol, with its antiproliferative effects on vascular endothelial and smooth muscle cells, may ameliorate monocrotaline (MCT)-induced PAH in rats. Methods and Results Male Sprague - Dawley rats (n=10/each group) were randomized to receive MCT (75 mg/kg) only (group 1), MCT plus cilostazol (20 mg ·kg^-1 · day^-1) (group 2) and saline injection only (group 3). Hemodynamic measurement on day 28 following MCT treatment indicated the development of significant PAH on MCT-treated groups (p<0.0001). Cilostazol was given to group 2 orally on days 28-90. By day 90 following MCT treatment, the right ventricular (RV) systolic blood pressure and RV hypertrophy were significantly higher in group 1 than in groups 2 and 3 (all values of p<0.01). Additionally, connexin43 and endothelial nitric oxide synthase gene expressions of lung and RV, and Bcl-2 protein expression of RV, were significantly lower in group 1 than in groups 2 and 3 (all values of p<0.01). Furthermore, the number of alveolar sac and small arterioles of the lung were significantly lower in group 1 than in groups 2 and 3 (all values of p<0.01). Conclusion Cilostazol therapy effectively attenuates of MCT-induced PAH. (Circ J 2008; 72: 825 - 831)

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Background Drug-eluting stent (DES) implantation is routine during coronary revascularization because DES significantly reduce rates of restenosis and target lesion revascularization compared with bare metal stent (BMS). However, available DES have limitations, such as late thrombosis because of delayed healing with poorer endothelialization and persistent local inflammation. Statins can inhibit cell proliferation, inflammation, and restore endothelial function. The present study evaluated the ability of stent-based cerivastatin delivery to reduce stent-induced inflammatory responses and adverse effects on endothelial function, and to inhibit neointimal hyperplasia in a porcine coronary model. Methods and Results Pigs were randomized into groups in which the coronary arteries (9 pigs, 18 coronaries in each group) had either a cerivastatin-eluting stent (CES) or a BMS. All animals survived without any adverse effects. Inflammatory cell infiltration evaluated using scanning electron microscopy on day 3 after stenting was significantly decreased in the treated vessels (inflammation score: 1.15±0.12 vs 2.43±0.34, p<0.0001). At day 28, endothelial function with intracoronary infusion of bradykinin was preserved in both the CES and BMS groups. Volumetric intravascular ultrasound images revealed decreased intimal volume in the CES group (28.3±5.4 vs 75.9±4.2 mm³, p<0.0001). Histomorphometric analysis showed reduced neointimal area (1.74±0.45 vs 3.83±0.51 mm², p<0.0001) in the CES group despite similar injury scores (1.77±0.30 vs 1.77±0.22, p=0.97). Conclusion In porcine coronary arteries CES significantly decreased neointimal hyperplasia with a decreased early inflammatory response and without endothelial dysfunction. (Circ J 2008; 72: 832 -838)

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Background Optical coherence tomography (OCT), a high resolution intravascular imaging technique, requires blood displacement for reliable image acquisition and the current technique uses a soft occlusion balloon plus saline injection in the coronary artery. A non-occlusive technique based on manual infusion of a viscous iso-osmolar solution has been developed and tested and validated through a 2-phase study. Methods and Results OCT assessment was performed with the M2 LightLab OCT (LightLab Imaging, Westford, MA, USA) image-wire in 3 swine by infusing 30 ml of each of 3 solutions differing in viscosity, osmolarity and electrolytic composition (A: iodixanol 320 and Lactated Ringer's; B: iodixanol 320 and 50% albumin; C: iodixanol 320). Image quality and adverse effects were evaluated. The solution with the best image quality/side-effect ratio was tested in 44 patients. The best image quality/side-effect ratio was obtained in the swine model with solution C, which enabled the study of arterial segments of 29.8±2.1 mm in length. The results were confirmed in the human study (average length of 28.3±2.5 mm and absence of major complications and/or major arrhythmias). Repeated OCT pull-back in the first 10 patients enabled comparison of 1,572 matched cross-sections with an excellent correlation for reproducibility (R=0.96; p<0.001). Conclusions The non-occlusive technique using iodixanol 320 has an excellent ratio of safety, feasibility and efficacy. (Circ J 2008; 72: 839 - 843)

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Background Type 1 plasminogen activator inhibitor (PAI-1) and adiponectin are produced by adipocytes and are important in the progression of coronary artery disease (CAD). Methods and Results Different concentrations of glucose, insulin and 1% triglycerides were used to assay PAI-1 and adiponectin production from cultured adipocytes. Triglycerides induced the highest PAI-1 production with 16.5 mmol/L glucose and 50 nmol/L insulin. In contrast, glucose and insulin decreased adiponectin production in a dose-dependent manner irrespective of triglycerides. Conclusion The metabolic syndrome risk factors alter PAI-1 and adiponectin production by adipocytes, in the presence or absence of triglycerides, which might play a role in the development of CAD. (Circ J 2008; 72: 844 - 846)

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Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction. (Circ J 2008; 72: 847 - 849)

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Tumor necrosis factor-α (TNF-α) is considered to be 1 of the factors that induce vasculitis, including coronary artery aneurysm (CA), in Kawasaki disease (KD), because the blood concentration of TNF-α is higher in patients with CA compared with those without. Therefore, an anti-TNF-αagent (infliximab) was administered to a 1-month-old girl with refractory KD complicated by CA and subsequently, the CA improved and KD was controlled without complications 20 months after the onset. (Circ J 2008; 72: 850 - 852)

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Peripartum cardiomyopathy (PPCM) is a disorder of unknown cause in which heart failure occurs during the peripartum period. A 32-year-old woman was diagnosed with PPCM 10 days after delivery. One month after the initial diagnosis, a newly formed left ventricular (LV) apical thrombus was revealed and warfarin was started. One week later, the thrombus became mobile and she underwent surgical thrombectomy. Warfarin was restarted on postoperative day (POD) 1; however, thrombi recurred at POD 3. Intravenous heparin was then supplemented, which subsequently resolved the thrombi without any embolism. Although there is currently no consensus as to whether patients with depressed LV function and sinus rhythm should be anticoagulated to prevent thrombus formation, PPCM presents a higher risk and might need aggressive and pre-emptive anticoagulation once diagnosis is made. (Circ J 2008; 72: 853 - 854)

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A case of reentrant ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT) is described. An electrophysiological study revealed that programmed stimulation from the right ventricle apex induced 2 types of VT with similar left bundle branch block configuration and inferior axis. Yet, VT cycle length (CL) was different; one was stable, sustained VT with a CL of 360 ms and the other was hemodynamically intolerable VT with a CL of 330 ms. Similarly for both VTs, perfect pace mapping was obtained at the anterior septum beneath the pulmonary valve in the RVOT, and exits of both VTs were very close. Entrainment mapping during stable VT was performed and the anterior septum RVOT was designated as the exit for the stable VT. Intriguingly, entrainment pacing from the ostium of the right coronary artery showed that the post-pacing interval was identical to VTCL. The stimulus to QRS interval was very long (340 ms) during entrainment with concealed fusion, and the right coronary artery ostium was therefore consistent with the VT reentry circuit inner loop or the upper portion of the VT reentry circuit exit. These findings suggest that the stable VT reentry circuit had a slow conduction zone from the ostium of the right coronary artery to the exit in the anterior septum RVOT. When radiofrequency catheter ablation was performed at the 2 exits of the anterior septum RVOT, both VTs then could not be induced. (Circ J 2008; 72: 855 - 860)

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