Background Cyclosporine (CsA), Mycophenolate mofetil (MMF) and prednisolone (PSL) are widely used for the prevention of acute rejection after heart transplantation. Recently, the serum concentration - time curves (AUC) of CsA and MMF have been demonstrated to be precise predictors of acute rejection. Methods and Results Fourteen heart transplant patients were treated concomitantly with CsA, MMF, and PSL between May 1999 and November 2005 at the National Cardiovascular Center and of them 3 had acute rejection episodes [International Society for Heart & Lung Transplantation grade 3a]. Two patients (man in his 30 s; woman in her 40 s) had acute rejection with a mycophenolic acid (MPA) AUC_{0-12 h} <30 μg · h · ml^-1 and low CsA AUC (AUC_{0-4 h}; 2,408 ng · h · ml^-1, 1,735 ng · h · ml^-1). However, 1 patient (man in his 30 s) with a high CsA AUC_{0-4 h} (4,019 ng · h · ml^-1) did not develop cardiac allograft rejection even if the MMF was temporarily stopped. These 3 patients were investigated to evaluate the relationship between acute rejection and pharmacokinetic parameters, including the CsA C₀, C₂, AUC_{0-4 h} and MPA AUC_{0-12 h}. Conclusions The findings suggest that a high CsA AUC_{0-4 h} may prevent rejection of a cardiac allograft, even if MMF is stopped or drastically reduced. (Circ J 2007; 71: 289 - 293)

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Background A double-blind, randomized, parallel-group, placebo-controlled trial was conducted in patients with paroxysmal atrial fibrillation or flutter (PAF/PAFL) experiencing 2 or more episodes of symptomatic PAF/PAFL during a 28-day observation period to determine the dose-response effect and safety of flecainide. Methods and Results A total of 143 patients at 30 centers were randomized to receive 25, 50, or 100 mg of flecainide or placebo twice daily (BID). In 123 patients (per protocol set), those remaining free from PAF/PAFL after the treatment were 3.1% on placebo, 7.7% on 25 mg/BID, 9.4% on 50 mg/BID, and 39.4% on 100 mg/BID of flecainide. As a whole group, a significant linear dose-response (p<0.001) was observed and a significant difference between placebo and 100 mg/BID was observed (p<0.001). A similar dose-response between the present study and Caucasian study was demonstrated. Although there were 5 patients who needed cardioversion or ablation because of frequent episodes of PAF/PAFL (2 in 25 mg/BID, 1 in 50 mg/BID, and 2 in 100 mg/BID of flecainide), neither death nor ventricular proarrhythmic event was reported. Conclusions This study indicated that flecainide exerted a significant dose-dependent effect on the prevention of symptomatic PAF/PAFL recurrence and showed that there was no inter-ethnic difference in the clinical effect of flecainide in patients with PAF/PAFL. (Circ J 2007; 71: 294 - 300)

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Background There is conflicting information about whether nitrate treatment aggravates long-term prognosis, so the present retrospective study was designed to determine the effects of long-term nitrate therapy on major adverse events after acute myocardial infarction (AMI) in the coronary interventional era. Methods and Results Using the Japanese Acute Coronary Syndrome Study database, 1,236 consecutive patients who were hospitalized within 48 h of onset of symptoms of AMI from January to December 2003 were evaluated. All-cause mortality, cardiac events and cardiovascular events were lower in patients treated with nitrates than in the untreated controls. However, these crude comparisons included several confounding factors on nitrate prescription. To minimize the effect of selection bias on outcomes, the technique of propensity score matching for clinical characteristics was used and distortion of effective nitrate treatment was excluded as much as possible. The results of propensity score matching showed that nitrate therapy had no impact on all-cause mortality, cardiac events and cardiovascular events at 30, 60 or 90 days, 6 months, 1 year, and 2 years follow-up. Conclusions Long-term nitrate therapy after AMI neither improves nor aggravates prognosis. Prospective randomized clinical trials are warranted to determine the effects of long-term nitrate therapy for secondary prevention of AMI. (Circ J 2007; 71: 301 - 307)

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Background Atrial fibrillation (AF) and congestive heart failure (CHF) are frequently coexistent, but their temporal relationship in Japanese patients is unclear. Methods and Results 248 AF patients (63.6±10.0 years old) without a history of CHF were enrolled for analysis of the development of CHF during the follow-up period of 49.7±29.8 months. Of them, 195 did not have structural heart disease, 22 had dilated or hypertrophic cardiomyopathy, 18 had an old myocardial infarction, and 15 had valvular heart disease. During the follow-up period, 16 patients (6.5%) developed CHF requiring hospitalization (2.0% per patient-year). Although age, gender, fractional shortening, left atrial diameter, hypertension and diabetes mellitus were not associated with CHF development, existence of structural heart disease and left ventricular hypertrophy by Cornell voltage criteria on ECG were significantly associated with CHF development. Cox-Hazard regression analysis revealed that the existence of structural heart disease was the only independent risk factor (hazard ratio 3.50, 95% confidence interval 1.21-10.1). Conclusions In the present group of Japanese AF patients, CHF requiring hospitalization occurred at a rate of 2% per year. The existence of structural heart disease was the only independent risk factor in this population. (Circ J 2007; 71: 308 - 312)

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Background The concentrations of atrial and brain natriuretic peptides (ANP and BNP) are elevated in patients with atrial fibrillation (AF), but the usefulness of their measurement before and after AF ablation has not been reported. Methods and Results The concentrations of the natriuretic peptides were evaluated in 54 patients undergoing catheter ablation for drug-resistant paroxysmal and persistent AF without heart failure. Based on the outcome, the patients were divided into 2 groups: successful (n=42) or failure (n=12). All patients were asked to keep a log of the duration and frequency of their symptoms and underwent 24-h ECG monitoring at least once after the ablation. The plasma BNP and ANP concentrations, most of which were well below the heart failure range, exceeded the normal range in 69% and 26% of the patients, respectively. The BNP concentration decreased after ablation in the success group (49±43 to 27±28 pg/ml; p<0.05), however, it was unchanged in the failure group (46±35 to 70±37 pg/ml; p=0.46). A value of the ΔBNP (BNP after ablation - BNP before ablation) of ≤0 pg/ml identified a successful ablation with a sensitivity of 83% and specificity of 83%. The plasma ANP concentration did not differ statistically between the 2 groups before and after the ablation. Conclusion A moderate elevation in the BNP concentration is often found in patients with symptomatic paroxysmal and persistent AF, and a reduction in the plasma BNP concentration shortly after the ablation may indicate a successful outcome. (Circ J 2007; 71: 313 - 320)

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Background The present study investigated serial changes in platelet activation (expressed by CD62p) and von Willebrand factor (VWF), and the correlation between increased CD62p expression, VWF and brain infarct volume (BIV: measured by magnetic resonance imaging), and prognostic determinants in non-valvular atrial fibrillation (NVAF) patients after acute ischemic stroke (IS). Methods and Results CD62p expression and plasma VWF concentrations were serially measured (<48 h, on days 7, 21 and 90) using flow cytometry and enzyme-linked immunosorbent assay, respectively after acute IS in 61 NVAF patients. CD62p expression and VWF concentrations were also examined in 50 NVAF-risk control and 30 healthy individuals. The VWF concentration had no significant changes at 4 intervals among the patients and did not differ among 3 groups at acute stroke phase. CD62p expression was significantly higher in the acute phase after IS than in both control groups (both p<0.0001). However, CD62p expression declined to a significantly lower level on day 7 and to a substantially lower level thereafter (p<0.0001). CD62p expression did not differ on day 90 in the 3 groups (both p>0.5). Linear regression analysis showed that BIV and modified Rankin scale score (>3) were independently associated with increased CD62p expression (<48 h) (both p<0.01). Furthermore, the Cox proportional hazards model showed that BIV was the only independent predictor of intermediate-term (8.8±4.4 months) combined recurrent stroke and death. Conclusions The CD62p expression, which reflected increased BIV, was significantly increased in NVAF patients in acute-phase IS and substantially declined thereafter. The BIV was predictive of unfavorable intermediate-term clinical outcomes. (Circ J 2007; 71: 321 - 326)

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Background Tenascin-C (TN-C), an extracellular matrix glycoprotein, is specifically expressed at high levels during embryonic development, but not in the adult heart. TN-C reappears at sites of inflammatory tissue remodeling or wound healing under various pathologic conditions, such as acute myocardial infarction, acute myocarditis, and some cases of cardiomyopathy. Therefore, the expression of TN-C might be useful for detecting the clinical characteristics of, and ventricular remodeling in, dilated cardiomyopathy (DCM). Methods and Results Circulating serum TN-C levels in 107 patients with DCM were measured using an ELISA kit. Clinical data were also assessed by Pearson's or Spearman's correlation analysis to estimate correlations between variables. Serum TN-C levels in DCM patients were higher than those in normal controls (p<0.001). TNC levels showed a significantly positive correlation with New York Heart Association functional class (p<0.001), B-type natriuretic peptide level (p<0.001), cardiothoracic ratio on chest X-ray (p<0.01), left ventricular end-diastolic diameter (p<0.05) and left ventricular end-systolic diameter (p<0.01), and a significantly negative correlation with left ventricular ejection fraction (p<0.01). Conclusions The findings suggest that increased serum TN-C levels indicate the severity of heart failure, left ventricular dysfunction and remodeling in patients with DCM. (Circ J 2007; 71: 327 - 330)

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Background The interaction between long-and short-term cardiac memory (CM) is unknown. Methods and Results The T-wave areas and QTc intervals in each ECG lead were analyzed in 11 patients with manifest Wolff-Parkinson-White syndrome with posterior or septal accessory pathway (4 females; mean age: 47±12 years) in the following ECGs: (1) immediately after catheter ablation (post-ablation ECG); (2) immediately after 20 min of right ventricular outlet pacing (post-pacing ECG); and (3) 1 week after ablation (recovery ECG). Compared with the post-ablation ECGs, the T-wave areas of the recovery ECGs in leads II and aV_F changed dramatically from negative to positive while that in lead III became less negative (p<0.01), and those in leads I, aV_L, and V_2-4 became less positive (p<0.05). Compared with the post-ablation ECGs, the T-wave areas of the post-pacing ECGs in leads III and aV_F became less negative (p<0.01), and those in leads I, aV_L, and V_2-4 became less positive (p<0.05). The QTc interval in the post-ablation ECG was significantly longer than in either the post-pacing or recovery ECGs (p<0.05). Conclusions Mechanisms involved in the expression of long-term CM could be affected by short-term CM. (Circ J 2007; 71: 331 - 337)

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Background Peroxisome proliferator-activated receptor (PPAR)-γ, a member of the nuclear hormone receptor family, which is involved in the differentiation of adipose tissue, is reported to be associated with the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. Whether the prevalence of coronary artery disease (CAD) is associated with Pro12Ala polymorphism in exon B of PPAR-γ was investigated in Korean adults. Methods and Results The study was conducted in 267 subjects (158 males, 109 females, mean age 58 years) who underwent coronary angiography because of chest pain. Cardiovascular risk factors, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles, were assessed in all subjects, who were divided into 4 groups according to the number of stenosed coronary arteries: normal, 1-vessel, 2-vessel and 3-vessel disease. Genotyping of Pro12Ala polymorphism was done with real-time polymerase chain reaction. Allelic frequency for proline was 0.955 and 0.045 for alanine, which was in Hardy-Weinberg equilibrium (p=0.74). One hundred and seventeen subjects (43.8%) had normal coronary arteries, 88 (33%) had 1-vessel disease, 39 (14.6%) had 2-vessel disease and 23 (8.6%) had 3-vessel disease. When the cardiovascular risk factors were compared among the 4 groups, there were no meaningful differences except for age and FBG levels, which were significant even after adjustment for age and BMI. There were no significant differences in the prevalence or severity of CAD according to the different genotypes of Pro12Ala, and in logistic regression analysis Pro12Ala polymorphism was not a predictor for CAD. Conclusions There was no significant association between Pro12Ala polymorphism in exon B of PPAR-γ and prevalence or severity of CAD in Korean adults. Further studies on the correlation between Pro12Ala polymorphism and CAD should be carried out in a larger Korean population in the future. (Circ J 2007; 71: 338 - 342)

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Background The role of the angiopoietin (Ang)/Tie-2 system in coronary collateral growth is not well understood, so the purpose of this study was to investigate and elucidate the relationship of this system to coronary collateral formation in patients with coronary artery disease (CAD). Methods and Results Fifty-nine patients with CAD were recruited. Blood samples from the left ventricle (LV) and coronary sinus (CS) were obtained during cardiac catheterization, and serum concentrations of Ang-1, Ang-2, and Tie-2 were measured by enzyme-linked immunosorbent assay. Patients were then classified as mild CAD (n=30), defined as ≤90% stenosis of the coronary arterial luminal diameter, or severe CAD (n=29), which was total (or near total) coronary occlusion requiring coronary collateral growth. Ang-1, Ang-2, and Tie-2 in the LV and CS sera were not significantly different between groups. In the severe CAD group, spillover of Tie-2 (CS-LV value) from the coronary circulation was found in comparison with the mild CAD group (3.43±2.22 vs -3.29±1.54 ng/ml, p=0.01), whereas the CS-LV values of Ang-1 and Ang-2 did not differ between groups. Tie-2 production was markedly increased in patients with well-developed collaterals. A positive and significant correlation was found between coronary Ang-2 and Tie-2 levels (r=0.44, p<0.001). Conclusions Tie-2 is probably produced in the coronary circulation and may induce the development or maintenance of coronary collaterals in CAD patients. Furthermore, the role of Ang-2 in the formation of coronary collaterals may be more important than that of Ang-1. (Circ J 2007; 71: 343 - 347)

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Background Elevated plasma plasminogen activator inhibitor-1 (PAI-1) is related to cardiovascular events, but its role in subclinical coronary microvascular dysfunction remains unknown. Thus, in the present study it was investigated whether elevated plasma PAI-1 activity is associated with coronary microvascular dysfunction in hypertensive patients. Methods and Results Thirty patients with untreated essential hypertension and 10 age-matched healthy controls were studied prospectively. Myocardial blood flow (MBF) was measured by using ¹⁵O-water positron emission tomography. Clinical variables associated with atherosclerosis (low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, homeostasis model assessment (HOMA-IR), and PAI-1 activity) were assessed to determine their involvement in coronary microvascular dysfunction. Adenosine triphosphate (ATP)-induced hyperemic MBF and coronary flow reserve (CFR) were significantly lower in hypertensive patients than in healthy controls (ATP-induced MBF: 2.77±0.82 vs 3.49±0.71 ml · g^-1 · min^-1; p<0.02 and CFR: 2.95 ±1.06 vs 4.25±0.69; p<0.001). By univariate analysis, CFR was positively correlated with HDL-cholesterol (r=0.46, p<0.02), and inversely with HOMA-IR (r=-0.39, p<0.05) and PAI-1 activity (r=-0.61, p<0.001). By multivariate analysis, elevated PAI-1 activity remained a significant independent determinant of diminished CFR. Conclusions Elevated plasma PAI-1 activity was independently associated with coronary microvascular dysfunction, which suggests that plasma PAI-1 activity is an important clue linking hypofibrinolysis to the development of atherosclerosis. (Circ J 2007; 71: 348 - 353)

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Background The relationship between plasma uridine levels and blood pressure (BP), and indicators of muscular purine degradation and insulin resistance (IR) has been evaluated in hypertensive (HT) patients. Methods and Results In 36 HT patients and 10 normotensive subjects, seated BP was measured, and blood samples were drawn after overnight fast. In 18 of the HT patients, the semi-ischemic forearm test was performed to examine the release of hypoxanthine, ammonium and lactate. Plasma uridine levels were significantly higher than in the normotensive subjects. Fasting plasma insulin levels and homeostasis model assessment of IR correlated with plasma uridine levels in the HT patients. Plasma uridine levels showed a significant correlation with hypoxanthine, ammonia and lactate released from the semi-ischemic exercising muscles of the HT patients. Conclusions Taken together with the positive correlation with indicators of IR, it is suggested that plasma uridine levels in HT are responsible for purine degradation and IR in skeletal muscles. (Circ J 2007; 71: 354 - 356)

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Background The aims of this study were to evaluate myocardial mechanics using pulsed tissue Doppler imaging (TDI), and to determine the relationship between abnormal myocardial performance and plasma brain natriuretic peptide (BNP) levels and oxidative stress in acute Kawasaki disease (KD). Methods and Results Consecutive TDI parameters, including peak systolic velocity (Sw) and early (Ew) and late diastolic excursion of the mitral annuli were obtained in 42 patients with KD (mean age: 2.4±0.4 years) in weeks 1, 2, and 3, and during convalescence. Plasma BNP level and urinary 8-isoprostane were also examined during the acute phase. These data were then compared with TDI profiles from 62 healthy children, plasma BNP levels in 38 controls with other febrile illnesses, and urinary 8-isoprostane levels in 13 healthy children. Ew in week 1 was significantly lower than in controls, subsequently normalizing in the convalescent stage. Plasma BNP level in acute KD patients was significantly higher (65±9 pg/ml) than in controls (13±2 pg/ml). Urinary 8-isoprostane level in acute KD patients was significantly higher as compared with control (596 ±37 vs 379±26 pg/ml Cr, p<0.05). There was a significant negative correlation between week 1 Sw and plasma BNP level (r=-0.55, p=0.0001). Change in Sw velocity in the BNP ≥51 group was significantly greater than in the BNP <51 group. There was a significant negative correlation between week 1 Sw and urinary 8-isoprostane level (r=-0.48, p=0.001). Conclusions Latent abnormal tissue Doppler profiles, possibly reflecting long-axis systolic and diastolic dysfunction have been noted in KD patients. Abnormal myocardial mechanics may contribute to the increased plasma BNP level and enhanced oxidative stress may contribute to cardiac dysfunction in KD. (Circ J 2007; 71: 357 - 362)

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Background It has been proposed that 0.5-mm-slice multislice computed tomography (MSCT) is a noninvasive tool for the detection of atherosclerotic plaque, but the validity of such an assessment has not been demonstrated by an invasive investigation. The present study was performed to compare the 0.5-mm-slice MSCT density of plaques with intravascular ultrasound (IVUS) findings. Methods and Results Atherosclerotic plaques were characterized in 37 consecutive patients undergoing percutaneous interventions. Based on the IVUS echogenecity, the plaques were classified as soft (n=18), fibrous (n=40) or calcified (n=40). In these 98 plaques, 0.5-mm-slice MSCT plaque density was calculated in 443 regions-of-interest, including 331 lesional foci and 112 luminal cross-sections, and represented as Hounsfield units (HU). MSCT density of the 3 types of plaque was 11±12 HU, 78±21 HU, and 516 ±198 HU respectively. Computed tomography density of the (contrast-filled) lumen was 258±43 HU. There were statistically highly significant differences in the densitometric characteristics among the 4 groups (soft, fibrous, calcified plaque and lumen) by nonparametric Kruskal-Wallis test (p<0.0001). Conclusions The IVUS-based coronary plaque configuration can be accurately identified by 0.5-mm slice MSCT. Noninvasive assessment of plaque characterization will ensure emphasis on the vessel wall beyond the vascular lumen. (Circ J 2007; 71: 363 - 366)

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Background Pulmonary arterial hypertension (PAH) is a progressive disease with high mortality. An orally active dual endothelin (ET) receptor antagonist, bosentan, has been reported to improve exercise capacity and survival in patients with PAH. Plasma ET-1 concentration is known to be increased in PAH patients; however, the effect of bosentan on ET-1 concentration has not yet been investigated. Methods and Results The concentration of ET-1 after bosentan administration was examined in 7 PAH patients, including 2 primary and 5 secondary cases. They were clinically assessed by pulmonary artery pressure (PAP), 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration. Baseline ET-1 concentration was significantly higher in patients with PAH than in normal individuals (2.19±0.71 pg/ml vs 1.45±0.10 pg/ml, p<0.05) and was significantly correlated with 6MWD and BNP. A single dose of 62.5 mg bosentan in patients with PAH significantly increased plasma ET-1 concentration to 2.04 times the basal concentration (p<0.01) with a peak at 8.1 h. The peak to base ratio of ET-1 after bosentan administration correlated negatively with severity of PAH as assessed by PAP. Conclusions The present study is the first study to show that bosentan administration increases plasma ET-1 in patients with PAH. The response of plasma ET-1 to bosentan administration might be useful for determining the severity of PAH. (Circ J 2007; 71: 367 - 369)

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Background Two randomized studies have shown a neurological benefit of therapeutic hypothermia in comatose survivors after out-of-hospital cardiac arrest, but there are no studies of the cardiac neurohormone of B-type natriuretic peptide (BNP) in patients treated with hypothermia. Methods and Results A prospective study was conducted of 109 comatose patients who were treated with mild hypothermia after out-of-hospital sudden cardiac arrest due to cardiac causes and whose BNP level was measured on arrival at the emergency room. The primary endpoint was a favorable neurological outcome at the time of hospital discharge. A total of 45 of the 109 patients had a favorable neurological outcome. The unadjusted rate of a favorable neurological outcome decreased in a stepwise fashion among patients in increasing quartiles of BNP level (p<0.001) and this association remained significant in subgroups of patients. The BNP cutoff value of 80 pg/ml for a favorable neurological outcome had an accuracy of 87.2%. In the multiple logistic-regression analysis, a BNP level of 80 pg/ml or less was an independent predictor of favorable neurological outcome. Conclusions The measurement of BNP was found to provide valuable information regarding the neurological outcome of comatose survivors treated with mild hypothermia after out-of-hospital cardiac arrest due to cardiac causes. (Circ J 2007; 71: 370 - 376)

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Background The aim of the present study was to evaluate the risk factors for peripheral arterial disease and the relationship between the ankle - brachial index (ABI) and mortality from all-cause and cardiovascular disease (CVD) in Chinese patients with type 2 diabetes mellitus (DM). Methods and Results ABI was identified at baseline by measuring systolic pressure in the bilateral brachial and tibial arteries. Mortality surveillance was completed from November 2004 to January 2006. Among 1,647 participants with type 2 DM at baseline, 531 (32.2%) were in the low-ABI group. Older age, female gender, higher serum level of total cholesterol, longer duration of DM and a history of smoking were associated with low ABI. During the 13-month follow-up, there were 132 deaths, of which 47 were from CVD. Low ABI was associated with mortality from all-cause and CVD, the adjusted relative risk of which was 1.851 (95% confidence interval 1.280-2.676) and 3.211 (1.703-6.053), respectively, in Cox regression models. The survival rate was significantly lower in the low-ABI group than in the normal-ABI group. Conclusion Low ABI was independently associated with a high risk of all-cause and CVD mortality in Chinese patients with type 2 DM. ABI should be promoted as an ideal tool for predicting mortality in diabetic patients. (Circ J 2007; 71: 377 - 381)

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Background Altered expression and distribution of gap junctions might provide substrates for abnormal conduction and arrhythmogenesis in the heart, but little is known about the regulation of gap junctions under pathological conditions. The organization and phosphorylation state of connexin43 (Cx43) in ventricular hypertrophy will be investigated. Methods and Results Right ventricular (RV) hypertrophy was induced in rats by treatment with monocrotaline. Subcellular Cx43 distribution was assessed by immunoconfocal and electron microscopy. Immunolabeling of Cx43 was confined to the intercalated disks in the normal ventricular myocytes of control rats, but hypertrophied RV cells from monocrotaline-treated rats showed dispersion of Cx43 immunolabeling over the cell surface and in the cytoplasm; cytoplasmic Cx43 was increased by ~7-fold (n=15). The Cx43 internalization was confirmed by the double staining of monocrotaline-treated RV tissues for Cx43/wheat germ agglutinin (WGA) and Cx43/zonula occludens protein-1 (ZO-1). Electron microscopy of hypertrophied RVs showed an increase in annular gap junctions immunolabeled with Cx43. Immunoblotting revealed a significant increase in non-phosphorylated Cx43 in hypertrophied RVs (by ~5-fold, n=8) without changes in the total amount of Cx43. The accumulation of non-phosphorylated Cx43 in hypertrophied RVs was also recognized by immunoconfocal-microscopy with an isoform-specific antibody. Conclusion Ventricular hypertrophy is associated with the dephosphorylation of Cx43 and its translocation from the intercalated disks to intracellular pools, suggesting accelerated gap junction degradation. (Circ J 2007; 71: 382 - 389)

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Background The contribution of conduction disturbances to susceptibility to ventricular tachycardia (VT) has not been directly examined in the process of left ventricular hypertrophy (LVH). Methods and Results Dahl salt-sensitive (S) and -resistant rats were raised on a high-salt diet. After echocardiography, a fractionation study was conducted using wavelet transform analysis, which reflects conduction disturbances, recording of monophasic action potential (MAP), measurement of conduction velocity, and programmed extrastimuli for the induction of VT, as well as patch-clamp analysis at 10, 13 and 16 weeks (W) (n=7, each). Systolic blood pressure, wall thickness and MAP duration significantly increased at 10W in S rats, whereas conduction velocity decreased and MAP duration and the power of wavelet transform increased at 13W and 16W. Paired extrastimuli induced polymorphic VT only at 13W and 16W in S rats. VT frequency correlated inversely with conduction velocity and positively with MAP duration. Power of wavelet transform correlated negatively with conduction velocity and positively with VT vulnerability. The patch-clamp study revealed that the action potential duration significantly increased in S rats with aging, and correlated with MAP duration. Conclusions Latently progressing slow and inhomogeneous conduction, as well as a repolarization abnormality, may contribute to VT vulnerability in hypertensive LVH. (Circ J 2007; 71: 390 - 396)

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Background Myosin-induced autoimmune myocarditis of rats is a model of human dilated cardiomyopathy. Resveratrol is a natural polyphenol found in grapes and wine that is reported to have cardioprotective and immunomodulatory effects. Methods and Results To examine the effect of resveratrol on myocarditis, vehicle or resveratrol (50 mg/kg per day) was administered to cardiac myosin immunized rats 1 day before the immunization. At 14 days after immunization, resveratrol had preserved cardiac function of myosin-immunized rats according to echocardiographic analysis. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.8-fold compared with unimmunized rats, and resveratrol attenuated the heart weight increase. Resveratrol significantly decreased cellular infiltration, fibrosis, and expression of inflammatory cytokines in the myocardium. Expressions of antioxidant genes were increased in myosin-immunized hearts, and resveratrol decreased those expressions. Resveratrol also attenuated myocarditis 21 days after immunization. SIRT1, a potential effector of resveratrol, was increased in the myocardium of myosin-immunized rats compared with unimmunized rats. The SIRT1 protein was localized mainly in infiltrating mononuclear cells. Conclusions Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis. Resveratrol may be a therapeutic modality for myocarditis. (Circ J 2007; 71: 397 - 404)

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Background It is not clear how hyperbaric oxygen therapy (HBO) affects ischemia-induced pathophysiological responses such as angiogenesis and skeletal muscle regeneration. In the present study the effects of HBO on the functional and morphological recovery of ischemic hind limbs, blood perfusion and the local production of angiogenic growth factors were studied in a mouse model. Methods and Results Mice were placed in pure oxygen under 3 atm for 1 h/day for 14 days after the removal of a segment of the left femoral artery. HBO-treated mice showed better functional recovery and greater blood flow in the ischemic hind limb than untreated mice. Histological examination revealed unatrophied muscle fibers with islands of small regenerating muscle cells only in HBO-treated mice. Regeneration of muscle was confirmed by the increase in myf5 mRNA. The amount of mRNA for vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) was slightly increased in the ischemic hind limbs. HBO eliminated the increase in VEGF mRNA. In contrast, the amount of mRNA for bFGF and HGF was further increased by HBO treatment. HBO transiently increased early growth response protein 1 (Egr-1) in the ischemic hind limbs. Conclusions HBO accelerates the recovery of ischemic hind limbs by increasing the production of bFGF and HGF and by promoting muscle regeneration in mice. (Circ J 2007; 71: 405 - 411)

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Background Whether the combined treatment with sustained-release basic fibroblast growth factor (bFGF) and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia was investigated. Methods and Results Wild-type C57BL/6 and low density lipoprotein receptor-deficient mice were assigned to 1 of the following 4 experimental groups and treated for 2 weeks after femoral artery extraction: group N, no treatment; group H, daily subcutaneous injection of heparin calcium; group F, single intramuscular injection of the sustained-release bFGF microspheres; and group FH, combined treatment with sustained-release bFGF and heparin. Among the wild-type mice at 4 weeks after femoral artery extraction, the laser Doppler perfusion image index (LDPII) in groups H, F, and FH was significantly higher than that in group N. The vascular density in group FH was the highest among the 4 groups. The maturation index in the 3 treated groups was significantly higher than that in group N. Among the hypercholesterolemic mice, the LDPII in group FH was significantly higher than that in the other 3 groups. The vascular density and maturation index in group FH were the highest among the 4 groups. Conclusions Combined treatment with sustained-release bFGF and heparin enhanced neovascularization in the hypercholesterolemic hindlimb ischemia model. (Circ J 2007; 71: 412 - 417)

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Background Although cigarette smoking is thought to constrict peripheral vessels, details have not been clarified because of the limitation of spatial resolution in conventional X-ray angiography systems. Synchrotron radiation microangiography can identify small arteries down to 50 μm in diameter. Method and Results Male Wistar rats (n=9) were made to smoke a cigarette using the modified Griffith snout exposure system. Angiography of the rat hind limb was performed before, during, and 15 min after smoking. Arteries were classified into 3 groups based on the pre-smoking diameter: Group S: <100 μm, Group M 100-200 μm, Group L: >200 μm). In Groups M and L, arteries were constricted with smoking (mean diameter 140-106 μm; p<0.001, 260-162 μm; p<0.00001, respectively), whereas no constriction was noted in Group S (82-83 μm). Constricted arteries in Groups M and L returned to pre-smoking levels at 15 min after cessation of smoking. Conclusion The acute changes brought about by cigarette smoking in rat peripheral arteries could be identified by synchrotron radiation microangiography. Cigarette smoking exclusively constricted arteries greater than 100 μm in diameter, which means there is vessel-size dependency of the impairment. (Circ J 2007; 71: 418 - 422)

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Background Ischemic - reperfusion (IR) injury is a multifactorial process that leads to tissue damage and rejection in composite tissue allotransplantation (CTA). Antioxidant or free radical scavenger may reduce IR injury, so the effects of resveratrol, a natural antioxidant, on amelioration of leukocyte - endothelial cell adhesive interaction and prevention of transplant rejection in CTA were investigated. Methods and Results In a microcirculatory study, resveratrol significantly reduced the number of IR-induced leukocytes rolling, adhering, and transmigrating in the postcapillary venules of the cremaster muscle. In the CTA study using groin skin flap allotransplantation across the MHC barrier 8-11-week-old Brown Norway donors (RT1ⁿ) and 10-11-week-old Lewis recipients (RT1^l) rats were randomized into 4 groups: isograft control, allograft control, and 2 groups that received different doses of resveratrol (0.1 or 0.5 mg/kg) for 7 days. Allograft control animals rejected their allograft between 5 and 7 days postoperatively, whereas resveratrol-treated recipients had a moderate survival prolongation compared with the allograft control group. Consistent with these observations, histology results also showed reduction of lymphocytic infiltration and necrosis in resveratrol-treated subjects. Conclusion Resveratrol treatment prolonged groin skin flap allotransplant survival in the recipient and ameliorated the leukocyte - endothelial cell adhesive interactions that may lead to attenuated and delayed rejection in CTA. (Circ J 2007; 71: 423 - 428)

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Background The identification of protein kinase A (PKA) anchoring proteins on mitochondria implies a direct effect of PKA on mitochondrial function. However, little is known about the relationship between PKA and mitochondrial metabolism. Methods and Results The effects of PKA on the mitochondrial redox state (flavin adenine dinucleotide (FAD)), mitochondrial membrane potential (Δψ_m) and reactive oxygen species (ROS) production were investigated in saponin-permeabilized rat cardiomyocytes. The PKA catalytic subunit (PKA_cat; 50 unit/ml) increased FAD intensities by 56.6±7.9% (p<0.01), 2'7'-dichlorofluorescin diacetate (DCF) intensities by 10.5±3.3 fold (p<0.01) and depolarized Δψ_m to 48.1±9.5% of the control (p<0.01). Trolox (a ROS scavenger; 100 μmol/L) inhibited PKA_cat-induced Δψ_m, FAD and DCF alteration. PKA_cat-induced Δψ_m depolarization was inhibited by an inhibitor of the inner membrane anion channel (IMAC), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS: 1 μmol/L) but not by an inhibitor of mitochondrial permeability transition pore (mPTP), cyclosporine A (100 nmol/L). Conclusions PKA _cat alters FAD and Δψ_m via mitochodrial ROS generation, and PKA_cat-induced Δψ_m depolarization was not caused by mPTP but rather by DIDS-sensitive mechanisms, which could be caused by opening of the IMAC. The effects of PKA on mitochondrial function could be related to myocardial function under the condition of extensive β-adrenergic stimulation. (Circ J 2007; 71: 429 - 436)

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Background Nanomaterials have numerous potential benefits for society, but the potential hazards of nanomaterials on human health are poorly understood. Nanomaterials are known to pass into the circulatory system in humans, causing vascular injuries that might play a role in the development of atherosclerosis. The present study aimed to determine the effects of chronic exposure to nanomaterials on macrophage phenotype and platelet aggregation. Methods and Results Cultured macrophages (RAW264.7) were treated with carbon black (CB) and water-soluble fullerene (C₆₀(OH)₂₄) from 7 to 50 days. Individually, CB had no significant effects on RAW264.7 cell growth, whereas C₆₀(OH)₂₄ alone or CB and C₆₀(OH)₂₄ together with oxidized low-density lipoprotein (Ox-LDL) (100 μg/ml) induced cytotoxic morphological changes, such as Ox-LDL uptake-induced foam cell-like formation and decreased cell growth, in a dose-dependent manner. C₆₀(OH)₂₄ induced LOX-1 protein expression, pro-matrix metalloprotease-9 protein secretion, and tissue factor mRNA expression in lipid-laden macrophages. Although CB or C₆₀(OH) ₂₄ alone did not induce platelet aggregation, C₆₀(OH) ₂₄ facilitated adenosine diphosphate (ADP)-induced platelet aggregation. Furthermore, C₆₀(OH)₂₄ acted as a competitive inhibitor of ADP receptor antagonists in ADP-mediated platelet aggregation. Conclusions The present study confirmed novel effects of nanomaterials in macrophages and platelets. These effects suggest that exposure to nanomaterials might be a risk for atherothrombotic diseases. (Circ J 2007; 71: 437 - 444)

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An infant with truncus arteriosus (Van Praagh A3; isolated left pulmonary artery (LPA) and ductal origin of the LPA) had an extremely stenotic ductus arteriosus (DA) and the LPA could not be demonstrated. As a salvage operation, balloon angioplasty was performed for the stenotic DA at 8 days of age. The minimum lumen diameter of the DA increased from 0.7 to 2.7 mm. After the procedure, the LPA tree was well demonstrated and total pulmonary blood flow increased. Nitrogen inhalation was begun with a nasal positive airway pressure system in order to regulate pulmonary blood flow. Repeat balloon angioplasty was performed at 33 days of age for the restenosed DA. The infant's general condition was stabilized until undergoing pulmonary artery reconstruction and modified Blalock-Taussig shunt at 4 months of age, and definitive repair at 11 months of age. The combination of balloon angioplasty and nitrogen inhalation therapy enabled simultaneous growth of the LPA tree and regulation of total pulmonary blood flow, which could be a useful strategy for complex congenital heart diseases with unbalanced pulmonary blood flow. (Circ J 2007; 71: 445 - 447)

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Wrong:Georgia Kurlaba, MSc.
Right:Georgia Kourlaba, MSc.

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