Coronary heart disease remains a leading cause of morbidity and mortality. Surrogate imaging endpoints may allow smaller sample sizes and shorter study durations to expedite the process of drug development and testing, and to evaluate potential benefits of novel antiatherosclerotic drugs before clinical endpoint data are available - an approach that may reduce cost and effort. Intravascular ultrasound (IVUS) is particularly suitable because it is readily available and because of its relatively high image resolution, accurate and reproducible measurements, ability to detect mild, angiographically silent atherosclerotic disease that can be a precursor of future coronary events, and suitability for serial (baseline and follow-up) imaging and analysis. However, there are significant limitations to the use of IVUS as an endpoint in progression/regression studies that must be considered when evaluating the results of such studies. (Circ J 2009; 73: 1557-1560)

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Cardiac contraction is activated by an increase of intracellular calcium concentration ([Ca²⁺]_i), most of which comes from the sarcoplasmic reticulum (SR) where it is released, via the ryanodine receptor (RyR), in response to Ca²⁺ entering the cell on the L-type Ca²⁺ current. This phenomenon is termed Ca²⁺-induced Ca²⁺ release (CICR). However, under certain circumstances, the SR can become overloaded with Ca²⁺ and once a threshold SR Ca²⁺ content is reached Ca²⁺ is released spontaneously. Such spontaneous Ca²⁺ release from the SR propagates as a Ca²⁺ wave by CICR. Some of the Ca²⁺ released during a wave is removed from the cell on the electrogenic Na - Ca exchanger resulting in depolarization. This is the cellular mechanism producing delayed afterdepolarizations and is common to those arrhythmias produced by digitalis toxicity and right ventricular outflow tract tachycardia. More recently it has been suggested that arrhythmogenic Ca²⁺ waves can also occur if the properties of the RyR are altered, resulting in increase of RyR open probability, for example by phosphorylation. However, in this review experimental evidence will be presented to support the view that such arrhythmias still require a threshold SR Ca²⁺ content to be exceeded and that this threshold is decreased by increasing RyR open probability. (Circ J 2009; 73: 1561-1567)

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568-1576)

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Considerable progress has been made in cardiac magnetic resonance imaging (MRI). Cine MRI is recognized as the most accurate method for evaluating ventricular function. Late gadolinium-enhanced MRI can clearly delineate subendocardial infarction, and the assessment of transmural extent of infarction on MRI is widely useful for predicting myocardial viability. Stress myocardial perfusion MRI allows for detection of subendocardial myocardial ischemia, and the diagnostic accuracy of stress perfusion MRI is superior to stress perfusion single-photon emission computed tomography in patients with multivessel coronary artery disease (CAD). In recent years, image quality, volume coverage, acquisition speed and arterial contrast of 3-dimensional coronary magnetic resonance angiography (MRA) have been substantially improved with use of steady-state free precession sequences and parallel imaging techniques, permitting the acquisition of high-quality, whole-heart coronary MRA within a reasonably short imaging time. It is now widely recognized that cardiac MRI has tremendous potential for the evaluation of ischemic heart disease. However, cardiac MRI is technically complicated and its use in clinical practice is relatively limited. With further improvements in education and training, as well as standardization of appropriate study protocols, cardiac MRI will play a central role in managing patients with CAD. (Circ J 2009; 73: 1577-1588)

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Background: There have been few studies of the clinical features of hypertrophic cardiomyopathy (HCM) in a community-based patient cohort in Japan. Methods and Results: Cardiomyopathy registration was established in Kochi Prefecture and named the Kochi RYOMA (registry of myocardial diseases) study, consisting of 9 hospitals that registered 261 patients with a diagnosis of HCM. At registration, 74 patients (28%) had documented paroxysmal or chronic atrial fibrillation (AF). Although most patients (93%) were in New York Heart Association (NYHA) class I or II, 17 of the 18 patients in NYHA III had AF; 37 of the 74 patients with AF suffered from morbid events (embolism and/or heart failure (HF) admission), and 15 of 19 patients with embolic events had AF prior to or at the time of embolism. Of the 29 patients who had a history of HF admission, 8 had left ventricular systolic dysfunction, and the other 21 patients were hospitalized because of diastolic HF. AF occurred prior to HF in 20 of those 21 patients. Furthermore, 19 of those 20 patients with AF and diastolic HF were hospitalized within 1 year after detection of AF. Conclusions: In an unselected regional registry, AF was the major determinant of clinical deteriorations in patients with HCM. (Circ J 2009; 73: 1599-1605)

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Background: Vagal denervation during pulmonary vein isolation (PVI) may reduce paroxysmal atrial fibrillation (PAF) recurrences. Valid predictors of late PAF recurrence after PVI were examined. Methods and Results: Successful segmental (S-PVI) or circumferential PVI (C-PVI) was achieved in 120 consecutive PAF patients. The 24-h Holter recordings were obtained before and after PVI. Logistic regression analysis was performed to determine independent predictors of PAF recurrence among the patient characteristics, PVI technique and heart rate variability (HRV). Of the 120 patients, 19 were excluded from analysis because of additional ablation for recurrent PAF after successful PVI. Among the remaining 101 patients, 68 were free from PAF (Group-I) and 33 had late PAF recurrences (Group-II) at 1-year follow-up. The incidence of PAF recurrence and conduction recovery in isolated PVs revealed in the second session was significantly lower for C-PVI (21.6% and 28.1%) than for S-PVI (44.0% and 58.3%) (P<0.05). There were no significant differences in the HRV high-frequency component (HF) reflecting parasympathetic activity or the low/high frequency component (LF/HF) reflecting sympathetic activity between the 2 techniques. By multivariate analysis, the PVI technique, HF and LF/HF were independent predictors of PAF recurrence (P<0.05). Conclusions: Vagal denervation may prevent late PAF recurrence independent of the PVI technique. (Circ J 2009; 73: 1606-1611)

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Background: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action. Methods and Results: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172 ±26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD₉₀s) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD₉₀ was greater in RVOT (~13%) than RVA (~8%). Bepridil flattened the MAPD₉₀ restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65 ±0.22 vs 0.95 ±0.38) and RVA (0.65 ±0.14 vs 0.94 ±0.29). The T_peak-end interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. Conclusions: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization. (Circ J 2009; 73: 1612-1618)

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Background: The efficacy of transcatheter cryoablation for ventricular tachycardia (VT) remains controversial because of the limited size of the lesion produced. An increased lesion size if the cryoablation catheter profile and catheter tip length were increased was hypothesized. Methods and Results: Closed-chest transcatheter cryoablation was applied with 7F, 6-mm tip (n=11, 7F group) and 9F, 8-mm tip (n=8, 9F group) catheters to the left ventricular (LV) endocardium and epicardium. Catheter-tip temperature was set to -70 to -80°C, and cryoablation duration was set to 240 s. In acute experiments in the 7F group, endocardial lesion volume was 144.1 ±86.0 mm³ and lesion depth was 5.1 ±1.6 mm, and epicardial lesion volume was 205.6 ±157.8 mm³ and lesion depth was 4.7 ±2.2 mm. In the 9F group, endocardial lesion volume was 301.5 ±177.4 mm³ (P<0.001 vs 7F group) and lesion depth was 8.4 ±1.9 mm (P<0.001 vs 7F group), and epicardial lesion volume was 375.3 ±167.6 mm³ (P<0.01 vs 7F group) and lesion depth was 5.0 ±2.3 mm. Conclusions: Transcatheter cryoablation of the LV endocardium and epicardium using a larger profile and longer tip electrode may be useful for treating VT originating from the midmyocardium or epicardium. (Circ J 2009; 73: 1619-1626)

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Background: There is a hypothesis that advanced neointimal stent coverage may protect against stent thrombosis. In the present study, differences in neointimal growth and prevalence of in-stent thrombus between paclitaxel- and sirolimus-eluting stent (PES and SES) were evaluated by optical coherence tomography (OCT). Methods and Results: Follow-up angiographic and OCT examinations at approximately 6 months were performed for 40 patients (20 PES, 20 SES). Late loss was measured by quantitative coronary angiography. Neointimal hyperplasia (NIH) thickness on stent struts was measured by cross-sectional OCT images at 1 mm intervals. After measuring the NIH area in each cross-section, NIH volume was calculated as integral of NIH area within the stent. Late loss, NIH thickness, and NIH volume were greater for PES than for SES (0.42 ±0.44 vs 0.13 ±0.12 mm, 118 ±141 vs 31 ±39 μm, 53.2 ±30.5 vs 24.3 ±14.0 mm³; P<0.05, respectively). In-stent thrombus was found more frequently in PES than in SES (50 vs 15%; P=0.02). Conclusions: Although the degree of neointimal growth in PES was generally greater, in-stent thrombus was more common compared with SES. Presence of thrombus in first-generation drug-eluting stents was not related to advanced neointimal growth. (Circ J 2009; 73: 1627-1634)

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Background: The impact of being overweight, as a component of the metabolic syndrome (MetS), for cardiovascular disease (CVD) mortality was investigated and compared with the predictive value of MetS by 2 different definitions. Methods and Results: A 12-year prospective study of 30,774 Japanese men and 60,383 women aged 40-79 years was conducted. The multivariate hazard ratio (HR; 95% confidence interval) of total CVD mortality for overweight subjects with ≥2 additional risk factors with reference to subjects with 0 of 4 MetS components was 1.83 (1.41-2.38) for men and 1.90 (1.45-2.49) for women, and for non-overweight subjects with ≥2 additional risk factors 1.75 (1.38-2.24) and 1.97 (1.52-2.55), respectively. The proportion of excess CVD deaths in the latter group was 1.5-fold higher than that in the former group. Multivariate HRs of coronary heart disease and total CVD mortality for MetS by the modified criteria of the American Heart Association/National Heart, Lung, and Blood Institute were 1.62 (1.31-2.00) and 1.23 (1.09-1.39), respectively, for men and 1.32 (1.05-1.65) and 1.12 (1.00-1.25), respectively, for women. The respective HRs for MetS by the International Diabetic Federation definition did not reach statistical significance, except for coronary heart disease in men. Conclusions: Non-overweight individuals with metabolic risk factors, as well as overweight individuals with such factors, should be targeted to reduce the CVD burden in the general population. (Circ J 2009; 73: 1635-1642)

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Background: Obesity is associated with diabetes mellitus, hypertension, dyslipidemia and increased cardiovascular disease (CVD) risk. Anthropometric indices, such body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR), were evaluated as predictors of the presence of CVD risk factors in Korean adults. Methods and Results: The data were obtained from the Third Korea National Health and Nutrition Examination Survey (KNHANES III, 2005). The study contained a nationally representative sample of Korean adults (2,327 men, 3,102 women) aged 20 years or older. The area under the receiver operating characteristic (ROC) curve for WHtR was higher than that for WC or BMI with respect to diabetes mellitus and hypertension in both men and women, whereas WC was a better predictor for low high-density lipoprotein cholesterol in men. The WHtR cut-off value to predict diabetes mellitus, hypertension, and dyslipidemia was approximately 0.50 in men and 0.51 in women. The WC cut-offs varied from 81.6 to 85.2 cm in men and from 78.1 to 81.9 cm in women. The optimal BMI cut-off point varied from 23.0 to 24.7 kg/m² in both men and women. Conclusions: WC or WHtR may be a better predictor of CVD risk factors than BMI in Korean adults. (Circ J 2009; 73: 1643-1650)

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Background: Clinical features of micturition syncope (MS) seem to be differ according to age and the present study sought to clarify this. Methods and Results: The 37 consecutive patients (mean age: 52.2 ±16.8 years, 26 men) with MS were divided into 2 groups by median age of 55: younger group (YG) consisting of 18 patients <55 years (average 38.2) and an older group (OG) consisting of 19 patients ≥55 years (average 65.5). Alcohol-related MS was significantly more frequent in the YG than in the OG (78% vs 42%, P=0.027). Daily distribution of MS was significantly different (P=0.0009): 85% of the MS in the YG occurred before midnight (PM), whereas 75% of the MS in the OG occurred after midnight (AM). Although overall positive responses of head-up tilt testing were more common in the OG (P=0.046), gender, number of syncope, and association with vasovagal syncope or cardiovascular disease were not different between both groups. Conclusions: In the YG, MS tended to occur in the evening or nighttime before midnight, whereas MS in the OG tended to occur after midnight or early in the morning. Alcohol intake may be an important precipitating factor for MS in young subjects. (Circ J 2009; 73: 1651-1654)

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Background: Although B-type natriuretic peptide (BNP) has emerged as an important predictor for cardiac events, its effect on scintigraphic parameters is unknown. Methods and Results: The Q-PROVE study is a multicenter study to evaluate the prognostic value of ECG-gated SPECT in 175 Japanese elderly patients. In addition, BNP was assessed in 102 patients. Outcome assessment included cardiac events and noncardiac deaths. Twelve elderly patients (12%) had increased BNP >130 pg/ml. The summed stress score (SSS) was greater in patients with increased BNP than in those with normal BNP. Kaplan-Meier survival estimation indicated event-free survival rates at 3 years of 83%, 78%, 88%, 80%, respectively, in patients with BNP >130 pg/ml, SSS ≥7, summed difference score (SDS) ≥2, and dilated end-diastolic volume (EDV), but 98%, 98%, 100%, 94% in those with BNP ≤130 pg/ml, SSS <7, SDS <2 and normal EDV (P=0.006, P=0.005, P=0.0008, P=0.01). Multivariate analysis demonstrated that an SDS was the only independent predictor for subsequent cardiac events (hazard ratio =4.0, P=0.04). Conclusions: Although BNP may have similar prognostic value to gated SPECT volumetric measurements in elderly patients with known or suspected coronary artery disease, myocardial ischemia as documented by SPECT is still indispensable for detecting high-risk patients compared with BNP alone. (Circ J 2009; 73: 1655-1660)

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Background: In ischemia-reperfusion, contraction band necrosis (CBN) is distributed mainly to the lateral border of the risk area and does not spread into the non-risk area beyond the border. It has been suggested that CBN is propagated through gap junctions (GJs), but it is unclear how GJs transmit CBN exclusively in the risk area. Methods and Results: Coronary occlusion for 30 min in rat increased the level of connexin43 (Cx43) protein in the 100,000 × g pellet fraction to 1.5-fold and decreased that in the 1,000 × g pellet to half in the risk area compared with the non-risk area. Immunohistochemical analysis showed an increase of Cx43 at intercalated disks in the risk area. A dye transfer assay demonstrated enhancement of GJ intercellular communication (GJIC) in the risk area compared with the non-risk area in the same section. Administration of a GJ blocker, carbenoxolone, at the onset of reperfusion following 30 min of ischemia reduced the CBN area (1/3 vs PBS) in 5 min of reperfusion and limited the infarct size (2/3 vs PBS) in 6 h of reperfusion. Conclusions: These data suggest that ischemia enhances translocation of Cx43 to GJs, thereby promoting propagation of CBN exclusively in the risk area through enhanced GJIC after reperfusion. (Circ J 2009; 73: 1661-1668)

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Background: Cystatin C is reportedly a better endogenous marker of glomerular filtration rate than serum creatinine, so the prognostic value of cystatin C in patients with ST-elevation myocardial infarction (MI) was evaluated in the present study. Methods and Results: A total of 71 patients who underwent percutaneous coronary intervention for ST-segment elevation MI <24 h from symptom onset were included. According to cystatin C level, patients were classified into 2 groups: (1) higher cystatin C group (n=33) and (2) lower cystatin C group (n=38). There was a trend toward more in-hospital deaths in patients with the higher cystatin C level compared with the lower cystatin C level group (15.2% vs 2.6%, P=0.06). Mean duration of clinical follow-up was 5.6 ±2.8 months. There was no significant difference in death, reinfarction, disabling stroke or target lesion revascularization between the 2 groups. However, a higher incidence of rehospitalization for congestive heart failure was observed in patients with the higher cystatin C level than in those with the lower cystatin C level (15.2% vs 0%, P=0.01). Conclusions: Cystatin C may be associated with more cardiovascular events, mainly rehospitalization for congestive heart failure, after percutaneous coronary intervention in patients with ST-elevation MI. (Circ J 2009; 73: 1669-1673)

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Background: Placental growth factor (PlGF), a homolog of vascular endothelial growth factor, is reported to stimulate angiogenesis and arteriogenesis in pathological conditions. It was recently demonstrated that PlGF is rapidly produced in myocardial tissue during acute myocardial infarction (MI). However, the effects of exogenous PlGF administration on the healing process after MI are not fully understood. The purpose of the present study was to examine whether PlGF treatment has therapeutic potential in MI. Methods and Results: Recombinant human PlGF (rhPlGF: 10 μg) was administered continuously for 3 days in a mouse model of acute MI. rhPlGF treatment significantly improved survival rate after MI and preserved cardiac function relative to control mice. The numbers of CD31-positive cells and α-smooth muscle actin-positive vessels in the infarct area were significantly increased in the rhPlGF group. Endothelial progenitor cells (Flk-1⁺Sca-1⁺ cells) were mobilized by rhPlGF into the peripheral circulation. Furthermore, rhPlGF promoted the recruitment of GFP-labeled bone marrow cells to the infarct area, but only a few of those migrating cells differentiated into endothelial cells. Conclusions: Exogenous PlGF plays an important role in healing processes by improving cardiac function and stimulating angiogenesis following MI. It can be considered as a new therapeutic molecule. (Circ J 2009; 73: 1674-1682)

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Background: Whether echo-Doppler-derived index of ventricular elastance or ventriculoarterial interaction can reliably reflect circulatory efficiency in various conditions was investigated in the present study and whether they can be helpful in predicting exercise capacity in patients with dilated cardiomyopathy (DCM). Methods and Results: The 25 patients with DCM, 25 age- and gender-matched hypertensive patients, and 25 marathon runners underwent symptom-limited graded supine bicycle exercise echocardiography after resting echo-Doppler evaluation. Echo-Doppler-derived left ventricular (LV) diastolic elastance index (Ed), ventricular-vascular coupling index (10 × Ea/Ees), based on arterial elastance index (Ea) to LV end-systolic elastance index (Ees), and hemodynamic parameters were measured during rest and exercise. DCM patients had lower Ees, higher Ed and Ea/Ees with blunted exercise responses of Ees than the other groups, and the hypertensive patients had lower Ees and ΔEes compared with the marathon runners. Resting Ed, Ea/Ees, and total stiffness index (10 × Ed × Ea/Ees) correlated with exercise duration independent of age and gender. A stiffness index of 0.8 could reliably predict impaired exercise capacity. Conclusions: Echo-derived elastance is predictive of exercise capacity in patients with DCM. (Circ J 2009; 73: 1683-1690)

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Background: Mutations of cardiac troponin C (cTnC) can cause dilated cardiomyopathy in humans. Methods and Results: Plasmids were constructed such that the reverse tetracycline-controlled transactivator (rtTA) was driven by the cardiac myosin light chain 2 promoter. This heart-specific rtTA bound another bidirectional promoter to express the green fluorescence protein reporter gene and the antisense RNA of cTnC in the presence of doxycycline. A transgenic line of zebrafish (CA17) with cTnC dysfunction was also generated. The heart rates of the embryos in the CA17 line were significantly slower than those of embryos in the control T03 transgenic line at 6 and 12 days post fertilization (dpf). In the CA17 line, cardiac chambers in the F2 embryos were significantly greater and the ventricular ejection fraction was lower than those in the T03 at both 6 and 12 dpf. The mortality rate of F2 adult fish of the CA17 line was also significantly higher (P<0.001). Conclusions: Using conditional expression of antisense RNA of zebrafish cTnC, a new animal model with phenotypes simulating dilated cardiomyopathy has been created. (Circ J 2009; 73: 1691-1697)

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Background: The maximum rate of the ventricular pressure rise (dp/dt_max) provides a reliable measure of ventricular contractility. However, its estimation requires invasive measurement of left ventricular (LV) pressure, limiting its bedside clinical applicability. In the present study, 2 hypotheses were tested: (1)that the ratio of dp/dt_max between the aorta (Ao) and LV is consistent among patients despite marked differences in underlying cardiac disease, contractile state and heart rate when vascular mechanical and loading properties are taken into account, and (2)that using such a relationship, LV dp/dt_max can be estimated from Ao dp/dt_max, potentially providing a method of noninvasive determination of LV contractility. Methods and Results: Data from 30 control children and 45 pediatric patients with various cardiovascular diseases revealed that the characteristic impedance (Zc) and mean arterial pressure were significant determinants of the Ao-LV dp/dt_max relationship in both control and disease groups. LV dp/dt_max estimated using the regression obtained in the control children (Ao dp/dt_max/LV dp/dt_max = 0.64+1.45*10^-4*Zc-3.73*10^-3*MAP, r=0.87) correlated well with the measured LV dp/dt_max in the disease group, including measurements taken after dobutamine and atrial pacing (r=0.89). Conclusions: Ao dp/dt_max and LV dp/dt_max are closely correlated through the vascular loading properties and LV dp/dt_max can be derived from Ao dp/dt_max, which has potential as a noninvasive method of determining LV contractility. (Circ J 2009; 73: 1698-1704)

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Background: Thromboembolic events account for significant morbidity and mortality after the Fontan procedure, but the underlying mechanisms remain unclear. P-selectin on platelets indicates platelet activation. Thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. The present study investigated the hypothesis that the balance between platelet activation and endothelial biological function is impaired in Fontan patients. Methods and Results: Platelet P-selectin as a marker of platelet activation, plasma TM levels and protein C activity, as markers of anticoagulant activity of the endothelium, and thrombin-antithrombin complex III (TAT) were examined in 43 Fontan patients. P-selectin levels on platelets (4.5 ±1.4 vs 3.4 ±0.4 mean fluorescence intensity, P<0.001) and TAT levels (80.2 ±322.6 vs 1.9 ±0.9 ng/ml, P<0.05) were significantly higher in Fontan patients than in control subjects. On the other hand, plasma TM levels (1.5 ±0.8 vs 2.2 ±0.3 FU/ml, P<0.01) and protein C activity (71 ±35 vs 118 ±25%, P<0.001) were significantly lower in Fontan patients compared with controls. These abnormalities were not seen in patients after other surgical procedures for congenital heart disease. Conclusions: Platelet activation is enhanced and endothelial function is impaired in patients after the Fontan procedure, which may partly explain the thromboembolic complications in Fontan patients. (Circ J 2009; 73: 1705-1710)

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Background: This study was performed to clarify the present global clinical status, including medication(s) and social abilities, of adult patients with single ventricular physiology (SVP). Methods and Results: Clinical charts were retrospectively reviewed to evaluate the global clinical status, including functional capacity, medication(s), complications, and social activities of 68 adult patients with SVP aged 20-53 years (41 males); 50 had undergone the Fontan operation and they were divided into the young adult (25 patients) and adult Fontan groups. The others were cyanotic patients without the Fontan operation (non-Fontan group). Although the Fontan groups showed better functional capacity, higher arterial oxygen saturation and brain natriuretic peptide levels, and a better renal function, there was no difference in the cardiovascular events during follow-up between the 3 groups. The most frequent complication was arrhythmia without a significant group difference, although the non-Fontan group showed a high percentage of heart failure. Only 41 patients (60%) had a job and 8 (12%) were married. Conclusions: Although the Fontan groups had favorable pathophysiological conditions, the high rate of cardiovascular events, as well as unsatisfactory social situations, indicate the importance of meticulous life-long management of patients with SVP, regardless of the type of surgical intervention. (Circ J 2009; 73: 1711-1716)

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Background: The role of radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT) in infants and toddlers is still unclear. Methods and Results: From 1993 to 2006, 27 (17 males, 10 females) of 210 patients underwent RFCA at an age less than 6 years. Indications included drug-refractory SVT or tachycardia-induced cardiomyopathy. The medical records were reviewed and the patients were interviewed regarding their current status. The 27 patients underwent RFCA at a median age of 4.4 years (8 months to 5.9 years) and a median body weight of 15 kg (6.6-30 kg). The SVT was mainly atrioventricular reentry tachycardia (15/27) and multiple mechanisms in 3. One-third of them had associated congenital heart disease, and 5 underwent RFCA using only 2-3 catheters. Immediate success rate was 92.6%, with low early (3.7%) and late recurrence (7.4%) after 5.4 ±3.7 years follow-up. Tachycardia-induced cardiomyopathy was noted in 4 and resolved in all after RFCA. Procedure-related complications included complete atrioventricular block in 1 and Bezold-Jarisch reflex in another. No other risk factors for outcomes were noted, even with low body weight. Conclusions: The outcome of RFCA for medically refractory SVT, even associated with tachycardia-induced cardiomyopathy, in infants and toddlers is favorable. (Circ J 2009; 73: 1717-1721)

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Background: Propylthiouracil (PTU) enhances nitric oxide production and inhibits smooth muscle cell proliferation, suggesting a possible role in the prevention of pulmonary arterial hypertension (PAH). Methods and Results: The 30 male Sprague-Dawley rats were randomized to receive saline injection only (group 1), monocrotaline (MCT) (70 mg/kg) only (group 2) or MCT + 0.1% PTU in drinking water (group 3) given on day 5 after MCT administration. By day 35, western blot showed lower connexin43 (Cx43) and membranous protein kinase C-ε expressions in the right ventricle (RV) of group 2 animals than in the other groups (all P<0.05). Conversely, Cx43 expression in the lung was higher in group 2 than in other groups (all P<0.02). Additionally, mRNA expressions of matrix metalloproteinase-9, tissue necrotic factor-α, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric oxide synthase were lower, in the lungs and RV of group 2 rats than in the other groups (all P<0.05). Moreover, the numbers of alveolar sacs and lung arterioles were also reduced in group 2 than in other groups (all P<0.05), and RV systolic pressure and RV weight were increased in group 2 compared with other groups (all P<0.001). Conclusions: PTU effectively attenuates complications associated with MCT-induced PAH. (Circ J 2009; 73: 1722-1730)

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Background: Direct evidence for Rho-kinase activation in patients with pulmonary hypertension (PH) is still lacking. Methods and Results: Rho-kinase activity in circulating neutrophils was examined by determining the ratio of phosphorylated/total forms of myosin-binding subunit, a substrate of Rho-kinase, in 40 consecutive PH patients and 40 healthy controls. Next, Rho-kinase expression and activity was examined in isolated human lung tissues (5 patients with idiopathic pulmonary arterial hypertension [IPAH], 5 controls) and vascular reactivity of isolated small human pulmonary arteries in vitro (4 IPAH, 4 controls). Rho-kinase activity in circulating neutrophils was significantly increased in the PH patients overall compared with controls (P<0.0001). Significant correlations were noted between Rho-kinase activity and the severity and duration of PAH (all P<0.05). Rho-kinase expression and activity in isolated lung tissues also were significantly increased in the IPAH patients compared with the controls (both P<0.0001). Endothelium-dependent relaxation was markedly impaired and serotonin-induced contraction (in the absence of the endothelium) markedly enhanced in the PAH patients compared with the controls, and the hypercontraction to serotonin was abolished by hydroxyfasudil, a specific Rho-kinase inhibitor. Conclusions: These results provide the first direct evidence for Rho-kinase activation in patients with PAH, suggesting the therapeutic importance of Rho-kinase in the disorder. (Circ J 2009; 73: 1731-1739)

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Background: There are plausible reasons to hypothesize that increased aortic stiffness and left ventricular (LV) dysfunction may occur in early renal insufficiency. Methods and Results: The correlation of glomerular filtration rate (GFR) with the augmentation index (AI) of ascending aortic pressure and indices of LV systolic and diastolic function (ejection fraction, LV pressure relaxation time constant, LV end-diastolic pressure and mitral inflow (E/A) and annular velocities (S' and E')) was examined in 359 consecutive patients undergoing cardiac catheterization for coronary artery disease (CAD). When patients were stratified according to GFR of 60, 75 and 90 ml · min^-1 · 1.73 m^-2, there was a progressive increase in AI and decreases in E/A and E' with decreasing GFR. There were no linear trends in other indices of systolic or diastolic function across GFR groups. After adjustment for potential confounders, reduced GFR was associated with increased AI, but not with decreased E/A or E'. Conclusions: Early renal impairment may be partly associated with increased aortic stiffness, but not with LV systolic or diastolic function in CAD patients. (Circ J 2009; 73: 1740-1745)

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Background: Tissue factor (TF) is the primary initiator of blood coagulation. In response to tumor necrosis factor (TNF)-α human umbilical vein endothelial cells (HUVECs) express 2 TF isoforms: a soluble alternatively spliced isoform (asHTF) and membrane-bound "full length" (fl)TF. How the differential TF isoform expression is regulated is still unknown. This study compared the impact of PI3K/Akt pathway inhibition on alternative splicing of TF in HUVECs, to the influence of transcriptional regulation by inhibiting nuclear factor κ B (NFκB). Methods and Results: The mRNA expression of TF isoforms was assessed by real-time PCR, the thrombogenic activity was measured by a chromogenic TF activity assay and the phosphorylation state of serine/arginine-rich (SR) proteins was analyzed by western blotting. Transfection of HUVECs was done 72 h before the inhibition experiments were performed. PI3K/Akt pathway inhibition reduced the mRNA expression of asHTF but not flTF. Inhibition of NFκB reduced the expression of both isoforms. Moreover, the PI3K/Akt pathway inhibition, but not that of NFκB, modified the phosphorylation of the SR proteins SRp75, SRp55 and SF2/ASF. Additionally, overexpression of SF2/ASF and SRp75 influenced the differential TF-isoform expression in HUVECs. Conclusions: The PI3K/Akt pathway modulates alternative splicing of TF in HUVECs, distinct from transcriptional regulation. (Circ J 2009; 73: 1746-1752)

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Pheochromocytoma is a rare cause of cardiogenic shock. Clinical management is directed at reducing the heart rate while maintaining blood pressure. However, medical treatment is often unsuccessful because of the high endogenous catecholamine level and low cardiac output. Percutaneous cardiopulmonary bypass system is a circulatory device that allows for safer use of heart-rate-reducing agents, which is advantageous when used early in the course of the cardiogenic shock induced by pheochromocytoma. (Circ J 2009; 73: 1753-1755)

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Pulmonary embolism (PE) is a fatal disease that is very rare in young people. A 21-year-old man developed PE because of a retroperitoneal tumor. The inferior vena cava (IVC) was obstructed by the tumor, and thrombus existed in the right common iliac vein. Thrombolysis and heparinization improved his symptoms prior to urgent tumor resection. A temporary IVC filter was inserted the day before the operation, but 8 h later fatal massive PE occurred. At autopsy, the retroperitoneal tumor was revealed as a metastatic choriocarcinoma. Prophylactic use of a temporary IVC filter might have paradoxically induced recurrence of massive PE in this case. (Circ J 2009; 73: 1756-1758)

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Stent thrombosis is one of the most feared complications after coronary stenting, because it often presents in a catastrophic way, triggering death or acute myocardial infarction. Previous studies report mechanical risk factors of stent thrombosis such as stent underexpansion and vessel dissection. This is a case report of early stent thrombosis associated with bare metal stent dislodgement because of dissolution of a mural thrombus in an unappreciated coronary artery aneurysm. (Circ J 2009; 73: 1759-1761)

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Stent thrombosis is defined as thrombotic occlusion of a stent resulting in acute coronary syndrome (ACS). However, all thrombotic occlusions of stents might not result in ACS. The present case report describes silent, very late thrombotic occlusion of a drug-eluting stent that was confirmed from specimens removed by directional coronary atherectomy. (Circ J 2009; 73: 1762-1764)

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