Obesity has reached epidemic proportions and complications related to obesity contribute substantially to both healthcare costs and mortality. Obesity, particularly when accompanied by an excess of visceral/ectopic fat, is a major risk factor for diseases ranging from insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The epidemic proportions reached by obesity has made these conditions a global problem in human health. Accordingly, preventive and/or therapeutic interventions should be considered in obese patients. Regular physical activity/exercise has numerous beneficial effects on the cardiometabolic risk profile and on the cardiovascular system. However, our current clinical environment is not designed to provide the regular support needed by patients to help them maintain over the long term their improved physical activity/nutritional habits. Because hypertension, dyslipidemia, hyperinsulinemia, and excess visceral adipose tissue are linked by complex reciprocal molecular interactions, it is logical to expect that targeting an interconnected pathway may provide multiple benefits. At this stage, combined therapy of statins or PPAR agonists and renin-angiotensin-aldosterone system blockers to target multiple therapeutic pathways may optimally improve the cardiometabolic risk profile through both distinct and interrelated mechanisms. In the present article, we will discuss updated novel approaches, including potential multi-targeted intervention strategies, based on underlying pathophysiological processes. (Circ J 2011; 75: 1019-1027)

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The burden of heart valve disease among adults is enormous in the developed world. Increased life expectancy and age-related valvular degeneration remain the predominant contributors to heart valve dysfunction, which if uncorrected lead to congestive heart failure and increased morbidity and mortality. Clinical evidence on the detrimental impact of valve disease on both pediatric and adult populations has fueled growing interest in diagnosis and therapy for heart valve disease, and also significant financial investment from hospitals and medical device manufacturers in hybrid operating rooms and novel medical device technologies. A wide array of surgical, minimally invasive and percutaneous heart valve technologies are available today, which have significantly enlarged the surgeon's armamentarium, and revolutionized the traditional role of a surgeon in correcting such lesions. Amid this revolution in heart valve technologies, we present recent advances in heart valve therapies, critically appraise their clinical need, and finally discuss the clinical experience and outcomes of some of these technologies. The expected outcome of this review is to provide the clinical reader with a reasonable scientific basis to enable appropriate adoption of these technologies into their clinical practice. (Circ J 2011; 75: 1028-1041)

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Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood-brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed. (Circ J 2011; 75: 1042-1048)

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Background: Mild hypothermia is an effective therapy for patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest. However, evidence of the effectiveness of therapeutic hypothermia (TH) remains unclear. Methods and Results: A multicenter registry in Japan (J-PULSE-HYPO study registry) was conducted to investigate the effectiveness of TH for post-resuscitation neurological dysfunction developing after out-of-hospital cardiac arrest from 14 institutions, between January 2005 and December 2009. The committee entrusted each hospital with the timing of cooling, cooling methods, target temperature, duration, and rewarming. There were 452 patients (375 men) enrolled into the registry. The mean age was 58.6±13.5 years. Initial electrocardiogram rhythm at the time of occurrence of the cardiac arrest showed 68.9% had ventricular fibrillation or pulseless ventricular tachycardia, 13.7% had pulseless electrical activity, and 9.1% had asystole. The median interval from the occurrence of cardiac arrest to ROSC was 26min. The target core temperature during TH was 33.9±0.4°C and the mean duration of cooling was 31.5±13.9h. Intra-aortic balloon pumping was used in 40.1% and percutaneous cardiopulmonary support in 22.6% of patients. At 30 days after cardiac arrest, the proportion of survival was 80.1% and the proportion of patients with favorable neurological functions, with a cerebral performance category score of 1 or 2, was 55.3%. Conclusions: The J-PULSE-HYPO study registry showed a clinical aspect of TH. (Circ J 2011; 75: 1063-1070)

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Background: A previous study reported that amlodipine retarded coronary plaque progression in patients with coronary artery disease. The goal of this multicenter study was to determine which calcium-channel blockers (CCBs) other than amlodipine attenuated the progression of plaque volume (PV) accessed by intravascular ultrasound (IVUS). Methods and Results: ALPS-J was a prospective, randomized open-label study conducted at 5 centers. Patients who had hypertension and were scheduled for coronary intervention were enrolled. Subjects were randomly assigned to receive 16mg/day of azelnidipine or 5mg/day of amlodipine administered for 48 weeks. The primary endpoint was the percent change in coronary PV measured by IVUS. Between 2007 and 2009, 199 patients were enrolled; 115 had evaluable IVUS images at both baseline and after 48 weeks of treatment. Blood pressure significantly reduced to 128/68mmHg at follow-up. The lipid profiles in the 2 groups were comparable (low-density lipoprotein cholesterol: 97mg/dl). The %change in PV showed a significant regression of 4.67 and 4.85% in the azelnidipine and amlodipine groups, respectively. The upper limit of the 95% confidence interval of the mean difference in %change PV between the 2 groups (0.18%, 95% confidence interval 4.62 to 4.98%) did not exceed the pre-defined non-inferiority margin of 6.525%. Conclusions: ALPS-J demonstrated that azelnidipine was not inferior to amlodipine for primary efficacy. In addition to standard medical therapy, dihydropyridine CCBs will retard PV progression in hypertensive patients. (Circ J 2011; 75: 1071-1079)

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Background: Atrial tachycardia (AT) occurring during atrial fibrillation (AF) ablation is sometimes difficult to identify and eliminate. EnSite Array (EA) visualizes beat-to-beat virtual activation of AT. The aim of the present study was to characterize AT occurring during AF ablation during ongoing AF, using EA. Methods and Results: Among 90 patients with AF (paroxysmal, n=67; persistent, n=23) who underwent radiofrequency catheter ablation during ongoing AF, 33 (37%) had 46 ATs that developed during ablation, and 9 (10%) of these patients had 9 ATs that developed before ablation. AT was sustained in 39 and non-sustained in 7. Nineteen ATs resulted from a focal mechanism and 27 from macroreentry. The major AT foci were distributed in the pulmonary vein (n=8) and left atrial roof (n=3), and macroreentrant ATs mainly consisted of peri-mitral AT (n=10), common atrial flutter (n=10), and roof reentrant AT (n=3). After EA-guided ablation of AT, 41 ATs in 28 patients (85%) were eventually rendered non-inducible. During 21±8 months of follow-up, 30 of the 33 patients (91%) were free from AF/AT recurrence. Conclusions: AT occurred in 37% of the patients during ongoing AF ablation, resulting from a focal or reentrant mechanism in diverse locations. Peri-mitral AT, common atrial flutter, and AT from the pulmonary vein were frequently observed. These ATs were eliminated by EA-guided radiofrequency ablation in most cases. (Circ J 2011; 75: 1080-1089)

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Background: Although atrial high rate episodes (AHRE) have been commonly used to detect atrial tachyarrhythmias (AT/AF) in pacemaker patients, its reliability and characteristics are unclear. Methods and Results: 39 patients with implanted dual chamber pacemakers (mean age 79.7±6.6 years), who had no history of AT/AF and were programmed in the setting of AHRE at >190beats/min in DDD mode, were studied. An atrial overdrive pacing (AOP) algorithm was randomly programmed "ON" in 19 and "OFF" in 20 patients. AHRE were detected in 20 patients (51%), consisting of AT/AF in 15 and repetitive non-reentrant ventriculoatrial synchrony (RNRVAS) in 8 patients, all included in the AOP "ON" group. A total of 257 of 1,528 episodes of AHRE were available for analysis, including 181 and 76 episodes in the AOP "ON" and "OFF" groups, respectively. Among 181 episodes in the AOP "ON" group, 72 (40%) were RNRVAS, whereas all episodes in the AOP "OFF" group (100%) were AT/AF. Detection of RNRVAS was closely associated with a high cumulative % atrial pacing. The specificity of AT/AF detection by AHRE was 40% when the AOP algorithm was activated, vs. 100% when not in use. Conclusions: AT/AF was common in pacemaker patients without a history of AT/AF. The increase in cumulative % atrial pacing and the use of an AOP algorithm might be closely associated with RNRVAS, non-AT/AF, detected by AHRE. (Circ J 2011; 75: 1090-1097)

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Background: Sirolimus-eluting stents (SES) are widely used in coronary artery disease as revascularization therapy. Although endothelial dysfunction induced by implanted SES can become a major clinical concern, therapeutic strategies to overcome this disorder remain unclear. The aim of the present study was therefore to identify effective therapies in a clinically relevant animal model. Methods and Results: Twenty-one pigs were randomized to control, candesartan (CAN) and candesartan plus pioglitazone (CAN+PIO) groups. Drugs were administered orally for 7 days before SES implantation until the time of death. Forty-two SES were used in porcine coronary arteries. Early inflammatory cell adhesion in SES evaluated on scanning electron microscopy at 3 days was significantly suppressed in the CAN and CAN+PIO groups compared with controls. Bradykinin-induced endothelium-dependent relaxation at an adjacent segment distal to the SES evaluated using organ chambers was reduced compared with intact segments in control coronaries at 28 days. Endothelial dysfunction was reversed by CAN and even more obviously improved in the CAN+PIO group. Conclusions: Candesartan protected against vascular inflammation and restored endothelial function after SES implantation. The combination of candesartan and pioglitazone was more effective than candesartan monotherapy and might confer vascular protection when administered before SES implantation. (Circ J 2011; 75: 1098-1106)

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Background: Primary percutaneous coronary intervention (PCI) is an important treatment option for patients with acute myocardial infarction (MI). Although an inverse association between a hospital's PCI volume and in-hospital mortality has been observed in Western studies, previous Japanese investigations have not found any such relationship. Methods and Results: A retrospective analysis of 8,391 cases of acute MI, obtained from administrative data from 2006. The primary outcome was in-hospital mortality. Hospitals were divided into quartiles based on the number of PCI procedures per half-year (6-13, 14-22, 23-38, 39-134) and mortality rates were compared across the groups. Crude-mortality in the lowest-volume quartile was 7.0%, compared with 4.9% in the highest-volume quartile. An inverse association was found between primary PCI procedure volume and crude in-hospital mortality (P=0.016). After case-mix adjustment, a significant decrease in mortality risk for patients treated at high-volume (3^rd and 4^th quartile) hospitals compared to the lowest-volume (1^st quartile) hospitals was found. Conclusions: Based on this administrative data, there is an inverse association between a hospital's primary PCI volume and in-hospital mortality for patients with acute MI. Periodic outcomes research is necessary in conjunction with progress in PCI practice and technology to establish the recommended PCI volume and regionalization for improvements in care. (Circ J 2011; 75: 1107-1112)

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Background: Second-generation drug-eluting stents (DES) are expected to show better arterial repair than older DES. We angioscopically compared the biodegradable polymer-coated biolimus A9-eluting stent (BES) and durable polymer-coated sirolimus-eluting stent (SES) to explore differences in arterial repair. Methods and Results: Angioscopy was performed 9±1 months after 15 BES and 16 SES were implanted initially in the native coronary artery. Heterogeneity of neointimal coverage (NIC) as well as the dominant NIC grade was examined. NIC was defined as: grade 0=fully visible struts; grade 1=struts bulging into the lumen, but covered; grade 2=embedded, but translucent struts; grade 3=invisible struts. Heterogeneity was judged when the NIC grade varied ≥1. In-stent late loss (0.06±0.23 vs. 0.07±0.18mm, P=0.80), and dominant NIC grade (1.5±0.8 vs. 1.3±0.7, P=0.45) were similar for BES and SES. Within the stents, NIC was more heterogeneous in SES than in BES (P=0.035). 80% of BES showed homogeneous NIC, while 56% of SES had heterogeneous NIC. Conclusions: BES showed limited late loss similar to that for SES. Nonetheless, the NIC with BES was more homogeneous than that with SES. Biodegradable polymer-coated BES may have an advantage in homogeneous NIC. (Circ J 2011; 75: 1113-1119)

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Background: The long-term impact of treating de novo coronary lesions in native vessels and challenging small vessel and long lesion subsets with TAXUS Liberté stents is unknown. This report examines the 3-year efficacy and safety from the TAXUS ATLAS program. Methods and Results: TAXUS ATLAS WH, Small Vessel, and Long Lesion are non-randomized studies comparing TAXUS Liberté (n=871), TAXUS Liberté 2.25mm (n=261), and TAXUS Liberté 38mm (n=150) stents, respectively, to case-matched TAXUS Express historical controls. TAXUS Liberté demonstrated comparable 3-year rates of major adverse cardiac events (19.0% vs. 20.2%, P=0.51) in de novo lesions, reduced target lesion revascularization (TLR, 10.0% vs. 22.1%, P=0.008) in small vessels, and reduced myocardial infarction (MI, 2.9% vs. 10.4%; P=0.01) and stent thrombosis (ST, 0.0% vs. 3.9%, P=0.03) in long lesions vs. TAXUS Express. After propensity score adjustment, no statistically significant effect of TAXUS Liberté on TLR (9.7% vs. 16.9%, P=0.12) in small vessels or MI (2.9% vs. 7.9%, P=0.05) in long lesions was noted, although reduced ST (0.0% vs. 2.7%, P=0.02) remained in long lesions. Multivariate analyses demonstrated that TAXUS Liberté treatment significantly reduced TLR by 66% in small vessels, and MI by 75% in long lesions, vs. TAXUS Express. Conclusions: TAXUS Liberté suggests durable 3-year effectiveness in reducing restenosis and improved clinical outcomes in small vessels and long lesions compared with TAXUS Express. (Circ J 2011; 75: 1120-1129)

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Background: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score was proposed as a method to evaluate the complexity of coronary anatomy. However, the reproducibility of assessment for the SYNTAX score in unprotected left main coronary artery (ULMCA) disease has not yet been adequately evaluated. The purpose of this study is to assess inter- and intra-observer variability for the assessment of the SYNTAX score in patients undergoing ULMCA stenting in daily clinical practice. Methods and Results: The SYNTAX score of 101 consecutive patients who underwent ULMCA stenting with sirolimus-eluting stent was independently assessed by 2 experienced interventional cardiologists. One of the 2 cardiologists evaluated all the cases again 6 months after the initial assessment. The κ value for inter-observer variability in estimating the SYNTAX score was 0.62 according to the dichotomized analysis (≥33, <33) and 0.58 according to the tertile analysis (<23, 23≤-<33, ≥33), while the intra-observer variability was 0.78 and 0.69, respectively. Patients with a high SYNTAX score (≥33, n=55) compared with those with low or intermediate score (<33, n=46) had a significantly higher rate of target-lesion revascularization (TLR) of the ULMCA lesion at 2 years (24% vs. 4.4%, P=0.01). Conclusions: Both inter- and intra-observer variability for estimating the SYNTAX score were within an acceptable range and a high SYNTAX score showed a higher rate of TLR in patients undergoing ULMCA stenting in daily clinical practice. (Circ J 2011; 75: 1130-1137)

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Background: Cerebrovascular accident (CVA) is a major adverse event following left ventricular assist device (LVAD) surgery. This study investigates pre- and post-operative factors associated with CVA in this population. Methods and Results: A total of 118 consecutive patients who underwent LVAD surgery at our institution between April 1994 and April 2009 were retrospectively reviewed. Clinical characteristics, hemodynamic data, and laboratory indexes associated with CVA after LVAD surgery were analyzed. In total, 57 (48.3%) patients developed CVA 133.5±184.7 days after surgery. The combination of baseline heart disease, type of LVAD surgery, mean right atrial pressure (mRA), serum total bilirubin and total protein concentration, and right ventricular end-diastolic dimension (RVEDd) was associated with CVA at any time after LVAD surgery, with a discriminant probability of 718%. With regard to CVA development later than 3 months after surgery, the combination of mRA and RVEDd before surgery [odds ratio (OR), 1.24, 1.20; 95% confidential interval (CI), 1.07-1.42, 1.06-1.34; P=0.004, P=0.006, respectively], positive blood culture, and C-reactive protein after surgery (OR, 7.66, 2.19; 95%CI, 1.50-39.0, 1.47-3.25; P=0.015, P<0.0001, respectively) was associated with CVA with a discriminant probability of 85.9%. Conclusions: Patients' general condition including malnutrition, in addition to device selection, contributed to overall CVA development after surgery. In the chronic phase after surgery, pre-LVAD right heart failure and post-LVAD systemic infection were highly associated with CVA development. (Circ J 2011; 75: 1138-1146)

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Background: Postoperative development of aortic insufficiency (AI) after implantation of left ventricular assist devices (LVADs) has recently been recognized, but the devices in the previous reports have been limited to the HeartMate I or II. The purposes of this study were to determine whether AI develops with other types of LVADs and to elucidate the factors associated with the development of AI. Methods and Results: Thirty-seven patients receiving LVADs without evident abnormalities in native aortic valves were enrolled (pulsatile flow LVAD [TOYOBO]: 76%, continuous flow LVAD [EVAHEART, DuraHeart, Jarvik2000, HeartMate II]: 24%). Frequency of aortic valve opening and grade of AI were evaluated by the most recent echocardiography during LVAD support. None of the patients had more than trace AI preoperatively. During LVAD support AI >- grade 2 developed in 9 patients (24%) across all 5 types of devices. More severe grade of AI correlated with higher plasma B-type natriuretic peptide concentration (r=0.53, P<0.01) and with less frequent of the aortic valve (r=0.45, P<0.01). Multivariate analysis revealed that lower preoperative left ventricular ejection fraction and a continuous flow device type were independent risk factors for higher incidence of AI. Conclusions: AI, which is hemodynamically significant, develops after implantation of various types of LVADs. Physicians need to be more alert to the development of AI particularly with continuous flow devices. (Circ J 2011; 75: 1147-1155)

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Background: This multicenter prospective cohort study aimed to identify both ability of echocardiographic parameters to detect cardiac resynchronization therapy (CRT) volume responders and relation of these parameters with clinical outcomes. Methods and Results: CRT responder was defined as ≥15% reduction of left ventricular (LV) end-systolic volume at 6 months. Seven echocardiographic dyssynchrony parameters were evaluated. The clinical endpoint comprised time to death from any cause or unplanned hospitalization for a major cardiovascular event. Of the 217 patients enrolled, 63 percent were classified as volume responders, in whom significantly fewer events occurred than in non-responders (log rank, P<0.001). No single echocardiographic criterion had significant power to detect volume responders, but a combining measurement of dyssynchrony between septum and LV free wall with M-mode and tissue Doppler imaging was independently associated with volume responders. In addition, this combined parameter was associated with the endpoint (hazard ratio, 0.66, 95% confidence interval 0.30-0.98, P=0.04). In contrast, left bundle branch block was identified as an independent predictor of volume responders and more strongly associated with the endpoint (hazard ratio, 0.38, 95% confidence interval 0.20-0.72, P=0.003). Conclusions: Echocardiographic parameters did not show significant power to detect CRT responders independently. (Circ J 2011; 75: 1156-1163)

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Background: It is unclear whether adaptive servo-ventilation (ASV) is effective for all patients with heart failure (HF). The aim of the present study was therefore to investigate the effectiveness of ASV for all patients with HF. Methods and Results: Sixty-one patients with HF were recommended for ASV treatment, regardless of sleep-disordered breathing (SDB) severity and type. On the basis of the apnea-hypopnea index (AHI) results, patients were classified into 3 groups: 28 patients with AHI ≥40/h were designated as group A; 20 patients with AHI ≥20/h and <40/h were designated as group B; and 13 patients with AHI <20/h were designated as group C. After ASV treatment, brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) were improved almost equally in the 3 groups (changes in BNP level: group A, -313±480pg/ml; group B, -401±801pg/ml; group C, -225±240pg/ml; P=0.69; changes in LVEF: group A, 8.5±11.3%; group B, 10.5±9.6%; group C, 2.4±12.4%; P=0.17). Conclusions: ASV treatment for patients with mild SDB resulted in almost equal improvements in BNP levels and LVEF compared to that in patients with moderate and severe SDB, demonstrating that ASV is effective for all patients with HF. (Circ J 2011; 75: 1164-1169)

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Background: The effect of gestational hypertension on left ventricular (LV) function in previously normotensive young women has not been evaluated. Methods and Results: A total of 106 gestational hypertensive women (GHW, 32.3±4.2 years) and 93 normotensive pregnant women (NPW, 30.2±4.4 years) were enrolled. Transthoracic echocardiography, including 2-dimensional strain echocardiography, was done and myocardial performance (Tei index), LV mass index (LVMI), and relative wall thickness (RWT) were analyzed. GHW had significantly increased wall thickness (interventricular septum, 9.5±0.9mm vs. 8.8±1.0mm, P<0.001; posterior wall, 9.0±1.1mm vs. 8.5±1.1mm, P=0.007; and RWT, 0.39±0.06 vs. 0.35±0.05, P=0.02), higher LVMI (95.6±17.3g/m² vs. 86.1±14.5g/m², P=0.03), longer isovolumetric relaxation time (117.7±18.2ms vs. 82.3±12.6ms, P=0.003), lower E/A ratio (1.00±0.29 vs. 1.27±0.33, P=0.002), and higher Tei index (0.48±0.23 vs. 0.33±0.13, P=0.003) compared to NPW. Global longitudinal LV strain, representing LV systolic function, was also significantly reduced in GHW compared with NPW (-17.6±2.95% vs. -21.2±2.14%, P=0.02). A total of 62% of GHW (n=66) had abnormal geometry, of whom, 42 (40%) had eccentric hypertrophy (EH). A total of 93% of NPW (n=86) had normal geometry, and only 7 NPW (7%) had abnormal geometry. Conclusions: GHW had aggravated diastolic and longitudinal systolic dysfunction. GHW had increased LVMI with the abnormal geometric pattern of EH. The reversibility of these morphological and functional impairments after delivery needs to be clarified. (Circ J 2011; 75: 1170-1176)

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Background: To evaluate the age-adjusted Framingham risk score (AFRS), flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) for the prediction of the coronary heart disease (CHD) in patients with stable angina. Methods and Results: In 138 consecutive patients with stable angina, the interrelationship and predictive power of CHD were compared between the study parameters. In total, 71 patients demonstrated CHD after scheduled coronary angiography. The AFRS showed significant correlation with FMD (r=-0.43, P<0.01) and baPWV (r=0.41, P<0.01). Based on AFRS, FMD, baPWV and other risk factors of CHD, multivariate analysis showed that AFRS and FMD (odds ratio (OR) 20.098, 95% confidence interval (CI) 4.773-84.627, P<0.01, and OR 0.865, 95%CI 0.752-0.995, P<0.05, respectively) were independent predictors of CHD. The area under the receiver operating characteristic (ROC) curves for detecting CHD, AFRS, inverse FMD (iFMD) and baPWV were 0.863, 0.726 and 0.694, respectively (all P<0.01). However, there was no difference of the area under the ROC curves between AFRS alone and combined complex parameters (AFRS plus iFMD, AFRS plus baPWV, and AFRS plus iFMD plus baPWV) for detecting CHD. Conclusions: AFRS was a better predictor of CHD than either FMD or baPWV in patients with stable angina. This means that conventional risk factors for cardiovascular disease do not affect uniformly for atherosclerosis in coronary and peripheral arteries. (Circ J 2011; 75: 1177-1183)

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Background: Procalcitonin (PCT) is an established biomarker for the diagnosis of sepsis. Evidence is growing that PCT concentration correlates with the extent of atherosclerosis and prognosis in patients with coronary artery disease (CAD). Methods and Results: A total of 2,131 patients with CAD were followed up for a median of 3.6 years. During follow-up, death from cardiovascular causes was registered in 95 patients and non-fatal myocardial infarction in 85 patients. Median and quartile 1 and 3 are reported for PCT concentration. Patients who died of cardiovascular causes had higher PCT concentrations [0.021 (0.012/0.036) ng/ml vs. 0.015 (0.010/0.023) ng/ml; P<0.0001]. Patients with acute coronary syndrome had increased concentrations of PCT in relation to patients with stable angina [0.016 (0.011/0.027) ng/ml vs. 0.014 (0.009/0.014) ng/ml; P for trend <0.0001]. PCT concentration across quartiles was associated with the event rate (P=0.026; log-rank test) and mortality (P=0.00018). On Cox regression analysis, elevated PCT concentration was related to cardiovascular mortality [hazard ratio (HR), 1.34; 95% confidence interval (CI): 1.08-1.65, P=0.0070], but not to cardiovascular events (HR, 1.09; 95%CI: 0.93-1.28, P=0.28). After adjustment for C-reactive protein (CRP), PCT did not provide additional prognostic information. Conclusions: PCT is associated with future cardiovascular mortality in patients with CAD, but PCT is not superior to CRP for prediction of outcome. (Circ J 2011; 75: 1184-1191)

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Background: Several animal experiments on acute myocardial infarction (AMI) have shown that the cardioprotective effects of ischemic preconditioning are more significant in hypertensive subjects. However, because there are no clinical data on the impact of hypertension on ischemic preconditioning in patients with AMI, whether clinical ischemic preconditioning of prodromal angina was beneficial in AMI patients with hypertension was investigated in the present study. Methods and Results: 125 patients with a first anterior AMI who had undergone successful reperfusion therapy were divided into 2 groups, with or without hypertension, and into 2 further subgroups based on the presence or absence of prodromal angina. Dual-isotope (thallium-201(TL)/Tc-99m pyrophosphate) single-photon emission computed tomography (SPECT) was performed within 1 week of reperfusion therapy. Left ventricular (LV) function and LV mass index (LVMI) were measured by left ventriculography and echocardiography, respectively. In patients without hypertension, prodromal angina resulted in significantly less myocardial damage on TL-SPECT, better LV ejection fraction and a greater myocardial blush grade compared to patients without prodromal angina. However, these cardioprotective effects of prodromal angina were significantly diminished in hypertensive patients. Importantly, the myocardial salvage effects of prodromal angina showed a significant negative correlation with LVMI, which was significantly greater in hypertensive patients. Conclusions: The cardioprotective effects of prodromal angina were attenuated in patients with hypertension. Hypertensive LV hypertrophy may crucially limit the effects of ischemic preconditioning in AMI. (Circ J 2011; 75: 1192-1199)

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Background: The aim of the present study was to analyze epicardial (EPI) and endocardial (ENDO) strain (S) in patients with transthyretin-related cardiac amyloidosis (TTR-CA) and hypertrophic cardiomyopathy (HCM) using echocardiography (TTE) with 2-dimensional feature tracking imaging (FTI). Methods and Results: Thirty-three subjects (11 with HCM, 11 with TTR-CA, and 11 healthy subjects as controls) with a New York Heart Association functional class ≤II underwent conventional TTE and FTI. TTE was used for the evaluation of left ventricle (LV) wall thickness, mass, systolic and diastolic function. FTI was used for the evaluation of EPI and ENDO longitudinal, and circumferential, and radial S. LV wall thickness and mass were higher in both TTR-CA and HCM in comparison with controls (P<0.001), but ejection fraction (EF) was similar among patients with TTR-CA, HCM and controls (63±6%, 64±6%, 61±5%, respectively). ENDO and EPI longitudinal and circumferential S and radial S were significantly lower in HCM and TTR-CA when compared with controls (P<0.01). No differences in EPI and ENDO longitudinal S, ENDO circumferential S and radial S were found between TTR-CA and HCM groups, while EPI circumferential S was significantly lower in the TTRCA group (6±3.3%) than in the HCM group (8.1±4.3%; P<0.0001). Conclusions: Longitudinal, circumferential and radial LV deformations are impaired in patients with TTR-CA and HCM with a preserved EF. Impairment of EPI circumferential strain is greater in TTR-CA than in HCM. (Circ J 2011; 75: 1200-1208)

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Background: The purpose of the present study was to determine the relationship of inferior vena cava diameter (IVCD) and its respirophasic variation (IVC collapsibility index: IVCCI) with central venous pressure (CVP), and thereby to provide reference cut-offs for such IVC parameters to estimate elevation in CVP in pediatric patients with cardiovascular disease. Methods and Results: The study involved consecutive pediatric patients (n=118) with various heart diseases who either had a central venous catheter in the cardiac intensive care unit or underwent cardiac catheterization. The maximum (IVCD_max) and minimum (IVCD_min) diameters of IVC were measured on ultrasound simultaneously with measurements of mean CVP. IVCD_max, IVCD_min and IVCCI correlated significantly with CVP (R²=0.26, 0.47 and 0.41, respectively) in spontaneously breathing patients, but not in mechanically ventilated patients. Receiver operator characteristic curve analysis indicated that IVCCI under spontaneous breathing had the best area under the curve, with sensitivity of 1.0 and specificity of 0.98 for a cut-off of 0.22 to predict elevated CVP ≥10mmHg. Conclusions: IVCCI seems to be a useful and accurate non-invasive index for estimation of elevated CVP in pediatric patients with cardiovascular disease. (Circ J 2011; 75: 1209-1214)

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Background: There are few reports describing the features of maternal anti-SSA antibody-associated congenital complete heart block (CCHB) patients developing endocardial fibroelastosis (EFE). The aim of this study was to describe the clinical features and the outcome of patients with CCHB, with or without EFE. Methods and Results: Over a 20-year period, 12 consecutive patients diagnosed with maternal anti-SSA antibody-associated CCHB were identified. The maternal anti-SSA antibody levels were measured and fetal echocardiographic findings were reviewed. The ratios of the thickness of the endocardium to that of the whole wall of the left ventricle (LE/W) and right ventricle (RE/W) were measured to investigate the degree of endocardial thickening. A total of 7 patients survived (living group) and were not diagnosed as having EFE. The remaining 5 patients died and were diagnosed with EFE during autopsy (dead group). Fetal echocardiography of the patients showed differences in the thickening and hyperintensity of the endocardium. The RE/W value was significantly higher in the dead group than in the living group. The titers of both maternal anti-52-kDa and anti-60-kDa SSA antibodies were high, but showed no significant differences between the 2 patient groups. Conclusions: EFE was the major negative prognostic factor for CCHB. Myocardial damage, predominantly in the right ventricle, was related to the outcome of CCHB associated with EFE. (Circ J 2011; 75: 1215-1221)

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Background: The 12-lead electrocardiogram (ECG) has relatively poor specificity for identifying acute pulmonary embolism (APE). The aim of this study was to investigate ECG abnormalities according to 2 different criteria and their usefulness for assessing changes in APE. Methods and Results: Fifty-two APE patients underwent ECG examinations in the acute and chronic phases. ECG abnormalities were assessed according to Stein's criteria (QRS complex abnormalities and T wave inversion in any lead except aV_L, III, aV_R, or V₁) and Kosuge's criteria (T wave inversion in any lead except aV_R or aV_L). Many patients had electrocardiographic abnormalities in the acute phase, but no specific abnormalities were found. According to Kosuge's criteria, the frequency of T wave inversion was higher than that of abnormal QRS complexes and T wave inversion according to Stein's criteria (P<0.01). In 20 cases with preclinical ECG records, the time-course of changes in the T wave inversion score (total numbers of T wave inversions per patient) was examined. The peak T wave inversion score was noted at 3 days after onset (P<0.01). Conclusions: These results suggest that the T wave inversion score, calculated according to Kosuge's criteria, is useful for predicting the time-course of APE. (Circ J 2011; 75: 1222-1226)

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Background: To investigate the association between aortic calcification, concentrations of stem-cell-mobilizing cytokines and osteocalcin-positive mononuclear cells in a mouse model and patients with peripheral artery disease. Methods and Results: We estimated the concentration of the stem-cell-mobilizing cytokines stromal cell-derived factor α (SDF-1α), granulocyte colony stimulating factor and stem cell factor in a mouse model of aortic calcification developed in osteoprotegerin-deficient (OPG^-/-) mice, as well as in patient plasma samples. Calcification was estimated by a colorimetric assay of extracts of harvested mice aortas and by computed tomographic angiogram images in patients. The cytokine concentrations were assessed for association with the severity of calcification and the percentage of osteocalcin-positive mononuclear cells (OCN⁺ MNC) using non-parametric analysis. The serum concentration of stromal SDF-1α and granulocyte-colony stimulating factor (G-CSF) were significantly greater in OPG^-/- compared to control mice. The percentage of circulating OCN⁺ MNC was correlated to the concentration of SDF-1α in OPG^-/- mice. These cytokines also correlated with the severity of calcification in OPG^-/- mice. Patients with more severe calcification had a higher plasma concentration of the cytokines than those with less marked aortic calcification. The concentrations also correlated with circulating OCN⁺ MNC and aortic calcification volumes. Conclusions: The association between stem cell cytokines, OCN⁺ MNC and calcification suggests a possible role of bone-derived osteoprogenitor cells in the pathogenesis of vascular calcification. (Circ J 2011; 75: 1227-1234)

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Background: Tissue factor (TF) is expressed in 2 isoforms: membrane-bound "full length" (fl)TF and soluble alternatively spliced (as)TF. flTF is the major thrombogenic form of TF. Although the function of asTF is poorly understood, it was suggested that asTF contributes to tumor-associated growth and angiogenesis. In the heart of a developing embryo, asTF is expressed much later compared to flTF, but in adult heart, asTF exhibits a distribution pattern similar to that of flTF. Thus, it is possible that asTF may play a role in heart development via pro-angiogenic signaling. The purpose of the present study was to examine the effects of murine asTF overexpression in murine cardiomyocyte-like HL-1 cells on their pro-angiogenic potential, the chemotaxis of monocytic cells, and the expression of fibroblast growth factor-2 (FGF2), cysteine-rich 61 (Cyr61), and vascular endothelial growth factor (VEGF). Methods and Results: Expression of FGF2, Cyr61 and VEGF was assessed on reverse transcription-polymerase chain reaction and western blot. Cell migration, proliferation, and endothelial tube formation assays were carried out. It was found that overexpression of murine asTF in HL-1 cells increases their proliferation and pro-angiogenic properties. The supernatant of murine asTF-overexpressing HL-1 cells induces the chemotaxis of monocytic cells. Conclusions: Overexpression of murine asTF in murine cardiomyocytic cells increases their proliferation, monocyte migration, and pro-angiogenic properties -possibly- mediated by the induction of the pro-migratory and pro-angiogenic factors FGF2, Cyr61 and VEGF. Thus, we propose that murine asTF may serve as a migration- and angiogenesis-promoting factor. (Circ J 2011; 75: 1235-1242)

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In the past, coronary artery bypass graft surgery has been applied to revascularization for unprotected left main coronary artery (ULMCA) disease. In recent years, due to the advent of drug-eluting stents (DES), restenosis rates have decreased in comparison to conventional bare-metal stents (BMS), and the range of applications of percutaneous coronary intervention (PCI) for ULMCA disease has been expanded. However, even if DES is used, outcomes of PCI for distal left main coronary artery bifurcation lesions are not sufficient. Moreover, problems specific to DES, such as late stent thrombosis and late catch-up phenomenon, have been identified. There are still unknown points regarding remote-stage outcomes of DES. Thus, further investigation is needed on PCI for ULMCA disease, along with further analysis of remote-stage outcomes of BMS. (Circ J 2011; 75: 1243-1249)

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Coronary artery bypass grafting has long been considered the standard revascularization treatment for unprotected left main trunk disease (ULMTD). Percutaneous coronary intervention (PCI) with bare metal stent (BMS) was performed on patients for whom coronary artery bypass grafting was a high risk or those selected by lesion anatomy such as large simple ostial or body lesion. However, its clinical indication is limited by the high rate of target lesion revascularization (TLR). PCI with drug-eluting stent (DES) is increasingly being performed because of its lower TLR rate. Randomized and meta-analysis studies demonstrate that PCI with DES for ULMTD, compared with BMS, could be more strongly associated with a significant reduction in the need for TLR without any additional adverse outcomes, although it has some limitations on indications. (Circ J 2011; 75: 1250-1254)

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(Circ J 2011; 75: 656-661)

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(Circ J 2011; 75: 571-579)

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