Prior important research is not always cited, exemplified by Oswald Avery's pioneering discovery that DNA is the genetic transforming factor; it was not cited by Watson and Crick 10 years later. My first laboratory research (National Institutes of Health 1950 s) resulted in the clinical development of transseptal left heart catheterization. Laboratory studies on cardiac muscle mechanics in normal and failing hearts led to the concept of afterload mismatch with limited preload reserve. At the University of California, San Diego in La Jolla (1968) laboratory experiments on coronary artery reperfusion after sustained coronary occlusion showed salvage of myocardial tissue, a potential treatment for acute myocardial infarction proven in clinical trials of thrombolysis 14 years later. Among 60 trainees who worked with me in La Jolla, one-third were Japanese and some of their important laboratory experiments are briefly recounted, beginning with Sasayama, Tomoike and Shirato in the 1970 s. Recently, we developed a method for cardiac gene transfer, and subsequently we showed that gene therapy for the defect in cardiomyopathic hamsters halted the progression of advanced disease. Cardiovascular research and medicine are producing continuing advances in technologies for gene transfer and embryonic stem cell transplantation, targeting of small molecules, and tissue and organ engineering. (Circ J 2009; 73: 3 - 12)

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It is recognized that obesity contributes to cardiovascular and metabolic disorders through alterations in the levels of adipocyte-derived cytokines (adipokines). Adiponectin is an adipokine that is downregulated in obese individuals. It has beneficial actions on the cardiovascular system by directly acting on the heart and blood vessels, and acute administration of adiponectin can minimize the tissue damage resulting from myocardial infarction. More recent research has been aimed at identifying novel adiponectin-like factors involved in metabolic and cardiovascular regulation. Activation of Akt, a protein kinase involved in cell signaling, has been implicated in the control of skeletal muscle hypertrophy. An experimental mouse model demonstrates that substantial increases in muscle fiber hypertrophy, weight and strength occur upon induction of Akt signaling in skeletal muscle. In a mouse model of obesity, the increase in muscle mass caused by myogenic Akt induction results in diminished fat deposition and improvements in whole body metabolism. Based on these findings a protocol to identify novel muscle-secreted proteins (myokines) that confer the phenotypic changes brought on by myogenic Akt induction has been devised. One of these newly discovered factors, referred to as follistatin-like 1, is able to promote revascularization in ischemic limbs and protect the heart from ischemic stress. (Circ J 2009; 73: 13 - 18)

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Left ventricular noncompaction (LVNC) is a recently defined cardiomyopathy characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be caused by arrest of normal endomyocardial morphogenesis. Although LVNC has been classified as a primary cardiomyopathy of genetic origin, its definition and diagnostic criteria are still being debated. Isolated LVNC was thought to be rare; however, heightened awareness has resulted in an increased detection of the morphological features of LVNC in routine clinical practice, especially in the adult population. Clinical manifestations are highly variable, ranging from no symptoms to disabling congestive heart failure, arrhythmias, and systemic thromboemboli. LVNC, like other forms of inherited cardiomyopathy, is genetically heterogeneous and can be inherited as an autosomal-dominant or X-linked recessive disorder. It has been linked to mutations in several genes, including LIM domain binding protein 3 (ZASP), α-dystrobrevin (DTNA), tafazzin (TAZ/G4.5) and those encoding sarcomeric proteins. However, the relatively small contribution of known mutations to the disease, compared with the higher proportion of familial cases suggests that other elusive genes remain to be identified. (Circ J 2009; 73: 19 - 26)

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The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD), and threatens to reduce life expectancy around the world. The con-cept of the metabolic syndrome (MetS) takes into account the essential role that visceral fat plays in the development of metabolic and CVDs, and indicates how waist circumference measurement aids patient identication in the clinical setting. However, MetS cannot be used to assess global CVD risk and is, at best, another modifiable risk factor. Thus, the global cardiometabolic risk (ie, global risk of CVD resulting from traditional risk factors combined with the additional contribution of MetS) should be considered individually. The contribution of abdominal obesity to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance, lipotoxicity and ectopic fat deposition in the heart components: (1) circulatory and locally recruited fat, (2) intra-and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. (Circ J 2009; 73: 27 - 34)

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Background The effects of d,l-sotalol at therapeutic concentrations (≤10 mg/L) on wavefront dynamics during ventricular fibrillation (VF) and electrophysiological heterogeneity remain unclear. Methods and Results By using an optical mapping system, epicardial activation patterns of VF were studied in 6 Langendorff-perfused rabbit hearts at baseline, during 10 mg/L d,l-sotalol infusion, and after washout. In an additional 4 hearts, action potential duration (APD), conduction velocity, and wavelength (WL) restitutions were determined. During d,l-sotalol infusion, VF was terminated in 3 of the 6 hearts. Only 1 heart developed transient ventricular tachycardia (VT). d,l-Sotalol reduced the number of phase singularities (ie, wavebreak) during VF (P<0.05), and it also increased the occurrence frequency (P<0.05) and lifespan (P<0.05) of epicardial reentry during VF. These reentries were non-stationary in nature and did not anchor on anatomical structures. Restitution data showed that d,l-sotalol flattened APD restitution. Furthermore, APD dispersion and spatial heterogeneity of restitutions were not enhanced by d,l-sotalol. Conclusions d,l-Sotalol at therapeutic concentrations decreased wavebreak and facilitated the occurrence of long-lasting, non-stationary reentry during VF. However, VT rarely occurred. The related mechanisms include: (1) flattening of APD restitution without enhancement of spatial heterogeneity of electrophysiological properties, causing wavefront organization, and (2) WL prolongation, preventing steady anchoring of reentry. (Circ J 2009; 73: 39 - 47)

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Background There is evidence that the autonomic nervous system may be involved in the mechanism of focal atrial fibrillation (AF), so the present study investigated the effects of the parasympathetic nervous system on the occurrence of focal AF originating from the pulmonary veins (PVs). Methods and Results In 10 mongrel dogs, programmed stimulation and local burst stimulation (12.5 Hz, impulse duration 0.5 ms) were performed at each of the PVs. Pacing thresholds at different sites were determined and shown as a terraced distribution. The closer to the ostium of the PV, the lower was the pacing threshold (P<0.05-0.001). The local effective refractory period (ERP), AF induction and AF threshold were measured at baseline and during bilateral vagal nerve stimulation (VNS). VNS led to local ERP shortening at each of the PV sites (P<0.05-0.001), increased the inducibility of AF at all sites in the 4 PVs (P<0.05-0.001), and decreased the AF threshold at most sites, especially in the distal portions of the 4 PVs (P<0.05-0.01). Conclusions VNS changes the electrophysiological characteristics of the PVs and facilitates the induction of AF. Interaction between the autonomic nervous system and local cardiac autonomic nerve system may be a potential mechanism. (Circ J 2009; 73: 48 - 54)

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Background Although T wave alternans (TWA) and the T wave peak-to-end (Tpte) interval are associated with vulnerability to ventricular tachyarrhythmia (VT), no previous reports have demonstrated that TWA immediately precedes spontaneous VT in the human ambulatory setting. Methods and Results Stored electrograms from the implantable cardioverter defibrillators (ICD) of 74 patients (59 males, 55.3±12.2 years) were analyzed. TWA (ΔT amplitude), Tpte interval, QT interval, and RR intervals were measured from magnified digital images immediately before spontaneous VT (VT_Clinical; n=73), or immediately after ICD shocks during artificially-induced VT (VT_Induced; n=74) or inappropriate shocks (Shock_Inapp; n=6). (1) TWA was significantly greater in VT_Clinical than VT_Induced (P<0.01) or Shock_Inapp (P<0.001), but Tpte was not (P=NS). (2) In the VT_Clinical group, TWA was significantly greater in patients with ischemic VT than in those with non-ischemic cardiomyopathy or idiopathic VF (P<0.05). (3) In the same patient, the TWA for VT_Clinical was significantly greater than that for VT_Induced (P<0.01). Conclusion TWA measured from ICD electrograms is significantly greater immediately before spontaneous VT than immediately after inappropriate shocks or shocks during induced VT. These findings indicate that repolarization alternans plays an important role in the induction of VT in humans. (Circ J 2009; 73: 55 - 62)

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Background Elevated plasma testosterone levels are thought to play a role in the male preponderance of cases of Brugada syndrome (BS) and the development of prostate cancer. Methods and Results The 34 Brugada-like electrocardiogram (ECG) cases were identified among 2,681 male survivors of the atomic bomb who had undergone at least 1 biennial health examination between July 1958 and December 1999 in Nagasaki, Japan. They were followed for incident prostate cancer from July 1958 through December 2004, and the risk of prostate cancer for Brugada-like ECG, age, smoking habit, and radiation exposure was analyzed using Cox proportional hazards analysis. Among the men with or without Brugada-like ECG there were 4 (11.8%) and 54 (2.0%) cases of prostate cancer, respectively. With age adjustment there was a higher risk of prostate cancer for Brugada-like ECG (relative risk (RR): 5.42, 95% confidence interval (CI) 1.96-15.00, P=0.001). With further adjustment for smoking habit and radiation dose, Brugada-like ECG remained a significant risk factor for prostate cancer (RR: 6.47, 95%CI 1.97-21.21, P=0.002). Conclusions Brugada-like ECG confers a higher risk of prostate cancer independent of age, smoking habit, and radiation exposure. Men with a Brugada-like ECG should be regularly examined for prostate cancer and vice versa, especially elderly subjects. (Circ J 2009; 73: 63 - 68)

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Background The mid-term outcome of quick proximal arch replacement with moderate hypothermia followed by aggressive rapid re-warming in emergency surgery for type A acute aortic dissection (AAD) was assessed. Methods and Results Eighty-five patients were divided into 2 groups: group I consisted of 43 patients undergoing surgery for deep hypothermic circulatory arrest and selective cerebral perfusion; and group II consisted of 42 patients who recently underwent aggressive rapid re-warming. During open distal anastomosis in group II patients with a rectal temperature of 28°C but who did not suffer any cerebral perfusion, circulating blood in the cardiopulmonary bypass (CPB) circuit was warmed to 40°C. As soon as distal anastomosis was completed, rapid re-warming was initiated by a 40°C blood perfusion. The duration of CPB (I: 182.1 vs II: 85.3 min), overall operation (305.0 vs 150.8 min), postoperative mechanical ventilation (44.3 vs 9.1 h), and hospital stay (31.4 vs 9.6 days) were significantly shorter in group II patients. The incidence of postoperative brain complication (I: 14.0 vs II: 2.4%), renal failure (14.0 vs 0%), pneumonia (18.6 vs 4.8%), and mortality (9.3 vs 0%) was significantly less in group II patients. Conclusions Moderate hypothermia followed by a rapid re-warming procedure was safe and effective in the proximal arch replacement for AAD. (Circ J 2009; 73: 69 - 72)

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Background Although saphenous vein grafts (SVG) have been used from 1975 to treat coronary stenosis caused by Kawasaki disease, long-term results after more than 20 years remain unknown. Methods and Results From 1981 to 1997, 13 patients underwent coronary artery bypass grafting using SVG (n=20). The age at operation ranged from 2 to 20 years (median 11 years), the age at latest angiography from 15 to 36 years (median 30 years) and the postoperative follow-up period was from 10 to 26 years (median 22 years). The patency rate of the SVG was determined by postoperative angiography, graft wall morphology was graded and the late clinical course was reviewed. The patency rates at 1, 10, and 25 years after operation were 84.4%, 57.2%, and 51.5%, respectively. Irregularity of the SVG wall was slight in 3 of 7 patients with long-term patency. One patient with obesity and hyperlipidemia underwent stent implantation in the SVG because of graft stenosis. Conclusion Although the patency rates for SVG are low, there are patients with long-term patency over 20 years. Obesity and hyperlipidemia in these patients should be vigorously pursued. (Circ J 2009; 73: 73 - 77)

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Background Accumulating evidence indicates that C-reactive protein (CRP) is an independent predictive factor for atherosclerotic vascular disease in Caucasians. Accordingly, this study sought to investigate the relationship between the serum level of CRP and cardiovascular events of Japanese patients with coronary artery disease (CAD). Methods and Results The Japanese CAD (JCAD) study enrolled 15,628 patients who had significant diameter stenosis (≥75%) in at least 1 coronary artery. Of these, 6,802 patients had their baseline serum CRP data available. Patients were followed up for a mean of 2.7 years (follow-up rate 88.3%). The primary endpoint of the JCAD study was all events. Baseline covariates possibly influencing the event rate were adjusted between the 2 groups with and without elevated serum CRP level. Kaplan-Meier analysis demonstrated a 30% higher all-events rate in patients with a serum level of CRP ≥0.1 mg/dl (P=0.0002). Cox proportional hazard analysis also showed that a serum level of CRP ≥0.1 mg/dl was an independent predictor of all events (P=0.0001), and of cardiac events and cardiac death (P=0.0005). Conclusions Elevated serum level of CRP is an independent predictor of cardiovascular events in JCAD patients. (Circ J 2009; 73: 78 - 85)

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Background Although approximately 50% of heart failure patients are reported as heart failure with preserved left ventricular systolic function (HFPSF), echocardiographic prognostic predictors have not been well investigated. Recently, the tissue Doppler-derived index, the ratio of the early transmitral flow velocity and the early mitral annular velocity (E/E'), was reported as useful in predicting prognosis of patients with heart diseases. The purpose of this study was to investigate whether E/E' predicts prognosis in HFPSF. Methods and Results A total of 50 patients with HFPSF (ejection fraction >50%) were consecutively enrolled and studied. Echocardiographic examination was performed on admission and repeated after optimized medical therapy. Cardiac events were defined as death and unplanned hospitalization because of congestive heart failure. Cardiac event-free survival curves from patients with E/E' >15 and E/E' ≤15 at baseline did not differ. On the other hand, patients with E/E' >15 after medical therapy showed significantly lower cardiac event-free survival than patients with E/E' ≤15 (log-rank, P=0.005). By multivariate logistic regression analysis, E/E' >15 after medical therapy was the only independent predictor of cardiac events (P=0.037, risk ratio=6.1, 95% confidence interval: 1.12-33.3) in patients with HFPSF. Conclusions Elevated E/E' after optimized medical therapy may be useful in predicting cardiac events in patients with HFPSF. (Circ J 2009; 73: 86 - 91)

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Background Left ventricle diastolic dysfunction is attracting increasing attention of one of the etiologies of chronic heart failure (CHF). Methods and Results The study sample included 560 patients with CHF who were hospitalized during the 5-year period. They were classified into 2 groups according to the left ventricular ejection fraction (LVEF): reduced group (LVEF <50%, n=431); or preserved group (LVEF ≥50%, n=129). The degree of cardiac symptoms did not differ between the 2 groups; however, no difference was found between the 2 groups in the mortality rate (P=0.898), and readmission rates (P=0.674). The results of a multivariate analysis using a Cox proportional hazards model to identify predictors of the prognosis of heart failure revealed no difference in prognosis according to the presence/absence of decreased LVEF, whereas renal dysfunction and anemia were identified as significant prognostic determinants. Also, in the reduced group, the administration of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARB), β-blockers reduced mortality. In the preserved group, ACE-I and/or ARB administration reduced mortality, whereas β-blockers did not. Conclusion In the present study, the likelihood of LVEF influencing prognosis was considered to be low, with the contribution of non-cardiac factors such as renal function and anemia concluded to be greater. (Circ J 2009; 73: 92 - 99)

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Background Myocardial fibrosis is a feature of diastolic dysfunction and target organ damage, which was compared among subjects with normotension (NT), white-coat hypertension (WCH) and essential hypertension (EH). Serum procollagen type I propeptide (PIP) level was assessed as a marker of diastolic dysfunction in WCH. Methods and Results Of 90 subjects, 30 had NT and 30 had WCH (ambulatory daytime blood pressure <135/85 mmHg) and 30 had EH (untreated mild to moderate hypertension); all underwent biochemical and echocardiographic examinations. Those with WCH had a lower left ventricular (LV) mass index than those with EH, but it was higher than in the NT group. WCH patients had a lower mitral valve E/A ratio and a higher LV E/E' (E': septal mitral annular peak velocity) ratio than NT patients, whereas these values were higher and lower respectively than in the EH group. The LV E/E' ratio, an estimate of LV diastolic function, correlated with the serum PIP concentration in WCH patients (r=0.39, P=0.03). Conclusion WCH is an intermediate group between NT and EH in respect of target organ damage. These results show a relationship between LV diastolic function and serum PIP in WCH, so the serum PIP level may be a useful marker of diastolic dysfunction and target organ damage in such patients. (Circ J 2009; 73: 100 - 105)

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Background A novel modified tissue-type plasminogen activator, monteplase, has been approved for acute major pulmonary embolism (PE) in Japan. Monteplase has rapid and sustained lytic effects because of a steep rise in concentration after bolus infusion and a longer half-life. Methods and Results To assess the efficacy and safety of thrombolysis with monteplase in combination with catheter-based treatment, acute hemodynamic changes and clinical outcomes were assessed in 50 patients with angiographically confirmed major PE. Thrombolysis with monteplase in combination with embolus fragmentation and thrombectomy was the acute phase treatment. The study population comprised 31 females and 19 males (mean age 62 years). All patients had right ventricular (RV) overload; 12 patients presented in shock. The mean pulmonary artery pressure decreased significantly from 32±9 mmHg to 25±6 mmHg after acute phase treatment (P<0.0001). The mean dosage of monteplase was 12,265 IU/kg. Death at 30 days occurred in 3 patients (6%). Major bleeding occurred in 12 patients (24%). RV overload at discharge remained in only 3% of the patients with typically acute onset. Conclusions Thrombolysis with monteplase, in combination with catheter-based treatment, is an effective and safe therapy for major PE. (Circ J 2009; 73: 106 - 110)

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Background Intensive lipid-lowering therapy with statins reduces levels of low-density lipoprotein (LDL)-cholesterol (C) and improves plaque volume and composition in patients with cardiovascular disease. Furthermore, rosuvastatin ameliorated carotid stenosis in the ASTEROID study, and altered the composition of plaques in a predominantly Caucasian study population in the ORION study. However, it is not known whether statin therapy achieves similar quantitative improvement in carotid artery plaque in other ethnic groups. Methods and Results Fifty patients with hypercholesterolemia (LDL-C ≥120 mg/dl) and a maximum carotid intima-media thickness ≥1.8 mm will be enrolled and treated with rosuvastatin at a dose of 5 mg/day for 96 weeks. The primary endpoints will be the percent change of carotid plaque volume and the change in plaque composition after 96 weeks of treatment, as evaluated by magnetic resonance imaging. Conclusions The CHALLENGER study will provide a noninvasive assessment of the changes in carotid plaque volume and composition achieved by reduction of LDL levels in Japanese patients with carotid stenosis on long-term rosuvastatin therapy. (Circ J 2009; 73: 111 - 115)

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Background Although multidetector computed tomography (MDCT) allows non-invasive assessment of coronary artery stenosis, the presence of calcified lesions often lead to an overestimation of the stenosis. The present study was an evaluation of whether enhancement of first-pass myocardial data can improve the diagnostic accuracy of 64-MDCT. Methods and Results Data from 70 patients with single-vessel disease who underwent 64-MDCT followed by catheter-based coronary angiography (CAG) were analyzed. Myocardial enhancement was quantified by exaimining the signal densities at diastole. Among a total of 83 plaque segments, 35 calcified plaque segments were detected and 46 segments were found to have more than 50% coronary stenosis on catheter-based CAG. The average diameter stenosis was 75.2±12.8%. Diagnosis by 64-MDCT of significant stenosis (segment-based analysis) had a sensitivity, specificity and accuracy for segments without calcified lesions of 92%, 100% and 99.7%, respectively, and 95.2%, 50%, and 77.1%, respectively, for calcified lesions. Taking into account the myocardial enhancement by calculating the decrease of the standardized signal densities in percent, these parameters could be improved to 95.2%, 85.7% and 91.4%, respectively, for segments with calcified lesions. Conclusions The diagnostic accuracy of 64-MDCT for stenosis with calcified lesions in particular can be improved by taking into account the myocardial enhancement data. (Circ J 2009; 73: 116 - 124)

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Background Post-systolic shortening (PSS) is a sensitive indicator of myocardial ischemia. Methods and Results We have developed a tissue Doppler imaging technique that portrays PSS, and whether PSS correlates with coronary artery disease (CAD) was investigated in 186 patients presenting with chest pain and normal echocardiograms. Delays of the displacement peaks from end-systole were calculated in the apical views and displayed from green (0 ms) to red (≥100 ms): detection of diastolic abnormality by dyssynchrony imaging (DADI). CAD was judged positive by DADI when the left ventricular segments were color-coded red. Patients subsequently underwent thallium-201 myocardial perfusion single-photon emission computed tomography (n=150), coronary angiography (CAG, n=74), or both (n=37). CAD(-) was defined as negative scintigraphy test and/or no significant coronary artery stenosis by CAG. In 43 patients (23%), CAD(+) was confirmed by CAG as >75% diameter stenosis. DADI predicted CAD with sensitivity of 60%, specificity of 75%, predictive accuracy of 72%, positive predictive value of 42%, and negative predictive value of 86%. Among 74 patients who underwent CAG, sensitivity was best for the left anterior descending artery. Conclusions DADI detected the regional diastolic abnormality, which correlated with the presence of CAD in patients presenting with visibly normal wall motion. (Circ J 2009; 73: 125 - 131)

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Background The association between metabolic syndrome (MetS) and the severity of coronary artery disease (CAD) as determined by multidetector row computed tomography (MDCT) is unclear. Methods and Results The number of significantly stenosed vessels (VD), coronary artery calcification score, visceral fat area (VFA), subcutaneous fat area (SFA), and abdominal circumference were quantified using MDCT. Plasma levels of metabolic factors were also measured. Plasma levels of adiponectin were negatively correlated with body mass index, diastolic blood pressure, triglycerides, hemoglobin A_1c, fasting glucose, SFA, VFA and waist circumference, and positively correlated with age and high-density lipoprotein-cholesterol (HDL-C). VD in the MetS group was significantly higher than in the non-MetS group. In the 5 groups classified according to the number of metabolic factors, adiponectin was significantly decreased, whereas VD was significantly increased as the number of factors increased. Multivariate logistic regression analysis revealed that the number of VD was most closely correlated with HDL-C (P=0.0014). Conclusions Of the metabolic factors, lower levels of HDL-C may be most useful for predicting CAD independent of other metabolic markers such as adiponectin, VFA or present medication. (Circ J 2009; 73: 132 -138)

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Background This study was designed to clarify the relationship between myocardial damage and platelet-neutrophil aggregation in patients with acute myocardial infarction (AMI). Methods and Results The study group comprised 107 patients with ST-segment elevation AMI, in whom aspiration catheter was used during emergency percutaneous coronary intervention. Patients were divided into 2 groups according to the cellular density of neutrophils in the aspirated sample: group L (n=53), ≤100 neutrophils/0.025 mm² thrombus; group H (n=54), >100 neutrophils/0.025 mm² thrombus. Myocardial blush grade (MBG) ≤1 and ST-segment resolution (STR) <50% were more frequently found in group H than in group L. Peak creatine kinase level tended to be higher and left ventricular ejection fraction (LVEF) at 6 months after onset was lower in group H than in group L. Multivariate analysis showed that high neutrophil density in aspirated thrombus was an independent predictor of MBG ≤1, STR <50%, and low LVEF at 6 months after onset. Conclusions Platelet-neutrophil aggregates retrieved from ruptured plaque may be associated with impaired coronary microcirculation and resultant myocardial necrosis/dysfunction. These findings underscore the clinical importance of the interaction between thrombosis and inflammation in the pathogenesis of AMI. (Circ J 2009; 73: 139 - 144)

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Background The efficacy and safety of abciximab were investigated in Japanese patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) or unstable angina. Methods and Results The 973 patients were randomized into 3 groups: the low-dose group (L group) received bolus injection of 0.20 mg/kg followed by 12-h infusion; the high-dose group (H group) received bolus injection of 0.25 mg/kg followed by 12-h infusion; the placebo group (P group) received bolus and infusion of placebo. The incidence of the primary endpoint (30-day post-PCI coronary events: death, MI or urgent revascularization) was 3.6%, 1.6%, and 4.1% in the P, L, and H groups, respectively, with no significant difference between the P and L groups (P=0.104) or between the P and H groups (P=0.772). The incidence of bleeding tended to increase in a dose-dependent manner. Conclusion No significant difference in the incidence of coronary events was found between the placebo and abciximab groups, so the efficacy of abciximab in preventing post-PCI coronary events in Japanese patients was not confirmed. (Circ J 2009; 73: 145 - 151)

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Background Osteopontin (OPN) mRNA is highly expressed in atherosclerotic plaques and plasma OPN levels are high in patients with coronary artery disease and in those with restenosis. OPN-overexpressing transgenic mice show markedly increased neointimal formation after arterial injury. Methods and Results The prognostic significance of the preprocedural plasma OPN level was investigated in 130 patients undergoing percutaneous coronary intervention (PCI). Patients were followed up for restenosis and major adverse cardiovascular events (MACE). At 7±3 months after PCI, angiography was performed again in 91 patients, of whom 40 had restenosis. Between patients with and without restenosis, OPN (492±200 vs 482±224 ng/ml) and C-reactive protein (CRP: 0.78 vs 0.70 mg/L) levels did not differ. During a 3-year follow-up, MACE occurred in 21 patients, who had higher OPN (586±230 vs 438±195 ng/ml) and CRP (1.30 vs 0.70 mg/L) levels than those without MACE (P<0.005). Both OPN and CRP levels were independent predictors for MACE. Hazard ratios for MACE were 1.3 (95% confidence interval (CI) 1.1-1.5) for a 100 ng/ml increase in OPN and 3.6 (95%CI 1.4-9.3) for CRP >1.0 mg/L. Conclusions In patients undergoing PCI, the preprocedural OPN and CRP levels are independent predictors for further cardiovascular events, but not for restenosis. (Circ J 2009; 73: 152 - 157)

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Background Mutations in FKTN encoding for fukutin cause Fukuyama-type congenital muscular dystrophy characterized by severe muscle wasting and hypotonia with mental retardation. Fukuyama-type congenital muscular dystrophy is a recessive genetic trait. FKTN mutations in patients with dilated cardiomyopathy (DCM) have been investigated by our research group. The patients showed hyper-CKemia with mild or no muscle weakness and without mental retardation, suggesting that the clinical spectrum of FKTN mutations are wider than previously thought. The current study was designed to further explore the association of FKTN mutations with DCM or hypertrophic cardiomyopathy (HCM). Methods and Results A total of 172 patients with DCM, 144 patients with familial HCM and 384 control individuals were analyzed for FKTN mutations. There was a DCM patient who was a compound heterozygote of a 3-kb insertion mutation and a missense mutation Cys101Phe. The patient showed hyper-CKemia with mild muscle involvement and no brain involvement. In contrast, 2 other DCM patients and 3 controls were heterozygous for the insertion mutation and normal allele, showing that the heterozygous insertion mutation itself was not associated with DCM. No mutation was found in the HCM patients. Conclusions These observations indicated that the compound heterozygous FKTN mutation was a rare cause of DCM. Hyper-CKemia might be indicative of FKTN mutation in DCM. (Circ J 2009; 73: 158 - 161)

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Background Bone marrow cells from humans and animals with diabetes exhibit decreased angiogenic potency, thought to be related to oxidative stress, so the present study investigated if antioxidant therapy would attenuate the diabetes-related impairment. Methods and Results Diabetic mice were given antioxidant therapy, as a daily subcutaneous injection of superoxide dismutase-mimic (10 mg · kg^-1 · day^-1). Diabetic and healthy mice given a vehicle treatment were used as the control. After 4 weeks of treatment, bone marrow mononuclear cells (BM-MNCs) were collected for analysis and the endothelial progenitor cells in BM-MNCs were evaluated by flow cytometry. The intracellular reactive oxygen species (ROS) levels in BM-MNCs were measured using 6-carboxy-2'7'-dichlorodihydrofluorescein diacetate. Endothelial differentiation from the BM-MNCs was estimated by immunostaining with VE-cadherin 7 days after culture. BM-MNCs from the control diabetic mice had fewer Flk-1/CD34 double-positive progenitor cells and higher intracellular ROS levels, with lower potency of endothelial differentiation than BM-MNCs from the healthy mice. Antioxidant therapy decreased the intracellular ROS level in BM-MNCs from that in the diabetic mice significantly (P<0.05), but increased significantly the percentage of endothelial progenitor cells (P<0.05) and their potency of differentiation into endothelial cells (P<0.05). Conclusions Antioxidant therapy attenuated the diabetes-related impairment of BM-MNCs by reducing oxidative stress. (Circ J 2009; 73: 162 - 166)

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Background Exercise training improves walking ability in patients with peripheral arterial disease (PAD), but whether exercise training improves the long-term outcome of these patients remains unknown. Methods and Results Participants were 118 PAD patients who were enrolled in a 12-week supervised exercise program. The long-term outcomes of 64 patients who completed the training were compared with the outcomes of 54 patients who did not. The primary endpoint was cardiovascular mortality, and the secondary endpoint was cardiovascular morbidity. Mean follow-up was 5.7±3.9 years. The cardiovascular death-free rate was higher in patients who completed the training program than in those who did not (P=0.022). Multivariate analysis showed independent predictors of cardiovascular death were age over 70 years, diabetes mellitus, maximum walking distance, history of coronary revascularization, and completion of training program. The cardiovascular event-free rate was also higher in patients who completed the training program (P=0.048). Conclusions Supervised exercise training improved cardiovascular mortality and morbidity in patients with PAD, which suggests that exercise training should be considered as a secondary prevention strategy for these patients. (Circ J 2009; 73: 167 - 173)

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Background Flow-mediated dilatation (FMD) of the brachial artery represents systemic endothelial function, so the relationship between FMD and blood pressure (BP) profile, in relation to the effects of cigarette smoking, was investigated in young healthy subjects. Methods and Results The 62 healthy subjects (14 females, 48 males; mean 29.7±5.5 years old), were divided into a smoking group (n=30) and non-smoking group (n=32). FMD was induced by reactive hyperemia. It was lower in the smoking group than in the non-smoking group (P<0.05). In the non-smoking group, there was an inverse correlation (r=-0.59, P<0.0005) between FMD and systolic BP (SBP), which was not recognized in the smoking group. Multiple stepwise regression analysis revealed that FMD was predicted by either the SBP or the brachial artery diameter in the non-smoking group, whereas it was predicted by the brachial artery diameter in the smoking group. Subdivision by cut-off value of SBP =120 mmHg demonstrated that although FMD with SBP <120 mmHg was preserved in subjects in the non-smoking group, it was depressed to a level comparable with SBP ≥120 mmHg in the smoking group. Conclusions Highly-preserved FMD in subjects with SBP <120 mmHg appears to be impaired by cigarette smoking, resulting in a loss of association between FMD and SBP. (Circ J 2009; 73: 174 - 178)

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A 58-year-old man had typical cavotricuspid-isthmus-dependent atrial flutter (AFL). Right atrial angiography and multidetector computed tomography revealed a deep pouch-like recess in the mid-isthmus region. Linear ablation from the pouch to the edge of the inferior vena cava resulted in widely split double potentials without any change in the AFL cycle length. This observation suggested that the pouch played an electrophysiological role by dividing the flutter wavefront into 2 parallel conduction wave fronts through both sides of the pouch along the isthmus during typical AFL. When a widely split potential is created on 1 side of the pouch, the other side of the pouch should be targeted. (Circ J 2009; 73: 179 - 182)

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Ischemic hepatitis, otherwise known as "shock liver", is characterized by a massive, but transient increase in serum transaminase levels, usually associated with cardiac failure. A patient who did not have a predisposition to hypoglycemia was discovered at home with disturbed consciousness caused by hypoglycemia. She had been diagnosed as having constrictive pericarditis several years earlier and had developed ischemic hepatitis. Though the high serum transaminase levels were rapidly normalized, severe jaundice gradually developed and the patient finally died of multiple organ failure. Hypoglycemia, which is considered secondary to reduced gluconeogenesis in the exhausted liver, is a rare complication of constrictive pericarditis. (Circ J 2009; 73: 183 - 186)

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A 58-year-old man underwent cardiac catheterization for unstable angina. The coronary angiogram revealed severe stenosis of the right coronary artery. Although 20-MHz, phased-array intravascular ultrasound (IVUS) only visualized eccentric, low echoic plaque at the culprit site, optical coherence tomography (OCT) clearly revealed ruptured plaque and an intraluminal thrombus. OCT also revealed a small ruptured plaque and an eroded plaque with intraluminal thrombi in a distal site remote from the culprit lesion, neither of which was visualized by IVUS. (Circ J 2009; 73: 187 - 189)

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A polytetrafluoroethylene (PTFE)-covered stent is specially used to treat coronary perforation complicating percutaneous intervention in order to prevent the aneurysm from rupturing, but until now it has not been known if endothelialization occurs inside this type of stent. A patient with a giant aneurysm of the right coronary artery underwent successful implantation of a PTFE-covered stent. Angiography at 9-month follow-up showed focal restenosis at the proximal edge of the stent and coronary angioscopy revealed restenosis as a result of thrombus formation. Absence of endothelialization in the covered stent was also detected by angioscopy and optical coherence tomography. These findings suggest that in-stent thrombosis must be prevented after PTFE-covered stent implantation. (Circ J 2009; 73: 190 - 193)

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