Reactive oxygen species (ROS) have long been viewed as deleterious chemicals that lead to oxidative stress. More recently, ROS, especially the stable ROS hydrogen peroxide (H₂O₂), have been shown to have roles in normal physiological responses in vascular cells. Endothelial nitric oxide synthase (eNOS) is dynamically targeted to plasmalemmal caveolae, and represents the principal enzymatic source of nitric oxide (NO^•) in the vascular wall. eNOS maintains normal vascular tone and inhibits the clinical expression of many cardiovascular diseases. Increases in oxidative stress are associated with eNOS dysfunction. In a paradigm shift in the conceptual framework linking redox biochemistry and vascular function, H₂O₂ has been established as a physiological mediator in signaling pathways, yet the intracellular sources of H₂O₂ and their regulation remain incompletely understood. The subcellular distributions of ROS and of ROS-modified proteins critically influence the redox-sensitive regulation of eNOS-dependent pathways. ROS localization in specific subcellular compartments can lead to selective oxidative modifications of eNOS and eNOS-associated proteins. Likewise, the dynamic targeting of eNOS and other signaling proteins influences their interactions with reactive nitrogen species and ROS that are also differentially distributed within the cell. Thus, the subcellular distribution both of eNOS and redox-active biomolecules serves as a critical basis for the control of the “redox switch” that influences NO^•- and oxidant-regulated signaling pathways. Here we discuss the biochemical factors, cellular determinants, and molecular mechanisms that modulate redox-sensitive regulation of eNOS and NO^• signaling under normal and pathological conditions.  (Circ J 2012; 76: 2497–2512)

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Tenascin-C (TN-C) is a matricellular protein expressed during embryonic development, as well as in wound healing and cancer invasion in various tissues, and may regulate cell behavior and matrix organization during tissue remodeling. In the cardiovascular system, TN-C is transiently expressed at several important steps of embryonic development, playing important roles in the differentiation of cardiomyocytes and in coronary vasculo/angiogenesis. TN-C is sparse in normal adults, but upregulated under pathological conditions such as myocarditis, myocardial infarction, cardiac fibrosis, atherosclerosis, stenotic neointimal hyperplasia, and aneurysm, and is closely associated with tissue injury and inflammation. In view of its specific expression, TN-C could be a realistic and promising biomarker and a target for molecular imaging for the diagnosis of various cardiovascular diseases. TN-C also has diverse functions, including weakening of cell adhesion, up-regulating the expression and activity of matrix metalloproteinases, modulating inflammatory responses, promoting recruitment of myofibroblasts, and enhancing fibrosis. TN-C could exert both harmful and protective effects and might be a therapeutic target as a key molecule in the control of the balance of beneficial and undesirable cellular responses during tissue remodeling.  (Circ J 2012; 76: 2513–2520)

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Heart failure is a common clinical feature of advanced cardiovascular disease that carries a high mortality risk. This review focuses on my journey seeking to understand the pathogenesis of heart failure and on how to translate experimental findings into the clinic.  (Circ J 2012; 76: 2521–2529)

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The Annual Congress of the European Society of Cardiology (ESC) was held in Munich from the 26^th to 29^th of August 2012. The daily attendance ranged from 26,600 to 27,407 up to the 28^th and several important issues were presented and discussed, including antiplatelet therapy for acute coronary syndrome (TRILOGY ACS), transcatheter aortic valve implantation, renal denervation, novel oral anticoagulants for atrial fibrillation (AFib), AFib ablation, the impact of the Great East Japan Earthquake on cardiovascular disease, management of vasospastic angina, plaque rupture and erosion (ESC-JCS [Japanese Circulation Society] joint session), heart failure, and FFR-guided percutaneous coronary intervention outcome. Three ESC “GOLD MEDALS” were awarded, including one to Professor Ryozo Nagai, the first Asian to receive this award. The ESC meeting has become one of the most important for updating not only general cardiologists’ education but also specialists’ expertise. Japan topped the number of abstracts submitted to ESC 2012 (>1,200 abstracts), while the ESC would like to establish a strong collaboration with the Japanese Cardiology Society. Relations between ESC and JCS will become closer and more favorable year by year.  (Circ J 2012; 76: 2530–2535)

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Background: Hyperthyroidism is usually regarded as a reversible cause of atrial fibrillation (AF); however, one-third of patients remain in AF despite euthyroid restoration. We hypothesized that a significant number of AF patients with hyperthyroidism (Hyperthyroid-AF) as well as those without (Non-thyroid-AF) would benefit from catheter ablation of AF (AF ablation). This study aimed to clarify the prevalence of hyperthyroidism in candidates for AF ablation and to compare the long-term outcome of AF ablation between the Hyperthyroid-AF and Non-thyroid-AF groups. Methods and Results: This study enrolled 337 consecutive patients with AF who underwent a first AF ablation that mainly involved extensive encircling pulmonary vein isolation. Sixteen (4.7%) patients had hyperthyroidism; the remaining 321 (95.3%) did not. In the Hyperthyroid-AF patients, a euthyroid state had been restored for at least 3 months before the ablation. During a mean follow-up period of 4±1 years after ablation, AF recurred in 7 patients (44%) with Hyperthyroid-AF and in 139 patients (43%) with Non-thyroid-AF (P=0.91 by the log-rank test). In the multivariate Cox regression models, the presence of hyperthyroidism was not associated with a higher risk of AF recurrence (hazard ratio, 0.87; 95% confidence interval, 0.40–1.88; P=0.73). Conclusions: In the AF ablation candidates without structural heart disease, hyperthyroidism was not rare. After euthyroid restoration on pharmacological treatment, hyperthyroidism was not associated with a higher risk of AF recurrence.  (Circ J 2012; 76: 2546–2551)

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Background: Activation of Rho-kinase plays a central role in the pathogenesis of drug-eluting stents (DES)-induced coronary hyperconstricting responses in pigs in vivo has been previously demonstrated. In the present study, Rho-kinase activation involved in those responses in patients with coronary artery disease (CAD) is examined. Methods and Results: In 24 patients with CAD who underwent coronary intervention with either DES or bare-metal stents (BMS), coronary vasomotor responses to intracoronary acetylcholine (ACh) before and after intracoronary pre-treatment with a Rho-kinase inhibitor, fasudil was examined. Coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT) was evaluated. QCA showed that the coronary vasoconstricting responses to ACh were significantly enhanced in the DES group compared with the BMS group both at the proximal and the distal segments adjacent to the stents (proximal: BMS –13.0±10.7% vs. DES –25.4±14.3%, P=0.036; distal: BMS –24.4±12.2% vs. DES –43.8±14.7%, P=0.003). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal 10.2±11.7%, distal 14.4±10.5% vs. before fasudil, both P<0.01). In the OCT imaging analysis, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. Conclusions: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD, suggesting the therapeutic importance of Rho-kinase pathway.  (Circ J 2012; 76: 2552–2560)

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Background: Delayed vessel healing after drug-eluting stent implantation is thought to be the underlying mechanisms of late stent thrombosis (LST). Methods and Results: In the animal model of stenting, 45 minipigs were divided into 3 groups (n=15 each): bare metal stent (BMS), sirolimus-eluting stent (SES), and SES plus atorvastatin treatment (SES+ator). Neointimal coverage and endothelium coverage were evaluated separately by optical coherence tomography (OCT), pathology, and scanning electron microscopy (SEM) at days 7, 14 and 28. OCT showed that SES significantly delayed neointimal coverage compared with BMS and the percentage of uncovered struts in the SES+ator group was significantly decreased on days 7 (42.7±1.3% vs. 56.8±5.7%, P<0.01) and 14 (24.8±4.3% vs. 45.3±2.8%, P<0.01) compared with the SES group. However, re-endothelialization was even more seriously delayed than neointima formation after SES deployment (P<0.05). Pathology and SEM revealed improved re-endothelialization of the neointima with atorvastatin therapy in terms of more struts covered by endothelium, less platelet adhesion, and higher endothelial nitric oxide synthase expression of the endothelial cells in the SES+ator group. Flow cytometry illustrated that the SES+ator group had more mobilized endothelial progenitor cells (EPCs) compared with the SES group at day 7 (0.21±0.02% vs. 0.11±0.03%, P=0.022). Conclusions: Atorvastatin pretreatment can accelerate both neointimal coverage and re-endothelialization after SES implantation, which may be mediated by the mobilization of EPC and enhancement of the endothelial function of the neointima.  (Circ J 2012; 76: 2561–2571)

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Background: Exercise training improves endothelial function in patients with coronary artery disease (CAD) through unclear mechanisms. We hypothesized that mitochondrial dysfunction related to a lower habitual physical activity level (PAL) is associated with endothelial dysfunction. Methods and Results: We assessed habitual PAL by a validated International Physical Activity Questionnaire, brachial flow-mediated dilation (FMD) and serum lactate, pyruvate, fasting glucose and lipid profiles in 105 CAD patients (age 68±10; 87% men). As defined by the lactate/pyruvate ratio (LP ratio) ≥75^th percentile of the age-and sex-matched controls (ie, ≥18), mitochondrial dysfunction was observed in 33/105 (31%) patients. With decreasing PAL tertiles, there were significant linear trends of lower FMD (P=0.004) and higher LP ratio (P=0.009). Multivariate logistic regression found that the lowest compared with the highest PAL tertile (adjusted odds ratio=3.78, P=0.02) had more patients with high LP ratio. After adjustment for cardiovascular risk factors and medications, the lowest compared to the highest PAL tertile had significantly lower FMD (absolute decrease 1.25%, P=0.03); and high LP ratio was associated with impaired FMD (absolute reduction 1.09%, P=0.03). Conclusions: In CAD patients, a lower level of habitual PAL is associated with impaired FMD and increased prevalence of mitochondrial dysfunction as defined by high LP ratio. Moreover, high LP ratio predicts a lower FMD, suggesting that the occurrence of mitochondrial dysfunction with lower habitual PAL is associated with endothelial dysfunction in CAD patients.  (Circ J 2012; 76: 2572–2578)

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Background: Although therapeutic hypothermia is an effective therapy for comatose adults experiencing out-of-hospital shockable cardiac arrest, there is insufficient evidence that is also applicable for those with out-of-hospital non-shockable cardiac arrest. Methods and Results: Of 452 comatose adults treated with therapeutic hypothermia after return of spontaneous circulation (ROSC) subsequent to an out-of-hospital cardiac arrest of cardiac etiology, 372 who had a bystander-witnessed cardiac arrest, target core temperature of 32–34°C and cooling duration of 12–72h were eligible for this study (75 cases of non-shockable cardiac arrest, 297 cases of shockable cardiac arrest). The median collapse-to-ROSC interval was significantly longer in the non-shockable group than in the shockable group (30min vs. 22min, P=0.008), resulting in a significantly lower frequency of 30-day favorable neurological outcome in the non-shockable group compared with the shockable group (32% vs. 66%, P<0.001). However, an analysis of data in quartiles assigned to varying lengths of collapse-to-ROSC interval revealed a similar frequency of 30-day favorable neurological outcome among both groups when the collapse-to-ROSC interval was ≤16min (90% non-shockable group vs. 92% shockable group; odds ratio 0.80, 95% confidence interval 0.09–7.24, P=0.84). Conclusions: Post-ROSC cooling is an effective treatment for patients with non-shockable cardiac arrest when the time interval from collapse to ROSC is short.  (Circ J 2012; 76: 2579–2585)

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Background: Because it remains unclear whether noninvasive ventilation (NIV) is an effective therapy for cardiogenic pulmonary edema secondary to acute myocardial infarction (AMI), we retrospectively evaluated our experience with NIV in the treatment of pulmonary edema secondary to AMI and other cardiac conditions. Methods and Results: The study group included 206 patients with cardiogenic pulmonary edema, divided into an AMI group (53 patients) and a non-AMI group (153 patients). The weaning rate from NIV was similar in the AMI and non-AMI groups (90.6% vs. 90.8%, P=0.950). Heart rate, blood pressure, and respiratory rate decreased significantly 1h after initiation of NIV in both groups, and were maintained until weaning from NIV. The frequency of endotracheal intubation after weaning from NIV was higher in the AMI group than in the non-AMI group (7.5% vs. 0.7%, P=0.016), although the overall frequency of intubation was similar in both groups. The in-hospital mortality rate was similar in the AMI and non-AMI groups (13.1% vs. 9.8%, P=0.489). Conclusions: NIV effectively improved vital signs and oxygenation and lowered the intubation rate in patients with cardiogenic pulmonary edema of all etiologies, including AMI. The outcome in patients with AMI treated with NIV depends primarily on the severity of the course of AMI and not on the severity of acute respiratory failure.  (Circ J 2012; 76: 2586–2591)

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Background: Cardiac resynchronization therapy/defibrillators (CRTD) and implantable cardioverter defibrillators (ICD) with continuous intrathoracic impedance monitoring might provide an early warning of thoracic fluid retention. In contrast, volume loss events such as dehydration and bleeding are also common events in heart failure patients treated with diuretics and anticoagulants. The correlation between intrathoracic impedance and a volume loss event is not known. Methods and Results: This study evaluated the association between intrathoracic impedance and volume loss events in 36 patients with chronic heart failure (New York Heart Association [NYHA] II, III and IV) who had received CRTD/ICD implantation. Elevation of thoracic impedance above the reference line was defined as a positive deviation of thoracic impedance (PDI). This study recorded 249 PDIs including 60 spike PDIs defined as over 5ohms elevation from the reference line and 17 large PDIs as over 5ohms elevation and continuing for at least 4 days. Clinically, 96 dehydration events and 2 bleeding events were observed over a 1-year period. The sensitivity and positive predictive value (PPV) for spike PDI was 31.6% and 51.7%, respectively, while those for large PDI were 17.3% and 100%, respectively. Conclusions: A large PDI reflected dehydration and bleeding events with a high PPV in severe heart failure patients. The large PDI criteria might therefore be useful for predicting volume loss events in chronic heart failure patients.  (Circ J 2012; 76: 2592–2598)

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Background: Diagnosis of left ventricular (LV) diastolic dysfunction by blood testing is expedient in the clinical setting. Methods and Results: In 98 patients with LV ejection fraction ≥50% who underwent cardiac catheterization for evaluation of coronary artery disease, LV pressure (LVP) was measured using a catheter-tipped micromanometer. A time constant, τ, of LV relaxation was computed from LVP decay; the inertia force (IF) of late systolic aortic flow, a surrogate index of LV elastic recoil, was also computed from the LVP−dP/dt relation (phase loop). Patients were classified into 2 groups: those with impaired LV relaxation (τ ≥48ms) and those with preserved LV relaxation (τ <48ms). Patients were also classified into another 2 groups: those with IF (≥0.5mmHg) and those without (<0.5mmHg). Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥56.5pg/ml had a sensitivity of 100%, specificity of 52.5%, and negative predictive value of 100% for identifying impaired LV relaxation. NT-proBNP ≥244.5pg/ml had a sensitivity of 62.5% and specificity of 93.9% for detecting lack of IF. Conclusions: NT-proBNP level <56.5pg/ml could be used as a value to sensitively identify patients with preserved LV systolic and diastolic function among those with coronary artery disease. NT-proBNP level ≥244.5pg/ml is able to specifically detect a lack of IF and has potential for specifically diagnosing LV isolated diastolic dysfunction.  (Circ J 2012; 76: 2599–2605)

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Background: The aim of this study was to investigate whether short-duration adaptive servo-ventilation (ASV) therapy improves cardiac function in heart failure (HF) patients. Methods and Results: Consecutive HF patients (n=86) were divided into 3 groups: group A, ASV for a mean of ≥4h; group B, ASV for ≥1 to <4h per day; and group C, no ASV or ASV <1h. The frequency of ASV use did not significantly differ between groups A (79.3±19.2%) and B (70.9±17.4%). After 6 months, a significant increase in left ventricular ejection fraction (LVEF), significant decrease in plasma brain natriuretic peptide (BNP) and decrease in LV end-diastolic volume (LVEDV) were observed in groups A (LVEF, 5.0±8.1%; BNP, −24.9±33.7%; LVEDV, −6.2±10.1%) and B (LVEF, 3.5±5.5%; BNP, −16.5±24.6%; LVEDV, −5.1±8.2%) as compared with group C (LVEF, −1.5±6.0%, P=0.004, P=0.017; BNP, 2.8±10.2%, P=0.002, P=0.017; LVEDV, 0.8±9.1%, P=0.031, P=0.043). Significant correlation was seen between the total ASV time and changes of LVEF (r=0.369, P=0.002), BNP (r=−0.445, P<0.001), and LVEDV (r=−0.374, P=0.001). Admission rate was lower in groups A (4.1%) and B (7.1%) than in group C (25%, log-rank test; P=0.042, P=0.045). Multivariate analysis showed that the frequency of ASV use was a strong parameter for the improvement of LVEF (coefficient=0.284, standard error=0.035, P=0.019). Conclusions: Even a short-duration of ASV therapy may improve cardiac function in HF patients.  (Circ J 2012; 76: 2606–2613)

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Background: Computed tomography venography (CTV) is clinically useful and widely available for the detection of deep vein thrombosis. Disadvantages of CTV are the need for a larger amount of i.v. contrast material (CM) and radiation exposure. A low-tube-voltage technique with iterative reconstruction may overcome this problem. The aim of this study was to investigate the effects of hybrid iterative reconstruction (HIR) on image quality at low-tube-voltage CTV. Methods and Results: Forty patients (26 women, 14 men; mean age, 59.2±18.3 years) underwent CTV under an 80- or 120-kV protocol (CT dose index volume=10.3mGy vs. 14.9mGy, CM dose=540mgI/kg vs. 690mgI/kg) on a 64-detector CT. Quantitative parameters (ie, venous attenuation, image noise, and contrast-to-noise ratio [CNR]) were calculated and the image quality was scored on a 4-point scale. In step 1, the 80- and 120-kV protocols were compared under filtered back projection (FBP). In step 2, the 80-kV protocol with HIR was compared with the 120-kV protocol with FBP. In step 1, the visual scores were significantly higher under the 120-kV protocol; there was no significant difference in CNR between the protocols. In step 2, CNR was significantly higher under the 80-kV protocol with HIR than the 120-kV protocol with FBP. The visual scores of the 2 protocols were comparable. Conclusions: The 80-kV CTV with HIR allows for a reduction in the radiation dose by 30% and the CM dose by 20% without image quality degradation.  (Circ J 2012; 76: 2614–2622)

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Background: To determine the normal range of left ventricular (LV) 2- dimensional (2-D) strain and vendor-specific differences, a multicenter prospective 2-D strain study endorsed by the Japanese Society of Echocardiography was conducted. Methods and Results: 2-D speckle tracking analysis was performed on 817 healthy subjects (age range, 0–88 years); the images included 3 LV short axis and 3 apical views using an ultrasound system from 1 of the 3 different vendors (V₁, n=333; V₂, n=330; V₃, n=337). With the 2-D speckle tracking software from each vendor, radial, circumferential and longitudinal strain were measured using an 18-segment model. Inter-vendor variability was also assessed in a subset of subjects. The feasibility for 2-D strain measurements was different among the 3 vendors (V₁, 83%; V₂, 70%; V₃, 88%, P<0.01). The global radial (V₁, 54.6±12.6%; V₂, 36.3±8.2%; V₃, 51.4±8.0%), circumferential (V₁, –22.8±2.9%; V₂, –22.2±3.2%; V₃, –30.5±3.8%), and longitudinal (V₁, –21.3±2.1%; V₂, –18.9±2.5%; V₃, –19.9±2.4%) strain measurements were significantly different for each of the vendors. Segmental strain was also different between the 3 vendors. On inter-vendor analysis, vendor agreement ranged from mild to moderate. Conclusions: Reference values are provided for normal 2-D strain for 3 different ultrasound vendors. Due to a low inter-vendor agreement, 2-D strain data are not interchangeable when conducting a longitudinal follow-up or a cross-sectional assessment of LV function.  (Circ J 2012; 76: 2623–2632)

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Background: Because of their high risk for cardiovascular events, we investigated the role of ¹²³I-betamethyl-p-iodophenyl-pentadecanoic acid (BMIPP) SPECT in evaluating the prognosis of diabetic patients with suspected coronary heart disease. Methods and Results: We retrospectively registered 186 diabetic patients with suspected coronary heart disease, but no previous diagnosis of heart disease, who had been examined by BMIPP and thallium (TL) dual SPECT. They were followed for over 2 years. The dual SPECT images were scored to obtain summed defect scores for each SPECT image (BMDS, TLDS and mismatch score [MS]). The primary endpoint was the first incidence of all-cause cardiac events. The secondary endpoint was cardiac death. Clinical classical risk factors in addition to the stage of chronic kidney disease (CKD), as well as cardiac function, were included in the prognostic analysis. Cardiac events occurred in 39 patients, including 8 cardiac deaths. Kaplan-Meier analysis revealed significantly more frequent cardiac event rates in patients with than without MS ≥5 or BMDS ≥6 (P<0.0001). Cox hazard multivariate analysis showed that MS and CKD stage or BMIPP and CKD stage were independent predictors. Only hemodialysis was a significant prognostic indicator for cardiac death. Conclusions: BMIPP SPECT when combined with CKD stage accurately predicts cardiac events among diabetic patients with suspected ischemic heart disease.  (Circ J 2012; 76: 2633–2639)

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Background: The current study was designed to investigate the correlation between the left ventricular (LV) vortex flow pattern and LV apical thrombus formation in patients with acute anterior wall myocardial infarction (MI). Methods and Results: Fifty-seven patients with acute anterior wall MI were enrolled in this study. Eighteen patients with apical thrombus (thrombus group) and 39 patients without apical thrombus (non-thrombus group) underwent 2-dimensional contrast echocardiography (CE). Morphology and pulsatility parameters of the LV vortex were measured using Omega flow^® and compared between the 2 groups. In the thrombus group, the vortex was located more centrally and did not extend to the apex. In the thrombus group, quantitative vortex parameters of vortex depth (0.409±0.101 vs. 0.505±0.092, respectively; P=0.002) and relative strength (1.574±0.310 vs. 1.808±0.376, respectively, P=0.034) were significantly lower than the non-thrombus group. Following multivariate analysis, the vortex depth below 0.45 remained a significant independent parameter for formation of the LV apical thrombus (odds ratio 9.714, 95% confidence interval 1.674–56.381, P=0.011). Conclusions: These findings suggest that the location and pulsatility power of the LV vortex are strongly associated with the LV thrombus formation in patients with anterior MI. Therefore, LV vortex flow analysis using CE can be clinically useful for characterizing and quantifying the risk of LV apical thrombus in patients with anterior MI.  (Circ J 2012; 76: 2640–2646)

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Background: S100A12, a calgranulin family protein released from white blood cells, is involved in inflammatory cardiovascular disease. It was hypothesized that the plasma level of S100A12 can be used to predict outcome in patients with chronic coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of S100A12 in patients with stable CAD. Methods and Results: A total of 652 patients with stable CAD were studied. All patients underwent percutaneous coronary intervention and successful revascularization. Major adverse cardiovascular events (MACE) were defined as a composite of events of CHF, recurrence of angina pectoris, acute myocardial infarction, stroke, critical arrhythmia, intervention to peripheral arteries and cardiac death. The mean follow-up period was 973±639 days. MACE occurred in 108 patients (16.6%). Plasma S100A12 level had a significant positive correlation with high-sensitivity C-reactive protein (hs-CRP) level. On Kaplan-Meier curve analysis the incidence of MACE was significantly different among S100A12 quartiles (P=0.026). The highest S100A12 quartile (Q4) had a significantly higher MACE rate than the lowest quartile (Q1) (P=0.002). In contrast, hs-CRP was not significant for predicting MACE in the present subjects (P=0.074). A Cox proportional hazard model showed that S100A12 was an independent factor for predicting MACE in multivariate models. Conclusions: S100A12 could be a novel biomarker for predicting cardiovascular events for predicting MACE in patients with stable CAD.  (Circ J 2012; 76: 2647–2652)

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Background: Factor VII activating protease (FSAP) is a circulating serine protease strongly expressed in unstable plaques and may serve as a marker of plaque destabilization. The aim of this study was to examine the relation between plasma concentrations of FSAP and clinical instability and outcome in coronary artery disease (CAD). Methods and Results: Circulating FSAP concentration and activity, as well as FSAP mRNA expression in monocytes, were measured in 231 sequential patients who underwent coronary angiography because of stable angina pectoris (n=50), unstable angina pectoris (n=43), or acute myocardial infarction (n=87). FSAP activity, but not FSAP antigen concentration, was elevated in patients with CAD compared with a control group. Elevated FSAP activity (≥1.035 plasma equivalent units [PEU]/ml) indicated a significantly increased risk of death or non-fatal myocardial infarction during 1 year of follow-up as compared with patients with low activity of FSAP (odds ratio 1.895 [95% confidence interval 1.093–3.283]; P=0.023). Furthermore, there were no significant changes in the FSAP expression in monocytes from CAD and control subjects in the basal state but there were differences after stimulation with proinflammatory factors. Conclusions: Plasma FSAP activity was significantly increased in patients with acute coronary syndrome and may be involved in the pathogenesis of these conditions. High levels of FSAP activity were predictive of adverse events during follow-up, suggesting its potential role in risk stratification and clinical management of CAD patients.  (Circ J 2012; 76: 2653–2661)

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Background: While statin induces plaque regression, its effects, particularly with different doses on plaque virtual histology composition, remain unknown. Methods and Results: In this prospective, randomized, double-blinded study, 40 consecutive statin-naive patients with stable angina requiring percutaneous coronary intervention (PCI) were randomized to 2 arms (20 patients each) receiving 6 months of atorvastatin 10mg or 40mg daily. The primary end-point was (VH-IVUS) changes from baseline to 6 months, as assessed by a core laboratory. Fifty-four VH-IVUS lesions were analyzed from the 10mg group and 57 from the 40mg group. Overall, plaque volume was reduced by 4.28% (–5.10±14.93mm³, P<0.001), absolute VH-IVUS fibrous volume by 10.54% (–4.87±10.74mm³, P<0.001), and relative percentage fibrous component by 3.29±7.84% (P<0.001), while relative percentage dense calcium increased by 1.50±3.08% (P<0.001), and necrotic core by 3.19±7.82% (P<0.001). Beneficial changes were more substantial in the higher dose (40mg) group, with significantly more percentage plaque volume regression (–1.50±3.85% vs. 0.38±4.05% increase in the 10mg group, P=0.014), less relative percentage necrotic core expansion (1.68±7.57% vs. 4.78±7.82% in the 10mg group, P=0.037), and without occurrence of major adverse cardiac events (vs. 6 patients in the 10mg group, P=0.020). Conclusions: In statin-naive patients requiring PCI, 6 months of atorvastatin induced a significant percentage of plaque volume reduction and substantial modification of VH-IVUS composition. In addition, these effects appeared to vary with different doses of atorvastatin, showing significantly better limitation of relative percentage necrotic core expansion at a higher dose.  (Circ J 2012; 76: 2662–2672)

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Background: It remains unclear whether concomitant use of omeprazole attenuates platelet function as compared with that of famotidine in patients with acute coronary syndromes (ACS) who receive clopidogrel. Methods and Results: In this prospective study, 130 ACS patients treated with aspirin and clopidogrel who underwent stent implantation were randomly assigned to receive a Japanese standard dose of omeprazole 10mg daily or famotidine 20mg daily for at least 4 weeks. Between 14 and 28 days after enrollment, there was no significant difference in the platelet reactivity index (PRI) measured with vasodilator-stimulated phosphoprotein phosphorylation assay between the omeprazole group (n=65) and famotidine group (n=65) (55±17% vs. 51±19%; P=0.26). The cumulative rate of adverse cardiovascular events at 12 months was similar in the groups (13% vs. 17%; P=0.81). The PRI was similar (54.9±17.9% vs. 54.0±17.8%; P=0.83) in the omeprazole group (n=33) and the famotidine group (n=39) among patients with ST-elevation myocardial infarction (STEMI). However, there was a trend toward a higher PRI (55.2±15.9% vs. 46.4±19.4%; P=0.06) in the omeprazole group (n=32) as compared with the famotidine group (n=26) among patients without persistent ST-segment elevation ACS. Conclusions: As compared with famotidine, concomitant use of low-dose omeprazole does not significantly attenuate the antiplatelet effects of clopidogrel in patients with ACS, especially in those with STEMI.  (Circ J 2012; 76: 2673–2680)

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Background: The rate of percutaneous coronary intervention (PCI) due to the development of significant atherosclerosis and the cardiac mortality rate in Korean patients with vasospastic angina (VSA) was estimated. Methods and Results: A total of 831 patients with VSA from 8 centers were registered in the Vasospastic Angina in the Catholic Medical Center (VA-CMC) registry. Their provocation tests for VSA showed positive results. The patients with significant atherosclerosis (>50% luminal narrowing) on the baseline angiography were excluded. Subjects were VSA patients without significant atherosclerosis. A total of 745 patients were included in the final analysis. The mean follow-up duration was 36.1±9.8 months. The PCI rate was 2.01% (15/745). Current smoking (odds ratio: 2.31, P<0.05) and high levels of baseline high-sensitivity C-reactive protein (hsCRP) (odds ratio: 1.57, P<0.05) were independent risk factors for PCI. The mortality rate was 2.55% (19/745). Eleven patients died of cardiac causes (1.48%). Cessation of medication was an independent risk factor for cardiac mortality (odds ratio: 1.47, P<0.05). The mean duration from the diagnosis to the cardiac deaths was 10.6±4.3 months. Conclusions: Korean patients with VSA demonstrated low rates of development of significant atherosclerosis leading to PCI and cardiac mortality. However, cessation of medication, smoking, and high baseline hsCRP were the independent risk factors for unfavorable outcomes.  (Circ J 2012; 76: 2681–2689)

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Background: Elevated blood glucose on admission may worsen outcome after acute myocardial infarction (AMI). No relationship has been identified between admission blood glucose level and myocardial salvage in patients with AMI. Methods and Results: This study assessed 150 consecutive patients with a first AMI who underwent percutaneous coronary intervention within 24h from onset of symptoms. Plasma blood glucose was measured on admission. Stress hyperglycemia was defined as blood glucose ≥10mmol/L (180mg/dl). The extent of myocardial salvage 7 days after AMI was evaluated on cardiovascular magnetic resonance imaging (CMRI) as the difference between areas of myocardium at risk (T2-weighted hyperintense lesion) and areas of late gadolinium enhancement. The association between stress hyperglycemia and myocardial salvage index (MSI) was investigated in patients with and without diabetes. Among non-diabetic patients, MSI was lower in those with stress hyperglycemia than in those without. No significant difference in MSI was noted between diabetes patients with or without stress hyperglycemia. On multivariate analysis, stress hyperglycemia in patients without diabetes was an independent predictor of MSI. Conclusions: Stress hyperglycemia affects MSI, indicating that the manipulation of glucose levels could be a potential therapeutic target for salvaging ischemic damage.  (Circ J 2012; 76: 2690–2696)

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Background: The patency and complications in aorto-iliac (AI) stenting remain poorly understood. The aim of this paper was to investigate the safety and efficacy after AI stenting. Methods and Results: This study was performed as a large-scale multicenter, retrospective registry. A total of 2,147 consecutive patients with AI disease were enrolled. The safety endpoints were procedure success, complications and 30-day mortality. The efficacy endpoints were primary, assisted primary and secondary patency, overall survival, freedom from major adverse cardiovascular events (MACE; all-cause death, myocardial infarction and stroke), and major adverse cardiovascular and limb events (MACLE; any repeat revascularization for limb and leg amputation in addition to MACE). Procedure success, complication rate and 30-day mortality were 97.6%, 6.4% and 0.7%. Primary patency was 92.5%, 82.6% and 77.5% at 1, 3 and 5 years, assisted primary patency was 97.0%, 92.7% and 91.9% at 1, 3 and 5 years and secondary patency was 99.0%, 98.7% and 98.5% at 1, 3 and 5 years. The overall survival rate was 95.0%, 87.6%, and 79.3% at 1, 3 and 5 years. The cause of death was cardiovascular in 44.1%. Freedom from MACE (MACLE) was 93.3% (89.9%), 84.4% (76.7%), and 74.9% (66.8%) at 1, 3 and 5 years. Female gender, diabetes, renal failure, absence of aspirin, reference vessel diameter <8.0mm and outflow lesion were found to be independent predictors of primary patency. Conclusions: The safety and efficacy after AI stenting are feasible compared to surgical reconstruction.  (Circ J 2012; 76: 2697–2704)

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Background: The absence of coronary artery calcium (CAC) is a marker of very low cardiovascular risk. Endothelial cells may have an effect on the initiation and propagation of arterial calcification. We aimed to identify the relationship between the absence of CAC and endothelial function in individuals without cardiovascular disease and diabetes. Methods and Results: CAC was assessed using electron-beam computed tomography and the calcium score was then computed. Endothelial function was measured by assessing reactive hyperemia-induced vasodilation and expressed by the reactive hyperemia index (RHI). Of 82 patients, 39 had non-detectable calcium (CAC score=0) and 43 had a CAC score >0. In the CAC score=0 group, the prevalence of normal endothelial function was 84.6%, compared to 48.8% in the CAC score >0 group, P=0.001. The absence of CAC was highly correlated with normal endothelial function (γ=0.704, P<0.001). On average, endothelial function was significantly better in the CAC score=0 group than in the CAC score >0 group (RHI 2.2±0.6 vs. 1.8±0.5, P=0.002). In a multivariate logistic regression model, only normal endothelial function (odds ratio [OR] 5.03, 95% confidence interval [CI] 1.55–16.27, P=0.007) and age (years) (OR 0.91, 95% CI 0.86–0.96, P=0.002) were independently associated with the absence of CAC. Conclusions: Normal functional status of the vasculature may be important for the prevention of coronary calcification and may partly account for the low cardiovascular risk of absent CAC.  (Circ J 2012; 76: 2705–2710)

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