Cardiac magnetic resonance imaging (MRI) has a central role in the management of patients with ventricular arrhythmias. Cardiac MRIs help to identify patients with risk for life-threatening arrhythmias. Delayed enhancement identifies scar tissue within the heart. Because scar harbors the arrhythmic substrate in patients with structural heart disease, areas of delayed enhancement can be targeted in order to eliminate ventricular arrhythmias with catheter ablation procedures. In this article, we will discuss the role of MRI in diagnosing different forms of non-ischemic cardiomyopathy and its role in risk stratification. Furthermore, we will discuss the role of MRI in imaging of the arrhythmogenic substrate in patients with structural heart disease. (Circ J 2012; 76: 1292-1298)

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A number of different ablation strategies for persistent atrial fibrillation (PeAF) have been used, including pulmonary vein isolation (PVI), targeting of complex fractionated atrial electrograms (CFAEs), multilinear lesions and various combinations and modifications of these lesion sets. The optimal ablation strategy for longstanding PeAF (LPeAF) is not yet established and there is still much that is understood. Extensive atrial remodeling poses a particular challenge for the ablation of LPeAF. Current catheter ablation techniques used in the therapy of PeAF and LPeAF are reviewed, together with the electrophysiological basis of catheter ablation. (Circ J 2012; 76: 1299-1306)

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Ischemic heart disease (IHD) accelerates cardiomyocyte loss, but the developing stem cell research could be useful for regenerating a variety of tissue cells, including cardiomyocytes. Diverse sources of stem cells for IHD have been reported, including embryonic stem cells, induced pluripotent stem cells, skeletal myoblasts, bone marrow-derived stem cells, mesenchymal stem cells, and cardiac stem cells. However, stem cells have unique advantages and disadvantages for cardiac tissue regeneration, which are important considerations in determining the specific cells for improving cell survival and long-term engraftment after transplantation. Additionally, the dosage and administration method of stem cells need to be standardized to increase stability and efficacy for clinical applications. Accordingly, this review presents a summary of the stem cell therapies that have been studied for cardiac regeneration thus far, and discusses the direction of future cardiac regeneration research for stem cells. (Circ J 2012; 76: 1307-1312)

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The multicenter Japanese-Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS), which involved 117 institutions and 4,629 patients, was the first attempt to quantify cardiac events and survival using stress-rest-gated single-photon emission computed tomography myocardial perfusion images (MPI) and QGS software in Japan. A 3-year follow-up study showed a relatively lower incidence of hard events than in the USA and some European countries, but a similar role of perfusion and left ventricular (LV) function. A low event risk with normal MPI and a higher incidence of major cardiac events in patients with large perfusion defects and LV dysfunction were defined. MPI was useful even among patients with proven coronary artery stenosis. The association between diabetes and chronic kidney disease (CKD) was an important predictor of cardiac events and the risk was evaluated using new software and risk charts. Additional studies were extended to include asymptomatic diabetes (J-ACCESS 2) and CKD (J-ACCESS 3). Because risk estimation is linked to the national healthcare system and clinical practice, optimal risk stratification and guidance for therapeutic strategies are recommended. (Circ J 2012; 76: 1313-1321)

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Background: Dietary habits are associated with obesity, and both are important contributing factors to lifestyle-related diseases. The STYLIST study examined the effects of dietary counseling by registered dietitians and the delivery of proper calorie-controlled meals (UMIN Registration No: 000006582). Methods and Results: Two-hundred adult patients with hypertension and/or diabetes mellitus were randomly divided into 2 groups with/without dietary counseling and consumed an ordinary diet for 4 weeks. Each group was then subdivided into 2 groups with/without dietary counseling and received calorie-controlled lunch and dinner boxes for the next 4 weeks. The calories in the delivered meals were based on the subject's ideal body weight (BW) and physical activity level. BW, waist circumference, blood pressure, and laboratory data, including glycoalbumin, were measured at 0, 4, and 8 weeks. BW and the other parameters were significantly reduced during the study period in patients who received diet counseling in the ordinary diet period and/or delivered meal period but not in patients without dietary counseling, as assessed by linear mixed models for longitudinal data. Conclusions: The combination of dietary counseling by dietitians and delivery of calorie-controlled meals was effective in reducing BW, as well as blood pressure and glycoalbumin, in patients with hypertension and/or diabetes mellitus. (Circ J 2012; 76: 1335-1344)

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Background: To determine the prevalence of anti-β-adrenoceptors autoantibodies (aβAA) in patients with idiopathic arrhythmias (IA) and to assess whether aβAA are predictive markers for concealed cardiomyopathy in such patients. Methods and Results: Sixty-seven patients (group 1) with IA [25 supraventricular (SVA) and 42 ventricular (VA)]; 14 patients (group 2) with suspected cardiomyopathy, 12 patients with definite cardiomyopathy (group 3); and 19 healthy controls (group 4) were tested with an enzyme immunoassay, using synthetic peptides corresponding to the second extracellular loop of the human β1-and β2-adrenoceptors. Endomyocardial biopsy was performed in 29 patients. As compared with group 4 [3/19 (15.7%)], anti-β1-adrenoceptor autoantibodies (aβ1AA) were more frequent in group-1 patients [38/67 (56.7%; P<0.01): 27/42 (64.2%; P<0.001) with VA and 11/25 (44%; P<0.05) with SVA]. 3 of the group 1 patients also had anti-β2-adrenoceptor autoantibodies (aβ2AA). 4 were positive for aβ2AA only. Biopsy performed in 11/67 group 1 patients was abnormal in all. Of them, 7/8 (87.5%) with VA and 3/3 (100%) with SVA were positive for aβ1AA. PCR analysis from paraffin blocks of the 11 group 1 biopsied patients was negative for EV, EBV, HCV, AV, PVB19, INF A/B,HSV1/2, HHV6 and HHV8 viral genomes. Conclusions: The second extracellular loop of the β-adrenoceptor is the molecular target of specific autoantibodies. Positivity for aβ1AA predicts abnormal histological findings in 90% of IA patients and suggests that autoimmunity might play an arrhythmogenic role. (Circ J 2012; 76: 1345-1353)

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Background: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca_i) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results: MHC-TGFcys³³ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Ca_i transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca_i transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca²⁺-ATPase 2a. Conclusions: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca_i transient, EAD and triggered activity. Inhibition of Ca²⁺ release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria. (Circ J 2012; 76: 1354-1362)

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Background: The anti-thrombotic strategy during coronary stenting is challenging in patients on long-term oral anticoagulation (OAC) because of atrial fibrillation (AF). Uninterrupted OAC (UAC) is increasingly used, but bridging therapy (BT) is still in common use. Methods and Results: Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) is a prospective multicenter European registry that recruited 963 patients with AF undergoing coronary stenting. To compare the safety of UAC and BT, bleeding complications and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, target vessel revascularization, stent thrombosis and stroke) were assessed in 290 patients treated with UAC and 161 patients with BT during a 30-day follow-up period. In the BT group, OAC was interrupted for a median of 5 days. Overall bleeding complications tended to be more common in the BT group (18.6% vs. 12.1%, P=0.07), with no significant difference in the rate of major bleeding (2.5% vs. 1.4%) or MACCE (6.2% vs. 3.8%). After adjustment for propensity score, BT was not associated with bleeding complications (odds ratio [OR], 1.38; 95% confidence interval [CI]: 0.77-2.48, P=0.28) or MACCE (OR, 1.16; 95%CI: 0.44-3.05, P=0.76). Periprocedural international normalized ratio was not associated with bleeding or MACCE. Conclusions: UAC does not increase perioperative complications during coronary stenting and is a simple and cost-effective alternative to conventional heparin bridging. (Circ J 2012; 76: 1363-1368)

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Background: Association of the type of statin and the achieved level of low-density lipoprotein cholesterol (LDL-C) with cardiovascular outcome has not been fully elucidated. Methods and Results: The study included 14,866 patients who underwent a first coronary revascularization in 2005-2007. We identified 7,299 patients with statin therapy at discharge (so-called strong statins [atorvastatin, rosuvastatin, and pitavastatin]: 4,742 patients; standard statins [pravastatin, simvastatin, and fluvastatin]: 2,557 patients). Unadjusted 3-year incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stoke) was significantly lower (7.5% vs. 9.6%, P=0.0008) in the strong statin group, and there was a trend in adjusted risk of MACE favoring strong statins (hazard ratio [HR] 0.87, [95% confidence interval (CI) 0.73-1.04], P=0.13). Among 4,846 patients with follow-up LDL-C data available, outcomes were evaluated according to achieved LDL-C level (<80, 80-99 [reference], 100-119, ≥120mg/dl). Compared with the reference group, the risk for MACE was significantly higher in the ≥120mg/dl group (adjusted HR 1.74 [95%CI 1.11-2.71], P=0.01), although it was comparable in the 100-119mg/dl group (adjusted HR 1.23 [95%CI 0.78-1.94], P=0.38) and in the <80mg/dl group (adjusted HR 1.15 [95%CI 0.75-1.75], P=0.52). Conclusions: Strong statin therapy was associated with a trend toward lower cardiovascular risk compared with standard statin therapy. When LDL-C <120mg/dl was achieved, risks for cardiovascular events were comparable irrespective of achieved LDL-C level. (Circ J 2012; 76: 1369-1379)

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Background: Patients with both cardiothoracic lesions and abdominal aortic aneurysm (AAA) are increasing in Japan. The objective of this study was to clarify the effect of 2-staged surgery on complication rates. Methods and Results: Three hundred and forty-six patients who underwent elective surgery for infrarenal AAA were entered. History of cardiac and thoracic aortic surgery within 1 year before AAA repair was recorded. A retrospective study regarding perioperative complications was performed. Operative mortality and complication rates were 0.6% and 10.7%, respectively. Seventy patients (20.2%) underwent prior cardiac and thoracic aortic surgery before AAA repair. There was no significant difference in preoperative characteristics between the group with prior cardiac and thoracic aortic surgery and the group without prior surgery. Significant risk factors for postoperative morbidity were: (1) prior cardiac and thoracic aortic surgery (odds ratio [OR] 2.5; 95%CI 1.1-5.1); (2) open aneurysm repair (OAR) (OR 2.7; 95%CI 1.3-5.1); and (3) VSG-CRI score ≥6 (OR 2.9; 95%CI 1.2-6.8). Subanalysis revealed that, although prior cardiac and thoracic aortic surgery was still a risk within patients undergoing OAR, it was not a risk factor for patients undergoing endovascular aneurysm repair (EVAR). Conclusions: Prior cardiac and thoracic aortic surgery carries high risk for AAA repair. To lower complication rates, we propose to perform EVAR on these patients if they are anatomically suitable. (Circ J 2012; 76: 1380-1384)

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Background: The in-hospital outcome of patients with profound cardiogenic shock (CS) undergoing extracorporeal membrane oxygenation (ECMO) and prognostic predictors were analyzed. Methods and Results: Between 2003 and 2010, 134 patients with profound CS undergoing 10-15min of cardiopulmonary cerebral resuscitation (CPCR) and ECMO were prospectively recruited, including 27.6% (37) with ST-elevation myocardial infarction (STEMI), 11.9% (16) with non-STEMI, 22.4% (30) with post-surgery pump failure, 10.5% (14) with refractory congestive heart failure, 19.4% (26) with fulminant acute myocarditis, 2.2% (3) with pediatric congenital diaphragmatic hernia, and 6.0% (8) with percutaneous coronary intervention-related complications. The mean systolic pressure was 49.8mmHg and 91.8% of patients required ventilatory support prior to ECMO. The Post-ECMO Mean Acute Physiology and Chronic Health Evaluation (APACHE) II score and peak creatine kinase level were 26.2 and 5,311IU/L, respectively. In-hospital mortality was 57.5%. Sixty-eight patients (50.7%) were successfully weaned from ECMO and 57 (42.5%) were discharged alive. Univariate analysis identified the APACHE II score as the strongest predictor of in-hospital mortality (P<0.0001) with respiratory failure, smoking, and male gender also related (all P<0.03). Multivariate analysis identified an APACHE II score ≥22 and successful ECMO weaning as the only independent predictor for in-hospital mortality and a determinant of survival, respectively (P=0.0003). Conclusions: Profound CS was associated with high mortality. Both successful weaning from ECMO and an APACHE II score might serve as outcome predictors for risk stratification. (Circ J 2012; 76: 1385-1392)

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Background: The purpose of this study was to investigate the clinical usefulness of myocardial contrast echocardiography (MCE) to distinguish stress-induced cardiomyopathy (SCMP) from acute myocardial infarction (AMI) in the emergency department (ED). Methods and Results: We investigated 51 patients (62±13 years, 29 women) who had suspected SCMP in the ED with acute chest pain and showed apical wall motion abnormality on 2-dimensional echocardiography. All patients were assessed by real-time MCE and the perfusion status and quantitative myocardial perfusion parameters were analyzed. After MCE, coronary angiography was performed within 24h. Of 51 patients, 27 had significant perfusion defects (group A) and 24 had preserved perfusion at the apex (group B) by MCE. In group A, 25 patients showed significant luminal stenosis in the left anterior descending artery (LAD) and 2 patients showed no critical luminal stenosis. In group B, 20 patients showed no luminal stenosis and 4 patients showed moderate LAD stenosis. Sensitivity, specificity, positive and negative predictive values of MCE for detection of SCMP were 91%, 86.2%, 83%, and 93%, respectively. Quantitative MCE parameters were significantly decreased in group A compared with group B. Conclusions: Myocardial perfusion measured by MCE is relatively preserved in patients with SCMP compared with those with AMI. Therefore, real-time MCE may be a useful noninvasive diagnostic tool to distinguish SCMP from AMI in the ED. (Circ J 2012; 76: 1393-1398)

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Background: Tissue Doppler imaging-obtained isovolumetric myocardial acceleration (IVA) is load independent, reportedly predicts systolic functions, and correlates with exercise capacity in patients with reduced ejection fraction (EF). We hypothesized that IVA correlates with the pulmonary capillary wedge pressure (PCWP) in patients with reduced EF. Methods and Results: Of 113 patients, correlations between PCWP and IVA were done for all patients, 48 patients with EF ≥55%, and 65 patients with EF <55%. Results were compared to the correlation between PCWP and other echocardiographic predictors. IVA correlated moderately with PCWP in all patients (r=0.54, P<0.0001) and was comparable to the E/A and E/e’ ratios. In patients with EF ≥55%, IVA lost correlation and the only predictor was the E/e’ ratio (r=0.08, 0.58, P=0.58, <0.0001). In patients with EF <55%, IVA was better than E/A and E/e’ (r=0.72, 0.61, 0.51, P<0.0001), especially for atrial fibrillation or when E/e’ fell between 8 and 15. Furthermore, IVA >1.60m/s² can predict PCWP ≥15mmHg, with a sensitivity of 95%, specificity of 73%, and an area under the curve of 0.867 (P<0.0001). Conclusions: IVA can predict PCWP in patients with reduced EF, and can be considered an alternative to the E/e’ ratio for patients with atrial fibrillation or E/e’ ratio between 8 and 15. (Circ J 2012; 76: 1399-1408)

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Background: Left ventricular (LV) hypertrophy is a powerful independent predictor of morbidity and mortality in hypertensive patients. Abnormal LV geometric patterns are also associated with hypertensive complications, and concentric hypertrophy is associated with the highest mortality in hypertensive patients. However, the relationship between geometric patterns and cardiac dysfunction is not fully established. We hypothesized that the Tei index, which is a measure of global cardiac function, is a feasible parameter for estimating cardiac dysfunction among the different LV geometric patterns in hypertensive patients. Methods and Results: We enrolled 60 consecutive patients with untreated essential hypertension. Subjects were divided into 4 groups: normal geometry, concentric remodeling, eccentric hypertrophy and concentric hypertrophy. We measured ejection fraction, mitral E/A ratio, Tei index, ejection time, and isovolumic contraction and relaxation times. There were significant correlations between LV mass index and systolic blood pressure (P<0.01), ejection fraction (P<0.05), mitral E/A ratio (P<0.05) and Tei index (P<0.0001). In multiple regression analysis, only the Tei index independently correlated with LV mass index (P<0.01). Concentric hypertrophy significantly increased the Tei index compared with the other 3 groups. Conclusions: The Tei index provides a better marker for LV dysfunction by hypertensive hypertrophy than conventional parameters. LV function in concentric hypertrophy was most impaired among all the geometric patterns in untreated hypertensive patients. (Circ J 2012; 76: 1409-1414)

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Background: In order to achieve target blood pressure levels to prevent cardiovascular disease, combination therapy of antihypertensive drugs is often required, although it is thought that requiring a patient to take many different pills would reduce adherence to the medication regimen. Whether antihypertensive treatment with a single pill combining antihypertensive drugs would improve medication adherence and blood pressure control was investigated. Methods and Results: A total of 207 hypertensive subjects were randomly assigned to a combination pill group (losartan 50mg/hydrochlorothiazide 12.5mg; n=103) or a control group (an angiotensin receptor blocker and a thiazide diuretic; n=104). Medication adherence was evaluated by pill counts at 1, 3, and 6 months after randomization. The mean adherence rates over 6 months were not different between the 2 groups: 98% in the combination pill group and 98% in the control group. Moreover, the 2 groups included similar numbers of subjects with relatively poor adherence rates (<90%) in each treatment period. The mean blood pressures over the 6-month treatment period were not different between the groups: 131/75mmHg in the combination pill group and 130/75mmHg in the control group (P=0.84/0.96). Conclusions: There were no appreciable effects of the combination pill of antihypertensive drugs on medication adherence or blood pressure control in Japanese patients over a 6-month period. (Circ J 2012; 76: 1415-1422)

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Background: Ghrelin is an acylated peptide hormone mainly secreted from the stomach. When administrated externally it modulates vascular tone mainly through the regulation of autonomic nerve activity. However, the effects of blood pressure (BP) on the production and secretion of ghrelin remain to be clarified. Methods and Results: We examined the stomach and plasma levels of ghrelin in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats after a 4-week-intervention with antihypertensive agents (candesartan-cilexetil [ARB], doxazosin [DZN], metoprolol [MP], reserpine [RES]) to clarify the influence of BP on the secretion of ghrelin. The effect of these agents on ghrelin production and secretion were examined by comparing vehicle-treated controls (WKY-Intact, SHR-Intact). Treatment with the 4 antihypertensive drugs all yielded a significant decline in systolic BP in both SHR and WKY. Under these conditions, significantly lower levels of stomach and plasma ghrelin were detected in WKY treated with ARB (P<0.05), DZN (P<0.05), MP (P<0.05) and RES (P<0.05) compared with WKY-Intact, whereas no significant change in the ghrelin levels in the stomach and plasma were detected in SHR under the same treatments. Conclusions: The findings imply that the production and secretion of ghrelin are controlled by the ambient vascular tone and vice versa in normotensive WKY. This inter-relationship between ghrelin and BP seems to be disrupted in SHR. (Circ J 2012; 76: 1423-1429)

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Background: Estimation of left atrial (LA) pump function is important for the management of cardiac patients. The purpose of this study is to elucidate the role of mitral annular late diastolic velocity (A') determined by transthoracic echocardiography as a parameter to predict LA pump function. Methods and Results: One hundred and four consecutive patients that were scheduled for paroxysmal atrial fibrillation (AF) ablation, in whom both multi-detector computed tomography (MDCT) and echocardiography during sinus rhythm prior to ablation were performed, were enrolled in this study. To determine the echocardiographic parameters that most accurately represent LA pump function, the relationship between LA emptying fraction (LAEF) obtained by MDCT and echocardiographic parameters including A' were examined. A' was the only echocardiographic parameter that was significantly correlated with LAEF (r=0.59, P<0.0001). Receiver-operating characteristic curve analysis showed that when impaired LA booster pump performance was defined as an LAEF <30%, an A' cutoff value of 7.4cm/s had a sensitivity of 93%, specificity of 81%, predictive accuracy of 83%, positive predictive value of 43% and a negative predictive value of 99%. Conclusions: A' is a simple, non-invasive and reliable method to estimate LA pump function in patients with paroxysmal AF. (Circ J 2012; 76: 1430-1435)

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Background: The differences in the coronary plaque characteristics between patients with mild chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] 30-59ml⋅min^-1⋅1.73m^-2) and those without CKD (eGFR ≥60) by 320-row area detector computed tomography (CT) have not been studied. Methods and Results: We enrolled 487 patients undergoing coronary CT angiography with suspected stable coronary artery disease (mean age: 66.6±10.8 years, 131 with mild CKD) and analyzed 6,352 segments. All coronary plaques were characterized for the presence of vessel remodeling, plaque consistency and the disposition of coronary calcification, and a plaque with positive vessel remodeling and/or low-attenuation was defined as high risk. The number of diseased segments per patient was higher in mild CKD patients than in those without CKD (4.61±3.83 vs. 2.95±3.11, P<0.0001). The prevalence of severe stenosis (≥70% luminal diameter) was significantly higher in cases of mild CKD than in no CKD (35.1% vs. 19.4%, P=0.0003), but there was no significant difference in the prevalence of high-risk plaque (13.0% vs. 9.8%, P=0.3189). Conclusions: The severity of coronary artery stenosis was higher in the patients with mild CKD, though there was no significant difference in the prevalence of high-risk plaque. We suggest that the high risk of coronary events in patients with CKD is related to the severity of stenosis rather than to the characteristics of plaque. (Circ J 2012; 76: 1436-1441)

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Background: The aim of the present study was to assess the effects of angiotensin II receptor blocker (ARB) on coronary plaque progression in patients with acute myocardial infarction (AMI) who received an angiotensin-converting enzyme inhibitor (ACEI). Methods and Results: After local ethics committee approval and obtaining of informed consent, 116 patients with AMI were randomly assigned to receive a combination of valsartan and captopril or captopril alone. Non-culprit intermediate coronary atherosclerosis was assessed on intravascular ultrasound. The primary and secondary endpoints were the nominal change in percent atheroma volume (PAV) and percent change in lumen volume (%ΔLV), respectively. The combination group had a significantly lower systolic blood pressure (117 vs. 125mmHg; P=0.02) and a lower plasma aldosterone level (56 vs. 75pg/ml; P=0.02) at follow-up. The nominal change in PAV was slightly lower in the combination group than in the ACEI group (-1.9 vs. -0.68%, P=0.06). %ΔLV was -0.3% in the ACEI group and was 4.3% in the combination group (P=0.03). Logistic regression analysis showed that additional ARB therapy was independently associated with LV enlargement (odds ratio, 2.144; 95% confidence interval: 1.818-5.618; P=0.03). Conclusions: In this study of patients with AMI, additional ARB therapy had minimal impact on the progression of coronary atherosclerosis as compared with an ACEI alone. The combination of these 2 drugs, however, induces coronary artery enlargement. (Circ J 2012; 76: 1442-1451)

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Background: The resolution of hyperglycemia is associated with suppression of in-hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an α-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. Methods and Results: ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. Conclusions: Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM. (Circ J 2012; 76: 1452-1460)

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Background: It remains unclear whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular diseases. We investigated the effects of adding the direct renin inhibitor (DRI), aliskiren, to an ACEI or an ARB on monocyte subsets and myocardial salvage in patients with primary acute myocardial infarction (AMI). Methods and Results: Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren combined with an ACEI or an ARB (DRI group). Two monocyte subsets (CD14⁺CD16^- and CD14⁺CD16⁺) were measured by flow cytometry. The extent of myocardial salvage 7 days after AMI was evaluated by cardiac magnetic resonance imaging. Both plasma renin activity and aldosterone levels were significantly lower in the DRI group than in the non-DRI group. Peak levels of CD14⁺CD16^- monocyte number and ratio were also significantly lower in the DRI group. The extent of myocardial salvage was significantly higher in the DRI group than in the non-DRI group (44.8 [41.2-53.1] vs. 36.0 [28.5-42.6], P=0.001). Conclusions: A DRI combined with an ACEI or an ARB can better improve the extent of myocardial salvage after AMI than an ACEI or an ARB alone in association with the decrease in circulating CD14⁺CD16^- monocytes. (Circ J 2012; 76: 1461-1468)

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Background: Little is known about the interrelationships among brachial flow-mediated vasodilatation (bFMD), brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (bIMT) in patients with and without coronary artery disease (CAD). Methods and Results: Two-hundred consecutive patients with stable angina pectoris (SAP) were enrolled as the CAD group and 50 age-, sex- and body mass index-matched patients without CAD were selected as the non-CAD group. bFMD, diastolic blood pressure (DBP) and high-density lipoprotein cholesterol (HDL-C) in the CAD group were significantly lower. The CAD group showed significantly higher levels of hemoglobin A_1c (HbA_1c) and low-density lipoprotein cholesterol (LDL-C), but not baPWV. CAD was independently associated with bFMD, DBP, HbA_1c and HDL-C. bFMD and HDL-C significantly decreased and LDL-C increased as the number of diseased vessels with significant stenosis increased. The number of diseased vessels was independently associated with bFMD and HDL-C. In addition, bFMD, bIMT, the time constant of the shear rate and the time constant of the flow rate as assessed by a new program, Trend Plus^®, were associated with the presence of CAD. Among these parameters, the presence of CAD was independently associated with bIMT as well as bFMD. Conclusions: bFMD was a better predictor of the severity of CAD than either baPWV or coronary risk factors in patients with SAP. In addition, bIMT may be a critical predictor of CAD. (Circ J 2012; 76: 1469-1475)

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Background: Epsilon-protein kinase C (εPKC) protects the heart from ischemic injury. However, the mechanism(s) of εPKC cardioprotection is still unclear. Identification of the εPKC targets may aid in elucidating the εPKC-mediated cardioprotective mechanisms. Previous studies, using εPKC transgenic mice and difference in gel electrophoresis, identified proteins involved in glucose metabolism, the expression of which was modified by εPKC. Those studies were accompanied by metabolomic analysis, suggesting that increased glucose oxidation may be responsible for the cardioprotective effect of εPKC. Whether these εPKC-mediated alterations were because of differences in protein expression or phosphorylation was not determined. Methods and Results: In the present study, we used an εPKC -specific activator peptide, ψεRACK, combined with phosphoproteomics, to find εPKC targets, and identified that the proteins whose phosphorylation was altered by selective activation of εPKC were mostly mitochondrial proteins. Analysis of the mitochondrial phosphoproteome led to the identification of 55 spots, corresponding to 37 individual proteins, exclusively phosphorylated, in the presence of ψεRACK. The majority of the proteins identified were involved in glucose and lipid metabolism, components of the respiratory chain as well as mitochondrial heat shock proteins. Conclusions: The protective effect of εPKC during ischemia involves phosphorylation of several mitochondrial proteins involved in glucose and lipid metabolism and oxidative phosphorylation. Regulation of these metabolic pathways by εPKC phosphorylation may lead to εPKC-mediated cardioprotection induced by ψεRACK. (Circ J 2012; 76: 1476-1485)

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Background: Despite the recent advances in bypass surgery and catheter interventional therapy for peripheral artery disease (PAD), the long-term outcome of revascularization therapy for infrapopliteal lesions remains unsatisfactory. We have previously demonstrated that low-energy extracorporeal shock wave (SW) therapy effectively induces neovascularization through upregulation of angiogenic factors and improves myocardial ischemia in pigs and humans and in hindlimb ischemia in rabbits. In this study, we thus examined whether our SW therapy also improves the walking ability of patients with PAD and intermittent claudication. Methods and Results: We treated 12 patients (19 limbs) in Fontaine II stage (males/females, 10/2; 60-86 years old) with low-energy SW therapy to their ischemic calf muscle 3 times/week for 3 consecutive weeks. After 24 weeks, the pain and distance subscale scores of the walking impairment questionnaire were significantly improved (33±25 vs. 64±26, 27±16 vs. 64±23, respectively, both P<0.01). Maximum walking distance was also significantly improved at 4 weeks (151±37% from baseline, P<0.01) and was maintained at 24 weeks (180±74% from baseline, P<0.01). Moreover, the recovery time of the tissue oxygenation index in the calf muscle during a treadmill test, which reflects local O₂ supply, was significantly shortened (295±222s vs. 146±137s, P<0.01). Importantly, no adverse effects were noted. Conclusions: Non-invasive SW therapy improves the walking ability of PAD patients. (Circ J 2012; 76: 1486-1493)

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Background: The recent development of various effective drugs, such as epoprostenol, sildenafil, and bosentan, has improved the prognosis for patients with idiopathic pulmonary arterial hypertension (IPAH). This study sought to determine survival rates and to identify predictive prognostic factors in patients with IPAH in the current era of combination therapy with new and more effective vasodilators. Methods and Results: In 65 consecutive IPAH patients treated from 2004 to 2009, hemodynamic parameters were significantly improved and brain natriuretic peptide was significantly decreased by combination therapy (observation period: 35±18 months). The Kaplan-Meier survival curves were determined, and 22 prognostic variables, including 9 hemodynamic variables and 6 biomarkers, were evaluated to obtain the best variables. The 1-year and 3-year survival rates were 98% and 86%, respectively. Only the platelet level was correlated with death (P<0.05), and the platelet level was significantly correlated with mean pulmonary arterial pressure (P<0.01). Patients with a lower platelet level (<20×10⁴/μl (median value)) before treatment had a higher mortality rate compared to the other patients (78% vs. 95% for 3-year survival, P<0.01). Conclusions: Combination therapy contributed to an improvement in the prognosis of IPAH patients. Platelet level is a significant prognostic predictor in this new treatment era. (Circ J 2012; 76: 1494-1500)

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Background: Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, the activin receptor-like kinase 1 (ALK1) gene, and SMAD8 gene have been reported in heritable pulmonary arterial hypertension (HPAH) and in idiopathic pulmonary arterial hypertension (IPAH). However, almost 30% of HPAH cases and 60-90% of IPAH cases have no mutations in those genes. This suggests that there remain unidentified genes associated with HPAH and IPAH. Methods and Results: This study screened for mutations in endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, SMAD7, bone morphogenetic protein receptor type 1A (BMPR1A) and bone morphogenetic protein receptor type 1B (BMPR1B) genes in 43 IPAH patients who had no mutations in BMPR2, ALK1 and SMAD8. Two missense mutations (c.479 G>A S160N, c.1176 C>A F392L) in BMPR1B were each identified in 2 IPAH patients. Immunoblot analysis revealed that the BMPR1B F392L protein promoted SMAD8 phosphorylation. The response to BMP was analyzed using promoter-reporter activities. The transcriptional activation of the BMPR1B F392L protein with SMAD8 increased above that of wild-type BMPR1B with SMAD8, and those of BMPR1B S160N and F392L with SMAD8 and SMAD4 were each increased above those of the wild-type BMPR1B with SMAD8 and SMAD4. Conclusions: We identified 2 novel mutations in BMPR1B in 2 patients with IPAH. Our study suggests that BMPR1B mutations are associated with the pathogenesis of IPAH. (Circ J 2012; 76: 1501-1508)

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Background: Vascular endothelial growth factor (VEGF) is induced by myocardial ischemia and is thought to facilitate cardiovascular repair after acute myocardial infarction (AMI). However, the association between the plasma VEGF levels and clinical outcome in AMI patients is unclear. Methods and Results: We evaluated 879 AMI patients undergoing successful primary revascularization within 24h of symptom onset. The patients were classified into 3 groups according to tertiles of plasma VEGF levels at 7 days after the onset of AMI. Major adverse cardiovascular and cerebrovascular events (MACCE), defined as cardiac death, recurrent acute coronary syndrome, hospital readmission for heart failure, or stroke, were assessed during the 6-month follow-up period. The incidence of MACCE was the least frequent in the middle tertile. Compared to the middle tertile, patients in the low tertile were at a significantly higher risk for MACCE even after adjusting for baseline characteristics (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.18-6.06, P=0.019). An absence of statin treatment before onset and a younger age (HR 0.54, 0.87; 95%CI 0.33-0.90, 0.76-0.99; P=0.017, 0.037; respectively) were significantly associated with low VEGF. Conclusions: Low plasma VEGF levels at 7 days after the onset of AMI were associated with a significantly increased risk for MACCE during 6 months of follow-up. (Circ J 2012; 76: 1509-1516)

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Background: Adipose tissue-derived stromal cells (ADSCs) might help repair ischemic cardiovascular tissue. Their in vivo effects on the bioenergetics and microcirculation of ischemic muscle through a variety of non-invasive techniques was examined. Methods and Results: Unilateral hindlimb ischemia was induced in 42 rats. One day after femoral artery ligation, 6 rats per group were randomly injected with intramuscularly allogeneic ADSCs (10⁶-10⁷-10⁸cells/ml), conditioned media from ADSC cultures (conditioned media [CM], control), saline (control), allogeneic fibroblasts (10⁷cells/ml, control) or a non-conditioned medium (control). Rats underwent magnetic resonance angiography (MRA), short-time inversion recovery (STIR) edema-weighed imaging, proton MR spectroscopy (¹H-MRS), thermal infrared imaging (IRI), immunoblotting and immunofluorescence analysis on both hindlimbs for 4 weeks. MRA and STIR documented arterial occlusion and ischemia, respectively. Muscle ¹H-MRS and IRI showed reductions of total creatine (tCr)/water and skin temperature in occluded hind limbs, respectively. At 4 weeks, the ADSC and CM groups had greater recovery of skin temperature and tCr/water in ischemic limbs compared with controls (P<0.01), with increased expression of α-sarcomeric actinin and vascular growth factors, such as hepatocyte growth factor (HGF), increased vessel density (capillaries, arterioles and venules) and less type III collagen. Conclusions: Allogeneic ADSCs improve ischemic muscle metabolism, increase neovasculogenesis and decrease fibrosis, largely through a paracrine mechanism. ¹H-MRS and IRI are useful tools to monitor attempts at salvaging the ischemic tissues with cell-derived novel therapies. (Circ J 2012; 76: 1517-1525)

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Background: There are few data that demonstrate a significant effect of aspirin therapy for diabetic patients. To clarify the effect of the primary prevention of aspirin therapy in diabetic patients, the relationship between blood pressure (BP) and the incidence of atherosclerotic events was investigated in participants in the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial. Methods and Results: We divided the JPAD participants according to their systolic (SBP) and diastolic (DBP) BPs at enrollment (SBP ≥140mmHg and/or DBP ≥90mmHg: unattained group, SBP <140mmHg and DBP <90mmHg: attained group). The incidence of the primary atherosclerotic events, especially cerebrovascular events, was higher in the unattained group than in the attained group. The incidence of cerebrovascular events was higher in the unattained group than in the attained group in patients without aspirin therapy; however, the incidence of cerebrovascular events in the unattained group was as low as the incidence in the attained group in patients undergoing aspirin therapy. Cox proportional hazards analysis revealed that BP level was an independent predictor for cerebrovascular events in diabetic patients. Conclusions: Aspirin therapy may reduce cerebrovascular events in diabetic patients with higher BP. Aspirin therapy could be an additional strategy as primary prevention for diabetic patients with higher BP. (Circ J 2012; 76: 1526-1532)

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Background: Total stroke work (TSW) is used for the estimation of cardiac efficiency in mitral regurgitation (MR). We should be cautious about the interpretation of this parameter, especially when it is assessed by non-invasive methods such as echocardiography. Methods and Results: For the calculation of regurgitant stroke work, regurgitant volume is usually multiplied by left atrial (LA) pressure. However, by considering the left ventricular (LV) pressure-volume loop, it would be more appropriate to multiply regurgitant volume and the LV pressure, not the atrial one. Conclusions: We might underestimate TSW when we use LA pressure for the estimation of regurgitant stroke work. (Circ J 2012; 76: 1533-1534)

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