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Background: The REAL-CAD trial, reported in 2017, demonstrated a significant reduction in cardiovascular events with high-intensity statins in patients with chronic coronary syndrome. However, data are scarce on the use of high-intensity statins in Japanese patients with acute coronary syndrome (ACS)., Methods and results: In STOPDAPT-2 ACS, which exclusively enrolled ACS patients between March 2018 and June 2020, 1,321 (44.2%) patients received high-intensity statins at discharge, whereas of the remaining 1,667 patients, 96.0% were treated with low-dose statins. High-intensity statins were defined as the maximum approved doses of strong statins in Japan. The incidence of the cardiovascular composite endpoint (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke) was significantly lower in patients with than without high-intensity statins (1.44% vs. 2.69% [log-rank P=0.025]; adjusted hazard ratio [aHR] 0.48, 95% confidence interval [CI] 0.24-0.94, P=0.03) and the effect was evident beyond 60 days after the index percutaneous coronary intervention (log-rank P=0.01; aHR 0.38, 95% CI 0.17-0.86, P=0.02). As for the bleeding endpoint, there was no significant difference between the 2 groups (0.99% vs. 0.73% [log-rank P=0.43]; aHR 0.96, 95% CI 0.35-2.60, P=0.93)., Conclusions: The prevalence of high-intensity statins has increased substantially in Japan. The use of the higher doses of statins in ACS patients recommended in the guidelines was associated with a significantly lower risk of the primary cardiovascular composite endpoint compared with lower-dose statins.

Background: The access site for primary percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI) recently shifted from femoral to radial. However, few real-world data on Japanese patients exist., Methods: To elucidate the clinical selection and impact of the access site in STEMI patients, we analyzed a Japanese observational prospective multicenter registry of acute myocardial infarction (K-ACTIVE: Kanagawa ACuTe cardIoVascular rEgistry) in 2015 to 2021. Data were analyzed in the entire population and a propensity score-matched population adjusted for confounding factors. Major adverse cardiac event (MACE) was defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Bleeding Academic Research Consortium (BARC) type 3 or 5 was used to assess bleeding events. MACE plus BARC type 3 or 5 bleeding were considered composite events. Clinical outcomes were followed for 30 days., Results: The 6802 STEMI patients included 4786 patients with radial access (70.3 %) and 2016 with femoral access (29.7 %). Femoral access tended to be selected for more severe conditions than radial access. The median door-to-device time in the radial access group was significantly shorter than the femoral access group in the entire population (75 min versus 79 min, p < 0.01). After propensity score matching (each group, n = 1208), the incidence of MACE tended to be lower in the radial access group [risk ratio (RR) 0.83, 95 % confidence interval (CI) 0.63-1.09, p = 0.17]. The incidence of BARC 3 or 5 bleeding was significantly less in the radial access group (RR 0.47, 95%CI 0.23-0.97, p = 0.04). The incidence of composite events was significantly less in the radial access group (RR 0.74, 95%CI 0.57-0.96, p = 0.02)., Conclusion: In STEMI patients undergoing primary PCI, in comparison to femoral access, radial access reduced composite events in the entire population and the matched population, through a reduction in MACE and BARC 3 or 5 bleeding., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood., Methods: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors., Results: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98)., Conclusion: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The clinical incidence and impact of atrial fibrillation (AF) in Japanese acute myocardial infarction (AMI) patients is not fully understood., Methods: To elucidate the clinical incidence and impact of AF on in-hospital mortality in AMI patients, we analyzed a Japanese observational prospective multicenter registry of acute myocardial infarction (K-ACTIVE: Kanagawa ACuTe cardIoVascular rEgistry), which spans 2015 to 2019. A major adverse cardiac event (MACE) was defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. For assessing bleeding events, Bleeding Academic Research Consortium (BARC) type 3 or 5 was used. MACE plus BARC type 3 or 5 bleeding were considered as composite events. The clinical outcomes were followed for 1 year., Results: The total of 5059 patients included 531 patients with AF (10.5%) and 4528 patients with sinus rhythm (SR; 89.5%). AF patients were significantly older and tended to have more comorbidities than SR patients. Oral anticoagulation therapy (OAC) was used in 44% of AF patients while single antiplatelet therapy was selected for 52% of patients with OAC. Crude in-hospital mortality was significantly greater in AF patients than in SR patients (10.4%, 5.0%, respectively, p < 0.01). The multivariate analysis was adjusted for age, sex, diabetes, hypertension, hemodialysis, smoking, previous MI, body mass index, Killip classification, out of hospital cardiac arrest, and OAC. In-hospital mortality was still significantly greater in AF patients than in SR patients in the logistic regression analysis [adjusted odds ratio 2.02 (1.31-3.14)]. AF was an independent risk factor for MACE and composite events in the Cox proportional hazards model [adjusted risk ratio (ARR) 1.91 (1.36-2.69), p < 0.01; ARR 1.72 (1.25-2.36), p < 0.01]. In contrast, AF was not an independent risk factor for bleeding [ARR 1.71 (0.79-3.71), p = 0.18]., Conclusion: In Japanese AMI patients, AF was often observed and was associated with worse MACE but not worse bleeding., (Copyright © 2022. Published by Elsevier Ltd.)

Importance: Clopidogrel monotherapy after short dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) has not yet been fully investigated in patients with acute coronary syndrome (ACS)., Objective: To test the hypothesis of noninferiority of 1 to 2 months of DAPT compared with 12 months of DAPT for a composite end point of cardiovascular and bleeding events in patients with ACS., Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial enrolled 4169 patients with ACS who underwent successful PCI using cobalt-chromium everolimus-eluting stents at 96 centers in Japan from December 2015 through June 2020. These data were analyzed from June to July 2021., Interventions: Patients were randomized either to 1 to 2 months of DAPT followed by clopidogrel monotherapy (n = 2078) or to 12 months of DAPT with aspirin and clopidogrel (n = 2091)., Main Outcomes and Measures: The primary end point was a composite of cardiovascular (cardiovascular death, myocardial infarction [MI], any stroke, or definite stent thrombosis) or bleeding (Thrombolysis in MI major or minor bleeding) events at 12 months, with a noninferiority margin of 50% on the hazard ratio (HR) scale. The major secondary end points were cardiovascular and bleeding components of the primary end point., Results: Among 4169 randomized patients, 33 withdrew consent. Of the 4136 included patients, the mean (SD) age was 66.8 (11.9) years, and 856 (21%) were women, 2324 (56%) had ST-segment elevation MI, and 826 (20%) had non-ST-segment elevation MI. A total of 4107 patients (99.3%) completed the 1-year follow-up in June 2021. One to 2 months of DAPT was not noninferior to 12 months of DAPT for the primary end point, which occurred in 65 of 2058 patients (3.2%) in the 1- to 2-month DAPT group and in 58 of 2057 patients (2.8%) in the 12-month DAPT group (absolute difference, 0.37% [95% CI, -0.68% to 1.42%]; HR, 1.14 [95% CI, 0.80-1.62]; P for noninferiority = .06). The major secondary cardiovascular end point occurred in 56 patients (2.8%) in the 1- to 2-month DAPT group and in 38 patients (1.9%) in the 12-month DAPT group (absolute difference, 0.90% [95% CI, -0.02% to 1.82%]; HR, 1.50 [95% CI, 0.99-2.26]). The major secondary bleeding end point occurred in 11 patients (0.5%) in the 1- to 2-month DAPT group and 24 patients (1.2%) in the 12-month DAPT group (absolute difference, -0.63% [95% CI, -1.20% to -0.06%]; HR, 0.46 [95% CI, 0.23-0.94])., Conclusions and Relevance: In patients with ACS with successful PCI, clopidogrel monotherapy after 1 to 2 months of DAPT failed to attest noninferiority to standard 12 months of DAPT for the net clinical benefit with a numerical increase in cardiovascular events despite reduction in bleeding events. The directionally different efficacy and safety outcomes indicate the need for further clinical trials., Trial Registration: ClinicalTrials.gov Identifiers: NCT02619760 and NCT03462498.

Acute cardiovascular disease, such as acute myocardial infarction and aortic disease, can lead to a serious life-threatening state within minutes to hours, so early accurate diagnosis, and appropriate treatment without delay are essential. To provide high-quality and timely treatment, 24-h availability of medical staff and cardiologists, as well as a cardiac catheterization laboratory are needed. In Japan, the number of patients with acute cardiovascular disease is increasing with the aging population and westernization of lifestyle; however, workstyle reforms for physicians, including a policy to limit overtime work, have been legislated. Under these conditions, it is necessary to centralize hospitals that treat cardiovascular emergency diseases as high-volume centers and build a patient triage system for allocating patients before hospital arrival. The prehospital 12-lead electrocardiogram (ECG) plays a central role in prehospital diagnosis and triage, and its importance will increase in future. We discuss the current and future state of the cardiovascular emergency medical care system utilizing prehospital 12-lead ECG in urban areas of Japan.

Background: Early reported beneficial effects of cardiac rehabilitation (CR) have recently been disputed. The present study aimed to investigate the clinical impact of CR on the mid-term outcomes of patients following ST-segment elevation myocardial infarction (STEMI) treated with currently available management., Methods: This study reviewed 145 consecutive patients who underwent primary coronary intervention and were discharged without any disability after STEMI during 2013-2015., Results: Among the patients, 66 (45.5%) completed an outpatient CR program (CR group) and 79 were their non-CR counterparts or patients who dropped out of the program (N-D group). There were no between-group differences in patient demographics and clinical profiles, including door-to-balloon times and prescriptions. A total of 27 patients developed major adverse cardiac and cerebrovascular events (MACCE) during follow-up. The MACCE-free survival rates were 88% and 76% in the CR and N-D groups, respectively (log-rank, p=0.04). Cox proportional analysis demonstrated that inclusion in the N-D group was a significant predictor of MACCEs (HR, 2.36; 95% CI, 1.07-5.74; p=0.03). In the CR group, peak oxygen consumption and ventilatory efficiency determined by cardiopulmonary exercise testing significantly improved after the program (p<0.01)., Conclusions: The impact of CR on the mid-term prognosis of patients with STEMI, even in the current myocardial infarction management era, was beneficial., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: The Global Registry of Acute Coronary Events (GRACE) score is the most accurate risk assessment system for acute myocardial infarction (AMI), which was proposed in Western countries. However, it is unclear whether GRACE score is applicable to the present Japanese patients with a high prevalence of emergent percutaneous coronary intervention (PCI) and vasospasm. This study aimed to clarify the usefulness of GRACE risk score for risk stratification of Japanese AMI patients treated with early PCI and to evaluate a novel risk stratification system, "angiographic GRACE score," which is the GRACE risk score adjusted by the information of the culprit coronary artery and its flow at pre- and post-PCI, to improve its predicting availability., Methods: The subjects were 1817 AMI patients who underwent PCI within 24 h of onset between October 2015 and August 2017 and were registered in Kanagawa Acute Cardiovascular (K-ACTIVE) Registry via survey form. The association between the clinical parameters and in-hospital mortality was investigated., Results: A total of 79 (4.3%) in-hospital deaths were identified. The C-statistics for the in-hospital mortality of the GRACE score was 0.86, which was higher than that of the other conventional risk factors, including age (0.65), systolic blood pressure (0.70), heart rate (0.62), Killip classification (0.77), and serum levels of creatinine (0.68) and peak creatine kinase (0.74). The angiographic GRACE score improved the C-statistics from 0.86 of the original GRACE score to 0.89 (p < 0.05). In the setting of the cut-off value at 200, in-hospital mortality in the patients with the angiographic GRACE score <200 was 0.6%, which was relatively lower than those with ≥200, 9.4%., Conclusions: The GRACE score is a useful predictor of in-hospital mortality among Japanese AMI patients in the PCI era. Moreover, the angiographic GRACE score could improve the predicting availability., (Copyright © 2020. Published by Elsevier Ltd.)

Ventricular septal perforation( VSP) leads to a high mortality rate after surgical treatment. The surgical procedure has not been established. Left ventricular (LV) incisions have mainly been performed, while we report a case of right ventricular (RV) approach that resulted in a favorable outcome in a 76-year-old male. The patient was diagnosed with myocardial infarction due to left anterior descending artery (LAD) occlusion. VSP was diagnosed after percutaneous coronary intervention (PCI) and surgery was performed on the 4th day of illness. The perforation site was identified near the anterior septum by epicardiac echography before incision, and a patch made of 3 layers using a pericardial patch, felt, and a Dacron patch was sewn on the perforation with a sandwich technique and closed with bio glue. The RV approach is a useful procedure because it avoids the hemostatic manipulation of left ventricle myocardial necrosis under high pressure and can preserve left cardiac function.

Purpose: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT)., Methods: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure., Results: The age, ratio of males, and HbA 1 C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints., Conclusion: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT., Trial Registration: Clinicaltrials.gov number: NCT00212017.

Objectives: Hepcidin-25 serves as a key peptide in the regulation of iron homeostasis and inflammation. It remains unknown whether hepcidin-25 plays an adverse role in atherosclerotic diseases. The aim of this study was to investigate whether hepcidin-25 is involved in the pathophysiology of coronary plaque vulnerability., Methods and Results: Serum hepcidin-25 levels were quantitatively determined by the LC-MS/MS assay system. Peripheral blood was collected from patients with acute myocardial infarction (MI, n=33) and patients with stable angina pectoris (sCAD, n=19). The levels of hepcidin-25, IL-6, and CRP were significantly higher in the patients with acute MI than in the patients with sCAD. Coronary blood was aspirated from the culprit arteries via a thrombectomy catheter in 16 of the MI patients. Serum from the aspirates contained higher levels of hepcidin-25 and IL-6 compared with the peripheral blood. In immunohistochemical staining, the macrophages of the plaques in the solid component of the aspirates were immunoreactive for hepcidin-25. To confirm the clinical observation, an in vitro study was performed using human macrophages and coronary endothelial cells. The hepcidin gene and protein were detected in the cultured macrophages but not in the endothelial cells. Hepcidin-25 exposure induced ferroportin degradation and reduced the survival rate of endothelial cells., Conclusions: The results of the present study demonstrated that circulating hepcidin-25 and IL-6 were both elevated in the acute phase of MI and that hepcidin-25 released from plaque macrophages and other cell sources contributed to the plaque instability by inducing endothelial cell death., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The specific cell surface markers on mesenchymal stem/progenitor cells (MSCs) have been poorly defined in vivo, but in one recent study, an MSC subpopulation was directly isolated from a CD271-positive fraction of human bone marrow cells. The aim of this study was to identify circulating CD271(+) MSCs in human peripheral blood and investigate whether the cells are mobilized after acute myocardial infarction (MI). A flow cytometric analysis identified CD45(low/-)CD34(+)CD271(+) cells in adult human peripheral blood. The numbers of circulating CD45(low/-)CD34(+)CD133(+) cells (hematopoietic linage progenitors) were significantly lower in elderly subjects without coronary artery disease than in healthy young subjects, whereas the numbers of CD45(low/-)CD34(+)CD271(+) cells were comparable between elderly subjects and younger subjects. The CD45(low/-)CD34(+)CD271(+) and CD133(+) cell counts were both higher in patients with acute MI than in patients with stable coronary artery disease. In our investigation of the time course changes after acute MI, the CD45(low/-)CD34(+)CD133(+) cell counts gradually increased up to day 7. Over the same period, the CD45(low/-)CD34(+)CD271(+) cell counts peaked at day 3 and then declined up to day 7. Importantly, the CD271(+) cell counts at day 3 were positively correlated with the peak concentrations of creatine kinase after acute MI. Results of the present study suggest that the CD271(+) MSCs are mobilized differently from the CD133(+) hematopoietic progenitors and may play a specific role in the tissue repair process during age-related changes and after acute myocardial infarction.

Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.

Background: Erythropoietin (EPO) has been found to have anti-apoptotic and tissue protective effects on the myocardium. The aim of the present pilot study was to observe the safety and efficacy of EPO administration for patients with acute myocardial infarction (AMI)., Methods and Results: Patients admitted with AMI had all undergone successful percutaneous coronary intervention (PCI). Patients were randomly assigned to 2 groups (control and EPO groups), and given 12,000 IU EPO iv or saline after PCI. The primary endpoints were the difference between the acute phase and chronic phase (6 months after the attack) regarding left ventricular function as measured on electrocardiogram-gated single-photon emission computed tomography. Thirty-six patients (control 16, EPO 20) were eligible for analysis. Left ventricular ejection fraction (LVEF) significantly increased in the EPO group (from 51.0+/-19.6% to 58.5+/-15.0%, P=0.0238), but not in the control group. Further analysis was separately undertaken in patients with occlusion in the left anterior descending artery (LAD) and others (non-LAD). LVEF was <50% in most patients in the LAD subgroup, and LVEF significantly increased in the EPO group (37.5+/-13.0 to 52.7+/-15.8, P=0.0049), but not in the control group. EPO administration did not trigger any adverse clinical events., Conclusions: EPO administration is a promising treatment for AMI.

Hepcidin, a key iron-regulator secreted from the liver, consists of 25 amino acids (hepcidin-25), blocks iron release from macrophages via internalization and degradation of cellular iron exporter ferroportin, and restrains the use of iron in organs. Hepcidin mRNA and protein are also expressed in the human heart. A short form of hepcidin that lacks 5 amino-acid residues in the N-terminus (hepcidin-20) has been found in human serum, although its physiological role is unknown. Here, we successfully measured the serum levels of hepcidin-25 and hepcidin-20 in 12 patients with acute myocardial infarction (AMI) using surface-enhanced laser desorption ionization time of flight mass spectrometry. Among the selected 10 patients, whose blood samples were taken within 4 hours after a heart attack, all the patients showed elevated serum levels of hepcidin-20 [between 31.7 and 285.1 arbitrary unit (AU); normal level < 9.3 AU], while 8 patients showed high levels of hepcidin-25 (9.3-271.4; normal < 25.5 AU). The hepcidin-20 level was decreased to nearly the normal level on day 7 (range of 2.9 to 12.5 AU) in the 12 patients, whereas the hepcidin-25 level remained high on day 7 in 8 patients. Furthermore, the elevated levels of hepcidin-25 and hepcidin-20 were not correlated with the serum levels of markers for inflammation, interleukin-6 and C-reactive protein, in the patients with AMI. In conclusion, the serum hepcidin-20 is transiently elevated in response to acute cardiac ischemia. Measurement of serum hepcidin-20, rather than hepcidin-25, is helpful for diagnosis of acute myocardial infarction.

Background: Angiotensin-converting enzyme inhibitors (ACEI) reduce the mortality in the chronic phase of myocardial infarction (MI), and similar effects of angiotensin receptor blockers (ARB) have been reported. However, these effects of ARB have not yet been established in Japanese patients. A multicenter randomized study was designed for the present study to examine the effect of valsartan as compared to that of ACEI against left ventricular dysfunction after MI., Methods and Results: Patients with acute MI were randomly allocated to either the valsartan group (n=120; mean age 63 +/-1.0) or the ACEI group (n=121; mean age 62.9 +/-1.0) and followed up until 6 months. Left ventriculography was performed during hospital admission and at 6 months. The blood pressure was similar in the 2 groups throughout the study. The incidences of cardiovascular events and target vessel revascularization were similar, although that of adverse events was significantly higher in the ACEI (12.4%) than in the valsartan group (3.3%; P<0.05). There were no differences in left ventricular ejection fraction and left ventricular end-diastolic volume index between the groups., Conclusions: Valsartan exhibits similar efficacy effective to that of ACEI in preventing left ventricular dysfunction in Japanese patients with acute MI, and is, in addition, better tolerated than ACEI.

Objectives: This study was conducted to examine the relationship between provoked coronary spasm and clinical course in patients with acute myocardial infarction (AMI)., Background: Coronary spasm has a pathogenetic role in the occurrence of AMI and progressive atherosclerosis. There is no report that focused on the prognostic significance of provoked coronary spasm in AMI patients., Methods: Our group investigated 240 consecutive patients who underwent spasm-provocation tests using acetylcholine after AMI. Coronary spasm was defined as a transient total or subtotal occlusion of the luminal diameter. The patients were divided into 2 groups (positive group: n = 174, negative group: n = 66)., Results: The clinical courses of the 2 groups were compared at long-term follow up (mean, 43 months). Major adverse cardiac events (death, acute coronary syndrome, or revascularization) occurred in 82 patients (47.1%) in the positive group and 18 patients (27.3%) in the negative group (p = 0.0055). The frequency of major adverse cardiac event-free survival was significantly lower in the positive group than in the negative group (p = 0.0018). Provoked coronary spasm was a significant independent predictor of poor prognosis., Conclusions: Provoked coronary spasm predicts adverse outcome in AMI patients.

Objective: Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may improve cardiac function after acute myocardial infarction (AMI) by accelerating angiogenesis or cardiomyogenesis, but negative results and side effect of G-CSF have also been reported. However, no previous studies have used large animal models of ischemia/reperfusion to investigate the effect and side effect of G-CSF after AMI., Methods: The diagonal branch of the left anterior descending coronary artery of swine was balloon-occluded for 1 h and then reperfused. The animals of the G-CSF group were injected with G-CSF subcutaneously (5.0 microg/kg/day) for 6 days after MI and then sacrificed after 4 weeks. The control group received the same volume of saline., Results: There were no differences between the groups in the rate of thrombotic obstruction or progression of stenosis lesion in coronary angiography. The ejection fraction and end-diastolic volume in the G-CSF group were not significantly improved over the control values. The fibrotic area was significantly smaller in the G-CSF group than in the controls (P<0.05), and the numbers of vessels counted in anti-von Willebrand factor and anti-alpha-smooth muscle actin-stained sections were significantly larger (P<0.005 and P<0.05, respectively). The expression of collagen III mRNA was significantly lower in the G-CSF group than in the control in the infarct (P<0.0005) and border areas (P<0.005), and TGF-beta mRNA was significantly lower in the G-CSF group in the border area (P<0.05)., Conclusions: G-CSF could modify the healing process after AMI by accelerating angiogenesis in a swine ischemia/reperfusion model. At the dose administered, however, G-CSF did not seem to improve the global cardiac function.

Background: Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A-deficient (SR-A(-/-)) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction., Methods and Results: Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A(-/-) and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A(-/-) mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A(-/-) mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Real-time reverse transcription-polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A(-/-) mice compared with WT mice. Furthermore, SR-A(-/-) mice showed augmented expression of tumor necrosis factor-alpha and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-alpha and decreased interleukin-10 expression in activated SR-A(-/-) macrophages., Conclusions: The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-alpha and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.

Background: Tumor necrosis factor (TNF)-alpha is linked to the pathogenesis of cardiovascular diseases, but how it affects myocardial infarction (MI), so the present study examined the effects of TNF-alpha and the involvement of intercellular adhesion molecule (ICAM)-1 on MI., Methods and Results: Left coronary arteries of C57BL/6 wild type (WT) and TNF-alpha knockout (KO) mice were ligated and the mice were killed 1, 3, and 7 days later. Fractional shortening on echocardiography of the KO mice was significantly higher than that of the WT mice from day 1 to 7 (p<0.01). The ICAM-1 mRNA in the infarcted area of the KO mice was significantly lower than that of the WT from day 1 (p<0.01) to 7. In immunohistochemistry, the expression of ICAM-1 was weaker in the KO than in the WT mice. The number of neutrophils in the KO mice peaked at day 1, but even this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT. The number of macrophages in the KO mice peaked at day 7, but this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT., Conclusion: In a permanent occlusion model of MI TNF-alpha decreased cardiac function and ameliorated myocardial remodeling through the induction of ICAM-1.

Although angiotensin-converting enzyme inhibitors (ACEIs) have been shown to reduce left ventricular remodeling after acute myocardial infarction (AMI), the effects of angiotensin receptor blockers have yet to be established. This study was conducted to examine the effects of candesartan on left ventricular remodeling after AMI. Consecutive AMI patients were assigned to a candesartan group or ACEI group after successful coronary intervention. The patients in the candesartan group (n = 77, mean age, 62.8 +/- 1.3) received candesartan and the patients in the ACEI group (n = 80, mean age, 63.3 +/- 1.2) received lisinopril, enalapril, or trandolapril. Four mg was the most frequent dose in the candesartan group at 6 months. Lisinopril, enalapril, and trandolapril were administered to 52%, 27%, and 21% of the patients in the ACEI group, respectively. No significant differences in the incidences of cardiac death, nonfatal MI, or hospitalization for heart failure (P = NS) were found between the groups. The candesartan group exhibited a somewhat higher percent increase in left ventricular ejection fraction and significantly lower percent increases in left ventricular end-diastolic volume index and left ventricular end-systolic volume index compared to the ACEI group (P < 0.05, P < 0.05, respectively). Candesartan is more effective than ACEI in preventing left ventricular remodeling after AMI.

Background: Although small dense low-density lipoprotein (sd-LDL) has an established association with diabetic dyslipidemia, previous studies have failed to show an association between sd-LDL and diabetes among coronary heart disease patients. This study investigated the prevalence of sd-LDL and abnormal glucose regulation in acute coronary syndrome (ACS)., Methods and Results: LDL size at the onset of ACS was measured by nondenatured gradient gel electrophoresis in 314 of 429 consecutive patients. Sd-LDL was prevalent in 54% of the patients, irrespective of the presence of previously known diabetes (50% vs 60% in nondiabetes and diabetes, respectively). Diabetes was present in 122 (28%) of the patients, and 110 patients without diabetes underwent an oral glucose tolerance test. Impaired glucose tolerance (IGT) and newly detected diabetes were found in as many as 44% and 22% of the patients tested, even though their hemoglobinA1c levels were in the normal range (5.3+/-0.5%). The prevalence of sd-LDL was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance (61% vs 42%)., Conclusion: IGT and diabetes were far more common than normal glucose regulation in ACS patients, and the abnormal glycometabolism was closely associated with highly atherogenic sd-LDL.

Background: Although the small dense low-density lipoprotein (sd-LDL) is associated with hypertriglyceridemia, more than 60% of myocardial infarction (MI) patients are normotriglyceridemic in the fasting state. This study was aimed to investigate the relationship between the low-density lipoprotein (LDL) phenotype and postprandial hyperlipemia (PPL) in MI patients., Methods and Results: Oral fat tolerance tests were performed in 71 patients with acute MI and fasting triglyceride concentrations below 200 mg/dl. Postprandial changes in the LDL particle diameter (LDL-PD) and lipids over a 6-h period after a meal were compared among 4 groups of patients classified according to fasting triglyceride levels (A, B as <150, and C, D as > or =150) and postprandial triglyceride levels (A, C as <230 and B, D as > or =230). Although fasting concentrations of triglyceride and remnant-like particle (RLP)-triglyceride were significantly higher in group C than in group B, the areas under the curves of the RLPs were significantly higher in group B. The triglyceride-to-cholesterol ratio in the RLPs was significantly higher in the PPL group than in the nonPPL group postprandially. The prevalence of sd-LDL (LDL-PD < or =25.5 nm) was significantly higher in group D but similar between groups B and C (23%, 42%, 50% and 83% in groups A, B, C and D, respectively)., Conclusion: These results suggest that postprandial accumulation of triglyceride-rich lipoproteins is strongly associated with sd-LDL in MI patients without hypertriglyceridemia.

Background: The small dense low-density lipoprotein (LDL) phenotype (pattern B), high concentrations of remnant-like particles (RLPs), and postprandial lipemia are newly recognized risk factors for coronary heart disease (CHD). However, the associations of these lipoprotein abnormalities remain unclear. The aim of this study was to investigate the relationships among LDL phenotype, very-low-density lipoprotein (VLDL) subclasses, and postprandial lipoprotein metabolism in CHD patients., Method: We performed an oral fat tolerance test in 32 patients with acute myocardial infarction and compared the following parameters between patients characterized by either large buoyant LDL (pattern A) versus pattern B: lipids and apolipoproteins (apo) in the plasma and Svedberg flotation rates (Sf) >400 (chylomicron), Sf 60-400 (large VLDL), and Sf 20-60 (small VLDL) fractions., Result: Fasting levels of triglyceride, RLP-cholesterol and RLP-triglyceride were slightly higher in the pattern B patients. Postprandial increases of RLP-cholesterol and the cholesterol and triglyceride of large VLDL fractions were significantly greater in the pattern B patients. The areas under the curves of cholesterol, triglyceride, and apo-B in large VLDL fractions were significantly higher in pattern B, while those in small VLDL were not. RLP-cholesterol and RLP-triglyceride in fasting and fed states correlated very highly with the corresponding cholesterol and triglyceride concentrations in large VLDL fractions., Conclusion: These results suggest that postprandial increase of large VLDL fractions and RLPs contribute to the formation of small dense LDL in CHD patients.

Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors, but the production of these growth factors in cardiomyocytes has also been demonstrated. However, there have been no reports focusing their attention on the changes in these growth factors after coronary intervention. We investigated the time-course changes of the serum VEGF and HGF levels in angina pectoris (AP) and acute myocardial infarction (AMI)., Methods: The serum HGF and VEGF levels were measured in 60 patients with AP, in 62 patients with AMI (AP, before heparin administration, and at 24 and 48 hours, and one week after intervention; AMI, before heparin, and at 48 and 72 hours, and one, two, three and four weeks) and in 56 patients with neurocirculatory asthenia as controls. We defined the patients with remodelling who showed an increase in left ventricular end-diastolic volume index (LVEDVI) in the sub-acute phase of AMI., Results: Hepatocyte growth factor levels in the AP and AMI were significantly higher than that in the control (p<0.0001). The AMI level was also significantly higher than AP (p<0.001). In the AMI and AP, HGF peaked at 48 hours. Vascular endothelial growth factor level in the AMI was significantly higher than that in the control and AP (p<0.0001). In the AMI, VEGF peaked at two weeks. There was a significant positive correlation between the peak VEGF and LVEDVI in the sub-acute phase of AMI (p=0.0089, r=0.436). Peak VEGF in the remodelling (+) group was significantly higher than that in the remodelling (-) group (p<0.001). In the AP, VEGF was unchanged., Conclusion: While both myocardial and vascular damage contribute to an increase in HGF level, vascular damage is not associated with the increase in VEGF. Vascular endothelial growth factor might be related to left ventricular remodelling in the sub-acute phase of myocardial infarction.

Mortality from coronary heart disease in Japan is the among lowest recorded in the industrialized nations; however, little is known about the rate of events including nonfatal cases. A survey of event registration and a review of death certificates was carried out to estimate event rates of acute myocardial infarction (AMI) and coronary deaths in the largest 2 cities of the Niigata prefecture where there are 480,720 residents aged between 15 and 65 years. The definitions for these cardiac events used for the WHO-MONICA project were: (1)'definite AMI', (2) 'possible AMI or coronary death' (not including unclassifiable fatal events), and (3) 'unclassifiable fatal events'. Age-adjusted rates for AMI and coronary deaths (per 100,000/year) according to the registration survey were 54.6 for men and 7.2 for women according to definition 1 and 41.9 for men, and 5.3 for women according to definition 2. When data from the death certificate review were taken into account for the estimation, these rates increased to 80.6 for men and 14.2 for women according to definition 1, and 50.0 for men and 9.0 for women according to definition 2. These estimated rates are considerably lower than those in other industrialized nations surveyed in the WHO-MONICA project, and these findings are consistent with those from other studies conducted in Japan.

Background: Dual antiplatelet therapy (DAPT) with aspirin plus P2Y12 inhibitor is used as a standard therapy for patients with acute myocardial infarction (AMI) treated with drug-eluting stents (DESs). In Japan, clopidogrel was the major P2Y12 inhibitor used for a decade until the new P2Y12 inhibitor, prasugrel, was introduced. Based on clinical studies considering Japanese features, the set dose for prasugrel was reduced to 20 mg as a loading dose (LD) and 3.75 mg as a maintenance dose (MD); these values are 60 and 10 mg, respectively, globally. Despite this dose discrepancy, little real-world clinical data regarding its efficacy and safety exist. Methods: From the K-ACTIVE registry, based on the DAPT regimen, patients were divided into a prasugrel group and a clopidogrel group. The ischemic event was a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The bleeding event was type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria. Results: Substantially more patients were prescribed prasugrel (n = 2786) than clopidogrel (n = 890). Clopidogrel tended to be selected over prasugrel in older patients with numerous comorbidities. Before adjustments were made, the cumulative incidence of ischemic events at 1 year was significantly greater in the clopidogrel group than in the prasugrel group (p = 0.007), while the cumulative incidence of bleeding events at 1 year was comparable between the groups (p = 0.131). After adjustments were made for the age, sex, body weight, creatine level, type of AMI, history of MI, approach site, oral anticoagulation therapy, presence of multivessel disease, Killip classification, and presence of intra-aortic balloon pumping, both ischemic and bleeding events became comparable between the groups. Conclusion: A Japanese dose of prasugrel was commonly used in AMI patients in the real-world database. Both the prasugrel and clopidogrel groups showed comparable rates of 1 year ischemic and bleeding events. [ABSTRACT FROM AUTHOR]

Patients with acute myocardial infarction (AMI) presenting with syncope have poor clinical outcomes partly due to a delay in the diagnosis. Although the impact of prehospital 12-lead electrocardiography (PHECG) on the reduction of first medical contact (FMC)-to-device time and subsequent adverse clinical events in patients with AMI has been demonstrated, the impact of PHECG for the patients presenting with syncope remains to be elucidated. This study aimed to explore the impact of PHECG on 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) presenting with syncope. From a cohort of multi-center registry [Kanagawa-ACuTe cardIoVascular rEgistry (K-ACTIVE)], a total of 90 consecutive patients with STEMI presenting with syncope were included. The 30-day mortality were compared between patients with PHECG (PHECG group, n = 25) and those without PHECG (non-PHECG group, n = 65). There was no significant difference in the baseline clinical characteristics between the 2 groups. FMC-to-device time was significantly shorter in the PHECG group than in the non-PHECG group (122 [86, 128] vs. 131 [102, 153] min, p = 0.03) due to the shorter door-to-device time. Thirty-day mortality was significantly lower in the PHECG group than in the non-PHECG group (16.0 vs. 44.6%, p = 0.03). In conclusion, PHECG was associated with shorter FMC-to-device time and lower 30-day mortality in patients with STEMI presenting with syncope. [ABSTRACT FROM AUTHOR]

The report deals with the induction of the inducible form of nitric oxide synthase (iNOS) in infarcted heart muscle of rabbit and man. In the rabbit, nitric oxide synthase was significantly increased in the infarcted area beginning on the third day following ligation of a coronary artery. iNOS induction occured primarily in macrophages. In man, iNOS immunoreactivity was also primarily localized in macrophages on the seventh day following death from myocardial infarction. Of the specific inhibitors of iNOS in infarcted heart muscle, S-methylisothiourea (SMT) was the most potent. Its greatest effect occured in the normal non-affected area of the heart. Dexamethasone and cyclosporin A failed to inhibit NOS. Apoptosis of macrophages commenced two days following ligation of a coronary artery. [ABSTRACT FROM AUTHOR]

Objective: Inducible nitric oxide synthase (iNOS) activity, as measured by conversion of L-14C-arginine to L-14C-citrulline is significantly increased in infarcted rabbit myocardium as compared to healthy myocardium 48 h after coronary occlusion. The aim of this study was to localise the nitric oxide synthase (NOS) isoforms in normal myocardium and compare these findings with NOS activity in cells of the infarcted region. Methods: Activities of NOS isoforms were enzymatically assayed in normal and infarcted myocardium. Localisation of NOS was performed on identical sections using specific monoclonal IgG antibodies against endothelial constitutive (cNOS) and macrophage inducible (iNOS) nitric oxide synthase. In addition, macrophages were identified using fluorescein conjugated ChromPure rabbit IgG, Fc fragment. Results: iNOS activity increased significantly in infarcted as compared to normal myocardium [0.42(SEM 0.03) v 0.85(0.08) fmol·μg−1·min−1, P = 0.02, respectively]. However, cNOS did not increase significantly in infarcted regions [0.18(0.04) v 0.24(0.06) fmol·μg−1·min−1; P = 0.16, respectively]. cNOS was immunohistochemically localised in endothelial and endocardial cells in normal and infarcted tissues. The presence of iNOS activity in macrophages in infarcted myocardium was identified immunohistochemically. Cardiomyocytes and neutrophils did not label with the antibodies to cNOS and iNOS. Conclusions: (1) Infiltrating macrophages are the main site of increased iNOS activity in infarcted rabbit myocardium. (2) cNOS activity is not significantly increased in infarcted tissues as compared to normal myocardium. (3) Neutrophils and cardiomyocytes do not express NOS imunoreactivity in infarcted and normal rabbit myocardium. [ABSTRACT FROM PUBLISHER]

Pathological reports have shown that plaque erosion (PE), a common cause of acute coronary syndrome (ACS), can form in both fibrous plaque and lipid-rich plaque (LRP). In plaque rupture (PR), which is the main cause of ACS, the underlying plaque is LRP with a thin fibrous cap. In this study, we aimed to investigate the clinical features and lipid profiles of PE with or without LRP in comparison with those of PR. A total of 166 patients with ACS, who underwent percutaneous coronary intervention using optical coherence tomography (OCT) and met the criteria for PR or PE, were included. LRP was defined as plaque with a maximal lipid arc (>180°). Culprit lesions were categorized into PR and PE with/without LRP [PE (Lipid) or PE (Fibrous) ]. The prevalence of PR, PE (Lipid) , and PE (Fibrous) was 104 (62.7%), 43 (25.9%), and 19(11.4%), respectively. The patients with PR and PE (Lipid) had a significantly higher peak creatine kinase level (1338 and 1584U/L, respectively, p < 0.01) and prevalence of ST-elevation myocardial infarction (71.2% and 79.1%, respectively, p < 0.01) than those with PE (Fibrous) (214U/L and 21.1%, respectively). The various lipid profiles were mostly comparable between the patients with PE (Lipid) and PR, but different in those with PE (Fibrous). The levels of small dense low-density lipoprotein cholesterol were significantly higher in the patients with PR and PE (Lipid) than in those with PE (Fibrous) (39.0, 35.3, and 25.7 mg/dL, respectively, p = 0.02). The clinical features and lipid profiles are substantially different between PE (Lipid) and PE (Fibrous) , but are somewhat similar between PE (Lipid) and PR. [Display omitted] • Approximately 70% of plaque erosion (PE) presented as PE (Lipid). • The prevalence of STEMI was lower in the PE (Fibrous) than in the PE (Lipid). • The lipid profiles of PE (Lipid) were different from those of PE (Fibrous). [ABSTRACT FROM AUTHOR]