Sen Matsumoto

Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction

Rationale: Despite a recent decline of in-hospital mortality attributable to acute myocardial infarction (AMI), the incidence of ischemic heart failure (HF) in post-AMI patients is increasing. Although various microRNAs have been proposed as diagnostic indicators for AMI, no microRNAs have been established as predictors of ischemic HF that develops after AMI. Objective: We attempted to identify circulating microRNAs that can serve as reliable predictors of ischemic HF in post-AMI patients. Methods and Results: Using sera collected a median of 18 days after AMI onset, we screened microRNAs in 21 patients who experienced development of HF within 1 year after AMI and in 65 matched controls without subsequent cardiovascular events after discharge. Among the 377 examined microRNAs, the serum level of only miR-192 was significantly upregulated in AMI patients with development of ischemic HF. Because miR-192 is reported to be p53-responsive, the serum levels of 2 other p53-responsive microRNAs, miR-194 and miR-34a, also were investigated. Interestingly, both microRNAs were coordinately increased with miR-192, particularly in exosomes, suggesting that these microRNAs function as circulating regulators of HF development via the p53 pathway. Furthermore, miR-194 and miR-34a expression levels were significantly correlated with left ventricular end-diastolic dimension 1 year after AMI. Conclusions: In the sera of post-AMI patients who experienced development of de-novo HF within 1 year of AMI onset, the levels of 3 p53-responsive microRNAs had been elevated by the early convalescent stage of AMI. Further investigations are warranted to confirm the usefulness of these circulating microRNAs for predicting the risk of development of ischemic HF after AMI.

A subset of circulating microRNAs are predictive for cardiac death after discharge for acute myocardial infarction

To investigate the prognostic impact of circulating microRNAs (miRs) in patients who survived acute myocardial infarction (AMI), we compared the circulating miR signature at the time of survival discharge among samples in the serum bank of the Osaka Acute Coronary Insufficiency Study. Using a high-throughput array consisting of 667 miRs, 11 miRs were found to be differentially expressed in the serum among patients at high-risk for cardiac death. Real-time RT-PCR confirmed that the serum levels of miR-155 and miR-380* were approximately 4- and 3-fold higher, respectively, in patients who experienced cardiac death within 1 year after discharge. Accordingly, a subset of circulating miRs might be predictive for cardiac death in post-AMI patients.

Living alone and risk of cardiovascular events following discharge after acute myocardial infarction in Japan

BACKGROUND Little is known about the long-term risk of cardiovascular events after discharge among acute myocardial infarction (AMI) survivors living alone in Japan. METHODS AND RESULTS A large-scale prospective, observational study in the Osaka region involved consecutive patients with AMI from January 2002 through December 2010. We evaluated the association between living alone and longitudinal risk of cardiovascular events following discharge after AMI. A Cox proportional-hazards model was used to assess the association between living alone and the primary composite endpoint consisting of major adverse cardiovascular events and total deaths. During the study period, 5845 patients (4415 male patients, 1430 female patients) were registered. Living alone was found to be independently associated with a higher risk of composite endpoint consisting of major adverse cardiovascular events and total deaths [adjusted hazard ratio (HR) 1.32; 95% confidence interval (CI): 1.11-1.58]. Multivariate-adjusted HRs of composite endpoint were 1.34 (95% CI: 1.08-1.68) among male patients and 1.31 (95% CI: 0.95-1.81) in the female patients. AMI survivors living alone tend to have a higher adjusted HR of composite endpoint than those not living alone irrespective of age and gender groups. CONCLUSIONS From this large AMI registry in Osaka, AMI survivors living alone after discharge had a higher risk of cardiovascular events and total deaths than those not living alone.

Oral treatment with nicorandil at discharge is associated with reduced mortality after acute myocardial infarction.

BACKGROUND Previous studies showed that nicorandil can reduce coronary events in patients with coronary artery disease. However, it is unclear whether oral nicorandil treatment may reduce mortality following acute myocardial infarction (AMI). METHODS AND RESULTS We examined the impact of oral nicorandil treatment on cardiovascular events in 1846 AMI patients who were hospitalized within 24 h after AMI onset, treated with emergency percutaneous coronary intervention (PCI), and discharged alive. Patients were divided into those with (Group N, n=535) and without (Group C, n=1311) oral nicorandil treatment at discharge. No significant differences in age, gender, body mass index, prevalence of coronary risk factors, or history of myocardial infarction existed between the two groups; however, higher incidences of multi-vessel disease, and a lower rate of successful PCI were observed in Group N. During the median follow-up of 709 (340-1088) days, all-cause mortality rate was 43% lower in Group N compared with Group C (2.4% vs. 4.2%, stratified log-rank test: p=0.0358). Multivariate Cox regression analysis revealed that nicorandil treatment was associated with all-cause death after discharge (Hazard ratio 0.495, 95% CI: 0.254-0.966, p=0.0393), but not for other cardiovascular events such as re-infarction, admission for heart failure, stroke and arrhythmia. CONCLUSIONS The results suggest that oral administration of nicorandil is associated with reduced incidence of death in the setting of secondary prevention after AMI.

Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction

BACKGROUND Acute hyperglycemia (AH) after the onset of acute myocardial infarction (AMI) is a manifestation of transient abnormal glucose metabolism that may reflect AMI severity, and thus be a predictor of poor prognosis. However, it remains unknown whether AH may predict development of de novo diabetes mellitus (dn-DM) in non-diabetic AMI patients. METHODS AND RESULTS Among AMI patients registered in the Osaka Acute Coronary Insufficiency Study between 1998 and 2007, we investigated hospital records of 1493 patients who had an admission glycated hemoglobin A1c (HbA1c) level of ≤6.0% and were subjected to glycometabolic profiling after survival discharge. dn-DM was defined as initiation of diabetic medication or documentation of an HbA1c level of ≥6.5% during the 5-year follow-up period. AH, defined as an admission serum glucose level of ≥200mg/dl, was observed in 133 (8.9%) patients. dn-DM development was more frequent in post-AMI patients with AH than those without [24.8% vs 12.0%, adjusted hazard ratio (HR) 1.776, p=0.021], particularly among patients with an HbA1c of <5.6% on admission. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a reduced incidence of dn-DM in patients with AH (adjusted HR 0.397, p=0.031). CONCLUSION Admission AH was a predictor of dn-DM in non-diabetic post-AMI patients. Renin-angiotensin system inhibitors were associated with reduced incidence of dn-DM in post-AMI patients with AH.

Clinical Impact of Ventricular Tachycardia and/or Fibrillation During the Acute Phase of Acute Myocardial Infarction on In-Hospital and 5-Year Mortality Rates in the Percutaneous Coronary Intervention Era

BACKGROUND The aim of this study was to investigate the prognostic impact of acute-phase ventricular tachycardia and fibrillation (VT/VF) on ST-segment elevation myocardial infarction (STEMI) patients in the percutaneous coronary intervention (PCI) era. METHODSANDRESULTS Using the database of the Osaka Acute Coronary Insufficiency Study (OACIS), we studied 4,283 consecutive patients with STEMI who were hospitalized within 12 h of STEMI onset and underwent emergency PCI. Acute-phase VT/VF, defined as ≥3 consecutive ventricular premature complexes and/or VF within the 1st week of hospitalization, occurred in 997 (23.3%) patients. In-hospital mortality risk was significantly higher in patients with acute-phase VT/VF than inthose without (14.6% vs. 4.3%, adjusted hazard ratio (HR) 1.83, P=0.0013). Among patients discharged alive, 5-year mortality rates were comparable between patients with and without acute-phase VT/VF. Subgroup analysis showed that acute-phase VT/VF was associated with increased 5-year mortality after discharge in high-risk patients (GRACE Risk Score ≥115; adjusted HR 1.60, P=0.043), but not in intermediate- or low-risk patients. CONCLUSIONS Even in the PCI era, acute-phase VT/VF was associated with higher in-hospital deaths of STEMI patients. However, the 5-year prognostic impact of acute-phase VT/VF was limited to high-risk patients. (Circ J 2016; 80: 1539-1547).

Effect of intracoronary thrombectomy on 30-day mortality in non-diabetic patients with acute hyperglycemia after acute myocardial infarction

BACKGROUND There is limited evidence about useful therapeutic interventions for patients with acute hyperglycemia (AH) after acute myocardial infarction (AMI). METHODS We studied 2433 consecutive non-diabetic AMI patients who underwent percutaneous coronary intervention (PCI) within 24h after the onset. Patients were divided into two groups according to the presence or absence of AH (admission serum glucose level ≥ 11.1 mmol/l). We assessed the association between intracoronary thrombectomy and the clinical outcome in AMI patients with AH. RESULTS Patients with AH had more risk factors than those without AH. The 30-day mortality rate of patients with AH was significantly higher than that of those without (11.7% vs 1.7%, p<0.001). Among patients with AH, the 30-day mortality rate was significantly lower for those with intracoronary thrombectomy than those without it (4.9% vs 17.2%, p=0.004). Among patients without AH, however, the 30-day mortality rate was similar between those with and without intracoronary thrombectomy (1.5% vs 1.9%, p=NS). Multivariate analysis showed that intracoronary thrombectomy was associated with an improved 30-day mortality rate for patients with AH (hazard ratio: HR 0.184, 95% CI 0.057-0.598, p=0.005). CONCLUSIONS In AMI patients with AH, intracoronary thrombectomy prior to PCI might improve the 30-day mortality rate.

Reduced risk of recurrent myocardial infarction in homozygous carriers of the chromosome 9p21 rs1333049 C risk allele in the contemporary percutaneous coronary intervention era: a prospective observational study.

Objectives Chromosome 9p21 single nucleotide polymorphism (SNP) is a susceptibility variant for acute myocardial infarction (AMI) in the primary prevention setting. However, it is controversial whether this SNP is also associated with recurrent myocardial infarction (ReMI) in the secondary prevention setting. The purpose of this study is to evaluate the impact of chromosome 9p21 SNP on ReMI in patients receiving secondary prevention programmes after AMI. Design A prospective observational study. Setting Osaka Acute Coronary Insufficiency Study (OACIS) in Japan. Participants 2022 patients from the OACIS database. Interventions Genotyping of the 9p21 rs1333049 variant. Primary outcome measures ReMI event after survival discharge for 1 year. Results A total of 43 ReMI occurred during the 1 year follow-up period. Although the rs1333049 C allele had an increased susceptibility to their first AMI in an additive model when compared with 1373 healthy controls (OR 1.20, 95% CI 1.09 to 1.33, p=2.3*10−4), patients with the CC genotype had a lower incidence of ReMI at 1 year after discharge of AMI (log-rank p=0.005). The adjusted HR of the CC genotype as compared with the CG/GG genotypes was 0.20 (0.06 to 0.65, p=0.007). Subgroup analysis demonstrated that the association between the rs1333049 CC genotype and a lower incidence of 1 year ReMI was common to all subgroups. Conclusions Homozygous carriers of the rs1333049 C allele on chromosome 9p21 showed a reduced risk of 1 year ReMI in the contemporary percutaneous coronary intervention era, although the C allele had conferred susceptibility to their first AMI.

Association of lifestyle-related factors with circadian onset patterns of acute myocardial infarction: a prospective observational study in Japan

Objective The onset of acute myocardial infarction (AMI) shows characteristic circadian variations involving a definite morning peak and a less-defined night-time peak. However, the factors influencing the circadian patterns of AMI onset and their influence on morning and night-time peaks have not been fully elucidated. Design, setting and participants An analysis of patients registered between 1998 and 2008 in the Osaka Acute Coronary Insufficiency Study, which is a prospective, multicentre observational study of patients with AMI in the Osaka region of Japan. The present study included 7755 consecutive patients with a known time of AMI onset. Main outcomes and measures A mixture of two von Mises distributions was used to examine whether a circadian pattern of AMI had uniform, unimodal or bimodal distribution, and the likelihood ratio test was then used to select the best circadian pattern among them. The hierarchical likelihood ratio test was used to identify factors affecting the circadian patterns of AMI onset. The Kaplan-Meier method was used to estimate survival curves of 1-year mortality according to AMI onset time. Results The overall population had a bimodal circadian pattern of AMI onset characterised by a high and sharp morning peak and a lower and less-defined night-time peak (bimodal p<0.001). Although several lifestyle-related factors had a statistically significant association with the circadian patterns of AMI onset, serum triglyceride levels had the most prominent association with the circadian patterns of AMI onset. Patients with triglyceride ≥150 mg/dL on admission had only one morning peak in the circadian pattern of AMI onset during weekdays, with no peaks detected on weekends, whereas all other subgroups had two peaks throughout the week. Conclusions The circadian pattern of AMI onset was characterised by bimodality. Notably, several lifestyle-related factors, particularly serum triglyceride levels, had a strong relation with the circadian pattern of AMI onset. Trial registration number UMIN000004575.

Lymphotoxin-α3 mediates monocyte–endothelial interaction by TNFR I/NF-κB signaling

We recently reported that the single nucleotide polymorphisms of the lymphotoxin-(LT)alpha gene, a member of the tumor necrosis factor (TNF) family, are closely related to acute myocardial infarction; however, the precise mechanism of LTalpha signaling in atherogenesis remains unclear. We investigated the role of LTalpha3, a secreted homotrimer of LTalpha, in monocyte-endothelial cell adhesion using cultured human umbilical vein endothelial cells (HUVEC). We found that LTalpha3 induced cell adhesion molecules and activated NF-kappaB p50 and p65. LTalpha3 also induced phosphorylation of Akt, phosphorylation and degradation of IkappaB, nuclear translocation of p65, and increased adhesion of THP1 monocytes to HUVEC. These effects were mediated by TNF receptor (TNFR) I and attenuated by the phosphatidylinositol triphosphate-kinase (PI3K) inhibitors LY294002 and Wortmannin. Thus, LTalpha3 mediates the monocyte-endothelial interaction via the classical NF-kappaB pathway following TNFR I/PI3K activation, indicating it may play a role in the development of coronary artery disease.