Daisaku Nakatani

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.

Depressive Symptoms Predict 12-month Prognosis in Elderly Patients with Acute Myocardial Infarction

Background Several studies have associated depressive symptoms with an increased risk for cardiac events after the onset of acute myocardial infarction (AMI). The aim of the present study is to investigate the impact of the depressive symptoms on prognosis of the elderly patients with AMI. Method Depression was assessed in consecutive patients with AMI (n=1042; mean age 63 ± 11 years) using the Zung Self-Rating Depression Scale (SDS). Patient with a score ≥ 40 was classified as having depressive symptoms. Cardiac events (cardiac death, nonfatal re-MI, coronary angioplasty or bypass surgery, readmission for heart failure, unstable angina, or uncontrolled arrhythmia) were examined during 12 months follow-up period. Results Depressive symptoms were observed in 438 patients (42.0%). Prevalence of depression was not dependent of age (P=0.60) and gender (P=0.91). The rate of cardiac events was 31.2% per year in patients with depressive symptoms whereas 23.9% per year in patients without depressive symptoms. Multiple logistic regression analyses showed that depression was significantly associated with 1-year cardiac events (odds ratio 1.41, 95% CI 1.03 to 1.92, P=0.03) after controlling for age, gender, severity of myocardial infarction, coronary risk factors, e.g. hypertension, diabetes mellitus and smoking habits. Depression was a significant risk factor for the cardiac events (log rank, P=0.02) in the elderly patients (≥65 years old, 501 patients). However, the association of depression with cardiac events in the young patients (< 65 years old, 541 patients) was not statistically significant (P=0.11). Conclusion Depression after AMI is a significant predictor of 1-year cardiac events for Japanese population, and its presence augments the risk especially in the elderly patients.

Impact of high-sensitivity c-reactive protein on predicting long-term mortality of acute myocardial infarction

Although the C-reactive protein (CRP) concentration measured shortly after acute myocardial infarction (AMI) is associated with infarct size, its prognostic value is controversial. The reduction of CRP is accelerated by reperfusion. Therefore, the CRP concentration, measured during the stable phase of AMI in patients treated predominantly with reperfusion therapies, may be independent of infarct size and may predict long-term mortality. We studied 1,309 patients with AMI enrolled in the Osaka Acute Coronary Insufficiency Study between April 1999 and June 2001. CRP was measured during the stable phase (mean 25 days after AMI onset). The patients were followed for an average of 522 days. Reperfusion therapies were performed in 90% of the patients. Patients in the highest quartile of CRP values (> or =0.38 mg/dl) were older, had higher prevalences of diabetes mellitus, and had higher Killip classes than patients in the lower 3 quartiles (<0.38 mg/dl). Multivariate logistic regression analysis revealed that CRP was independently associated with age and the absence of revascularization therapies. Patients in the highest quartile had a higher long-term mortality rate than patients in the lower 3 quartiles (8.9% vs 2.0%; p <0.001). Multivariate Cox regression analysis revealed that the highest quartile of CRP values was an independent predictor of long-term mortality (hazard ratio 4.94, 95% confidence interval 1.13 to 21.6). We conclude that CRP measured during the stable phase of AMI is not associated with infarct size in the reperfusion era but is significantly associated with long-term mortality of 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.

Effect of successful late reperfusion by primary coronary angioplasty on mechanical complications of acute myocardial infarction.

It has been suggested that early treatment decreases, but late treatment increases, the risk of mechanical complications for a thrombolytic strategy. However, few studies have evaluated whether late reperfusion (LR) by primary coronary angioplasty decreases the risk of mechanical complications. A total of 2,209 patients with acute myocardial infarction treated with primary coronary angioplasty within 24 hours after the onset of symptoms were divided into 3 groups: early reperfusion (ER; < or =12 hours, n = 1,647), LR (>12 hours, n = 219), and failed reperfusion (FR; n = 343). We evaluated the incidence, risk ratio, and predictors of mechanical complications. The overall incidence of mechanical complications was 2.0%. The incidence of mechanical complications was highest in the FR group (ER 1.4%, LR 1.8%, FR 5.0%; p <0.01). After adjusting for clinical variables, the risk ratio for mechanical complications increased in the FR group compared with the LR group (risk ratio 7.34, 95% confidence interval [CI] 1.02 to 52.80; p = 0.04). Predictors of an increased risk of mechanical complications by multivariate analysis were age > or =70 years (odds ratio [OR] 3.68, 95% CI 1.56 to 8.64; p <0.01), Killip class > or =II (OR 3.73, 95% CI 1.53 to 9.12; p <0.01), absence of collateral vessels (OR 4.09, 95% CI 1.17 to 14.26; p = 0.03), and FR (OR 2.68, 95% CI 1.09 to 6.61; p = 0.03). In conclusion, successful LR by primary coronary angioplasty is associated with the reduced risk of mechanical complications in patients with acute myocardial infarction.

Variation during the week in the incidence of acute myocardial infarction: increased risk for Japanese women on Saturdays

Background: Variations in the incidence of acute myocardial infarction during the week may differ between and within communities, according to lifestyle. Objective: To identify potential triggering factors for acute myocardial infarction by examining variations in incidence in the days of the week within the Osaka area of Japan. Patients: Of 2511 consecutive patients in this region who were admitted to hospital for acute myocardial infarction between April 1998 and March 2001 and consented to take part, 2400 who had a definitely identified time of onset were enrolled. Results: For this group as a whole, no significant difference in incidence was noted between days of the week. However, in subgroup analyses women were shown to have significant variation through the week, peaking on Saturday with a 39% increase in relative risk (p = 0.037); working subjects showed a peak on Monday, with a 26% increase in relative risk (p = 0.038). Stratified analyses showed that in working men there was a prominent Monday peak in the onset of infarction, with a 30% increase in relative risk (p = 0.022), while in working women, there was no significant variation through the week. Conclusions: Earlier findings of a Monday peak linked to increased physical and mental occupational stress are confirmed. There is also an increase in uncertain risk factors on Saturdays for Japanese women, possibly involving a stressful weekend burden for women. Confirmation of this finding in other communities may help identify triggers of acute myocardial infarction and be useful in prevention.

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A>G, P=2.60 × 10−9, odds ratio (OR)=0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A>C, P=3.84 × 10−9, OR=0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A>G: P=1.14 × 10−14, OR=1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci.

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.

Optical coherence tomography and intravascular ultrasound evaluation of cardiac allograft vasculopathy with and without intimal neovascularization

AIMS Neovascularization is closely associated with plaque progression in non-heart transplantation subjects; on the other hand, cardiac allograft vasculopathy causes unfavourable outcomes. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can provide microscopic assessment in vivo. The aim of this study was to investigate the impact of neovascularization on intimal proliferation. METHODS AND RESULTS Both IVUS and OCT were attempted in 45 consecutive patients during annual catheterization after heart transplantation. There were 115 vessels [28 vessels were catheterized within 8 weeks of heart transplantation (baseline)]. IVUS analysis assessed vessel, luminal, and intimal (vessel-lumen) volume using Simpsons method. Qualitative parameters including microchannel were assessed by OCT. A microchannel was defined as a no-signal tubuloluminal structure with a sharply delineated border considered to represent neovascularization. Microchannel was observed more often in patient who had their heart transplant more than a year prior to the imaging, compared with shorter periods (39.1 vs. 10.7%, P = 0.023). All microchannels were seen in thickness >0.5 mm, and intimal volume index (mm(3)/mm) correlated with frequency of microchannel (r = 0.54, P = 0.04). The risks for microchannels were donor age [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.22; P = 0.007], cytomegalovirus infection (OR 16.21; 95% CI 1.79-220.09; P = 0.012), diabetes (OR 9.5; 95% CI 1.21-116.10; P = 0.032), LDL-cholesterol (OR 1.07; 95% CI 1.01-1.13; P = 0.010), and intimal volume (OR 2.47; 95% CI 1.13-6.36; P = 0.023). CONCLUSION OCT-identified microchannels increased sharply within the first year and were correlated with intimal volume and coronary risks. This suggests that neovascularization may play an important role in the progression of cardiac allograft vasculopathy.

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.