Impact of the Great East Japan Earthquake and Tsunami on the Incidence of Takotsubo Syndrome Using a Multicenter, Long-Term Regional Registry.

BACKGROUND: This study aimed to clarify the incidence of takotsubo syndrome (TTS) after the Great East Japan earthquake (GEJ-E) between inland and coastal areas.Methods and Results:Consecutive hospitalized patients with TTS were registered between 2009 and 2016 in Iwate Prefecture. Patients were divided into 2 groups, by whether they lived inland or in the coastal area (both max. seismic intensity, 6-). The incidence of TTS was calculated using the standardized incidence ratio (SIR) before and after the earthquake. The long-term prognosis of the 2 groups was compared by Kaplan-Meier analysis. A total of 112 patients with TTS were registered from the acute coronary syndrome records of each hospital (n=4,163); 9 patients with TTS were registered within 2 months of the earthquake. A significant monthly variation was observed in March and April 2011 compared with the other months (P=0.029). At 2 years after the earthquake, the SIR was significantly increased in the coastal area (P<0.01), but decreased after ≥3 years. There were no significant differences in the long-term prognosis between the 2 groups (P=0.20). CONCLUSIONS: The incidence of TTS was increased in the acute phase after the GEJ-E, particularly in the coastal area. The magnitude of the tsunami damage is presumed to be a factor in the increased incidence of TTS, even though the seismic intensity in both areas was comparable.

Ability of B-Type Natriuretic Peptide Testing to Predict Cardioembolic Stroke in the General Population　- Comparisons With C-Reactive Protein and Urinary Albumin.

BACKGROUND: The ability of cardiovascular biomarkers to predict the incidence of stroke subtypes remains ill-defined in the general population.Methods and Results:The blood levels of B-type natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) and urinary albumin corrected by urinary creatinine (UACR) were determined in a general population (n=13,575). The ability to predict the incidence of ischemic stroke subtypes (lacunar, atherothrombotic, cardioembolic) for each biomarker was assessed based on the area under the receiver-operating characteristic curve (AUC-ROC) and using Cox proportional hazard modeling. The predictive abilities of UACR and hs-CRP for any subtype of ischemic event were found to be suboptimal. However, the ability of BNP to predict the incidence of cardioembolic stroke was excellent (AUC-ROC=0.81). When BNP was added to established stroke risk factors, the ability to predict cardioembolic stroke in terms of the AUC-ROC significantly improved (4-year follow-up, P=0.018; 8-year follow-up, P=0.009). Furthermore, when BNP was added to the JPHC score, the ability to predict cardioembolic stroke was significantly improved (net reclassification improvement=0.968, P<0.0001: integrated discrimination improvement=0.039, P<0.05). CONCLUSIONS: In the general population, plasma BNP was an excellent biomarker for predicting the incidence of cardioembolic stroke when used alone or in combination with established stroke risk factors.

Impact of Water- and Lipid-Soluble Statins on Nonculprit Lesions in Patients with Acute Coronary Syndrome.

Statins can be differentiated into two types, based on their solubility, which have potentially differing effects on the coronary artery wall. However, suspected differences in statins' effects on plaque composition have not been systemically investigated.Sixty-seven patients with acute coronary syndrome (ACS) were randomly assigned to either atorvastatin (10 mg/day) or rosuvastatin (2.5 mg/day). Intravascular ultrasound (IVUS) and integrated backscatter (IB)-IVUS, an established tool to quantify each plaque's components, were performed immediately after emergent percutaneous coronary intervention (PCI). Follow-up IVUS was performed between 6 and 12 months after PCI. Serial changes in serum lipid profiles and plaque composition volumes were compared between the two groups.Thirty-five patients were eligible for serial IB-IVUS analyses. The mean low-density lipoprotein-cholesterol level significantly decreased in the atorvastatin and rosuvastatin groups (P < 0.001); plaque volumes were also significantly reduced from 82.0 ± 46.2 to 74.9 ± 41.3 mm3 (P = 0.01) and from 74.7 ± 35.3 to 67.7 ± 27.0 mm3 (P = 0.02), respectively. IB-IVUS revealed a significant reduction in fibrous volume from 33.8 ± 20.0 to 27.5 ± 14.9 mm3 (P < 0.01) and from 29.6 ± 13.6 to 24.8 ± 7.6 mm3 (P < 0.05), respectively; however, significant changes were not noted in the volume of the lipid pool for the atorvastatin group and the rosuvastatin group, respectively.Water- and lipid-soluble statins may be similarly effective in reducing coronary plaques in patients with ACS as judged qualitatively and quantitatively. Further study is needed to determine whether differences between water- and lipid-soluble statins affect plaque components.

Genetic Predisposition to Ischemic Stroke: A Polygenic Risk Score.

BACKGROUND AND PURPOSE: The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk. METHODS: We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets). RESULTS: In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33-2.31) and 1.99 (95% confidence interval, 1.19-3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001). CONCLUSIONS: The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors.

Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease.

Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a, low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9-14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a.

Temporal Trends in the Incidence and Clinical Features of Acute Myocardial Infarction in a Japanese Rural Area From 2006 to 2014.

BACKGROUND: Recent temporal trends in the incidence and clinical features of acute myocardial infarction (MI) in the Japanese population are not well known.Methods and Results:This study used comprehensive registration for first-ever MI during the 9-year period from 2006 to 2014 in a rural area of northeastern Japan. The study period was divided into three 3-year terms (T1, 2006-2008; T2, 2009-2011; T3, 2012-2014). During the study period, a total of 814 patients with MI were registered. Although the age-adjusted incidence rate (100,000 person-years) in the middle-aged group (<70 years) was relatively stable, the rate for the elderly group (≥70 years) in T3 was significantly lower than that in T1 in both men (368 vs. 279; P<0.01) and women (204 vs. 108; P<0.01). In the general population of the study area, the rate of prescribed anticholesterol drugs was significantly increased during the study period, especially in the elderly population (P<0.01). From a clinical perspective, although the performance rate of primary percutaneous coronary intervention significantly increased with a shortened duration of hospital stay, the in-hospital mortality rate, especially in the elderly, did not significantly decrease during the study period. CONCLUSIONS: The present study is the first to demonstrate a decreased age-adjusted incidence of MI during the period from 2006 to 2014 in a Japanese rural population, especially in the elderly.

Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension.

BACKGROUND: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD. CONCLUSIONS: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s.

Risk of stroke and heart failure attributable to atrial fibrillation in middle-aged and elderly people: Results from a five-year prospective cohort study of Japanese community dwellers.

BACKGROUND: The relative and absolute risks of stroke and heart failure attributable to atrial fibrillation (AF) have not been sufficiently examined. METHODS: A prospective study of 23,731 community-dwelling Japanese individuals was conducted. Participants were divided into two groups based on the presence or absence of prevalent AF (n = 338 and n = 23,393, respectively). Excess events (EE) due to AF and relative risks (RRs) determined using the non-AF group as the reference for incident stroke and heart failure were estimated using Poisson regression stratified by age groups (middle-aged: 40-69 years old; elderly: 70 years of age or older) after adjustment for sex and age. RESULTS: There were 611 cases of stroke and 98 cases of heart failure during the observation period (131,088 person-years). AF contributed to a higher risk of stroke both in middle-aged individuals (EE 10.4 per 1000 person-years; RR 4.88; 95% confidence interval [CI], 2.88-8.29) and elderly individuals (EE 18.3 per 1000 person-years; RR 3.05; 95% CI, 2.05-4.54). AF also contributed to a higher risk of heart failure in middle-aged individuals (EE 3.7 per 1000 person-years; RR 8.18; 95% CI, 2.41-27.8) and elderly individuals (EE 15.4 per 1000 person-years; RR 7.82; 95% CI, 4.11-14.9). Results obtained from multivariate-adjusted analysis were similar (stroke: EE 8.9 per 1000 person-years; RR 4.40; 95% CI, 2.57-7.55 in middle-aged and EE 17.4 per 1000 person-years; RR 2.97; 95% CI, 1.99-4.43 in elderly individuals; heart failure: EE 3.1 per 1000 person-years; RR 7.22; 95% CI, 2.06-25.3 in middle-aged and EE 14.1 per 1000 person-years; RR 7.41; 95% CI, 3.86-14.2 in elderly individuals). CONCLUSIONS: AF increased the risk of stroke by the same magnitude as that reported previously in Western countries. AF increased the RR of heart failure more than that in Western populations.

The Impact and Effectivity of an Inventory Survey for a Stroke Registry in Iwate Prefecture.

BACKGROUND: The accuracy of a stroke registration program in Iwate prefecture was greatly affected by cooperation from medical facilities and doctors in the field. The number of registered cases from noncore hospitals was less, but the accuracy of registration was unknown. This report presents the impact and effectivity of an inventory survey of the stroke registry. SUBJECTS AND METHODS: Details of subjects living in coastal and northern regions of Iwate Prefecture who developed a cerebrovascular attack between 2012 and 2014 were obtained from the Iwate Stroke Registry through an inventory survey. Annual incidence rate from core hospitals and noncore hospitals were compared. To evaluate factors registered from noncore hospitals, multivariate analyses were performed for sex, age, living area, type of stroke, and past history of cerebrovascular diseases. RESULTS: Annual crude incidence rate for 100,000 residual populations were 428.8 in men and 351.2 in women from core hospitals and 38.5 in men and 43.7 in women from noncore hospitals. Ratios of noncore hospitals against all the hospitals were 8.3% for men and 11.1% for women. Multivariate analyses for age, ischemic type of stroke, past history of cerebrovascular diseases, and living in areas without a core hospital were significant; however, sex was not a significant factor. CONCLUSION: The inventory survey of the stroke registry program in the Iwate prefecture was useful to prevent missing data of stroke cases from noncore hospitals, including patients who are elderly, with ischemic stroke onset, with a past history of stroke, or living in areas without core hospitals.

Characteristics of Anatomy and Function of the Left Atrial Appendage and Their Relationships in Patients with Cardioembolic Stroke: A 3-Dimensional Transesophageal Echocardiography Study.

BACKGROUND: Increasing attention is being paid to the left atrial appendage (LAA) in the context of risk stratification in cardioembolic stroke (CES) and the requirement for meticulous planning of percutaneous closure device implantation. However, detailed systematic assessment of the LAA remains limited. METHODS: This study evaluated the anatomy and function of LAA using 3-dimensional transesophageal echocardiography (3D-TEE) on 194 consecutive patients older than 50 years old hospitalized exclusively for CES. Patients were stratified into 3 groups on the basis of cardiac rhythm: (1) chronic atrial fibrillation (AF), n = 53; (2) paroxysmal AF, n = 26; and (3) no detected AF, n = 115. RESULTS: Significant differences between the groups were observed for anatomical (orifice area [OA], depth, diastolic volume) and functional parameters (ejection fraction [EF], flow velocity [FV]), as measured by 3D-TEE. The anatomical parameters were consistently the greatest, and functional parameters were the poorest, in the group with chronic AF. There were significant inverse correlations between them (r = -.33, P = .0003 for depth and EF; r = -.27, P = .0020 for depth and FV; r = -.22, P = .016 for OA and EF; and r = -.38, P < .0001 for OA and FV). CONCLUSIONS: LAA morphology and function were strongly affected by cardiac rhythm disturbances. Patients with chronic AF had the greatest LAA dimensions, areas, and volumes as well as the lowest LAA functions. An inverse correlation was observed between LAA size and function.

Dysregulation of ossification-related miRNAs in circulating osteogenic progenitor cells obtained from patients with aortic stenosis.

CAVD (calcific aortic valve disease) is the defining feature of AS (aortic stenosis). The present study aimed to determine whether expression of ossification-related miRNAs is related to differentiation intro COPCs (circulating osteogenic progenitor cells) in patients with CAVD. The present study included 46 patients with AS and 46 controls. Twenty-nine patients underwent surgical AVR (aortic valve replacement) and 17 underwent TAVI (transcatheter aortic valve implantation). The number of COPCs was higher in the AS group than in the controls (P<0.01). Levels of miR-30c were higher in the AS group than in the controls (P<0.01), whereas levels of miR-106a, miR-148a, miR-204, miR-211, miR-31 and miR-424 were lower in the AS group than in the controls (P<0.01). The number of COPCs and levels of osteocalcin protein in COPCs were positively correlated with levels of miR-30a and negatively correlated with levels of the remaining miRNAs (all P<0.05). The degree of aortic valve calcification was weakly positively correlated with the number of COPCs and miR-30c levels. The number of COPCs and miR-30c levels were decreased after surgery, whereas levels of the remaining miRNAs were increased (all P<0.05). Changes in these levels were greater after AVR than after TAVI (all P<0.05). In vitro study using cultured peripheral blood mononuclear cells transfected with each ossification-related miRNA showed that these miRNAs controlled levels of osteocalcin protein. In conclusion, dysregulation of ossification-related miRNAs may be related to the differentiation into COPCs and may play a significant role in the pathogenesis of CAVD.

Standardized Prevalence Ratios for Atrial Fibrillation in Adult Dialysis Patients in Japan.

BACKGROUND: While it is assumed that dialysis patients in Japan have a higher prevalence of atrial fibrillation (AF) than the general population, the magnitude of this difference is not known. METHODS: Standardized prevalence ratios (SPRs) for AF in dialysis patients (n = 1510) were calculated compared to data from the general population (n = 26 454) living in the same area. RESULTS: The prevalences of AF were 3.8% and 1.6% in dialysis patients and the general population, respectively. In male subjects, these respective values were 4.9% and 3.3%, and in female subjects they were 1.6% and 0.6%. The SPRs for AF were 2.53 (95% confidence interval [CI], 1.88-3.19) in all dialysis patients, 1.80 (95% CI, 1.30-2.29) in male dialysis patients, and 2.13 (95% CI, 0.66-3.61) in female dialysis patients. CONCLUSIONS: The prevalence of AF in dialysis patients was twice that in the population-based controls. Since AF strongly contributes to a higher risk of cardiovascular mortality and morbidity in the general population, further longitudinal studies should be conducted regarding the risk of several outcomes attributable to AF among Japanese dialysis patients.

The Tohoku Medical Megabank Project: Design and Mission.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Comparison between urine albumin-to-creatinine ratio and urine protein dipstick testing for prevalence and ability to predict the risk for chronic kidney disease in the general population (Iwate-KENCO study): a prospective community-based cohort study.

BACKGROUND: This study compared the combination of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) vs. eGFR and urine protein reagent strip testing to determine chronic kidney disease (CKD) prevalence, and each method's ability to predict the risk for cardiovascular events in the general Japanese population. METHODS: Baseline data including eGFR, UACR, and urine dipstick tests were obtained from the general population (n = 22 975). Dipstick test results (negative, trace, positive) were allocated to three levels of UACR (<30, 30-300, >300), respectively. In accordance with Kidney Disease Improving Global Outcomes CKD prognosis heat mapping, the cohort was classified into four risk grades (green: grade 1; yellow: grade 2; orange: grade 3, red: grade 4) based on baseline eGFR and UACR levels or dipstick tests. RESULTS: During the mean follow-up period of 5.6 years, 708 new onset cardiovascular events were recorded. For CKD identified by eGFR and dipstick testing (dipstick test ≥ trace and eGFR <60 mL/min/1.73 m(2)), the incidence of CKD was found to be 9 % in the general population. In comparison to non-CKD (grade 1), although cardiovascular risk was significantly higher in risk grades ≥3 (relative risk (RR) = 1.70; 95 % CI: 1.28-2.26), risk predictive ability was not significant in risk grade 2 (RR = 1.20; 95 % CI: 0.95-1.52). When CKD was defined by eGFR and UACR (UACR ≥30 mg/g Cr and eGFR <60 mL/min/1.73 m(2)), prevalence was found to be 29 %. Predictive ability in risk grade 2 (RR = 1.41; 95 % CI: 1.19-1.66) and risk grade ≥3 (RR = 1.76; 95 % CI: 1.37-2.28) were both significantly greater than for non-CKD. Reclassification analysis showed a significant improvement in risk predictive abilities when CKD risk grading was based on UACR rather than on dipstick testing in this population (p < 0.001). CONCLUSIONS: Although prevalence of CKD was higher when detected by UACR rather than urine dipstick testing, the predictive ability for cardiovascular events from UACR-based risk grading was superior to that of dipstick-based risk grading in the general population.

Relationship between the seismic scale of the 2011 northeast Japan earthquake and the incidence of acute myocardial infarction: A population-based study.

BACKGROUND: Previous studies have reported a relationship between large earthquakes and acute coronary events, but have yielded conflicting results. On March 11, 2011, a massive magnitude 9.0 earthquake hit the northeastern coast of Japan and generated repeated aftershocks. The aim of this study is to clarify the influence of this earthquake on the risk of acute myocardial infarction (AMI) including sudden cardiac death based on the data from a population-based analysis. METHODS: The study subjects were residents in the northeast of Iwate prefecture, Japan. Cases corresponding to the definition of AMI according to the criteria of the World Health Organization MONICA project were registered from 4 weeks before to 8 weeks after the disaster and in the corresponding periods in 2009 and 2010. RESULTS: The relative risk of AMI was 2.03 (95% CI 1.55-2.66) for the 4-week period after the disaster compared with the corresponding periods in the preceding years. The number of events peaked within the first week after the earthquake decreased to levels seen in the preceding years and then increased again after high-magnitude aftershocks. The incidence of AMI was positively correlated with the seismic scale of the earthquake (r = 0.75, P < .01). CONCLUSIONS: This population-based study suggests that the increase in AMI events after a major earthquake varies depending on the seismic scale of the initial shock and each aftershock.

Cellular and molecular mechanisms of statins: an update on pleiotropic effects.

Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti-atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis.

Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin-angiotensin system blockade.

The extracellular miRNAs circulate in the bloodstream and may serve as novel diagnostic and therapeutic biomarkers. The aim of the present study was to investigate circulating Toll-like receptor 4 (TLR4)-responsive miRNA expression in patients with coronary artery disease (CAD) and to examine the effects of renin-angiotensin system (RAS) blockade and statins on miRNA levels. This study included 41 patients with CAD and 20 subjects without CAD (non-CAD). Plasma TLR4-responsive miRNA samples were analysed using a microarray assay for 1700 human miRNA. The candidate miRNAs were verified with real-time reverse transcription (RT)-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin [angiotensin II receptor blocker (ARB)] or enalapril and atorvastatin [angiotensin-converting enzyme inhibitor (ACEI)]. Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in seven TLR4-responsive miRNAs between the CAD and non-CAD groups (P<0.05). Real-time PCR verified that miR-31, miR-181a, miR-16 and miR-145 were significantly lower in the CAD group than in the non-CAD group (P<0.01). Levels of TLR4 protein were higher in the CAD group than in the non-CAD group (P<0.01) and were negatively correlated with levels of TLR4-responsive miRNAs. Receiver operating characteristic (ROC) curve analysis revealed that a panel of these four miRNAs was sensitive and specific enough to distinguish CAD from non-CAD [area under the curve (AUC)=0.93, 95% CI (confidence interval)=0.99-0.87]. Both ARB and ACEI groups showed increased TLR4-responsive miRNAs and diminished levels of TLR4 protein (P<0.05). Changes in miRNAs and TLR4 levels were greater in the ARB group than in the ACEI group (P<0.05). Circulating TLR4-responsive miRNAs including miR-31, miR-181a, miR-16 and miR-145 were significantly lower in patients with CAD compared with controls and these miRNAs may be involved in the pathogenesis of CAD.

Comparison of cardiovascular mortality in the Great East Japan and the Great Hanshin-Awaji Earthquakes　- a large-scale data analysis of death certificates.

BACKGROUND: Large earthquakes have been associated with cardiovascular disease (CVD) mortality. In Japan, the 1995 Great Hanshin-Awaji (H-A) Earthquake was an urban-underground-type earthquake, whereas the 2011 Great East Japan (GEJ) Earthquake was an ocean-trench type. In the present study, we examined how these different earthquake types affected CVD mortality. METHODS AND RESULTS: We examined death certificate data from 2008 to 2012 for 131 municipalities in Iwate, Miyagi, and Fukushima prefectures (n=320,348) and from 1992 to 1996 for 220 municipalities in Hyogo, Osaka, and Kyoto prefectures (n=592,670). A Poisson regression model showed significant increases in the monthly numbers of acute myocardial infarction (AMI)-related deaths (incident rate ratio [IRR] GEJ=1.34, P=0.001; IRR of H-A=1.57, P<0.001) and stroke-related deaths (IRR of GEJ=1.42, P<0.001; IRR of H-A=1.33, P<0.001) after the earthquakes. Two months after the earthquakes, AMI deaths remained significant only for H-A (IRR=1.13, P=0.029). When analyzing the standardized mortality ratio (SMR) after the earthquakes using the Cochran-Armitage trend test, seismic intensity was significantly associated with AMI mortality for 2 weeks after both the GEJ (P for trend=0.089) and H-A earthquakes (P for trend=0.005). CONCLUSIONS: Following the GEJ and H-A earthquakes, there was a sharp increase in CVD mortality. The effect of the disaster was sustained for months after the H-A earthquake, but was diminished after the GEJ Earthquake.

Elevated blood pressure at the first measurement predicts cardiovascular disease independently from the subsequent second reading in men, but not in women.

BACKGROUND AND METHODS: There have been no investigations concerning the association of each blood pressure (BP) reading with future cardiovascular disease (CVD) when multiple measurements are taken on one occasion. This community-based, prospective cohort study (n = 23 344, mean age = 62.4 years) investigated the associations between the BP obtained from the first and second of two consecutive measurements on one occasion and future cardiovascular events in men and women. RESULTS: During the mean follow-up of 5.5 years, 624 CVD events were identified. On the Cox regression analysis of age- and BP-adjusted models, the increased CVD risk of a hypertensive first measurement (systolic BP ≥ 140 mmHg) was independent from the second measurement in men. Even in subjects without a hypertensive second measurement, the CVD risk of the hypertensive first measurement was increased in men. In women, despite a hypertensive first measurement, subjects with a systolic BP < 130 mmHg on the second measurement showed a significantly reduced risk for CVD compared with subjects who retained a hypertensive level during the two measurements. CONCLUSIONS: An elevated BP on the first measurement should not be disregarded for CVD risk estimation in men, even if the second BP moves to the normal range. In women, elevated BP on the first measurement may have relatively less meaning for CVD prediction if the second BP shifts to a normal range.

NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin.

The NLRP-3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The aim of the present study was to determine whether NLRP3 inflammasome is expressed in patients with CAD (coronary artery disease) and whether statins (atorvastatin or rosuvastatin) might affect NLRP3 levels. In an in vitro study, human THP-1 cells treated with statins were analysed for NLRP3 inflammasome levels. The present study included 60 patients with CAD and 30 subjects without CAD (non-CAD). Patients with CAD randomly received either 8 months of treatment with atorvastatin or rosuvastatin. PBMCs (peripheral blood mononuclear cells) were obtained from peripheral blood at baseline and after 8 months of statin therapy. Levels of NLRP3 inflammasome, IL (interleukin)-1ß and IL-18 were measured by real-time RT-PCR (reverse transcription-PCR) and FACS. Levels of NLRP3 inflammasome were higher in the CAD group than in the non-CAD group. There was a positive correlation between NLRP3 inflammasome and cytokines (IL-1ß and IL-18) levels. A randomized clinical study has shown that atorvastatin markedly diminished NLRP3 inflammasome levels, whereas rosuvastatin had no impact on these levels. Levels of NLRP3 inflammasome decreased in THP-1 cells treated with statins compared with those treated with vehicle, and the fold changes in NLRP3 inflammasome were higher in THP-1 cells treated with atorvastatin compared with those treated with rosuvastatin. The present study suggests that atorvastatin down-regulates NLRP3 inflammasome expression in CAD, possibly contributing to the inhibitory effects of atorvastatin on chronic inflammation and atherogenic progression in this disorder.