永井 良三

BACKGROUND: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins.Methods and Results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70-100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70-100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58-1.18, P=0.32, and HR 1.25, 95% CI 0.88-1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60-1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08-5.17, P<0.001). CONCLUSIONS: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70-100 mg/dL) in patients receiving the same doses of statins.

Background: Even with high-dose statin therapy, residual cardiovascular event risks remain in patients with chronic coronary syndrome (CCS). Thus, future treatment targets need to be elucidated. This study determined the factors associated with residual cardiovascular risk in patients with CCS treated with high-dose statins. Methods and Results: This study was a subanalysis of the REAL-CAD study. This study enrolled 5,540 patients with CCS receiving 4 mg/day pitavastatin and assessed the impacts of 3 representative risk factors (i.e., blood pressure, glucose level, and renal function), alone or in combination, on clinical outcomes. Each risk factor was classified according to its severity. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization. After adjusting for the effects of confounders, a significantly worse prognosis was observed in the group with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 (hazard ratio [HR] 1.36; 95% confidence interval 1.03-1.80; P=0.028). No other factors or combinations were associated with the primary endpoint. An eGFR ≤60 mL/min/1.73 m2 was also associated with cardiac (HR 2.38; P=0.004) and all-cause (HR 1.51; P=0.032) death. Conclusions: Insufficient renal function was associated with a worse prognosis in patients with CCS undergoing high-dose statin therapy, suggesting that renal function is the next target for reducing the risk of residual cardiovascular events.

BACKGROUND: It is unknown whether beneficial effects of higher-dose statins on cardiovascular events are different according to the thrombotic risk in patients with chronic coronary syndrome (CCS).Methods and Results: The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study is a randomized trial comparing 4 mg and 1 mg pitavastatin in patients with CCS. This study categorized 12,413 patients into 3 strata according to the CREDO-Kyoto thrombotic risk score: low-risk (N=9,434; 4 mg: N=4,742, and 1 mg: N=4,692), intermediate-risk (N=2,415; 4 mg: N=1,188, and 1 mg: N=1,227); and high-risk (N=564; 4 mg: N=269, and 1 mg: N=295). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. Cumulative 4-year incidence of the primary endpoint was significantly higher in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001). In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the 4 mg than in the 1 mg group (4.0% and 4.9%, P=0.02), whereas in the intermediate- and high-risk strata, it was numerically lower in the 4 mg than in the 1 mg group. There was no significant treatment-by-subgroup interaction for the primary endpoint (P-interaction=0.77). CONCLUSIONS: High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events irrespective of the thrombotic risk in patients with CCS.

Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11∆K/∆K aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11∆K/+ mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11∆K/∆K aortas, and the smooth muscle cell lineage cells that differentiated from Myh11∆K/∆K induced pluripotent stem cells. The contractility of the Myh11∆K/∆K aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.

BACKGROUND: The causal relationship between hyperuricemia and cardiovascular diseases is still unknown. We hypothesized that hyperuricemic patients after percutaneous coronary intervention (PCI) had a higher risk of major adverse cardiovascular events (MACE). METHODS: This was a large-scale multicenter cohort study. We enrolled patients with chronic coronary syndrome (CCS) after PCI between April 2013 and March 2019 using the database from the Clinical Deep Data Accumulation System (CLIDAS), and compared the incidence of MACE, defined as a composite of cardiovascular death, myocardial infarction, and hospitalization for heart failure, between hyperuricemia and non-hyperuricemia groups. RESULTS: In total, 9,936 patients underwent PCI during the study period. Of these, 5,138 patients with CCS after PCI were divided into two group (1,724 and 3,414 in the hyperuricemia and non-hyperuricemia groups, respectively). The hyperuricemia group had a higher prevalence of hypertension, atrial fibrillation, history of previous hospitalization for heart failure, and baseline creatinine, and a lower prevalence of diabetes than the non-hyperuricemia group, but the proportion of men and age were similar between the two groups. The incidence of MACE in the hyperuricemia group was significantly higher than that in the non-hyperuricemia group (13.1 vs. 6.4%, log-rank P < 0.001). Multivariable Cox regression analyses revealed that hyperuricemia was significantly associated with increased MACE [hazard ratio (HR), 1.52; 95% confidential interval (CI), 1.23-1.86] after multiple adjustments for age, sex, body mass index, estimated glomerular filtration rate, left main disease or three-vessel disease, hypertension, diabetes mellitus, dyslipidemia, history of myocardial infarction, and history of hospitalization for heart failure. Moreover, hyperuricemia was independently associated with increased hospitalization for heart failure (HR, 2.19; 95% CI, 1.69-2.83), but not cardiovascular death or myocardial infarction after multiple adjustments. Sensitive analyses by sex and diuretic use, B-type natriuretic peptide level, and left ventricular ejection fraction showed similar results. CONCLUSION: CLIDAS revealed that hyperuricemia was associated with increased MACE in patients with CCS after PCI. Further clinical trials are needed whether treating hyperuricemia could reduce cardiovascular events or not.

AIM: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy. METHODS: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population. RESULTS: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002). CONCLUSIONS: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

BACKGROUND: It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS: The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS: The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION: Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death.

AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.

OBJECTIVE: We previously established a new animal model (Klf5+/- ;Fli1+/- mice) broadly recapitulating fundamental pathologic features of systemic sclerosis (SSc). SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism has remained unknown. To address this issue, we investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow-derived endothelial progenitor cells (BM-EPCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs), a precursor of pericytes, in Klf5+/- ;Fli1+/- mice. METHODS: Neovascularization and angiogenesis were assessed by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of BM-EPCs and BM-MSCs were assessed in in vitro studies. Dermal vasculature was visualized in vivo by FITC-dextran injection. RESULTS: Neovascularization was diminished in skin-embedded Matrigel plug in Klf5+/- ;Fli1+/- mice. Klf5+/- ;Fli1+/- DMECs showed defective tubulogenic activity, decreased expression of VE-cadherin and CD31, and imbalance of Notch1/delta-like ligand 4, suggesting that angiogenesis and anastomosis are disturbed. Klf5+/- ;Fli1+/- BM-MSCs exhibited enhanced proliferation, migration and collagen production by transforming growth factor-β1, indicating the preferential differentiation into myofibroblasts rather than pericytes. Klf5+/- ;Fli1+/- BM-EPCs displayed the transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in Klf5+/- ;Fli1+/- mice (15.67 ± 0.82 days versus 13.50 ± 0.84 days; P = 0.0017), and vascular network was poorly developed in wound scar tissue. CONCLUSION: Klf5+/- ;Fli1+/- mice represent impaired neovascularization and vascular maturation similar to those of SSc at least partially due to the induction of SSc-like properties in DMECs, BM-EPCs and BM-MSCs, indicating the critical contribution of KLF5 and Fli1 deficiency in vascular cells and related precursors to SSc vasculopathy.

AIMS: The aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N-oxide (TMAO) levels and heart failure (HF) outcomes. METHODS AND RESULTS: Trimethylamine N-oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all-cause mortality and/or HF rehospitalization within 1 year post-admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2-22.8)] than in Caucasian [5.9 μM (3.6-10.8)] and South Asian [4.5 μM (3.1-8.4)] (P < 0.001) patients. There were no differences in the rate of mortality and/or HF rehospitalization between the ethnic groups (P = 0.096). Overall, higher TMAO levels showed associations with mortality and/or rehospitalization after adjustment for confounders ( P = 0.002). Despite no differences between ethnicity and association with mortality/HF after adjustment (P = 0.311), only in Caucasian patients were TMAO levels able to stratify for a mortality/HF event (P < 0.001). CONCLUSIONS: Differences were observed in the association of mortality and/or rehospitalization based on circulating TMAO levels. Elevated TMAO levels in Caucasian patients showed increased association with adverse outcomes, but not in non-Caucasian patients.

Proper resolution of inflammation is vital for repair and restoration of homeostasis after tissue damage, and its dysregulation underlies various noncommunicable diseases, such as cardiovascular and metabolic diseases. Macrophages play diverse roles throughout initial inflammation, its resolution, and tissue repair. Differential metabolic reprogramming is reportedly required for induction and support of the various macrophage activation states. Here we show that a long noncoding RNA (lncRNA), lncFAO, contributes to inflammation resolution and tissue repair in mice by promoting fatty acid oxidation (FAO) in macrophages. lncFAO is induced late after lipopolysaccharide (LPS) stimulation of cultured macrophages and in Ly6Chi monocyte-derived macrophages in damaged tissue during the resolution and reparative phases. We found that lncFAO directly interacts with the HADHB subunit of mitochondrial trifunctional protein and activates FAO. lncFAO deletion impairs resolution of inflammation related to endotoxic shock and delays resolution of inflammation and tissue repair in a skin wound. These results demonstrate that by tuning mitochondrial metabolism, lncFAO acts as a node of immunometabolic control in macrophages during the resolution and repair phases of inflammation.

Background: Post hoc analysis was used to investigate the effects of renal function on the efficacy and safety of landiolol using data from the J-Land II study, which evaluated landiolol in patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF) who were refractory to Class III antiarrhythmic drugs. Methods and Results: Patient data from the J-Land II study (n=29) were stratified by renal function (estimated glomerular filtration rate [eGFR] <45 and ≥45 mL/min/1.73 m2) and analyzed. Continuous landiolol infusion (1 μg/kg/min, i.v.) was initiated after VT/VF was suppressed with electrical defibrillation; subsequent dose adjustments were made (1-40 μg/kg/min). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF during the assessment period. Safety endpoints were also assessed. In the eGFR <45 and ≥45 mL/min/1.73 m2 groups, the median doses of landiolol during the assessment period were 9.44 and 8.97 μg/kg/min, the proportions of patients free from recurrent VT/VF were 69.2% and 81.8%, and adverse events occurred in 9 and 10 of 13 patients in each group, respectively. There were no apparent differences in the efficacy or safety of landiolol between the 2 groups. Conclusions: The data suggest that renal function may not affect the efficacy and safety of landiolol for hemodynamically unstable VT or VF.

For treatment of complex congenital heart disease, computer simulation using a three-dimensional heart model may help to improve outcomes by enabling detailed preoperative evaluations. However, no highly integrated model that accurately reproduces a patient's pathophysiology, which is required for this simulation has been reported. We modelled a case of complex congenital heart disease, double outlet right ventricle with ventricular septal defect and atrial septal defect. From preoperative computed tomography images, finite element meshes of the heart and torso were created, and cell model of cardiac electrophysiology and sarcomere dynamics was implemented. The parameter values of the heart model were adjusted to reproduce the patient's electrocardiogram and haemodynamics recorded preoperatively. Two options of in silico surgery were performed using this heart model, and the resulting changes in performance were examined. Preoperative and postoperative simulations showed good agreement with clinical records including haemodynamics and measured oxyhaemoglobin saturations. The use of a detailed sarcomere model also enabled comparison of energetic efficiency between the two surgical options. A novel in silico model of congenital heart disease that integrates molecular models of cardiac function successfully reproduces the observed pathophysiology. The simulation of postoperative state by in silico surgeries can help guide clinical decision-making.

BACKGROUND: Previous studies have reported that being overweight, obese, or underweight is a risk factor for ischemic cardiovascular disease (CVD); however, CVD also occurs in subjects with ideal body mass index (BMI). Recently, the balance of n-3/n-6 polyunsaturated fatty acids (PUFAs) has received attention as a risk marker for CVD but, so far, no study has been conducted that investigates the association between BMI and the balance of n-3/n-6 PUFAs for CVD risk. METHODS: We evaluated the association between n-3/n-6 PUFA ratio and acute coronary syndrome (ACS) in three BMI-based groups (< 25: low BMI, 25-27.5: moderate BMI, and ≥ 27.5: high BMI) that included 1666 patients who visited the cardiovascular medicine departments of five hospitals located in urban areas in Japan. RESULTS: The prevalence of ACS events was 9.2, 7.3, and 10.3% in the low, moderate, and high BMI groups, respectively. We analyzed the relationship between ACS events and several factors, including docosahexaenoic acid/arachidonic acid (DHA/AA) ratio by multivariate logistic analyses. In the low BMI group, a history of smoking (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.40-4.35) and low DHA/AA ratio (OR: 0.30, 95% CI: 0.12-0.74) strongly predicted ACS. These associations were also present in the moderate BMI group but the magnitude of the association was much weaker (ORs are 1.47 [95% CI: 0.54-4.01] for smoking and 0.63 [95% CI: 0.13-3.10] for DHA/AA). In the high BMI group, the association of DHA/AA (OR: 1.98, 95% CI: 0.48-8.24) was reversed and only high HbA1c (OR: 1.46, 95% CI: 1.03-2.08) strongly predicted ACS. The interaction test for OR estimates (two degrees of freedom) showed moderate evidence for reverse DHA/AA ratio-ACS associations among the BMI groups (P = 0.091). CONCLUSIONS: DHA/AA ratio may be a useful marker for risk stratification of ACS, especially in non-obese patients.

OBJECTIVES: To evaluate condition-specific antibiotic prescription rates and the appropriateness of antibiotic use in outpatient settings in Japan. METHODS: Using Japan's national administrative claims database, all outpatient visits with infectious disease diagnoses were linked to reimbursed oral antibiotic prescriptions. Prescription rates stratified by age, sex, prefecture, and antibiotic category were determined for each infectious disease diagnosis. The proportions of any antibiotic prescription to all infectious disease visits and the proportions of first-line antibiotic prescriptions to all antibiotic prescriptions were calculated for each infectious disease diagnosis. RESULTS: Of the 659 million infectious disease visits between April 2012 and March 2015, antibiotics were prescribed in 266 million visits (704 prescriptions per 1000 population per year). Third-generation cephalosporins, macrolides, and quinolones accounted for 85.9% of all antibiotic prescriptions. Fifty-six percent of antibiotic prescriptions were directed toward infections for which antibiotics are generally not indicated. The diagnoses with frequent antibiotic prescription were bronchitis (184 prescriptions per 1000 population per year), viral upper respiratory infections (166), pharyngitis (104), sinusitis (52), and gastrointestinal infection (41), for which 58.3%, 40.6%, 58.9%, 53.9%, and 26.1% of visits antibiotics were prescribed, respectively. First-line antibiotics were rarely prescribed for pharyngitis (8.8%) and sinusitis (9.8%). More antibiotics were prescribed for children aged 0-9 years, adult women, and patients living in western Japan. CONCLUSIONS: Antibiotic prescription rates are high in Japan. Acute respiratory or gastrointestinal infections, which received the majority of the antibiotics generally not indicated, should be the main targets of antimicrobial stewardship intervention.

This study, conducted at major Japanese companies, aimed to determine if asymptomatic workers in workplaces with a high prevalence of metabolic syndrome have a greater risk of developing metabolic syndrome. Data were obtained from the health records of 298,145 people, from 2011 to 2015. We collected data on the participants' age, sex, physical examinations, laboratory tests, and lifestyle behaviors. To test whether the risk of metabolic syndrome in asymptomatic workers differed between groups with a higher and lower prevalence in 2011, Cox proportional hazards regression model was performed, with the covariates being controlled for. The analysis showed that the risk of metabolic syndrome among asymptomatic workers in the high-prevalence group was about 1.1-fold elevated compared to those within the low-prevalence group. As a follow-up to these results, interventions aimed at asymptomatic workers should be provided in workplaces with a high prevalence of metabolic syndrome.

Objective To examine case reports presented at the Regional Meeting of the Japanese Society of Internal Medicine in order to clarify the underlying disease and prognosis of heart failure, which is often caused by non-cardiovascular diseases. Methods We examined 49,693 case reports from the Japanese Society of Internal Medicine database. A total of 2,893 reports were included after excluding 46,022 reports that did not include the term "heart failure" and 778 reports with no indications of symptoms of heart failure. We assessed each patient's basal disease, and according to the abstracts, we reported their prognosis as dead or alive. Results Of the 2,893 reports included, 1,952 (67.5%) and 941 (32.5%) had cardiovascular and non-cardiovascular diseases as the causes, respectively; these cases were attributed to 725 different diseases, 196 (27.0%) and 529 (73.0%) of which were cardiovascular and non-cardiovascular diseases, respectively. In addition, 91 different side effects were identified. The percentage of cases of heart failure-related mortality was significantly higher among the patients with non-cardiovascular diseases than in those with cardiovascular diseases (17.8% vs. 10.8%; p <0.001). Of the diseases reported as causes of heart failure in more than 10 reports, pulmonary tumor thrombotic microangiopathy (87%), multiple myeloma (50%), and amyloidosis (47%) accounted for the highest percentages of heart failure-related mortality. Conclusion Because heart failure is often caused by non-cardiovascular diseases, a broad study of case reports on internal medicine is important for cardiologists.

Aortic dissection is a life-threatening condition, which is characterised by separation of the constituent layers of the aortic wall. We have recently shown that monocyte/macrophage infiltration into the aortic wall is a pathogenic mechanism of the condition. In the present study, we investigated whether the anti-inflammatory agent, indomethacin, could inhibit monocyte/macrophage accumulation in the aortic wall and ensuing dissection. Indomethacin was administered (from 3 days prior with daily oral administration) to mice in which aortic dissection was induced using beta-aminopropionitrile (BAPN) and angiotensin II (Ang II) infusion (2 weeks). Indomethacin prevented death from abdominal aortic dissection and decreased incidence of aortic dissection by as high as 40%. Histological and flow cytometry analyses showed that indomethacin administration resulted in inhibition of monocyte transendothelial migration and monocyte/macrophage accumulation in the aortic wall. These results indicate that indomethacin administration reduces rate of onset of aortic dissection in a murine model of the condition.

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.

OBJECTIVES: To investigate oral antibiotic prescribing patterns and identify factors associated with antibiotic prescriptions, with the aim of guiding future interventions to reduce inappropriate prescribing. DESIGN: Retrospective cohort study. SETTING: Database of public health insurance claims in Kumamoto prefecture (Japan). PARTICIPANTS: Beneficiaries of the national or late elders' health insurance system between April 2012 and March 2013. MAIN OUTCOME MEASURES: Of the 7 770 481 outpatient visits, 682 822 had a code for antibiotics (860 antibiotic prescriptions per 1000 population). Third-generation cephalosporins (35%), macrolides (32%) and quinolones (21%) were the most frequently prescribed. Acute respiratory tract infections (ARTIs), including viral upper respiratory infections (URI) (22%), pharyngitis (18%), bronchitis (11%) and sinusitis (10%) were the most frequently diagnosed for antibiotic prescribing, followed by gastrointestinal (9%), urinary tract (8%) and skin, cutaneous and mucosal infections (5%). Antibiotic prescribing rates for viral URI, pharyngitis, bronchitis, sinusitis and gastrointestinal infections were 35%, 54%, 53%, 57% and 30%, respectively. In multivariable analysis for ARTIs and gastrointestinal infections, patient age (10-19 years especially), patient sex (male) and facility scale (free-standing clinics or small-scale hospital-based clinics) were associated with increased antibiotic prescribing. CONCLUSIONS: Broad-spectrum antibiotics constituted 88% of oral outpatient antibiotic prescriptions. Approximately 70% of antibiotics were prescribed for ARTIs and gastroenteritis with modest benefit from antibiotic treatment. The quality of antibiotic prescribing needs to be improved. Antimicrobial stewardship interventions should target ARTIs and gastroenteritis, as well as young patients and small-scale institutions.

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

The utilization of electronic medical records and multimodal medical data is an ideal approach to build a real-time and precision registry type study with a smaller effort and cost, which may fill a gap between evidence-based medicine and the real-world clinical practice. The Japan Ischemic heart disease Multimodal Prospective data Acquisition for preCision Treatment (J-IMPACT) project aimed to build an clinical data registry system that electronically collects not only medical records, but also multimodal data, including coronary angiography and percutaneous coronary intervention (PCI) report, in standardized data formats for clinical studies.The J-IMPACT system comprises the standardized structured medical information exchange (SS-MIX), coronary angiography and intervention reporting system (CAIRS), and multi-purpose clinical data repository system (MCDRS) interconnected within the institutional network. In order to prove the concept, we acquired multimodal medical data of 6 consecutive cases that underwent PCI through the J-IMPACT system in a single center. Data items regarding patient background, laboratory data, prescriptions, and PCI/cardiac catheterization report were correctly acquired through the J-IMPACT system, and the accuracy of the multimodal data of the 4 categories was 100% in all 6 cases.The application of J-IMPACT system to clinical studies not only fills the gaps between randomized clinical trials and real-world medicine, but may also provide real-time big data that reinforces precision treatment for each patient.

BACKGROUND: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death). METHODS: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death). RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P<0.001). CONCLUSIONS: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Background: Cardiac resynchronization therapy is an effective device therapy for heart failure patients with conduction block. However, a problem with this invasive technique is the nearly 30% of non-responders. A number of studies have reported a functional line of block of cardiac excitation propagation in responders. However, this can only be detected using non-contact endocardial mapping. Further, although the line of block is considered a sign of responders to therapy, the mechanism remains unclear. Methods: Herein, we created two patient-specific heart models with conduction block and simulated the propagation of excitation based on a cellmodel of electrophysiology. In one model with a relatively narrow QRS width (176 ms), we modeled the Purkinje network using a thin endocardial layer with rapid conduction. To reproduce a wider QRS complex (200 ms) in the second model, we eliminated the Purkinje network, and we simulated the endocardial mapping by solving the inverse problem according to the actual mapping system. Results: We successfully observed the line of block using non-contact mapping in the model without the rapid propagation of excitation through the Purkinje network, although the excitation in the wall propagated smoothly. This model of slow conduction also reproduced the characteristic properties of the line of block, including dense isochronal lines and fractionated local electrocardiograms. Further, simulation of ventricular pacing from the lateral wall shifted the location of the line of block. By contrast, in the model with the Purkinje network, propagation of excitation in the endocardial map faithfully followed the actual propagation in the wall, without showing the line of block. Finally, switching the mode of propagation between the two models completely reversed these findings. Conclusions: Our simulation data suggest that the absence of rapid propagation of excitation through the Purkinje network is the major cause of the functional line of block recorded by non-contact endocardial mapping. The line of block can be used to identify responders as these patients loose rapid propagation through the Purkinje network.

INTRODUCTION: The association among smoking history, eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio and acute coronary syndrome (ACS) is yet to be investigated. The present study aimed to clarify the association between the EPA/AA ratio and ACS prevalence in patients admitted to the cardiology department based on their smoking history. METHODS: We enrolled 1733 patients from five cardiology divisions located in Tokyo, Japan, and measured their levels of polyunsaturated fatty acids, including EPA and AA, from January 2004 to May 2011. We assessed the association between the EPA/AA ratio and ACS in the subgroups stratified according to smoking history (never, former, current smokers) using multivariate logistic models. RESULTS: A high EPA/AA ratio was significantly associated with decreased odds of ACS among patients without a smoking history (adjusted odds ratio AOR=0.20, 95% CI: 0.04-0.86) but not in patients with a smoking history (former smoker, AOR=1.50, 95% CI: 0.44-5.03; current smoker, AOR=3.73, 95% CI: 0.34-40.6). CONCLUSIONS: The EPA/AA ratio and ACS occurrence were found to be significantly associated in patients without a smoking history; however, no such association existed in patients with a smoking history. ABBREVIATIONS: AA: arachidonic acid, ACS: acute coronary syndrome, CVD: cardiovascular disease, DGLA: dihomo-gamma-linolenic acid, DHA: docosahexaenoic acid, EPA: eicosapentaenoic acid, JELIS: Japan EPA Lipid Intervention Study, PUFA: polyunsaturated fatty acid, RAS: renin angiotensin system, TG: triglyceride.