Role of Small Dense Low-density Lipoprotein Cholesterol in Cardiovascular Events in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus Receiving Statin Treatment.

AIM: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. METHODS: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. RESULTS: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL. CONCLUSIONS: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.

Reduced reactive hyperemia of the brachial artery in diabetic patients assessed by repeated measurements: The FMD-J B study.

Type 2 diabetes mellitus (T2DM) is a major cause of microvascular dysfunction. However, its effect on blood flow patterns during ischemic demand has not been adequately elucidated. In this study, we investigated the hypothesis that microvascular dysfunction in patients with T2DM manifests as brachial reactive hyperemia (BRH), defined as the ratio of peak blood flow velocities in a brachial artery before and after forearm cuff occlusion. The study enrolled 943 subjects (men, n = 152 [T2DM] and n = 371 [non-T2DM]; women, n = 107 [T2DM] and n = 313 [non-T2DM], respectively) with no history of cardiovascular disease. Semiautomatic measurements were obtained three times at 1.5-year intervals to confirm the reproducibility of factors involved in BRH for each sex. An age-adjusted mixed model demonstrated attenuated BRH in the presence of T2DM in both men (p = 0.022) and women (p = 0.031) throughout the study period. Post hoc analysis showed that the estimated BRH was significantly attenuated in patients with T2DM regardless of sex, except at baseline in women. In multivariate regression analysis, T2DM was a negative predictor of BRH at every measurement in men. For women, BRH was more strongly associated with alcohol consumption. Repeated measurements analysis revealed that T2DM was associated with attenuated postocclusion reactive hyperemia.

Liposome-Encapsulated Hemoglobin Vesicle Improves Persistent Anti-arrhythmogenesis through Improving Myocardial Electrical Remodeling and Modulating Cardiac Autonomic Activity in a Hemorrhagic Shock-Induced Rat Heart Model.

OBJECTIVE: Shock heart syndrome (SHS) is associated with lethal arrhythmias (ventricular tachycardia/ventricular fibrillation, VT/VF). We investigated whether liposome-encapsulated human hemoglobin vesicles (HbVs) has comparable persistent efficacy to washed red blood cells (wRBCs) for improving arrhythmogenesis in the subacute to chronic phase of SHS. METHODS: Optical mapping analysis (OMP), electrophysiological study (EPS), and pathological examinations were performed on blood samples from Sprague-Dawley rats following induction of hemorrhagic shock. After hemorrhagic shock, the rats were immediately resuscitated by transfusing 5% albumin (ALB), HbV, or wRBCs. All rats survived for 1 week. OMP and EPS were performed on Langendorff-perfused hearts. Spontaneous arrhythmias and heart rate variability (HRV) were evaluated using awake 24-h telemetry, cardiac function by echocardiography, and pathological examination of Connexin43. RESULTS: OMP showed significantly impaired action potential duration dispersion (APDd) in the left ventricle (LV) in the ALB group whereas APDd was substantially preserved in the HbV and wRBCs groups. Sustained VT/VF was easily provoked by EPS in the ALB group. No VT/VF was induced in the HbV and wRBCs groups. HRV, spontaneous arrhythmias, and cardiac function were preserved in the HbV and wRBCs groups. Pathology showed myocardial cell damage and Connexin43 degradation in the ALB group, all of which were attenuated in the HbV and wRBCs groups. CONCLUSION: LV remodeling after hemorrhagic shock caused VT/VF in the presence of impaired APDd. Similar to wRBCs, HbV persistently prevented VT/VF by inhibiting persistent electrical remodeling, preserving myocardial structures, and ameliorating arrhythmogenic modifying factors in the subacute to chronic phase of hemorrhagic shock-induced SHS.

A Low Arginine/Ornithine Ratio is Associated with Long-Term Cardiovascular Mortality.

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p＜0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.

Association of serum nitric oxide metabolite level with mortality in patients undergoing coronary angiography.

BACKGROUND: Nitric oxide (NO) is a relevant molecule for vascular homeostasis. The level of serum NO metabolites (NOx), which consist of nitrite and nitrate, has been investigated as an alternative biomarker of NO production, but its clinical value has not yet been determined. METHODS AND RESULTS: 143 patients (66 ±â€¯12 years old) were followed up after coronary catheterization. During a median (inter-quartile range) observation period of 6.13 (3.32-9.21) years, there were 20 (14 %) all-cause deaths, including 11 (8 %) cardiovascular deaths, 17 (12 %) major adverse cardiovascular events, and 17 (12 %) hospital admissions for heart failure. Median NOx level was 34.5 µmol/L (23.9-54.3). NOx was a risk factor for all-cause death [hazard ratio (HR) by unit increase, 1.010, 95 % confidence interval (CI) 1.001-1.018; p = 0.021] and heart failure (HR 1.010, CI 1.001-1.019; p = 0.029). Even after adjustment for age, sex, coronary risk factors, C-reactive protein, log-transformed brain natriuretic peptide, estimated glomerular filtration rate, and nitrate treatment, NOx was a risk factor for all-cause death (HR 1.015, CI 1.004-1.027; p = 0.008) and admission with heart failure (HR 1.018, CI 1.005-1.018, p = 0.007). CONCLUSIONS: An increase in serum NOx level does not herald a benign clinical course but is an independent predictor of high risk of any-cause mortality and heart failure.

Effect of Novel Stratified Lipid Risk by "LDL-Window" and Flow-Mediated Dilation on the Prognosis of Coronary Artery Disease Using the FMD-J Study A Data.

BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Delayed Vasovagal Reaction with Reflex Syncope Following COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) has become a pandemic, and vaccines remain the only effective tools available for ending it. However, their side effects, such as syncope, which mimics sudden cardiac death, are serious concerns. We herein report 6 cases of delayed vasovagal syncope and presyncope (VVR) caused by COVID-19 vaccination among 25,530 COVID-19 patients. The prevalence of delayed VVR due to COVID-19 vaccination was 0.026%. In addition, no delayed VVR was found among 17,386 patients who received the influenza vaccine. Delayed VVR is likely to be overlooked if medical staff are not aware of this symptom. This report provides significant information regarding effects of COVID-19 vaccination.

Vasospasm-induced ST-segment elevation myocardial infarction in a premenopausal woman with endothelial dysfunction.

ST-segment elevation myocardial infarction (STEMI) can be caused by coronary artery vasospasm (VSA) due to endothelial dysfunction. However, the clinical role of endothelial function tests in VSA-induced STEMI is not fully understood. We present the case of a 43-year-old woman with atypical chest pain and no coronary risk factors. STEMI caused by VSA was diagnosed. Flow-mediated vasodilatation (FMD) and EndPAT tests were performed; the FMD and reactive hyperaemia index were 3.8% and 1.23, respectively. Endothelial dysfunction is the putative cause of STEMI. FMD and EndPAT tests might be useful for predicting adverse outcomes in young premenopausal women with VSA.

Association between Smoking and Urine Indole Levels Measured by a Commercialized Test.

Indoles are formed from dietary tryptophan by tryptophanase-positive bacterium. A few amounts of indole are excreted in the urine. On the other hand, cigarette smoke contains indoles, which could also change the urine indole levels. This study sought to elucidate the relationship between urine indole levels and smoking habits. A total of 273 healthy men (46 ± 6 years old) were enrolled in the study. Fasting urine and blood samples were obtained in the morning. The indole concentration was measured by a commercialized kit with a modified Kovac's reagent. The relationship with smoking status was evaluated. The median value of the urine indole test was 29.2 mg/L (interquartile range; 19.6-40.8). The urine indole level was significantly elevated in the smoking subjects (non-smoking group, 28.9 (20.9-39.1) mg/L, n = 94; past-smoking group, 24.5 (15.7-35.5) mg/L, n = 108; current-smoking group, 34.3 (26.9-45.0) mg/L, n = 71). In the current-smoking group, urine indole levels correlated with the number of cigarettes per day (ρ = 0.224, p = 0.060). A multivariate regression test with stepwise method revealed that the factors relating to urine indole level were current smoking (yes 1/no 0) (standardized coefficient ß = 0.173, p = 0.004), blood urea nitrogen (ß = 0.152, p = 0.011), and triglyceride (ß = -0.116, p = 0.051). The result suggests that smoking is associated with increased urine indole levels. The practical test might be used as a screening tool to identify the harmful effect of smoking.

Effectiveness of the d-ROMs oxidative stress test to predict long-term cardiovascular mortality.

BACKGROUND: The long-term prognostic value of the derivatives of reactive oxidative metabolites (d-ROMs) oxidative stress test, which measures hydroperoxide in blood, has not been fully investigated. METHODS AND RESULTS: We administered the d-ROMs test to 265 patients with cardiovascular disease (204 men, 61 women; age, 65 ± 13 years) and followed these patients for up to 10 years. During the observational period of 5.82 (2.47-8.34) years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, and 33 (12%) had major adverse cardiovascular events (MACEs). Cox regression analysis revealed that patients with a d-ROMs value ≥395 U.CARR had a greater risk for all-cause mortality [unadjusted hazard ratio (95% confidence interval), 3.586 (1.772-7.257)], cardiovascular death [7.034 (2.805-17.640)], and MACEs [4.440 (2.237-8.814)] (p < 0.001 for all). In a model adjusted for age, sex, estimated glomerular filtration rate, C-reactive protein, diabetes, hypertension, hyperlipidemia, coronary artery diseases, current smoking, and log-transformed brain natriuretic peptide, all-cause death [2.311 (1.059-5.135), p = 0.036], cardiovascular death [4.398 (1.599-12.099), p = 0.004], MACEs [2.696 (1.266-5.739), p = 0.010] were still significant in patients with high d-ROMS values. CONCLUSION: A high d-ROMs value is an independent predictor of the long-term risk of cardiovascular mortality. A d-ROMs value of 395 U.CARR was considered to be an appropriate threshold for distinguishing prognosis.

Differential effect of a xanthine oxidase inhibitor on arterial stiffness and carotid atherosclerosis: a subanalysis of the PRIZE study.

Atherosclerosis and arterial stiffness are phenotypes of atherosclerotic vascular damage. Atherosclerosis originates from endothelial vascular damage and forms focal morphological lesions; arterial stiffness originates from diffuse medial-layer damage in the arterial tree. Thus, the two phenomena reflect different facets of atherosclerotic vascular damage, and they both gradually progress. We conducted a subanalysis to compare the long-term effects of febuxostat on atherosclerosis and arterial stiffness in the PRIZE study (a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial to examine the effect of febuxostat on carotid atherosclerosis). Among 514 study participants, arterial stiffness parameters (brachial-ankle pulse wave velocity or cardio-ankle vascular index) were obtained at baseline, 12 months, and 24 months in 100 subjects. Among them, 48 subjects were allocated to the control group (i.e., nonpharmacological lifestyle modification for hyperuricemia), and 52 subjects were allocated to the febuxostat treatment group. While the decrease in serum uric acid was greater in the febuxostat group than in the control group, the adjusted percentage decrease in arterial stiffness parameters at month 24 was greater in the febuxostat group than in the control group, with a mean between-group difference (febuxostat - control) of -5.099% (95% confidence interval (CI) -10.009% to -0.188%, p = 0.042). Thus, long-term treatment with febuxostat may exert beneficial effects on arterial stiffness without improving carotid atherosclerosis. A long-term study to examine the effect of febuxostat on cardiovascular outcomes related to increased arterial stiffness is warranted.

Intraosseous infusion of liposome-encapsulated hemoglobin (HbV) acutely prevents hemorrhagic anemia-induced lethal arrhythmias, and its efficacy persists with preventing proarrhythmic side effects in the subacute phase of severe hemodilution model.

BACKGROUND: Artificial oxygen carriers (HbV) can treat hemorrhagic shock with lethal arrhythmias (VT/VF). No reports exist on subacute HbV's effects. METHODS: Acute and subacute resuscitation effects with anti-arrhythmogenesis of HbV were studied in 85% blood exchange rat model (85%-Model). Lethal 85%-Model was created by bone marrow transfusion and femoral artery bleeding in 80 SD rats in HbV-administered group (HbV-group), washed erythrocyte-administered group (wRBC-group), and 5% albumin-administered group (ALB-group). Survival rates, anti-arrhythmic efficacy by optical mapping system (OMP) with electrophysiological study (EPS) in Langendorff heart, cardiac autonomic activity by heart rate variability (HRV) and ventricular arrhythmias by 24-h electrocardiogram telemetry monitoring (24 h-ECG) in awake, and left ventricular function by echocardiography (left ventricular ejection fraction [LVEF]) were measured. RESULTS: All rats in HbV- and wRBC-groups survived for 4 weeks, whereas no rats in ALB-group. HbV and wRBC acutely suppressed VT/VF in Langendorff heart through ameliorating action potential duration dispersion (APDd) analyzed by OMP with EPS. For subacute analysis, 50% blood exchange by 5% albumin was used (ALB-group 50). Subacute salutary effect on APDd and VT/VF inducibility was confirmed in HbV- and wRBC-groups. 24 h-ECG showed that HbV and wRBC suppressed none-sustained ventricular tachycardia (NSVT) and sympathetic component of HRV (LF/HF) with preserved LVEF (HbV-group, wRBC-group vs. ALB-group 50; NSVT numbers/days, 0.5 ± 0.3, 0.4 ± 0.3 vs. 3.9 ± 1.2*; LF/HF, 1.1 ± 0.2, 0.8 ± 0.2 vs. 3.5 ± 1.0*; LVEF, 84 ± 5, 83 ± 4, vs. 77 ± 4%*; *p < 0.05). CONCLUSIONS: Collectively, HbV has sustained antiarrhythmic effect in subacute 85%-Model by ameliorating electrical remodeling and improving arrhythmogenic modifying factors (HRV and LVEF). These findings are useful in now continuing clinical trials of HbV.

Artificially Created Reentry Circuit by Laser Irradiation Causes Atrial Tachycardia to Persist in Murine Atria.

BACKGROUND: There is a gradual progression from paroxysmal to persistent atrial fibrillation (AF) in humans. To elucidate the mechanism involved, the creation of an artificial atrial substrate to persist AF in mice was attempted.Methods and Results:This study used wild type (WT) mice, but it is difficult to induce AF in them. A novel antegrade perfusion method from the left ventricle (LV) to enlarge both atria for artificial atrial modification was proposed in this study. Short duration AF was induced by burst pacing under this method. Optical mapping analysis revealed non-sustained focal type and meandering spiral reentrants after short duration AF. A tiny artificial substrate (~1.2 mm in diameter) was added in by laser irradiation to create a critical atrial arrhythmogenic substrate. Burst pacing was performed in a non-laser group (n=8), a circular-shape laser group (n=8), and a wedge-shaped dent laser group (n=8). We defined AF and atrial tachycardia (AT) as atrial arrhythmia (AA). Long-lasting AA was defined as lasting for ≥30 min. Long-lasting AA was observed in 0/8, 0/8, and 6/8 (75%) mice in each group. Optical mapping analysis revealed that the mechanism was AT with a stationary rotor around the irradiated margin. CONCLUSIONS: Regrettably, this study failed to reproduce persistent AF, but succeeded in creating an arrhythmic substrate that causes sustained AT in WT mice.

Effectiveness of pulsatility index of carotid Doppler ultrasonography to predict cardiovascular events.

PURPOSE: The pulsatility index (PI) obtained from carotid ultrasonography is considered to be a marker of cerebrovascular resistance. However, the impact of PI on cardiovascular events has yet to be fully addressed. METHOD: Fifty-four patients who underwent both carotid ultrasonography and coronary angiography were followed for 5.9 ± 3.2 years. The relationship between the incidence of cardiovascular events and PI was investigated. RESULT: There were 10 (19%) deaths, four (7%) cardiovascular deaths, and nine (17%) major adverse cardiovascular events (MACEs). The cardiovascular events-defined as all hospitalization for MACEs plus heart failure, revascularization, and cardiovascular surgery-occurred in 21 patients (39%). The patients were divided into two groups according to each threshold of PI value for common carotid arteries (CCA), internal carotid arteries (ICA), and external carotid arteries (ECA), respectively. The thresholds were calculated based on receiver-operating characteristic curves for cardiovascular events. Log-rank test showed that the groups with CCA-PI ≥ 1.71, ICA-PI ≥ 1.20, and ECA-PI ≥ 2.46 had a higher incidence of cardiovascular events, respectively (p < 0.05). ECA-PI ≥ 2.46 was associated with an increased incidence of MACEs. Multivariate Cox regression analysis adjusting for cardiovascular risk factors showed that high PI of CCA, ICA, or ECA was a risk factor for cardiovascular events, respectively (CCA-PI ≥ 1.71, hazard ratio (HR) 3.242, p = 0.042; ICA-PI ≥ 1.20, HR 3.639, p = 0.012; ECA-PI ≥ 2.46, HR 11.322, p = 0.001). CONCLUSION: The results suggested that carotid PIs were independent predictive factors for further cardiovascular events. In particular, high ECA-PI levels may reflect severe arteriosclerosis.

Liposome-encapsulated hemoglobin (HbV) transfusion rescues rats undergoing progressive lethal 85% hemorrhage as a result of an anti-arrhythmogenic effect on the myocardium.

Liposome-encapsulated hemoglobin vesicles (HbV) can serve as a blood substitute with oxygen-carrying capacity comparable to that of human blood and lethal hemorrhage is associated with lethal arrhythmias. To investigate the resuscitation effect of HbV on lethal hemorrhage and anti-arrhythmogenesis, we performed optical mapping analysis (OMP) and electrophysiological study (EPS) in graded blood exchange (85% blood loss) in the rat model. We also measured cardiac autonomic activity, as assessed by heart rate variability (HRV), and changes in plasma norepinephrine and left ventricle ejection fraction (LVEF) by echocardiography. Pathological study on Connexin43 was performed. A 5% albumin (ALB group), washed rat erythrocytes (wRBC group), and HbV (HbV group) were used as a resuscitation fluid. The survival effects over 24 hours were examined. All rats died in the ALB group, whereas almost all survived for 24-hours period in wRBC and HbV groups. OMP showed impaired action potential duration dispersion (APDd) in the ALB group, whereas normal APDs in HbV and wRBC groups. Lethal arrhythmias were induced by EPS in the ALB group, but not in wRBC and HbV groups. HRV indices, LVEF, Connexin43 were preserved in HbV and wRBC groups. Lethal hemorrhage causes lethal arrhythmias in the presence of impaired APDd. HbV acutely rescues lethal hemorrhage by preventing lethal arrhythmias and preserving arrhythmogenic factors.

Endothelial function is preserved in light to moderate alcohol drinkers but is impaired in heavy drinkers in women: Flow-mediated Dilation Japan (FMD-J) study.

Light to moderate alcohol consumption has protective effects on all-cause death and coronary artery disease in women. It is thought that light to moderate alcohol consumption has a beneficial effect on vascular function in women. We measured flow-mediated vasodilation (FMD) in 702 women aged 17-86 years who provided information on alcohol consumption. We divided the subjects into four groups: non-drinkers (0 g/week), light drinkers (>0 to 140 g/week), moderate drinkers (>140 to 280 g/week) and heavy drinkers (>280 g/week). There was no significant difference in FMD among the four groups. Multivariate regression analysis revealed that alcohol consumption in non-drinkers and light drinkers was not an independent predictor of FMD (ß = -0.001, P = 0.98). We compared 50 moderate drinkers and 50 non-drinkers matched for age and medical histories and 22 heavy drinkers and 22 non-drinkers in matched pair analysis. There was no significant difference in FMD between moderate drinkers and non-drinkers (8.2±4.3% vs. 8.1±3.5, P = 0.91), while FMD in heavy drinkers was significantly lower than that in non-drinkers (5.9±2.5% vs. 8.9±3.5%, P = 0.002). These findings suggest that heavy alcohol consumption is associated with endothelial dysfunction but that light to moderate alcohol consumption is not associated with endothelial dysfunction in women. Clinical trial registration information This study was approved by principal authorities and ethical issues in Japan (University Hospital Medical Information Network UMIN000012952, 01/12/2009). www.umin.ac.jp/.