Sex Differences in Cardiovascular Disease-Related Hospitalization and Mortality in Japan　- Analysis of Health Records From a Nationwide Claim-Based Database, the Japanese Registry of All Cardiac and Vascular Disease (JROAD).

BACKGROUND: The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease.Methods and Results: This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD. CONCLUSIONS: Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.

Reinforcement of pimobendan with guideline-directed medical therapy may reduce the rehospitalization rates in patients with heart failure: retrospective cohort study.

BACKGROUND: Pimobendan reportedly improves the subjective symptoms of heart failure. However, evidence of improved prognosis is lacking. This study aimed to determine whether reinforcing guideline-directed medical therapy (GDMT) improved rehospitalization rates for worsening heart failure in patients administered pimobendan. METHODS: A total of 175 patients with heart failure who were urgently admitted to our hospital for worsening heart failure and who received pimobendan between January 2015 and February 2022 were included. Of the 175 patients, 44 were excluded because of in-hospital death at the time of pimobendan induction. The remaining 131 patients were divided into two groups, the reduced ejection fraction (rEF) (n = 93) and non-rEF (n = 38) groups, and further divided into the GDMT-reinforced and non-reinforced groups. RESULTS: In patients with rEF, the rate of rehospitalization for heart failure was significantly lower in the GDMT-reinforced group than in the non-reinforced group (log-rank test, P = .04). However, the same trend was not observed in the non-rEF group. CONCLUSIONS: Reinforcing GDMT may reduce the heart failure rehospitalization rate in patients with pimobendan administration and rEF. However, multicenter collaborative research is needed. TRIAL REGISTRATION: IRB Approval by the Nippon Medical School Hospital Ethics Committee B-2021-433 (April 10, 2023).

Impact of Red Blood Cell Transfusion on Subsequent Cardiovascular Events in Patients with Acute Heart Failure and Anemia.

Red blood cell (RBC) transfusion therapy is often performed in patients with acute heart failure (AHF) and anemia; however, its impact on subsequent cardiovascular events is unclear. We examined whether RBC transfusion influences major adverse cardiovascular events (MACE) after discharge in patients with AHF and anemia.We classified patients with AHF and anemia (nadir hemoglobin level < 10 g/dL) according to whether they received RBC transfusion during hospitalization. The endpoint was MACE (composite of all-cause death, non-fatal acute coronary syndrome/stroke, or heart failure readmission) 180 days after discharge. For survival analysis, we used propensity score matching analysis with the log-rank test. As sensitivity analysis, we performed inverse probability weighting analysis and multivariable Cox regression analysis.Among 448 patients with AHF and anemia (median age, 81 years; male, 55%), 155 received RBC transfusion and 293 did not. The transfused patients had worse clinical features than the non-transfused patients, with lower levels of nadir hemoglobin and serum albumin and a lower estimated glomerular filtration rate. In the propensity-matched cohort of 87 pairs, there was no significant difference in the MACE-free survival rate between the 2 groups (transfused, 73.8% vs. non-transfused, 65.3%; P = 0.317). This result was consistent in the inverse probability weighting analysis (transfused, 76.0% vs. non-transfused, 68.7%; P = 0.512), and RBC transfusion was not significantly associated with post-discharge MACE in the multivariable Cox regression analysis (adjusted hazard ratio: 1.468, 95% confidence interval: 0.976-2.207; P = 0.065).In conclusion, this study suggests that RBC transfusions for anemia may not improve clinical outcomes in patients with AHF.

Intima-Media Thickness in the Carotid Bifurcation is Related to Silent Brain Infarction: A Cross-Sectional Study.

AIMS: Carotid intima-media thickness (IMT) measurement is used to assess subclinical atherosclerosis. We aimed to examine the association between the maximum IMT by location and the occurrence of silent brain infarction (SBI). METHODS: Overall, 280 Japanese individuals (92 females, 52.6±5 years old) underwent a medical check-up at our hospital in Tokyo in 2015. Carotid IMT was measured at each site on ultrasound images (common carotid artery [CCA], internal carotid artery, or bifurcation). The risk factors for arterial dysfunction were evaluated. SBI was assessed using magnetic resonance imaging (MRI). The cross-sectional relationship between carotid maximum IMT and SBI was evaluated. RESULTS: Of the 280 individuals, 18 (6.4%) were diagnosed with SBI on MRI. The mean age of the SBI(-) and SBI(+) groups was 51.9±10.6 and 63.6±18.6 years, respectively. The correlation coefficients between the carotid maximum IMT at each location were very weak (correlation coefficient range: 0.180-0.253). The percentage of participants with SBI increased significantly with increasing maximum CCA and bIMT values. After adjusting for confounders, SBI was found to be significantly associated with the maximum bIMT (per 0.1-mm increase) (adjusted odds ratio [aOR], 1.10; 95% confidence interval [CI]: 1.03-1.17). When bIMT was categorized according to three groups (＜1.0 mm, 1.0-＜2.0 mm, and ≥ 2.0 mm), a significant SBI risk was also observed with an increase by each category of bIMT (aOR: 3.96, 95% CI: 1.63-9.52, P=0.002). CONCLUSION: The maximum bIMT was found to be the main determinant of SBI. A significant SBI risk was associated with an increase in each category of the maximum bIMT. Therefore, the maximum bIMT might be a useful predictor of future stroke in Japanese stroke-free medical check-up participants.

Fractional excretion of urea nitrogen can identify true worsening renal function in patients with heart failure.

AIMS: Fractional excretion of urea nitrogen (FEUN), used to differentiate the cause of acute kidney injury, has emerged as a useful fluid index in patients with heart failure (HF). We hypothesized that FEUN could be useful in identifying worsening renal function (WRF) associated with poor outcomes in patients with acute HF (AHF). METHODS AND RESULTS: Overall, 1103 patients with AHF (median age, 78 years; male proportion, 60%) were categorized into six groups according to the presence of WRF and FEUN values (low, ≤32.1%; medium, >32.1% and ≤38.0%; and high, >38.0%) at discharge. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level from admission to discharge. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). The cut-off values for low, medium, and high FEUN were based on a previous study. The primary outcome of this study was HF readmission after hospital discharge. During the 1 year follow-up, 170 HF readmissions occurred. Kaplan-Meier analysis revealed significantly higher HF readmission rates in patients with WRF than in those without WRF (log-rank test, P < 0.001). Additionally, among patients with WRF, HF readmission rates were lowest in those with medium FEUN values, followed by those with low FEUN values and those with high FEUN values. On multivariable analysis, the presence of WRF with low or high FEUN values was independently associated with increased HF readmission, as compared with the absence of WRF with medium FEUN values. Notably, no association was noted between WRF with medium FEUN values and HF readmission. CONCLUSIONS: The prognostic impact of WRF was significantly mediated by the FEUN values and was associated with worse outcomes only when the FEUN values were either low or high. Our study suggests that FEUN can identify prognostically relevant WRF in patients with AHF.

Efficacy of dotinurad in patients with severe renal dysfunction.

BACKGROUND: Although hyperuricemia is associated with the progression of chronic kidney disease (CKD), a reduction in CKD progression by uric acid (UA)-lowering therapy has been controversial. Recently, dotinurad, a uricosuric drug with selective urate reabsorption inhibitory properties, has been developed. However, its efficacy in lowering serum UA levels and its effects on renal function in patients with severe renal dysfunction are unclear. Thus, this study aimed to determine the effects of dotinurad on renal function in patients with severe renal dysfunction. METHODS: Data from 53 outpatients with hyperuricemia who newly received dotinurad between December 2020 and October 2022 were retrospectively analyzed. The mean baseline estimated glomerular filtration rate (eGFR) was 38.7 ± 17.0 mL/min/1.73 m2. The patients were divided into three groups based on their baseline eGFR: eGFR < 30 (n = 17), 30 ≤ eGFR < 45 (n = 17), and eGFR ≥ 45 (n = 19). RESULTS: The mean follow-up period was 9.8 ± 4.5 (range, 3-21) months. Serum UA levels significantly decreased in all groups. Although eGFR did not significantly change in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45 (P = 0.918 and P = 0.535, respectively), it improved significantly in patients with eGFR < 30 (P = 0.032). The proportion of patients with improved eGFR was significantly higher in patients with eGFR < 30 (P = 0.038) than in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45. In the multivariate logistic regression analysis, baseline eGFR < 30 and achieving a serum UA level of ≤ 6.0 mg/dL were significantly associated with improved eGFR (P = 0.033 and P = 0.015, respectively). CONCLUSIONS: Dotinurad may have UA-lowering effects and the potential to improve kidney function in patients with severe renal dysfunction.

Utility of fractional excretion of urea nitrogen in heart failure patients with chronic kidney disease.

AIMS: Maintenance of euvolaemia with diuretics is critical in heart failure (HF) patients with chronic kidney disease (CKD); however, it is challenging because no reliable marker of volume status exists. Fractional excretion of urea nitrogen (FEUN) is a useful index of volume status in patients with renal failure. We aimed to examine whether FEUN is a surrogate marker of volume status for risk stratification in HF patients with CKD. METHODS AND RESULTS: We examined 516 HF patients with CKD (defined as discharge estimated glomerular filtration rate < 60 mL/min/1.73 m2 ) whose FEUN was measured at discharge (median age, 80 years; 58% male). The patients were divided into four groups according to quartile FEUN value at discharge: low-FEUN, FEUN ≤ 32.1; medium-FEUN, 32.1 < FEUN ≤ 38.0; high-FEUN, 38.0 < FEUN ≤ 43.7; and extremely-high-FEUN, FEUN > 43.7. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). During the 3 year follow-up, 131 HF readmissions occurred. Kaplan-Meier analysis showed that the HF readmission rate was significantly lower in the medium-FEUN group than in the other three groups (log-rank test, P = 0.029). Multivariate Cox regression analysis identified the low-FEUN, high-FEUN, and extremely-high-FEUN values as independent factors associated with post-discharge HF readmission. In the analysis of 130 patients who underwent right heart catheterization during hospitalization, a significant correlation between FEUN value and right atrial pressure was observed (R = 0.243, P = 0.005). Multivariate linear regression analysis revealed that FEUN value at discharge decreased in a dose-dependent manner with loop diuretics. CONCLUSIONS: In HF patients with CKD, FEUN is a potential marker of volume status for risk stratification of post-discharge HF readmission. Low FEUN value (FEUN ≤ 32.1) may represent intravascular dehydration, whereas high FEUN value (FEUN > 38.0) may represent residual congestion; both of them were independent risk factors for HF readmission. FEUN may be useful to determine euvolaemia and guide fluid management in HF patients with CKD.

Effect of holiday admission for acute aortic dissection on in-hospital mortality in Japan: A nationwide study.

BACKGROUND: Patients admitted on weekends have higher mortality than those admitted on weekdays. However, whether the "weekend effect" results in a higher mortality after admission for acute aortic dissection (AAD),-classified according to Stanford types-remains unclear. This study aimed to examine the association between admission day and in-hospital mortality in AAD Type A and B. METHODS: We used data from the Japanese registry of all Cardiac and Vascular Diseases Diagnostic Procedure Combination, a nationwide claim-based database with data from 953 certified hospitals, and enrolled in-patients with AAD admitted between April 1, 2012, and March 31, 2016. Based on the admission day, we stratified patients into groups (Weekdays, Saturdays, and Sundays/holidays). The influence of the admission day on in-hospital mortality was assessed via multi-level logistic regression analysis. We also performed a Stanford type-based stratified analysis. RESULTS: Among the included 25,641 patients, in-hospital mortality was 16.0%. The prevalence of patients admitted with AAD was relatively higher on weekdays. After adjustment for covariates, patients admitted on a Sunday/holiday showed an increased risk of in-hospital mortality (odds ratio [OR] 1.20; 95% confidence interval [CI] 1.07-1.33, p<0.001) than patients admitted on weekdays. Among patients admitted on a Sunday/holiday, only the subgroup of Stanford Type A showed a significantly increased risk of in-hospital mortality. (Stanford Type A, non-surgery vs. surgery groups: 95% CI 1.06-1.48 vs. 1.17-1.68, p<0.001 for both groups, OR 1.25 vs. 1.41, respectively, Stanford Type B, non-surgery vs. surgery groups: 95% CI 0.64-1.09 vs. 0.40-2.10; p = 0.182 vs. 0.846; OR 0.84 vs. 0.92). CONCLUSIONS: In conclusion, patients with AAD Type A admitted on a Sunday/holiday may have an increased in-hospital mortality risk.

Non-cardiovascular disorders in a contemporary cardiovascular intensive care unit in Japan.

BACKGROUND: In the modern US cardiovascular intensive care unit (CICU), the incidence of non-cardiovascular disorders has increased and non-cardiovascular disorders are associated with an increase in morbidity and mortality. In Japan, however, data regarding the association between non-cardiovascular disorders and outcomes in the CICU are limited. METHODS: This study examined 490 consecutive admissions to a closed CICU at the Nippon Medical School Hospital from January to December 2017. Characteristics, diagnoses, treatments, and outcomes of admitted patients were identified. RESULTS: The most common primary diagnosis was acute coronary syndrome (50.4%), followed by acute heart failure (20.0%), arrhythmia (6.7%), and non-cardiovascular diseases (3.7%). The mortality rate and median length of stay (LOS) in the CICU were 4.7% and 4 (interquartile range, 2-8) days, respectively. Of all patients, 42.2% (n = 207) developed non-cardiovascular complications such as acute respiratory failure, acute kidney injury, or sepsis during CICU stay. Multivariate logistic regression analysis revealed that acute respiratory failure and sepsis were significantly associated with mortality in the CICU (odds ratio, 11.014 and 25.678, respectively; both p<0.05). The multiple linear regression analysis showed that acute kidney injury was significantly associated with LOS in the CICU (ß=0.144, p = 0.002). CONCLUSIONS: Approximately half of patients admitted to the CICU had non-cardiovascular disorders including non-cardiovascular disease and non-cardiovascular complications, which were significantly associated with mortality and LOS in the CICU.

Elevated C-reactive Protein Levels Independently Predict the Development of Prediabetes Markers in Subjects with Normal Glucose Regulation.

AIMS: Prediabetes is a precursor of diabetes and increases the risk of cardiovascular disease. Individuals with prediabetes reportedly have higher C-reactive protein levels, which is a risk factor for diabetes, relative to individuals with normal glucose regulation. Inflammation may play a role in the very early-phase deterioration of glucose metabolism, although there is insufficient knowledge regarding this relationship. Thus, we examined the association between serum C-reactive protein level and the development of three prediabetes markers. METHODS: This study included 743 subjects with normal glucose regulation at baseline who completed oral glucose tolerance tests at baseline and after approximately 5 years. Subjects with a history of cardiovascular disease were excluded. RESULTS: During the 5-year follow-up, 55 subjects developed isolated impaired glucose tolerance (IGT; 2h-plasma glucose levels of 7.8-11.0 mmol/L), 24 subjects developed isolated impaired fasting glucose (IFG; fasting plasma glucose levels of 6.1-7.0 mmol/L), 3 subjects developed IFG plus IGT, and 53 subjects developed isolated elevated glycated hemoglobin levels (HbA1c; level of 41-47 mmol/mol). The multivariate analysis revealed that, relative to the lowest quartile, the highest serum C-reactive protein quartile was independently associated with an increased risk of developing isolated elevated HbA1c levels (odds ratio: 2.95, 95% confidence interval: 1.16-7.51, P=0.024) and marginally associated with an increased risk of developing impaired glucose tolerance plus diabetes. However, C-reactive protein levels were not associated with an increased risk of developing IFG. CONCLUSIONS: Elevated serum C-reactive protein levels independently predicted elevated HbA1c levels, but not IFG.

Association between time of out-of-hospital cardiac arrest and survival: Examination of the all-Japan Utstein registry and comparison with the 2005 and 2010 international resuscitation guidelines.

BACKGROUND: Existing studies have yielded conflicting results regarding the relationship between the time of occurrence of out-of-hospital cardiac arrests and the associated outcomes. We examined whether the one-month survival rate for out-of-hospital cardiac arrests differed depending on whether the cardiac arrest occurred during the day or night. Further, we examined whether this rate differed when comparing the period succeeding the 2005 International Resuscitation Guidelines (2006-2010) with that following the 2010 guidelines (2011-2015). METHOD: Using data from the All-Japan Utstein Registry for 2006-2015, adult out-of-hospital cardiac arrest patients whose collapse was witnessed and for whom the collapse-to-hospital-arrival interval was shorter than 120 min were included in this study. Patients were categorized in terms of whether their arrest occurred during the post-2005- or post-2010-guideline period. The primary measure was the one-month survival with a favorable neurological outcome. RESULTS: Of 481,624 cases analyzed, 20% occurred at night. For both guideline periods, nighttime out-of-hospital cardiac arrests were associated with significantly lower one-month survival rates than daytime incidents (used as a reference; adjusted odds ratio: 0.69 and 0.63, 95% confidence interval: 0.65-0.73 and 0.60-0.65, and P < 0.001 and <0.001 for the 2005 and 2010 guideline periods, respectively). CONCLUSIONS: One-month survival with a favorable neurological outcome was significantly lower for patients who experienced nighttime out-of-hospital cardiac arrests, compared to daytime out-of-hospital cardiac arrests. This could be addressed by improving cardiopulmonary resuscitation training for bystanders and expanding and improving nighttime emergency medical services.

Nrf2 Lowers the Risk of Lung Injury via Modulating the Airway Innate Immune Response Induced by Diesel Exhaust in Mice.

In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2+/+ and Nrf2-/- mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2-/- mice compared with Nrf2+/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2+/+ mice and mild suppression of the level of TNF-α in Nrf2-/- mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2-/- mice than in Nrf2+/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2-/- mice than in Nrf2+/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2-/- mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2+/+ mice than in Nrf2-/- mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

Elevated cardio-ankle vascular index may be related to future stroke risk in Japanese subjects.

BACKGROUND: The cardio-ankle vascular index (CAVI) has been proposed as a useful parameter for arteriosclerotic diseases. However, whether it is associated with stroke risk in Japanese subjects remains unclear. METHODS: In total, 280 Japanese subjects (92 females, 52.6 ± 5 years old) underwent a medical check-up. CAVI value and risk factors for arterial dysfunction were evaluated; the predicted 10-year stroke risk was measured by the Japan Public Health Center study. RESULTS: Age, sex, body mass index, and systolic blood pressure were significant independent predictors of CAVI. CAVI values were significantly elevated in the high, compared with the medium-low and low predicted risk groups. A significant odds ratio (OR) for the high-risk group was noted in the highest quartile of CAVI values (OR, 14.67; 95% confidence interval [CI], 3.17-68.0), compared with the lowest quartile, after adjusting for potential confounders. A significant OR for very high predicted stroke risk was also found for each quartile increase (OR, 3.04; 95% CI, 1.87-4.94) and 1-standard deviation increase (OR, 2.24; 95% CI, 1.52-3.30) in CAVI value. CONCLUSION: Elevated CAVI values were related to an elevated predicted stroke risk, suggesting that CAVI could be a suitable surrogate marker for finding subjects at an increased risk of first-ever stroke.

Association Between Elevated C-Reactive Protein Levels and Prediabetes in Adults, Particularly Impaired Glucose Tolerance.

OBJECTIVES: Prediabetes is a precursor of diabetes and increases the risk for cardiovascular disease. A high C-reactive protein (CRP) level is a risk factor for diabetes, and individuals with prediabetes have higher CRP levels than those with normal glucose tolerance. In addition, systemic inflammation may play a role in the early-phase deterioration of glucose metabolism. We examined the association between serum CRP levels and prediabetes. METHODS: Overall, 4,101 subjects without diabetes underwent oral glucose tolerance tests. Levels of serum CRP were divided into quartiles; the lowest quartile was used as the reference when calculating odds ratios (ORs) and confidence intervals. Isolated fasting glucose, isolated glucose tolerance and elevated glycated hemoglobin levels (i.e. between 42 and 47 mmol/mol [6.0% to 6.4%]) were indicative of prediabetes. RESULTS: In the multiple logistic regression analysis, the ORs (95% confidence intervals) for impaired glucose tolerance, impaired fasting glucose and elevated glycated hemoglobin levels corresponding to the highest quartile of CRP levels were 1.67 (1.31 to 2.14); 1.62 (1.15 to 2.28); and 1.47 (1.14 to 1.90), respectively. In the stratified analysis, the ORs for impaired glucose tolerance were consistently higher in the uppermost quartile than in the reference quartile in both the presence and absence of hypertension or dyslipidemia. In contrast, the ORs for impaired fasting glucose in the uppermost quartile were higher only in the presence of hypertension and dyslipidemia, and the OR for elevated glycated hemoglobin levels in the uppermost quartile was higher only in the presence of hypertension. CONCLUSIONS: Elevated serum CRP levels are associated with prediabetes, particularly impaired glucose tolerance.

Postprandial Hyperchylomicronemia and Thin-Cap Fibroatheroma in Nonculprit Lesions.

Objective- Although postprandial hypertriglyceridemia can be a risk factor for coronary artery disease, the extent of its significance remains unknown. This study aimed to investigate the correlation between the postprandial lipid profiles rigorously estimated with the meal tolerance test and the presence of lipid-rich plaque, such as thin-cap fibroatheroma (TCFA), in the nonculprit lesion. Approach and Results- A total of 30 patients with stable coronary artery disease who underwent a multivessel examination using optical coherence tomography during catheter intervention for the culprit lesion were enrolled. Patients were divided into 2 groups: patients with TCFA (fibrous cap thickness ≤65 µm) in the nonculprit lesion and those without TCFA. Serum remnant-like particle-cholesterol and ApoB-48 (apolipoprotein B-48) levels were measured during the meal tolerance test. The value of remnant-like particle-cholesterol was significantly greater in the TCFA group than in the non-TCFA group ( P=0.045). Although the baseline ApoB-48 level was similar, the increase in the ApoB-48 level was significantly higher in the TCFA group than in the non-TCFA group ( P=0.028). In addition, the baseline apolipoprotein C-III levels was significantly greater in the TCFA group ( P=0.003). These indexes were independent predictors of the presence of TCFA (ΔApoB-48: odds ratio, 1.608; 95% confidence interval, 1.040-2.486; P=0.032; apolipoprotein C-III: odds ratio, 2.581; 95% confidence interval, 1.177-5.661; P=0.018). Conclusions- Postprandial hyperchylomicronemia correlates with the presence of TCFA in the nonculprit lesion and may be a residual risk factor for coronary artery disease.

Basal-Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study.

INTRODUCTION: Although reduction in the incidence of nocturnal hypoglycemia, as estimated by symptom or self-monitored plasma glucose, was shown to be more pronounced with 300 units/mL insulin glargine (Gla-300) than with 100 units/mL insulin glargine (Gla-100) in type 2 diabetes patients, the exact frequency of nocturnal hypoglycemia estimated with continuous glucose monitoring (CGM) has not been reported. METHODS: Forty patients with type 2 diabetes who were admitted for glycemic control with basal-bolus insulin therapy (BBT) were randomized into the Gla-100 and Gla-300 groups. Insulin doses were adjusted to maintain blood glucose levels within 100-120 mg/dL at each meal. Plasma glucose and C-peptide profiles were estimated serially after admission and before discharge. Daily CGM was also performed before discharge. RESULTS: In the Gla-100 and Gla-300 groups, the mean duration of hospitalization was 15 ± 2 and 15 ± 1 days, respectively, and the mean basal insulin dose before discharge was 13 ± 7 and 15 ± 10 units, respectively. The dose of meal-time insulin was not different between the two groups. Compared with the Gla-300 group, the Gla-100 group had significantly lower nocturnal profiles of plasma glucose and C-peptide, but significantly higher frequency of CGM-estimated nocturnal hypoglycemia (10.7% ± 18.4% versus 1.2% ± 3.6%, P = 0.033). CONCLUSION: In type 2 diabetic patients, reduction in the incidence of CGM-estimated nocturnal hypoglycemia by BBT under tightly controlled diet therapy was higher with Gla-300 than with Gla-100. TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000023360).

Effect of Glycemic Control on Chylomicron Metabolism and Correlation between Postprandial Metabolism of Plasma Glucose and Chylomicron in Patients with Type 2 Diabetes Treated with Basal-bolus Insulin Therapy with or without Vildagliptin.

AIM: Glucagon-like peptide-1 can reduce both postprandial plasma glucose (PG) and chylomicron (CM) levels in patients with type 2 diabetes. However, there have been no reports regarding the relationship between the postprandial metabolism of PG and CM. METHODS: Patients with type 2 diabetes who were admitted for glycemic control were randomized to insulin alone (Ins; n=16) or insulin plus vildagliptin 100 mg (InsV; n=16) groups. The insulin dose was adjusted to maintain normal blood glucose levels. The daily profiles of serum TG, remnant lipoprotein cholesterol (RemL-C), and apolipoprotein B48 (ApoB48) were estimated by frequent blood collection on admission and before discharge, and the daily glucose fluctuation profile was also estimated using continuous glucose monitoring (CGM) before discharge. RESULTS: The daily profiles of serum TG and RemL-C indicated a significant decrease before discharge compared with on admission; however, no significant changes in serum ApoB48 levels were observed in either group. At discharge, daily glucose fluctuation profile and the change in the serum ApoB48 level from fasting to the peak of the daily profile was significantly smaller in the InsV group than in the Ins group. The increment of serum ApoB48 level was significantly correlated with the mean amplitude of glycemic excursions calculated using CGM data only in the Ins group (R2= 0.5242,P＜0.001). CONCLUSIONS: Short-term glycemic control decreased serum TG and RemL-C levels, but not ApoB48 levels, and the postprandial metabolism of PG and CM might be regulated by the same mechanism except GLP-1 effect.

Left ventricular stiffness estimated by diastolic wall strain is associated with paroxysmal atrial fibrillation in structurally normal hearts.

BACKGROUND: Left ventricular (LV) diastolic dysfunction depends on an impaired relaxation and stiffness. Abnormal LV relaxation contributes to the development of atrial fibrillation (AF), but the role of LV stiffness in AF remains unclear. HYPOTHESIS: Diastolic wall strain (DWS), a load-independent, noninvasive direct measure of LV stiffness, correlates with prevalent AF. METHODS: This study included 328 consecutive subjects with structurally normal hearts: 164 paroxysmal AF patients and 164 age- and sex-matched (1:1) controls. We calculated the DWS from the M-mode echocardiographic measurements of the LV posterior wall thickness at end-systole and end-diastole during sinus rhythm. RESULTS: The DWS was lower in the AF patients (0.35 ± 0.07) than in the controls (0.41 ± 0.06; P < 0.001). After adjusting for the risk factors of AF using a conditional logistic regression analysis, a history of hypertension, plasma brain-type natriuretic peptide level, and DWS were independently associated with AF prevalence, whereas body mass index, LV mass index, left atrial volume, and any conventional indices of the diastolic function were not. A low DWS (<0.380) was the strongest indicator of AF (odds ratio: 6.22, 95% confidence interval: 3.08-14.2, P < 0.001). CONCLUSIONS: Increased LV stiffness estimated by DWS was a strong determinant of the prevalence of AF. LV stiffness may play a role in the pathogenesis of paroxysmal AF in structurally normal hearts.

Blunted renal vasoconstriction in patients with subclinical contrast-induced renal injury.

Contrast media are considered to cause acute kidney injury by activating various factors that induce renal vasoconstriction. We analysed the renal microvascular haemodynamic response using the Doppler flow wire method. Then changes in urinary liver-type fatty acid-binding protein levels following contrast medium administration were compared between groups with or without a micro-injury of the kidney. In the group without renal micro-injury, the average peak velocity (APV) decreased significantly, whereas the renal artery resistance index (RI) increased significantly following contrast medium administration. In contrast, there was no significant change in either the APV or RI in the group with a renal micro-injury. A blunted microvascular response was found in the micro-injury group, whereas microvascular resistance increased in the non-micro-injury group.

Impact of Diabetic Retinopathy on Vulnerability of Atherosclerotic Coronary Plaque and Incidence of Acute Coronary Syndrome.

Although an association has been reported between the microvascular complications of diabetic patients and their poor prognosis after cardiovascular events related to advanced atherosclerosis, it is not clear whether there is a relation between diabetic retinopathy (DR) and the severity of plaque vulnerability. Fifty-seven diabetic patients with coronary artery disease, classified as non-DR (n = 42) or DR (n = 15), underwent angioscopic observation of at least 1 entire coronary artery. The number of yellow plaques (NYP) through the observed coronary artery was counted and their color grades, defined as 1 (light yellow), 2 (yellow), or 3 (intense yellow), were evaluated. The NYP per vessel and the maximum yellow grade were determined. The association between the presence of DR and incidences of acute coronary syndrome (ACS) was analyzed during the follow-up period (mean 7.1 ± 3.3 years; range, 0.83 to 11.75 years). Mean NYP per vessel and maximum yellow grade were significantly greater in DR than in non-DR patients (2.08 ± 1.01 vs 1.26 ± 0.77, p = 0.002, and 2.40 ± 0.74 vs 1.90 ± 0.82, p = 0.044, respectively). The cumulative incidences of ACS were higher in the DR group (p = 0.004), and the age-adjusted hazard ratio for ACS was 6.943 (95% CI 1.267 to 38.054; p = 0.026) for DR compared with non-DR patients. Our findings indicate that coronary atherosclerosis and plaque vulnerability are more severe in patients with DR. DR as a microvascular complication may be directly linked with macrovascular plaque vulnerability and fatal cardiovascular events such as ACS.