Cognitive function in post-cardiac intensive care: patient characteristics and impact of multidisciplinary cardiac rehabilitation.

New/worsening cognitive and physical impairments following critical care pose significant problems. Multidisciplinary cardiac rehabilitation (CR) can improve physical function after cardiac intensive care (CIC). This observational study aimed to evaluate cognitive function in patients participating in multidisciplinary CR and to identify correlates of impaired cognitive function after CIC. We analyzed 111 consecutive patients admitted to our comprehensive care ward at least 7 days after CIC and assessed factors associated with cognitive function using the Functional Independence Measure (FIM). Patients were stratified into two groups based on the median FIM-Cognitive scores: impaired (n = 56) and preserved cognition (n = 55) groups. Multiple logistic regression analysis identified age [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.00-1.13; p = 0.042], Mini-Nutrition Assessment-Short Form (MNA-SF; OR 0.73; 95% CI 0.56-0.95; p = 0.017), and FIM-Physical scores (OR: 0.94; 95% CI 0.90-0.99; p = 0.012) as significant and independent factors associated with impaired cognition. The median length of hospital stay was 28 (interquartile range: 18, 43) days. The FIM-Cognitive and FIM-Physical scores significantly increased from admission to discharge [32.0 (27.0, 35.0) vs. 34.0 (29.0, 35.0) points; p < 0.001; 67.0 (53.0, 75.0) vs. 85.0 (73.5, 89.0) points; p < 0.001, respectively]. On subgroup analysis within the impaired cognition group, increased FIM-Cognitive scores positively and significantly correlated with increased FIM-Physical scores (ρ = 0.450; p = 0.001). Multiple linear regression analysis identified atrial fibrillation (AF; ß = - 0.29; p = 0.016), ln(glycated hemoglobin; HbA1c) (ß = 0.29; p = 0.018), and ln(high-sensitivity C-reactive protein; hs-CRP) (ß = - 0.26; p = 0.034) as significant and independent factors correlated with increased FIM-Cognitive scores. In conclusion, advanced age, low MNA-SF score, and FIM-Physical score were independent factors associated with impaired cognition in post-CIC patients. Multidisciplinary CR improved both physical and cognitive functions, and AF, HbA1c, and hs-CRP were independent factors correlated with increased FIM-Cognitive score.

Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study.

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.

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. METHODS: The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period. DISCUSSION: EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).

Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction.

BACKGROUND: Several studies have reported that colchicine attenuated the infarct size and inflammation in acute myocardial infarction (MI). However, the sustained benefit of colchicine administration on survival and cardiac function after MI is unknown. It was hypothesized that the short-term treatment with colchicine could improve survival and cardiac function during the recovery phase of MI.Methods and Results:MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then orally administered colchicine 0.1 mg/kg/day or vehicle from 1 h to day 7 after MI. Colchicine significantly improved survival rate (colchicine, n=48: 89.6% vs. vehicle, n=51: 70.6%, P<0.01), left ventricular end-diastolic diameter (5.0±0.2 vs. 5.6±0.2 mm, P<0.05) and ejection fraction (41.5±2.1 vs. 23.8±3.1%, P<0.001), as assessed by echocardiogram compared with vehicle at 4 weeks after MI. Heart failure development as pulmonary edema assessed by wet/dry lung weight ratio (5.0±0.1 vs. 5.5±0.2, P<0.01) and B-type natriuretic peptide expression in the heart was attenuated in the colchicine group at 4 weeks after MI. Histological and gene expression analysis revealed colchicine significantly inhibited the infiltration of neutrophils and macrophages, and attenuated the mRNA expression of pro-inflammatory cytokines and NLRP3 inflammasome components in the infarcted myocardium at 24 h after MI. CONCLUSIONS: Short-term treatment with colchicine successfully attenuated pro-inflammatory cytokines and NLRP3 inflammasome, and improved cardiac function, heart failure, and survival after MI.

Low-Normal Serum Sodium and Heart Failure-Related Events in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Hyponatremia has been shown to be a prognostic factor in heart failure (HF) with preserved ejection fraction (HFpEF). Serum sodium (sNa) cut-off, however, is not defined in HFpEF. Therefore, we investigated the relationship between sNa and HF-related events (cardiovascular death and hospitalization for HF decompensation) in HFpEF patients. METHODS AND RESULTS: We assessed cardiac function using echocardiography and measured sNa in HFpEF patients with New York Heart Association class II (n=321) or III (n=84) in a compensated condition after implementing medical therapy for HF. During a mean follow-up of 27 months, 73 patients developed HF-related events. On multivariate Cox hazard analysis including established predictors in HF, sNa level as a continuous variable was identified as an independent predictor for HF-related events in HFpEF (per 1.0 mmol/L: HR, 0.93; 95% CI: 0.87-0.98; P<0.01). Kaplan-Meier analysis demonstrated significantly higher probability of HF-related events in the lower sNa group (sNa <140 mmol/L) than in the higher sNa group (sNa ≥140 mmol/L; P<0.001, log-rank test). Further, the low-normal sNa group (135 mmol/L

Prognostic Significance of Peripheral Microvascular Endothelial Dysfunction in Heart Failure With Reduced Left Ventricular Ejection Fraction.

BACKGROUND: Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODS AND RESULTS: The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695). CONCLUSIONS: Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.

A pilot study of ezetimibe vs. atorvastatin for improving peripheral microvascular endothelial function in stable patients with type 2 diabetes mellitus.

BACKGROUND: Elevated cholesterol in type 2 diabetes mellitus (DM) can cause endothelial dysfunction. An effective clinical therapy to improve endothelial dysfunction remains to be established. Different cardiovascular actions between treatments for the inhibition of cholesterol absorption and the suppression of cholesterol synthesis for achieving improvement in endothelial function are unknown in DM. METHODS: Stable patients with type 2 DM and mildly elevated low-density lipoprotein cholesterol were enrolled. We evaluated peripheral microvascular endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT) examination and calculated a natural logarithmic transformed value for the RH-PAT index (LnRHI). We randomly assigned 33 patients to each monotherapy: cholesterol synthesis suppression using atorvastatin (5 mg/day, n=16) or cholesterol absorption inhibition using ezetimibe (10 mg/day, n=17). Patients were prospectively followed for 6 months. Serum lipids and LnRHI were repeatedly examined before and after each therapy. RESULTS: LDL significantly decreased in both groups, but the percent changes of LDL showed a greater decrease in the atorvastatin group compared with the ezetimibe group (-34.5±7.8% vs. -21.9±9.6%, p<0.01). Serum levels of non-esterified free fatty acids (NEFA) significantly decreased in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 561.1±236.8 to 429.7±195.9, p<0.01; atorvastatin group: 538.8±319.5 to 520.2±227.3, p=0.75). The percent decrease in NEFA was significantly greater in the ezetimibe group compared with the atorvastatin group (-19.9±27.4% vs. 11.3±44.1%, p<0.05). LnRHI showed a significant increase in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 0.471±0.157 to 0.678±0.187, p<0.01; atorvastatin group: 0.552±0.084 to 0.558±0.202, p=0.64). The percent changes in LnRHI were significantly greater in the ezetimibe group compared with the atorvastatin group (63.3±89.2% vs. 7.4±41.2%, p<0.05). CONCLUSIONS: In patients with type 2 DM, ezetimibe monotherapy significantly reduced LDL and NEFA, and improved peripheral microvascular endothelial dysfunction. Ezetimibe could potentially exhibit beneficial effects on lipid disorders and microvascular endothelial dysfunction in DM.

Differences between rosuvastatin and atorvastatin in lipid-lowering action and effect on glucose metabolism in Japanese hypercholesterolemic patients with concurrent diabetes. Lipid-lowering with highly potent statins in hyperlipidemia with type 2 diabetes patients (LISTEN) study ­.

BACKGROUND: Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM). METHODS AND RESULTS: The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group. CONCLUSIONS: Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels.

Utility of noninvasive endothelial function test for prediction of deep vein thrombosis after total hip or knee arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) is a common and sometimes lethal postoperative complication of arthroplasty. Endothelial dysfunction is important in the pathogenesis of thrombus formation. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) can noninvasively evaluate endothelial function. This study investigated the predictive value of RH-PAT for deep vein thrombosis (DVT) after lower limb arthroplasty. METHODS AND RESULTS: A prospective observational study of 126 osteoarthritic patients who underwent total knee arthroplasty (TKA) or hip arthroplasty (THA) was conducted. The RH-PAT index (RHI) was measured on the day before surgery, and presence of DVT was checked by ultrasonography or phlebography before and after surgery. Following arthroplasty, DVT was diagnosed in 51 patients (40.5%). RHI in the DVT group (0.58±0.25) was significantly lower than in the non-DVT group (0.71±0.25, P=0.004). RHI was a significant and independent predictor of postoperative DVT in multivariate logistic regression analyses and improved a net reclassification index (23.8%, P=0.022). Subgroup analyses according to operation site with adjustment for Qthrombosis score demonstrated that RHI significantly predicted postoperative DVT in the THA group (odds ratio per 0.1, 0.77; 95% confidence interval 0.60-0.98; P=0.03), but did not reach statistical significance in the TKA group. CONCLUSIONS: Low RHI was significantly associated with DVT after lower limb arthroplasty. Endothelial dysfunction, as assessed by RH-PAT, is potentially useful for identifying patients at high risk for VTE especially after THA.

Intravascular ultrasound morphology of culprit lesions and clinical demographics in patients with acute coronary syndrome in relation to low-density lipoprotein cholesterol levels at onset.

Despite current standards of care aimed at achieving targets for low-density lipoprotein cholesterol (LDL-C), many patients remain at high residual risk of cardiovascular events. We sought to assess the LDL-C-dependent differences in culprit intravascular ultrasound (IVUS) morphologies and clinical characteristics in patients with acute coronary syndrome (ACS). Eighty-six consecutive ACS patients whose culprit lesions imaged by preintervention IVUS were divided into two groups based on the fasting LDL-C level on admission: a low-LDL-C group (LDL-C <2.6 mmol/l, n = 45) and a high-LDL-C group (LDL-C ≥2.6 mmol/l, n = 41). Patients with stable angina with LDL-C <2.6 mmol/l (n = 30) were also enrolled as an age- and gender-matched control. The low-LDL-C ACS group was significantly older (72 ± 12 vs 64 ± 14 years, P = 0.007) and more diabetic (47 % vs 15 %, P = 0.001). Importantly, IVUS morphologies were comparable between low- and high-LDL-C ACS groups (all P not significant), whereas culprit plaque was more hypoechoic and less calcified in the low-LDL-C ACS group than in the low-LDL-C stable angina group. Furthermore, compared with the low-LDL-C ACS nondiabetic group, the low-LDL-C ACS diabetic group was more obese, more triglyceride rich (1.3 ± 0.6 vs 0.9 ± 0.4 mmol/l, P = 0.003), and more endothelially injured, but no different for the culprit IVUS morphologies. In multivariate analysis, diabetes was independently associated with a low LDL-C level on admission in patients with ACS. There was no relationship between the LDL-C level at onset and culprit-plaque IVUS morphologies in ACS patients, although culprit plaque in the low-LDL-C ACS group was more vulnerable than in the low-LDL-C stable angina group. In patients with low-LDL-C levels, diabetes with atherogenic dyslipidemia might be the key residual risk.

Growth differentiation factor 15 can distinguish between hypertrophic cardiomyopathy and hypertensive hearts.

To distinguish hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) based on a morphological examination is often challenging. Growth differentiation factor 15 (GDF-15) is a novel diagnostic and prognostic biomarker for several cardiovascular diseases. In patients with LVH, GDF-15 promises to be a useful biomarker to distinguish between HCM and H-LVH. We evaluated 93 patients with H-LVH, 28 with HCM, and 28 disease control individuals. Serum GDF-15 concentrations were measured with an enzyme-linked immunosorbent assay. Circulating GDF-15 levels were significantly higher in patients with H-LVH than with HCM (P = 0.003). On the other hand, values for plasma B-type natriuretic peptide (BNP) levels were significantly lower in patients with H-LVH than with HCM (P = 0.004). Serum GDF-15 and plasma BNP levels positively correlated in patients with H-LVH but not with HCM. Multivariate logistic regression analysis revealed GDF-15 (odds ratio 12.06, confidence interval 1.85-78.77, P < 0.01) as an independent predictor of H-LVH among patients with LVH. In receiver-operating characteristic analysis, GDF-15 achieved an area under the curve of 0.70 for the identification of H-LVH. We found that GDF-15 might be a useful biomarker for discriminating HCM from H-LVH. Understanding serum GDF-15 values may have clinical utility for patients with LVH because the therapeutic strategies for treating HCM and H-LVH differ.

Neointimal tissue component assessed by tissue characterization with 40 MHz intravascular ultrasound imaging: comparison of drug-eluting stents and bare-metal stents.

OBJECTIVES: The present study used iMap IVUS system to compare neointimal tissue components between DES and bare-metal stents (BMSs). BACKGROUND: Drug-eluting stents (DESs) can cause impaired arterial healing, which constitutes the most important pathological substrate underlying late DES thrombosis. Intravascular ultrasound (IVUS)-based tissue characterization allows for the in vivo identification of neointimal tissue components. METHODS AND RESULTS: Follow-up IVUS data after coronary stenting (9.8 ± 9.4 months from index procedures) was obtained from consecutive 61 lesions (34 in DES, 27 in BMS). The iMap tissue components (fibrotic, lipidic, necrotic, and calcified) were measured in every recorded frame and expressed as percentages of mean neointimal cross-sectional area for the stented segment. Patients' characteristics were comparable between DES and BMS. When compared with BMSs, smaller (2.9 ± 0.4 mm vs. 3.2 ± 0.4 mm, P = 0.004) and longer (34 ± 18 mm vs. 26 ± 14 mm, P = 0.03) DESs were implanted. When compared with BMS group, minimum lumen area at follow-up was significantly greater in DES group (3.9 ± 1.8 mm(2) vs. 3.1 ± 1.5 mm(2) , P < 0.04), mainly attributable to suppression of neointimal hyperplasia (1.7 ± 0.8 mm(2) vs. 3.1 ± 1.5 mm(2) , P < 0.0001). The iMap analyses showed that neointima after DES placement was composed of smaller fibrotic component (67 ± 8% vs. 78 ± 7%, P < 0.0001), larger necrotic (14 ± 4% vs. 9 ± 3%, P < 0.0001) and calcified (15 ± 6% vs. 7 ± 4%, P < 0.0001) components compared with BMS. Logistic regression analysis showed that only intra-DES neointima was a significant predictor of necrotic neointima at follow-up. CONCLUSIONS: DES implantation would be associated with iMap-derived necrotic and less-fibrotic neointimal formation. In vivo iMap evaluation of neointimal tissue may provide useful information in detecting impaired healing after stenting.

Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes.

BACKGROUND: Dipeptidyl peptidase 4 (DPP4) inhibitors are used for treatment of diabetes mellitus (DM). We hypothesized that sitagliptin, a DPP4-inhibitor, could improve endothelial dysfunction in DM patients with coronary artery disease (CAD). METHODS AND RESULTS: The 40 patients with CAD and uncontrolled DM, aged 68.7±9.4 years (mean±standard deviation) (50% males, hemoglobin A1c [HbA1c] 7.4±1.0%) were assigned to either additional treatment with sitagliptin (50 mg/day, n=20) or aggressive conventional treatment (control, n=20) for 6 months. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry index (RHI). The clinical characteristics at baseline were not different between the groups. After treatment, fasting blood glucose and insulin levels, and lipid profiles were not different between the groups. HbA1c levels significantly improved similarly in both groups. The percent change in RHI was greater in the sitagliptin group than in the control group (62.4±59.2% vs. 15.9±22.0%, P<0.01). Furthermore, treatment with sitagliptin resulted in a significant decrease in the high-sensitivity C-reactive protein (hsCRP) level, but no such change was noted in the control group. Linear regression analysis demonstrated a significant negative relation between changes in RHI and hsCRP, but not between RHI and HbA1c. CONCLUSIONS: Sitagliptin significantly improved endothelial function and inflammatory state in patients with CAD and uncontrolled DM, beyond its hypoglycemic action. These findings suggest that sitagliptin has beneficial effects on the cardiovascular system in DM patients.

Effect of low-dose aspirin on primary prevention of cardiovascular events in Japanese diabetic patients at high risk.

BACKGROUND: Benefit of low-dose aspirin for primary prevention of cardiovascular events in diabetes remains controversial. The American Diabetes Association (ADA), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) recommend aspirin for high-risk diabetic patients: older patients with additional cardiovascular risk factors. We evaluated aspirin's benefit in Japanese diabetic patients stratified by cardiovascular risk. METHODS AND RESULTS: In the JPAD trial, we enrolled 2,539 Japanese patients with type 2 diabetes and no history of cardiovascular disease. We randomly assigned them to aspirin (81-100 mg daily) or no aspirin groups. The median follow-up period was 4.4 years. We stratified the patients into high-risk or low-risk groups, according to the US recommendation: age (older; younger) and coexisting cardiovascular risk factors. The risk factors included smoking, hypertension, dyslipidemia, family history of coronary artery disease, and proteinuria. Most of the patients were classified into the high-risk group, consisting of older patients with risk factors (n=1,804). The incidence of cardiovascular events was higher in this group, but aspirin did not reduce cardiovascular events (hazard ratio [HR], 0.83; 95% confidence interval [CI]: 0.58-1.17). In the low-risk group, consisting of older patients without risk factors and younger patients (n=728), aspirin did not reduce cardiovascular events (HR, 0.55; 95% CI: 0.23-1.21). These results were unchanged after adjusting for potential confounding factors. CONCLUSIONS: Low-dose aspirin is not beneficial in Japanese diabetic patients at high risk.

Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients.

BACKGROUND: Simple office-based counseling for diet and exercise does not appear to positively affect success rates in metabolic syndrome (MetS) patients. The utility of the lifestyle modification self-assessment score (Self-AS) in the improvement of endothelial function by office-based counseling for patients with MetS was investigated. METHODS AND RESULTS: Patients with MetS (n=207) and age- and sex-matched individuals without MetS (n=124) were enrolled in this cross-sectional study. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI). Patients with MetS had significant endothelial dysfunction compared with those without MetS (RHI, 0.502±0.178 vs. 0.614±0.229; P<0.001). Seventy MetS patients participating in the prospective interventional study received simple office-based lifestyle modification counseling that was accompanied by Self-AS questionnaire after 10 months. RHI was significantly improved following lifestyle modifications (from 0.452±0.136 to 0.547±0.202, P<0.001). Reductions in waist circumference (R(2)=0.094, P=0.01) and increased high-density lipoprotein cholesterol (R(2)=0.227, P<0.001) independently correlated with improved RHI. Self-AS significantly correlated with changes in waist circumference (r=-0.57, P<0.001) and RHI (r=0.30, P=0.02). Patients with a good achievement of lifestyle modifications (higher Self-AS) had significant improvement in endothelial function compared with those with lower scores (% change in RHI, +48.7±61.6 vs. +7.8±35.1, P=0.001). CONCLUSIONS: Good achievement of lifestyle modifications as evaluated on Self-AS significantly improved endothelial function with concomitant reductions in waist circumferences in MetS patients.

Reduced Number of Remaining or Healthy Teeth in Patients with Type 2 Diabetes Mellitus: A Cross-sectional Study Assessed by Dentists or Dental Hygienists in Japan.

Objective This study assessed the relationships between oral health (number of remaining and healthy teeth and periodontal disease) and type 2 diabetes mellitus (T2DM) to contribute to improved patient care. Patients We conducted a cross-sectional cohort study of consecutive patients being regularly treated for chronic diseases (T2DM, hypertension, and dyslipidemia). A dentist or dental hygienist accurately evaluated the oral environment. Patients with fewer than 20 teeth were classified as having reduced remaining teeth (RRT). Results A total of 267 patients were enrolled, including 153 patients (57%) with T2DM and 114 without (43%). Patients with T2DM had 3 fewer remaining teeth on average than those without DM [median: 22 (interquartile range (IQR): 11-27) vs. median: 25 (IQR: 17.3-28), p=0.02]. In addition, patients with T2DM had 4 fewer healthy teeth on average than those without DM [median: 8 (IQR: 2.8-15) vs. median: 12 (IQR: 6-16), p=0.02]. The frequency of RRT was higher in the T2DM group (n=63; 41%) than in the non-DM group (n=31; 27%, p=0.02). Multivariable logistic regression for the presence of RRT in the T2DM group found that age [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.03-1.13; p<0.01] and regular dental consultations (OR, 0.28; 95% CI, 0.10-0.76; p=0.01) were independently and significantly associated. Conclusion The number of remaining or healthy teeth was significantly lower in patients with T2DM than in those without T2DM in current Japanese clinical practice. Regular dental consultation is recommended to preserve remaining teeth in patients with T2DM.

Passive exercise using whole-body periodic acceleration enhances blood supply to ischemic hindlimb.

OBJECTIVE: Whole-body periodic acceleration (WBPA) has been developed as a passive exercise technique to improve endothelial function by increasing shear stress through repetitive movements in spinal axis direction. We investigated the effects of WBPA on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease. METHODS AND RESULTS: After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice, suggesting that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease. CONCLUSIONS: WBPA increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle. WBPA is a potentially suitable noninvasive intervention to facilitate therapeutic angiogenesis.

Significance of coronary vasospasm in the perioperative management of non-cardiac surgery.

BACKGROUND: The number of patients undergoing non-cardiac surgery has been increasing. Thus, the reduction of cardiac events is important during the perioperative period. The prevalence of Japanese patients with coronary vasospasm is higher as compared with Western countries. The present study reported the role of coronary vasospasm in the perioperative period in a Japanese university hospital. METHODS AND RESULTS: A total of 77,745 consecutive patients who underwent non-cardiac surgery in Kumamoto University Hospital between April 2003 and March 2010 were retrospectively examined. Forty-two cases in which patients underwent coronary catheterization due to cardiovascular events in the perioperative period were reviewed, and data were collected on the type of surgery, urgency of surgery, cardiac risk factors, previous history and the cardiology consultation. The Revised Cardiac Risk Index (RCRI) was also calculated. A total of 18 patients were diagnosed as having definite vasospastic angina. In the definite vasospastic angina group, 9 patients had cardiovascular events intraoperatively. Six patients were in the group undergoing high-risk surgery. The RCRI score in the definite vasospastic angina group was 0.5±0.6 (mean±SEM), and only 2 patients had a preoperative consultation with a cardiologist. CONCLUSIONS: Coronary vasospasm is not often encountered, but it can be a cause of cardiac trouble in the perioperative period. It should be taken into consideration at the time of planning of operation in Japanese patients even if they apparently have low cardiac risk.

Aspirin reduces cerebrovascular events in type 2 diabetic patients with poorly controlled blood pressure. Subanalysis from the JPAD trial.

BACKGROUND: There are few data that demonstrate a significant effect of aspirin therapy for diabetic patients. To clarify the effect of the primary prevention of aspirin therapy in diabetic patients, the relationship between blood pressure (BP) and the incidence of atherosclerotic events was investigated in participants in the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial. METHODS AND RESULTS: We divided the JPAD participants according to their systolic (SBP) and diastolic (DBP) BPs at enrollment (SBP ≥140 mmHg and/or DBP ≥90 mmHg: unattained group, SBP <140 mmHg and DBP <90 mmHg: attained group). The incidence of the primary atherosclerotic events, especially cerebrovascular events, was higher in the unattained group than in the attained group. The incidence of cerebrovascular events was higher in the unattained group than in the attained group in patients without aspirin therapy; however, the incidence of cerebrovascular events in the unattained group was as low as the incidence in the attained group in patients undergoing aspirin therapy. Cox proportional hazards analysis revealed that BP level was an independent predictor for cerebrovascular events in diabetic patients. CONCLUSIONS: Aspirin therapy may reduce cerebrovascular events in diabetic patients with higher BP. Aspirin therapy could be an additional strategy as primary prevention for diabetic patients with higher BP.

Potential Identification of Type 2 Diabetes with Elevated Insulin Clearance.

BACKGROUND: Decreased blood insulin concentrations resulting from reduced pancreatic ß-cell insulin secretion and elevated insulin clearance (IC) could be involved in impaired glucose metabolism in diabetes. Recently, we reported a patient with type 2 diabetes mellitus (T2DM) who had decreased blood insulin concentrations and elevated IC. METHODS: For this study, we recruited patients with newly diagnosed, treatment-naïve T2DM and measured the metabolic clearance rate of insulin (MCRI) determined by a hyperinsulinemic-euglycemic clamp examination. We defined elevated IC as an MCRI of more than 700 ml/min/m2. Using this tentative cutoff, we identified patients with T2DM with elevated IC and investigated their clinical characteristics. RESULTS: We enrolled 101 patients in this study; 78.2% were men. Patients had a mean age of 54.1 years, a median body-mass index (BMI) of 25.1 kg/m2 (interquartile range [IQR], 22.9 to 28.4 kg/m2), a median hemoglobin A1c of 10.0% (IQR, 8.0 to 12.3%), and a median MCRI of 655 ml/min/m2 (IQR, 562 to 810 ml/min/m2). Our case definition for elevated IC was met by 44 patients whose median MCRI was 842 ml/min/m2 (IQR, 747 to 975 ml/min/m2) compared with those without elevated IC (570 ml/min/m2; IQR, 500 to 628 ml/min/m2). On the basis of this division, fasting blood glucose and insulin levels were 178 mg/dl (IQR, 140 to 218 mg/dl) and 4.2 mU/l (IQR, 2.7 to 5.5 mU/l), respectively, in patients with elevated IC compared with 146 mg/dl (IQR, 128 to 188 mg/dl) and 9.6 mU/l (IQR, 6.6 to 14.9 mU/l), respectively, in patients without elevated IC. The BMI of patients with elevated IC was 22.9 kg/m2 (IQR, 20.7 to 24.2 kg/m2) compared with 27.3 kg/m2 (IQR, 25.2 to 29.4 kg/m2) in patients who did not have elevated IC. There were no clinically significant differences in renal or hepatic function test results. CONCLUSIONS: Our data suggest that there is a group of patients with T2DM with elevated IC, and that they are nonobese and have decreased blood insulin concentrations. If confirmed, this novel form of T2DM could affect the treatment of such patients. (UMIN Clinical Trials Registry number, UMIN000032014.)