Hideaki Jinnouchi

Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial

CONTEXT Previous trials have investigated the effects of low-dose aspirin on primary prevention of cardiovascular events, but not in patients with type 2 diabetes. OBJECTIVE To examine the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective, randomized, open-label, blinded, end-point trial conducted from December 2002 through April 2008 at 163 institutions throughout Japan, which enrolled 2539 patients with type 2 diabetes without a history of atherosclerotic disease and had a median follow-up of 4.37 years. INTERVENTIONS Patients were assigned to the low-dose aspirin group (81 or 100 mg per day) or the nonaspirin group. MAIN OUTCOME MEASURES Primary end points were atherosclerotic events, including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Secondary end points included each primary end point and combinations of primary end points as well as death from any cause. RESULTS A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the nonaspirin group (17.0 per 1000 person-years) (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.58-1.10; log-rank test, P = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group (HR, 0.10; 95% CI, 0.01-0.79; P = .0037). A total of 34 patients in the aspirin group and 38 patients in the nonaspirin group died from any cause (HR, 0.90; 95% CI, 0.57-1.14; log-rank test, P = .67). The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and nonaspirin groups. CONCLUSION In this study of patients with type 2 diabetes, low-dose aspirin as primary prevention did not reduce the risk of cardiovascular events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00110448.

A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.

OBJECTIVES The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS). BACKGROUND The new class of anti-type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1. METHODS Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E-deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease. RESULTS DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10(-4) mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001). CONCLUSIONS A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.

Significance of a Multiple Biomarkers Strategy Including Endothelial Dysfunction to Improve Risk Stratification for Cardiovascular Events in Patients at High Risk for Coronary Heart Disease

OBJECTIVES We investigated whether a multiple biomarkers strategy that includes plasma levels of endothelium-derived microparticles (EMP), reflecting endothelial dysfunction, can improve prediction of future cardiovascular events in patients at high risk for coronary heart disease (CHD). BACKGROUND Detailed risk stratification using multiple biomarkers can provide clinical benefits in high-risk patients. Endothelial dysfunction has been described as a predictor of cardiovascular complications. METHODS We measured 3 biomarkers in 488 consecutive patients with various CHD risks: B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), and EMP. We followed 387 stable patients at high risk for CHD and examined future cardiovascular events. RESULTS During a mean follow-up of 36 months, 55 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis adjusted for established risk factors identified age, BNP, hsCRP, and EMP as significant and independent predictors of future cardiovascular events (age: hazard ratio [HR]: 1.042, 95% confidence interval [CI]: 1.007 to 1.080, p = 0.02; BNP: HR: 1.242, 95% CI: 1.004 to 1.536, p = 0.046; hsCRP: HR: 1.468, 95% CI: 1.150 to 1.875, p = 0.002; EMP: HR: 1.345, 95% CI: 1.094 to 1.652, p = 0.005). The C statistics for cardiovascular events increased when each biomarker or combinations of biomarkers were added to the Framingham risk model (C statistics: Framingham risk model alone 0.636, Framingham risk + BNP 0.695, Framingham risk + hsCRP 0.696, Framingham risk + EMP 0.682, and Framingham risk + BNP + hsCRP + EMP 0.763). CONCLUSIONS The assessment of endothelial dysfunction by plasma levels of EMP can independently predict future cardiovascular events in patients at high risk for CHD. A multiple biomarkers strategy that includes endothelial dysfunction assessed by EMP can identify patients vulnerable to cardiovascular disease. (University Hospital Medical Information Network number: UMIN000000876).

Digital assessment of endothelial function and ischemic heart disease in women.

OBJECTIVES We investigated the utility of digital reactive hyperemia peripheral arterial tonometry (RH-PAT) in predicting ischemic heart disease (IHD), including obstructive coronary artery disease (CAD) and nonobstructive coronary artery disease (NOCAD), in women. BACKGROUND IHD is the leading cause of mortality, and its pathogenesis is diverse in women. Fingertip RH-PAT is a new device that provides noninvasive, automatic, and quantitative evaluation of endothelial dysfunction. METHODS RH-PAT was measured using Endo-PAT2000 (Itamar Medical, Caesarea, Israel) before cardiac catheterization in 140 stable women scheduled for hospitalization to examine chest pain. NOCAD was diagnosed by angiography with measurement of coronary blood flow and cardiac lactate production during intracoronary acetylcholine provocation test and cardiac scintigraphy with stress tests. RESULTS Sixty-eight women (49%) had obstructive CAD and 42 women (30%) had NOCAD. RH-PAT indexes were significantly attenuated in both obstructive CAD and NOCAD as compared with non-IHD (n = 30) (obstructive CAD: median 1.57, interquartile range [IQR] 1.42 to 1.76; NOCAD: median 1.58, IQR 1.41 to 1.78; non-IHD: median 2.15, IQR 1.85 to 2.48, p < 0.001). By multivariate logistic regression analysis, only RH-PAT index was significantly associated with IHD, including obstructive CAD and NOCAD (odds ratio 0.51; 95% confidence interval: 0.38 to 0.68; p < 0.001). In receiver-operating characteristic analysis, RH-PAT index was a significant predictor of IHD (area under the curve 0.86; p < 0.001). Furthermore, only RH-PAT was useful for the prediction of NOCAD after excluding obstructive CAD (area under the curve 0.85; p < 0.001; RH-PAT index of <1.82 had 81% sensitivity and 80% specificity). CONCLUSIONS RH-PAT indexes were significantly attenuated in women with IHD. Digital RH-PAT can predict patients with IHD, especially NOCAD before angiography. RH-PAT is potentially useful for identifying high-risk women for IHD. (Endothelial Dysfunction and Coronary Artery Spasm; NCT00619294).

Peripheral Endothelial Function and Cardiovascular Events in High-Risk Patients

Background Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high‐risk patients. Methods and Results We undertook a two‐center prospective study in 528 stable patients at high‐risk for cardiovascular events from the years 2006–2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow‐up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure‐induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person‐years of follow‐up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B‐type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C‐statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031). Conclusions Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high‐risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc. Clinical Trial Registration URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Association of pericardial fat accumulation rather than abdominal obesity with coronary atherosclerotic plaque formation in patients with suspected coronary artery disease

OBJECTIVES The purpose of this study was to examine the association of pericardial fat with the presence of coronary plaques. BACKGROUND Waist circumference, reflecting abdominal obesity, is a risk factor of metabolic syndrome and coronary artery disease (CAD). Adipose tissue secretes many factors implicated in atherogenesis, however, the role of pericardial fat (ectopic visceral fat around coronary arteries) in the pathogenesis of CAD is not clear. METHODS We measured total pericardial fat volume (PFV) and determined presence and characteristics of coronary plaques using 64-slice computed tomography in 171 consecutive patients suspected of CAD (101 men; mean age, 66+/-11 years, +/-SD). RESULTS PFV correlated with age (p<0.05), body mass index (p<0.05), waist circumference (p<0.01), and high-density lipoprotein cholesterol (p<0.01) by multivariate regression analysis. PFV was significantly larger in patients with coronary plaques, even nonstenotic or noncalcified ones, than those without plaques (any plaques, n=123; 201+/-71cm(3), nonstenotic plaques, n=51; 192+/-63, noncalcified plaques, n=32; 196+/-56 vs. no plaque, n=48; 144+/-45, p<0.001, respectively). Multivariate backward logistic regression analysis demonstrated that PFV, but not waist circumference, significantly associated with the presence of any coronary plaques (odds ratio [OR]; 2.876, 95% confidence interval [95% CI]; 1.614-5.125, p<0.001), nonstenotic plaques confirmed by coronary angiography (OR; 3.423, 95% CI; 1.764-6.642, p<0.001), and noncalcified plaques (OR; 3.316, 95% CI; 1.435-7.661, p<0.01). CONCLUSIONS PFV correlated significantly with the presence of nonstenotic and noncalcified coronary plaques assessed by multislice computed tomography. Pericardial fat is more highly associated with early development of CAD than simple anthropometric measures of abdominal obesity.

Prognostic value of endothelial microparticles in patients with heart failure

Heart failure (HF) is associated with endothelial dysfunction. Endothelium‐derived microparticles (EMPs) are a novel quantitative plasma marker of endothelial dysfunction. We investigated whether plasma levels of EMPs can predict future cardiovascular events in patients with HF.

Cys34-Cysteinylated Human Serum Albumin Is a Sensitive Plasma Marker in Oxidative Stress-Related Chronic Diseases

The degree of oxidized cysteine (Cys) 34 in human serum albumin (HSA), as determined by high performance liquid chromatography (HPLC), is correlated with oxidative stress related pathological conditions. In order to further characterize the oxidation of Cys34-HSA at the molecular level and to develop a suitable analytical method for a rapid and sensitive clinical laboratory analysis, the use of electrospray ionization time-of-flight mass spectrometer (ESI-TOFMS) was evaluated. A marked increase in the cysteinylation of Cys34 occurs in chronic liver and kidney diseases and diabetes mellitus. A significant positive correlation was observed between the Cys-Cys34-HSA fraction of plasma samples obtained from 229 patients, as determined by ESI-TOFMS, and the degree of oxidized Cys34-HSA determined by HPLC. The Cys-Cys34-HSA fraction was significantly increased with the progression of liver cirrhosis, and was reduced by branched chain amino acids (BCAA) treatment. The changes in the Cys-Cys34-HSA fraction were significantly correlated with the alternations of the plasma levels of advanced oxidized protein products, an oxidative stress marker for proteins. The binding ability of endogenous substances (bilirubin and tryptophan) and drugs (warfarin and diazepam) to HSA purified from chronic liver disease patients were significantly suppressed but significantly improved by BCAA supplementation. Interestingly, the changes in this physiological function of HSA in chronic liver disease were correlated with the Cys-Cys34-HSA fraction. In conclusion, ESI-TOFMS is a suitable high throughput method for the rapid and sensitive quantification of Cys-Cys34-HSA in a large number of samples for evaluating oxidative stress related chronic disease progression or in response to a treatment.

Alogliptin, a Dipeptidyl Peptidase 4 Inhibitor, Prevents the Progression of Carotid Atherosclerosis in Patients With Type 2 Diabetes: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A)

OBJECTIVE Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1–dependent and –independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (−0.3 ± 0.7% vs. −0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (−0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; −0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and −0.079 mm [SE 0.018] vs. −0.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

Pericardial fat inflammation correlates with coronary artery disease

OBJECTIVES We sought to assess the association between inflammation in pericardial fat (PF) and coronary artery disease (CAD) by pathological examination and clinical evaluation with cardiac computed tomography (CT). BACKGROUND Inflammation of adipose tissue is involved in cardio-metabolic disorders and shows high density in CT. METHODS We quantified, by immunohistochemical means, the PF inflammation in 39 autopsy cases by counting leukocyte common antigen (LCA)-positive cells. We then measured the CT density of PF in 39 patients with acute coronary syndromes and 69 patients suspected of CAD. RESULTS Pericoronary PF had significantly more LCA-positive cells in CAD autopsy cases (n=21) than non-CAD cases (n=18) (44 ± 21 vs. 24 ± 22 cells/mm(2), p=0.006). The CT density of PF around culprit lesions was significantly higher than non-culprit lesions in patients with acute coronary syndromes (-72 ± 11 vs. -82 ± 14 HU, p=0.002), which may reflect PF inflammation. Among patients suspected of CAD, the pericardial CT density gradient (PDG; difference in CT density between pericoronary PF and PF apart from coronary arteries) was significantly greater in CAD patients (n=30) than non-CAD patients (n=39) (22 ± 16 vs. 16 ± 10 HU, p=0.046). Multiple logistic regression analysis demonstrated that the PF inflammation index (PFI; PDG × PF volume, which could be the integrated index of inflammatory activity and abundance of PF) was significantly associated with the presence of CAD (odds ratio [95% confidence interval]; 1.234 [1.012-1.503] per 1000 HU cm(3), p=0.037) independent of other metabolic risk factors such as hypertension, dyslipidemia, and diabetes. CONCLUSIONS Active inflammation in PF correlates with CAD. PF inflammation may be involved in pathogenesis of CAD.