Pre-procedural peripheral endothelial function is associated with increased serum creatinine following percutaneous coronary procedure in stable patients with a preserved estimated glomerular filtration rate.

BACKGROUND: Worsening renal function, indicated by increased serum creatinine (SCr), is a common complication of percutaneous coronary procedures. Risk factors for increased SCr overlap with coronary risk factors involved in endothelial dysfunction. We hypothesized that endothelial dysfunction, measured using the reactive hyperemia peripheral arterial tonometry index (RHI), can predict periprocedure-increased SCr. METHODS: RHI was assessed before elective coronary procedures in 316 consecutive stable patients with a preserved estimated glomerular filtration rate (eGFR, >60mL/min/1.73m2). SCr was measured before and 2 days after procedures. RESULTS: There was no significant correlation between natural logarithmic transformations of RHI (Ln-RHI) and basal Ln-eGFR. Periprocedure increase in SCr was observed in 148 (47%) patients. The increased SCr group had significantly lower Ln-RHI [0.48 (0.36, 0.62) vs. 0.59 (0.49, 0.76), p<0.001]. Multivariate linear regression analysis identified body mass index (BMI) (ß=0.148, p=0.005) and Ln-RHI (ß=-0.365, p<0.001) as significant determinants of percent changes in SCr. Multivariate logistic regression analysis identified Ln-RHI (per 0.1) [odds ratio (OR) 0.672, 95% confidence interval (95% CI) 0.586-0.722; p<0.001], Ln-B-type natriuretic peptide (OR: 1.484, 95% CI: 1.130-1.974; p=0.004), current smoking (OR: 2.563, 95% CI: 1.379-4.763, p=0.003), BMI (OR: 1.113, 95% CI: 1.031-1.203; p=0.007), coronary intervention (OR: 1.736, 95% CI: 1.036-2.909; p=0.036), and Ln-hemoglobin A1c (OR: 6.728, 95% CI: 1.093-41.392, p=0.040) as independent determinants of increased SCr. Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with increased SCr (area under the curve, 0.684, 95% CI: 0.626-0.742, p<0.001). The optimum cut-off point of Ln-RHI for the periprocedure increased SCr was 0.545. CONCLUSIONS: Pre-procedure measurement of endothelial function by RHI is an effective strategy to assess the patient's risk conditions for worsening renal function after percutaneous coronary procedures.

Advanced peripheral microvascular endothelial dysfunction and polyvascular disease in patients with high cardiovascular risk.

BACKGROUND: Polyvascular disease (PolyVD) refers to the coexistence of coronary artery disease (CAD), peripheral arterial disease (PAD), and/or cerebrovascular disease (CVD), and carries a high risk of cardiovascular mortality. Endothelial dysfunction plays a crucial role in cardiovascular pathophysiology. This study investigated the association between PolyVD and the presence of microvascular endothelial dysfunction. METHODS: Consecutive stable patients (n=533) with diabetes mellitus and/or multiple cardiovascular risk factors were enrolled. Peripheral microvascular endothelial function in the finger microvasculature was assessed using the reactive hyperemia peripheral arterial tonometry index (RHI), and ankle-brachial index was measured for diagnosis of lower-extremity PAD prior to coronary angiography. Diagnosis of CVD was based on clinical symptoms, carotid ultrasound, and magnetic resonance imaging. PolyVD was defined as two or more coexisting vascular diseases from CAD, lower-extremity PAD, and CVD. RESULTS: Natural logarithmic transformations of RHI (Ln-RHI) were significantly attenuated in 93 patients with PolyVD (0.44±0.20) compared with those in 440 patients without PolyVD (0.56±0.19; p<0.001) or in 299 patients with a single vascular disease (0.54±0.19; p<0.001). There was an independent correlation between Ln-RHI (per 0.1) and the presence of PolyVD in all high-risk patients [odds ratio (OR): 0.724; 95% confidence interval (CI): 0.610-0.859; p<0.001] and one or more vascular diseases (OR: 0.724; 95% CI: 0.605-0.867, p<0.001). Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with PolyVD (area under the curve, 0.682, 95% CI: 0.625-0.740, p<0.001). The optimum cut-off point of Ln-RHI for the existence of PolyVD was 0.479. CONCLUSIONS: Microvascular endothelial dysfunction is significantly associated with the presence of PolyVD. Severe impairment of endothelial function in peripheral microvasculature may be an important pathophysiological component of PolyVD.

Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway.

OBJECTIVE: Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK. CONCLUSIONS: Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation.

Incremental prognostic significance of the elevated levels of pentraxin 3 in patients with heart failure with normal left ventricular ejection fraction.

BACKGROUND: Pentraxin 3 (PTX3) is a novel inflammatory marker produced by various cell types including those of the vasculature and the heart. The relationship between inflammatory markers and prognosis of patients with heart failure with normal ejection fraction (HFNEF) remains unknown. We investigated whether plasma PTX3 levels can predict future cardiovascular events in patients with HFNEF. METHODS AND RESULTS: Plasma PTX3, high-sensitivity C-reactive protein, and B-type natriuretic peptide levels were measured prospectively in 360 stable patients with HFNEF. The subsequent incidence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction (MI), unstable angina pectoris, nonfatal ischemic stroke, hospitalization for heart failure decompensation, and coronary revascularization, was determined. During a mean 30-month follow-up, 106 patients experienced cardiovascular events. These events were more frequent in patients with high plasma PTX3 levels (>3.0 ng/mL) than low levels (≤3.0 ng/mL). Multivariable Cox hazard analysis showed that PTX3 (hazard ratio: 1.16; 95% CI: 1.05 to 1.27; P<0.01) and B-type natriuretic peptide (hazard ratio: 1.08; 95% CI: 1.03 to 1.14; P<0.001), but not high-sensitivity C-reactive protein levels, were significant predictors of future cardiovascular events. Multivariable Cox analysis with the forced inclusion model, including 5 previously identified prognostic factors, found that PTX3 was a significant predictor of cardiovascular events (hazard ratio: 1.16; 95% CI: 1.06 to 1.27; P<0.01). The C-statistics for cardiovascular events substantially increased from 0.617 to 0.683 when PTX3 was added to the 5 previously identified prognostic factors. CONCLUSIONS: High plasma PTX3 levels, but not other inflammatory markers, are correlated with future cardiovascular events in patients with HFNEF. PTX3 may be a useful biomarker for assessment of risk stratification in HFNEF. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp; Unique identifier: UMIN000002170.

Contrast material and radiation dose reduction strategy for triple-rule-out cardiac CT angiography: feasibility study of non-ECG-gated low kVp scan of the whole chest following coronary CT angiography.

BACKGROUND: Dedicated coronary computed tomography (CT) scan has been proven to be an accurate diagnostic modality in evaluating coronary artery disease. A second phase scan starting immediately after the coronary CT scan might enable visualization of the different vascular territories of the entire chest. PURPOSE: To investigate the feasibility of a contrast material and radiation dose reduction triple-rule-out (TRO) CT angiography (CTA) protocol with serial non-ECG-gated low kVp scan of the whole chest, which utilizes a recirculated contrast agent. MATERIAL AND METHODS: Thirty patients were scanned with the new TRO-CTA protocol; after the coronary scan with retrospective ECG-gating, non-ECG-gated whole-chest CTA was performed at 80 kVp to evaluate aortic arch (AAr) and pulmonary trunk (PT). Another 30 patients were scanned by our conventional TRO-CTA protocol at 120 kVp with retrospective ECG-gating. We compared the estimated effective dose (ED), contrast material (CM) dose, contrast-to-noise ratio (CNR) of the ascending aorta (AAo), and the rate of patients who could achieve adequate attenuation of the AAr and PT between the two protocols. RESULTS: The total ED of the new TRO-CTA protocol was 29.6% lower than that of the conventional protocol (P < 0.01). The amount of CM used for the new TRO-CTA protocol was significantly lower than in the conventional protocol (60.1 ± 9.6 mL vs. 91.8 ± 22.6 mL, P < 0.01). The CNR of the AAo was 30.2% higher with the new TRO-CTA protocol than with the conventional protocol (P < 0.01). There was no significant difference in the success rate of adequate attenuation of the AAr and PT between the two protocols (P > 0.05). CONCLUSION: The new TRO-CTA protocol can reduce the total dose of radiation and the contrast dose and yield adequate vascular enhancement compared with the conventional protocol.

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.

Basal and ischemia-induced transcardiac troponin release into the coronary circulation in patients with suspected coronary artery disease.

BACKGROUND: Cardiac troponin is a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes. Troponin release from the coronary circulation remains to be determined because of the lower sensitivity of the conventional assay. We sought to determine basal and angina-induced troponin release using a highly sensitive troponin assay. METHODS AND RESULTS: The cardiac troponin T levels in serum sampled from the peripheral vein (PV), the aortic root (AO), and the coronary sinus (CS) were measured in 105 consecutive stable patients with coronary risk factor(s) and suspected coronary artery disease (CAD) and in 33 patients without CAD who underwent an acetylcholine provocation test. At baseline, there was a significant increase in the troponin levels from AO [9.0 (6.4, 13.1) pg/mL for median (25(th), 75(th) percentiles)] to CS [10.3 (7.3, 15.5) pg/mL, p<0.001] in 96 (91.4%) patients and the difference was 1.1 (0.4, 2.1) pg/mL, which reflected basal transcardiac troponin release (TTR). TTR was positively correlated with PV levels (r = 0.22, p = 0.03). Male sex, left ventricular hypertrophy determined by echocardiography, T-wave inversion, and CAD correlated with elevated TTR defined as above: median, 1.1 pg/mL. A significant increase in TTR was noted in 17 patients with coronary spasms [0.6 (0.2, 1.2) pg/mL, p<0.01] but not in 16 patients without spasms [0.0 (-0.5, 0.9) pg/mL, p = 0.73] after the acetylcholine provocation. CONCLUSION: Basal TTR in the coronary circulation was observed in most of the patients with suspected CAD and risk factor(s). This sensitive assay detected myocardial ischemia-induced increases in TTR caused by coronary spasms.

Low radiation dose protocol in cardiac CT with 100 kVp: usefulness of display preset optimization.

To evaluate the radiation dose and image quality of 100 kVp cardiac CT, and the effects of display setting optimization. We randomly assigned 100 patients undergoing cardiac CT to one of following two protocols. Fifty patients underwent our conventional protocol with 120 kVp, and the other 50 patients underwent our low radiation dose protocol with 100 kVp. We compared effective dose (ED); CT number, image noise, and contrast noise ratio (CNR) of ascending aorta at 120 and 100 kVp protocol. We also performed quantitative analysis and qualitative analysis for bitmap image of 120, 100 kVp, and display preset optimization for 100 kVp images. The estimated ED was 48 % lower with the 100 kVp protocol than the 120 kVp protocol (2.8 vs. 5.5 mSv, p < 0.01). There is no significant difference in the CNR between 100 and 120 kVp protocol (18.5 ± 3.6 vs. 18.6 ± 3.8, p = 0.84). Display preset optimization significantly improved image quality of 100 kVp cardiac CT, and there is no significant difference in qualitative analysis and quantitative analysis between 100 kVp scan with optimized display preset and 120 kVp scan (p > 0.05). The 100 kVp scanning with optimized display preset offers almost same image quality at cardiac CT of thin adults under 48 % decreased radiation dose.

Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction.

OBJECTIVES: The purpose of this study was to investigate whether peripheral endothelial dysfunction could predict the occurrence of cardiovascular events in patients with heart failure (HF) with normal left ventricular ejection fraction (HFNEF). BACKGROUND: Endothelial dysfunction plays an important role in HF, but the relation between peripheral endothelial dysfunction and prognosis in HFNEF remains unknown. METHODS: We conducted a prospective cohort study of 321 patients with HFNEF. We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index (RHI), and followed cardiovascular events. RESULTS: A total of 59 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 20 months; log-rank test: p < 0.001). Multivariate Cox hazard analysis identified RHI (per 0.1) (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.67 to 0.94; p = 0.007), E/e' (Ln[E/e'] [per 0.1]) (HR: 1.15; 95% CI: 1.04 to 1.26; p = 0.006), and B-type natriuretic peptide (BNP) (Ln[BNP] [per picogram/milliliter]) (HR: 1.81; 95% CI: 1.44 to 2.28; p < 0.001) as independent predictors of cardiovascular events. The C-statistics for cardiovascular events substantially increased when the RHI was added to the HFNEF prognostic 5 factors (PF5)-age, diabetes, New York Heart Association classification, HF hospitalization history, and left ventricular ejection fraction-which were identified in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (PF5 alone: 0.671; PF5 + RHI: 0.712). The net reclassification index was significant after addition of the RHI (19.0%, p = 0.01). CONCLUSIONS: Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF. (Endothelial Dysfunction Assessed by Reactive Hyperemia Peripheral Arterial Tonometry and Heart Failure with Preserved Left Ventricular Ejection Fraction; UMIN000002640).

Accumulation of pericardial fat correlates with left ventricular diastolic dysfunction in patients with normal ejection fraction.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) plays an important role in heart failure with normal left ventricular ejection fraction (LVEF). Obesity is one of the major comorbid conditions of LVDD. Pericardial fat (PF) is an ectopic fat depot with possible paracrine or mechanical effects on the coronary circulation and myocardial function. METHODS: We measured PF volume on 64 slice computed tomography and analyzed echocardiographic parameters to confirm LVDD in 229 consecutive patients suspected of coronary artery disease with LVEF of more than 50% and no symptomatic heart failure (59% men, 67±12 years). LVDD was defined as the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') >10. RESULTS: PF volume correlated significantly with E/e' (r=0.21, p<0.01), left ventricular mass index (r=0.23, p<0.001), and left atrial diameter (r=0.32, p<0.001). The mean PF volume was significantly greater in patients with LVDD (184±61cm(3), n=141) than in those without LVDD (154±58, n=88, p<0.001). Multivariate logistic regression analysis indicated that PF volume correlated significantly with the presence of LVDD (odds ratio: 2.00 per 100cm(3) increase in PF volume, p=0.02) independent of age, gender, abdominal obesity, hypertension, and diabetes. CONCLUSIONS: PF volumes are significantly associated with LVDD, independent of other factors such as hypertension or diabetes. PF may be implicated in the pathogenesis of LVDD in patients with normal LVEF.

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.

Microvascular coronary artery spasm presents distinctive clinical features with endothelial dysfunction as nonobstructive coronary artery disease.

BACKGROUND: Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers. METHODS AND RESULTS: Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor-borderline ischemic electrocardiogram findings at rest, limited-baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate-induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months. CONCLUSIONS: Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided. CLINICAL TRIAL REGISTRATION: URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Total coronary artery plaque burden measured by cardiac computed tomography is associated with metabolic syndrome.

AIM: Increased coronary plaque burden, which could be involved in the pathogenesis of atherothrombotic events, is difficult to evaluate in the three major coronary arteries. The purpose of this study was to quantify coronary plaque volume using 64-slice computed tomography (CT). METHODS: We measured coronary plaque volume with our new protocol in 23 consecutive patients (48% men; 66 ± 11 years old) who underwent cardiac CT for suspicion of coronary artery disease and had noncalcified plaques. We counted the total pixel volume of noncalcified plaques in the three major coronary arteries. RESULTS: The coronary plaque volume was 1.29 ± 0.56 cm(3) in the right coronary artery, 1.29 ± 0.42cm(3) in the left main coronary artery and left anterior descending artery, and 0.88 ± 0.32 cm(3) in the left circumflex artery. The total coronary plaque burden (TCPB) was 3.45 ± 1.02 cm(3)/patient and had a positive correlation with waist circumference (r =0.44, p < 0.05) and insulin resistance (r = 0.46, p < 0.05). TCPB was significantly greater in men (3.89 ± 1.07 cm(3) vs. 3.06 ± 0.82 cm(3) in women, p < 0.05), patients with diabetes or impaired glucose tolerance (3.77 ± 0.94 cm(3) vs. 2.86 ± 0.92 cm(3) in non-diabetics, p < 0.05), and patients with metabolic syndrome (3.91 ± 0.95 cm(3) vs. 3.03 ± 0.91 cm(3) in patients without metabolic syndrome, p < 0.05). CONCLUSIONS: Cardiac CT can provide a noninvasive assessment of TCPB, which was significantly associated with metabolic syndrome and its components. Measuring TCPB by CT could be an important strategy for identifying high-risk patients with suspected coronary artery disease.

Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction.

OBJECTIVES: This study investigated the clinical significance of plasma pentraxin 3 (PTX3) levels in patients with heart failure with normal ejection fraction (HFNEF) and whether PTX3 is produced from coronary circulation. BACKGROUND: Pentraxin 3 is a novel inflammatory marker and a member of pentraxin superfamily including C-reactive protein (CRP). The relationship between inflammatory markers and HFNEF remains unclear. METHODS: We measured peripheral blood levels of PTX3, high-sensitivity CRP, tumor necrosis factor-alpha, and interleukin-6 in 323 patients comprising 82 HFNEF, 70 heart failure (HF) with reduced EF, and 171 non-HF patients. Levels of PTX3 were also measured at the aortic root and the coronary sinus in 75 patients. RESULTS: The levels of PTX3, tumor necrosis factor-alpha, and interleukin-6, but not high-sensitivity CRP, were significantly higher in HFNEF patients than in non-HF patients. Multivariate logistic regression analysis identified only high levels of PTX3 as the independent inflammatory marker correlated with the presence of HFNEF in patients with normal left ventricular (LV) EF (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.11 to 1.98, p < 0.01) and with the presence of left ventricular diastolic dysfunction (LVDD) in non-HF patients (OR: 1.23, 95% CI: 1.02 to 1.50, p < 0.05). Levels of PTX3 at the coronary sinus were significantly higher than at the aortic root in HFNEF patients (p < 0.05) and in non-HF patients with LVDD (p < 0.01), but not different in non-HF patients without LVDD (p = 0.33). CONCLUSIONS: Pentraxin 3 is significantly elevated in HFNEF patients and produced in the coronary circulation in patients with LVDD. Pentraxin 3, but not high-sensitivity CRP, is an independent inflammatory marker correlated with the presence of LVDD and HFNEF. (The Clinical Significance of Plasma Pentraxin 3 levels for Patients with Diastolic Heart Failure; UMIN000002170).

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.

Prognostic value of endothelial microparticles in patients with heart failure.

AIMS: 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. METHODS AND RESULTS: We enrolled 169 consecutive HF patients (70 ischaemic, 99 non-ischaemic HF) with New York Heart Association (NYHA) class I or more. Plasma CD144-positive EMP levels were measured by flow cytometry in the HF patients and in 31 healthy subjects. We followed the HF patients for mean 30 months. Endpoints were: a composite of cardiovascular events (myocardial infarction, stroke, re-hospitalization for HF, and cardiovascular death) and all-cause mortality. Endothelium-derived microparticle levels increased significantly with NYHA functional class [EMP median (range): healthy, 0.325 (0.164-0.354) ×106/mL; NYHA I, 0.484 (0.426-0.575); II, 0.646 (0.439-0.795); and III/IV, 0.786 (0.569-1.026), P < 0.001]. A total of 33 cardiovascular events and 22 all-cause deaths were registered. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the high-EMP group, but there was only a borderline difference for all-cause mortality (above median; log rank test P = 0.01, P = 0.053, respectively). Multivariate Cox regression analysis adjusted for clinical factors, identified high-EMP levels as an independent predictor of future cardiovascular events, but not for all-cause mortality in HF patients [hazard ratio (95% confidence interval): 2.423 (1.034-5.681), P = 0.04 for cardiovascular events; and 2.095 (0.825-5.323), P = 0.12 for all-cause mortality]. CONCLUSION: Endothelial dysfunction assessed by plasma levels of EMPs can independently predict future cardiovascular events in patients with HF. Endothelium-derived microparticles are a potentially useful biomarker of endothelial dysfunction in HF risk stratification.

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).

Cannabinoid 1 receptor blockade reduces atherosclerosis with enhances reverse cholesterol transport.

AIM: A recent clinical study using coronary intravascular ultrasound showed that rimonabant, a cannabinoid 1 (CB1) receptor antagonist, significantly reduced total atheroma volume, suggesting that CB1 receptor blockade could be beneficial in anti-atherogenic therapy. The reverse cholesterol transport (RCT) system plays important roles in atherogenesis. We investigated whether CB1 receptor blockade could modulate atherogenesis in mice. METHODS AND RESULTS: Oral administration of rimonabant (8 mg/kg/day) to apolipoprotein E-deficient mice for 3 months significantly reduced the relative area of atherosclerotic lesions in the aorta (vehicle; 12.6+/-4.0% vs. rimonabant; 9.7+/-2.3, n=12 each, p<0.05) with an increase in serum adiponectin levels (15.6+/-2.3 microg/mL vs. 12.2+/-2.1, n=12 each, p<0.001), without affecting body weight or serum cholesterol levels. Rimonabant tended to increase serum high-density lipoprotein cholesterol (HDL-C) (p=0.05). The relative area of atherosclerotic lesions in the aorta correlated inversely with serum HDL-C levels (r=-0.45, n=24, p<0.05). Rimonabant upregulated the mRNA expression levels of various components of the RCT system on THP-1 cell-derived macrophages (scavenger receptor B1: 1.15+/-0.12 fold, n=6; p<0.05, ATP-binding cassette [ABC] transporter G1: 1.23+/-0.11 fold, n=6; p<0.01), but not ABCA1 (1.13+/-0.20 fold, n=6; p=0.13). CONCLUSION: CB1 receptor blockade reduced atherosclerosis in apoE-deficient mice through an increase in serum adiponectin levels and activation of the RCT system. CB1 receptor blockade may be therapeutically beneficial for atherogenesis by increasing the serum adiponectin level and enhancing of the RCT system.

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.