Measurement of the platelet retention rate in a column of collagen-coated beads is useful for the assessment of efficacy of antiplatelet therapy.

INTRODUCTION: A simple, validated method to measure platelet function is unavailable for bedside use. Measurement of platelet retention rate using a column of collagen-coated beads and whole blood is a new, simple assay that reflects platelet aggregation. This study was aimed to examine the utility of this assay to assess efficacy of antiplatelet drug therapy. METHODS: Citrated whole blood (1.5 ml) in a syringe was passed through a polyvinyl tube packed with collagen-coated beads for 40 seconds using a syringe pump. Platelet retention rate in the column was calculated from platelet counts in blood before and after passage. An increase in the retention rate reflects an increase in platelet activity. This new platelet retention assay and the traditional optical aggregometry assay were performed in 331 patients with stable coronary artery disease (CAD). RESULTS: The retention rate was significantly reduced in patients taking dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine) compared with aspirin alone. There was a significant linear correlation between the platelet retention rate and platelet aggregability measured by the traditional method (r=0.44, p<0.001). In multivariate Cox proportional hazards analysis, higher platelet retention rate was an independent predictor of future cardiovascular events in patients on dual antiplatelet therapy (hazard ratio 3.9, 95% CI 1.6 to 9.5, p=0.003). CONCLUSIONS: Measurement of the platelet retention rate in a column of collagen-coated beads may be useful for monitoring the efficacy of antiplatelet drug therapy in patients with CAD.

Adiponectin is released from the heart in patients with heart failure.

BACKGROUND: Plasma levels of adiponectin are decreased in patients with ischemic heart disease, but increased in patients with heart failure (HF). The source of increased adiponectin levels in patients with HF remains unknown. This study examined whether adiponectin, an adipocyte-derived protein with cardioprotective actions, is released from the heart in patients with HF. METHODS: Plasma adiponectin levels sampled from the aorta, coronary sinus (CS), and peripheral vein (PV) were measure by ELISA in 138 consecutive patients with left ventricular ejection fraction (LVEF) <40% and in 40 normal controls. RESULTS: PV adiponectin levels were significantly higher in patients with either non-ischemic HF (n=81) or ischemic HF (n=57) than controls; levels were similar between patients with non-ischemic HF and those with ischemic HF. There was a significant step-up in adiponectin levels from the aorta to the CS in patients with either non-ischemic HF or ischemic HF but not in controls. The CS-aorta difference in adiponectin levels, which reflect cardiac release of adiponectin, positively correlated with PV levels in patients with either non-ischemic HF or ischemic HF. The CS-aorta difference in adiponectin levels positively correlated with PV levels of brain natriuretic peptide and inversely with LVEF in patients with either non-ischemic HF or ischemic HF. CONCLUSIONS: Adiponectin is released from the heart into the peripheral circulation in proportion to the extent of LV dysfunction in patients with HF irrespective of etiologies of HF.

Rapid stabilization of vulnerable carotid plaque within 1 month of pitavastatin treatment in patients with acute coronary syndrome.

We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 +/- 3.3 dB at pretreatment versus -12.7 +/- 2.3 dB at 1 month *P < 0.001; placebo: -19.0 +/- 3.5 dB versus -16.9 +/- 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFalpha at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.

Low adiponectin levels predict late in-stent restenosis after bare metal stenting in native coronary arteries.

BACKGROUND: Adiponectin, the most abundant protein secreted from adipose tissue, possesses anti-atherogenic properties. This study tested whether adiponectin plasma levels predict in-stent restenosis (ISR) after successful percutaneous coronary intervention (PCI) with bare-metal stents. METHODS: The study included 148 consecutive patients who had elective PCI with bare-metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease. Adiponectin levels were measured by ELISA 3 days or less before PCI. RESULTS: Angiographic ISR (defined as >50% diameter stenosis) was found in 49 (33%) patients during 6 months of the follow-up. Adiponectin levels were lower in patients with ISR than those without ISR (3.5+/-0.3 vs. 6.9+/-0.4 microg/ml, respectively, p<0.01). Adiponectin levels were inversely correlated with late luminal loss of the stented lesions (r=-0.40, p<0.01). Using multivariate logistic regression analysis, low adiponectin levels (<4.5 microg/ml, arbitrarily determined from a receiver operating characteristic curve) served as a predictor of ISR that was independent of angiographic and procedural variables, and clinical factors known to be associated with ISR (odds ratio, 7.9; 95% CI, 3.0-21; p<0.01). Furthermore, low adiponectin levels also independently predicted target lesion revascularization (n=35) during follow-up (odds ratio, 3.7; 95% CI, 1.4-9.7; p<0.01). CONCLUSIONS: Low adiponectin levels have a predictive value for late ISR after PCI with bare-metal stents in native coronary arteries.

Echolucent carotid plaques predict in-stent restenosis after bare metal stenting in native coronary arteries.

Echolucent carotid plaque is considered to predict coronary events. This study examined whether echolucent carotid plaque may predict in-stent restenosis (ISR) in coronary arteries. This study included 202 patients who had elective and successful percutaneous coronary intervention (PCI) with bare metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease (CAD). Carotid plaque echolucency was assessed by ultrasound with integrated backscatter (IBS) analysis (intima-media IBS value minus adventitia IBS) 1 day before PCI. All patients underwent planned coronary angiography (CAG) at 6 months after PCI, or CAG before 6 months due to acute coronary syndromes. ISR (defined as >50% diameter stenosis) was found in 65 (32%) patients. The calibrated IBS values of carotid plaques were inversely correlated with late luminal loss of the stented lesions. Using multivariate logistic regression analysis, the presence of echolucent carotid plaques (

Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute myocardial infarction.

OBJECTIVES: This study examined whether sirolimus-eluting stent (SES) implantation may affect endothelial vasomotor dysfunction in resistance and epicardial infarct-related coronary arteries in acute myocardial infarction (AMI). BACKGROUND: Myocardial ischemia-reperfusion causes endothelial injury entirely in the vasculature of the infarct-related coronary artery. Sirolimus-eluting stent implantation inhibits re-endothelialization at the site of stenting. METHODS: This study included 29 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy using a SES (n = 13) or bare-metal stent (BMS) (n = 16). The diameter of the epicardial segment distal to the site of SES deployment and coronary blood flow in the LAD in response to an intracoronary infusion of acetylcholine were measured at 2 weeks after AMI. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunoadsorbent assay in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in all patients. RESULTS: The epicardial coronary artery was more severely constricted in response to acetylcholine in the SES than in the BMS group. The increase in coronary blood flow in response to acetylcholine was lower in the SES than in the BMS group. Vascular endothelial growth factor levels in the AIV were significantly lower than in the AO in the SES group but not in the BMS group. CONCLUSIONS: During the course of AMI, SES implantation adversely affects endothelium-dependent vasomotor function in resistance and epicardial coronary arteries after the ischemia-reperfusion in association with a reduction in myocardial VEGF secretion.

Association of high levels of plasma free dopamine with future coronary events in patients with coronary artery disease.

BACKGROUND: There is an intimate relationship between activation of the sympathetic nervous system and myocardial ischemia. This study examined whether plasma levels of dopamine, a precursor of norepinephrine, may provide prognostic information in coronary artery disease (CAD). METHODS AND RESULTS: Plasma levels of free dopamine were measured by high-performance liquid chromatography in 210 consecutive patients with stable CAD. The patients were prospectively followed up for a period of < or =36 months until occurrence of a clinical coronary event. Coronary events occurred in 37 patients during follow-up. In Kaplan-Meier survival analysis, higher dopamine levels (> or =30 pg/ml) resulted in a higher event probability (p<0.01). Multivariate Cox hazards analysis showed that higher dopamine levels were a significant and independent risk factor for future coronary events (hazard ratio 3.3, 95% confidence interval 1.3-8.1, p<0.01). Furthermore, patients with higher dopamine levels had lower left ventricular (LV) ejection fraction and higher levels of brain natriuretic peptide, C-reactive protein, and fibrinogen than those with lower dopamine levels. CONCLUSIONS: Plasma levels of free dopamine are increased in association with a decrease in LV function and an increase in inflammatory risk markers. Higher free dopamine levels are an independent risk factor for future coronary events in CAD patients.

High prevalence of paroxysmal atrial fibrillation and/or atrial flutter in metabolic syndrome.

BACKGROUND: Because metabolic syndrome is associated with cardiovascular diseases, its association with the risk of paroxysmal atrial fibrillation (PAF) and/or atrial flutter (PAFL) was examined in the present study. METHODS AND RESULTS: A prospective analysis was performed in 592 consecutive hospitalized patients without obvious structural heart diseases. Sinus rhythm was confirmed by electrocardiography in all patients. PAF/PAFL occurred in 32 (5%) and metabolic syndrome was present in 127 (21%) of the patients enrolled. PAF/PAFL occurred in 12 (9%) of the patients with metabolic syndrome, but only 20 (4%) of patients without metabolic syndrome (p=0.02). Multivariate logistic regression analysis showed that metabolic syndrome was a significant risk factor for PAF/PAFL that was independent of left atrial diameter (> 44 mm) or age (> 70 years) (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.3-6.2, p<0.01). Among the 5 components of the metabolic syndrome, body mass index > or = 25 kg/m2 was the most strongly associated with PAF/PAFL (OR; 3.0, 95% CI 1.2-7.4, p=0.02). CONCLUSIONS: Metabolic syndrome is highly associated with PAF/PAFL in patients without structural heart diseases and obesity may be an underlying mechanism for the higher prevalence.

Relation between transcardiac gradient of VEGF and coronary flow response in humans.

BACKGROUND: Angiogenic growth factors, produced in the myocardium and coronary vascular bed, increase myocardial blood flow. This study examined whether plasma levels of vascular endothelial growth factor (VEGF) in coronary circulation may be related to coronary blood flow responses. METHODS: Blood flow responses in the left anterior descending coronary artery to an intracoronary infusion of acetylcholine (ACh) were measured by an intracoronary flow wire technique in 46 consecutive control subjects with normal coronary angiograms and left ventriculograms. Circulating VEGF levels were measured by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV). RESULTS: The transcardiac gradient of VEGF, calculated by the difference in VEGF concentrations between the AIV and AO, showed a positive correlation with the coronary blood flow increase in response to ACh independently of traditional coronary risk factors. In patients with cardiac syndrome X (n=17), defined as a positive exercise stress test with a normal coronary angiograms and left ventriculogram, the transcardiac VEGF gradient was significantly lower than in the risk factors-matched control subjects (n=21). CONCLUSIONS: The transcardiac gradient of plasma VEGF was independently and positively correlated with the coronary blood flow increase in response to ACh. A reduced transcardiac VEGF gradient was present in cardiac syndrome X, a condition with a blunted coronary blood flow response.

Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans.

Adiponectin, an adipocyte-derived protein, has been shown to have vasculoprotective effects. This study examined the possible relationship between coronary vasomotor function and the transcardiac gradient of adiponectin, reflecting adiponectin utilization and/or accumulation in the coronary vascular bed. The epicardial diameter and blood flow response of the left anterior descending coronary artery to intracoronary infusions of ACh was analyzed in 108 consecutive subjects who had a normal coronary angiogram and left ventriculogram. Adiponectin levels were measured by ELISA in plasma obtained from the aortic root (Ao) and the anterior interventricular vein (AIV). Adiponectin levels in the AIV were lower than levels in the Ao. In multivariate linear regression analysis, the transcardiac gradient of adiponectin (Ao - AIV levels) showed a positive correlation with increases in epicardial coronary diameter and coronary blood flow in response to ACh that was independent of traditional coronary risk factors. The transcardiac gradient of adiponectin was not significantly associated with the coronary dilator response to isosorbide dinitrate and the coronary flow response to sodium nitroprusside. In other groups of patients with coronary spastic angina (n = 41) or microvascular angina (n = 32) who had impaired coronary vasomotor responses, there was no significant gradient of adiponectin between the Ao and AIV. The transcardiac gradient of adiponectin may modulate endothelial vasomotor function in large and resistance coronary arteries and may play a role in the pathogenesis of diseases presenting with coronary vasomotor dysfunction.

Atorvastatin increases plasma soluble Fms-like tyrosine kinase-1 and decreases vascular endothelial growth factor and placental growth factor in association with improvement of ventricular function in acute myocardial infarction.

OBJECTIVES: This study examined whether atorvastatin increases plasma levels of soluble Fms-like tyrosine kinase 1 (sFlt-1) and reciprocally decreases vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels in patients with acute myocardial infarction (AMI). BACKGROUND: Statins exert cardioprotective actions partly through anti-inflammatory actions. By capturing VEGF and PlGF in plasma, sFlt-1 acts as a natural inhibitor of VEGF and PlGF, which have proinflammatory properties. METHODS: Left ventriculography and enzyme-linked immunosorbent assay of plasma levels of sFlt-1, VEGF, and PlGF were repeated after AMI in 50 consecutive patients with a first AMI. Patients were randomized to treatment with atorvastatin (10 mg/day; n=25) or placebo (n=25) within 3 days after AMI, and therapy was continued for 6 months. RESULTS: The sFlt-1 levels were low in the acute phase, followed by an increase at 2 weeks after AMI, whereas free VEGF and PlGF levels were high in the acute phase, followed by a decrease at 2 weeks. Atorvastatin increased sFlt-1 levels and reciprocally decreased VEGF and PlGF levels at 6 months compared with placebo. The increase in sFlt-1 levels and the decrease in VEGF and PlGF levels were correlated with improvement of left ventricular ejection fraction during the follow-up period. CONCLUSIONS: There was a reciprocal relationship between changes in sFlt-1 levels and changes in VEGF and PlGF levels after AMI; and atorvastatin increased sFlt-1 levels while decreasing VEGF and PlGF levels. These changes were associated with late improvement of post-MI ventricular function, and may represent an additional benefit of statin therapy.

Endothelial vasomotor dysfunction in the brachial artery is associated with late in-stent coronary restenosis.

OBJECTIVES: This study examined whether endothelial dysfunction in the brachial artery might be associated with late in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). BACKGROUND: Simple and noninvasive identification of late ISR might help to select patients who require further angiographic evaluation. METHODS: Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was measured before (initial FMD) and at six months (follow-up FMD) after PCI in 141 consecutive patients who had elective and successful PCI with bare metal stents in de novo lesions of native coronary arteries for symptomatic coronary artery disease. Follow-up angiography was performed at six months after PCI in all patients. RESULTS: With multivariate logistic regression analysis, the impairment (< or = 4.8% dilation from baseline diameter) of FMD at follow-up showed the strongest association with late ISR (defined as > 50% diameter stenosis, n = 46) independently of other clinical and angiographic variables known to be associated with ISR (odds ratio 7.4, 95% confidence interval 2.8 to 19.2, p < 0.001), whereas the initial FMD did not have the association. The sensitivity of impaired FMD at follow-up (69%) in detecting ISR was higher than chest pain during the follow-up period (45%), with comparable specificity. The impaired FMD in combination with the chest pain increased the sensitivity to 90%. CONCLUSIONS: The impairment of FMD in the brachial artery at the time of follow-up was independently and closely associated with late ISR in native coronary arteries. The noninvasive assessment of FMD at the time of follow-up might be useful for identification of late ISR.

Remnant lipoproteinemia is a risk factor for endothelial vasomotor dysfunction and coronary artery disease in metabolic syndrome.

This study aimed to determine whether elevated levels of remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, might be associated with coronary artery disease (CAD) and endothelial vasomotor dysfunction in metabolic syndrome. The fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 210 patients with metabolic syndrome meeting ATP III criteria. Flow-mediated endothelium-dependent dilatation (FMD) in the brachial artery during reactive hyperemia was examined by high-resolution ultrasound technique. This study found that elevated RLP-C levels were a significant and independent risk factor for impaired FMD and angiographically proven coronary artery disease (CAD). Treatment with bezafibrate (n = 20) or atorvastatin (n = 20) for 4 weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. The % reduction in RLP-C levels from baseline after the treatment was independently correlated with the magnitude of improvement in FMD after adjustment for the % changes in levels of triglyceride, hsCRP, and IL-6, and HOMA index. Thus, elevated levels of RLP-C are a risk factor for CAD and endothelial vasomotor dysfunction, a predictor of coronary events, in metabolic syndrome. Measurement of RLP-C is useful for assessment of CAD risk and therapeutic effects in metabolic syndrome.

Increased ambulatory pulse pressure is a strong risk factor for coronary endothelial vasomotor dysfunction.

OBJECTIVES: This study was aimed to determine the relationship between pulse pressure (PP) and coronary vasomotor dysfunction, a predictor of coronary events. BACKGROUND: Pulse pressure is a strong risk factor for coronary artery disease (CAD). However, the mechanisms by which an increase in PP affects the pathogenesis of CAD are unclear. METHODS: Ambulatory blood pressure (BP) monitoring for 24 h was performed in 103 consecutive patients with normal coronary angiograms (51 hypertensive and 52 normotensive; age 42 to 70 years). The relationship between changes in coronary arterial diameter and blood flow during an intracoronary infusion of acetylcholine (ACh) (5, 10, 50 microg/min), and BP parameters, and other traditional risk factors was evaluated using univariate and multivariate linear regression analyses. RESULTS: With multivariate analyses, the 24-h PP showed an inverse correlation with the epicardial coronary dilator response to ACh independently of other covariates including age, smoking, and 24-h systolic BP in normotensive as well as hypertensive patients. Furthermore, multivariate analysis showed that the 24-h PP was inversely and independently correlated with the increase in coronary blood flow in response to ACh. The dilator response of epicardial coronary arteries to nitrate was not significantly correlated with 24-h PP. CONCLUSIONS: Increased 24-h PP is independently associated with endothelial vasomotor dysfunction in conduit and resistance coronary arteries irrespective of the presence of hypertension. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.