A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction.

OBJECTIVES: The aim of this study was to evaluate the pharmacogenetic role of the factor XIII (FXIII) valine 34 leucine (Val34Leu) polymorphism in the fibrinolytic therapy of acute myocardial infarction (MI). BACKGROUND: Fibrinolytic therapy is an established treatment for acute MI, but up to 40% of treated patients do not achieve optimal tissue reperfusion. The FXIII Val34Leu polymorphism is one of the most relevant functional polymorphisms described in the haemostatic system. The common Leu34 allele associates with an increased FXIII-transglutaminase activity, which results in an increased and faster rate of fibrin stabilization. METHODS: We genotyped this polymorphism in 293 consecutive MI patients (62 +/- 12 years; 231 males) from two different European populations. All patients were treated with standard doses of fibrinolytic drugs. Noninvasive assessment of the efficacy of coronary fibrinolysis was evaluated by serial electrocardiograms and creatine kinase time-activity curves. The clinical outcome was also re-evaluated at 24 h (death, reinfarction, or urgent revascularization). RESULTS: Multivariate analysis showed that Leu34 carriers displayed a significantly less efficient fibrinolysis than carriers of Val/Val genotype (p = 0.021; odds ratio [OR] 1.90, 95% confidence interval [CI] 1.10 to 3.28). At 24 h, Leu34 allele carriers had the worst outcome (p = 0.006; OR 2.14, 95% CI 1.25 to 3.68). Interestingly, the combination of the Leu34 allele and nonsmoking status increased the risk of non-reperfusion criteria (p = 0.003, OR 3.77), and worse outcomes at 24 h (p = 0.001, OR 4.55). CONCLUSIONS: In a large cohort of nonselected and consecutive acute MI patients from two different European populations, we show clinical evidence that the presence of the Leu34 allele reduces the efficacy of fibrinolytic therapy.

Effects of omega-3 polyunsaturated fatty acids on plasma indices of thrombogenesis and inflammation in patients post-myocardial infarction.

OBJECTIVE: To determine the effects of n-3 PUFAs supplementation on plasma indices of coagulation (fibrinogen), fibrin D-Dimer (an index of thrombogenesis and fibrin turnover), endothelial damage/dysfunction (von Willebrand factor (vWf)), platelet activation (soluble P-selectin (sP-sel)) and inflammation (interleukin-6, IL-6) in patients following acute myocardial infarction. METHODS: Open-labelled randomised controlled trial. Seventy-seven post-myocardial infarction (MI) patients stabilized on standard secondary prevention therapy were randomised either to 3 months' treatment with Omacor 1 g/day (n=37) or 'usual care' control (n=40). Plasma levels of fibrinogen, D-Dimer, vWf, sP-sel, IL-6 and plasma viscosity at baseline and after 3 months were determined. RESULTS: At baseline, there were no significant differences between the groups in all research indices, except vWf levels were higher in patients allocated to Omacor supplementation. After 3 months, there were no significant changes in the levels of any research indices in either the Omacor supplemented or the 'usual care' control patients when compared to baseline. Patients who received Omacor experienced a fall in total cholesterol (p=0.019), total/HDL-cholesterol ratio (p=0.009) and LDL-cholesterol (p=0.023). However, the relative changes in plasma lipids and lipoproteins did not differ between the two groups. CONCLUSIONS: Three-month supplementation of Omacor at 1 g per day in post-MI patients is not associated with an improvement in the levels of peripheral indices of coagulation potential, endothelial function, platelet reactivity and inflammation.

Inter-relationships of indices of endothelial damage/dysfunction [circulating endothelial cells, von Willebrand factor and flow-mediated dilatation] to tissue factor and interleukin-6 in acute coronary syndromes.

BACKGROUND: Increased circulating endothelial cells (CECs, reflecting endothelial damage) in acute coronary syndromes (ACS) has been reported. However, the inter-relationships of indices of endothelial damage/injury with development of vascular (dys)function, plasma levels of tissue factor (TF, an index of coagulation) and interleukin-6 (IL-6, a pro-inflammatory cytokine) have not been investigated in ACS. We hypothesized that increased CECs can be related to impaired flow-mediated vasodilatation (FMD, an index of endothelial dysfunction) and elevated plasma von Willebrand factor (vWf, also marking endothelial damage/dysfunction), TF and IL-6 in patients with ACS. METHODS: We studied 120 patients with ACS (80 acute myocardial infarction and 40 unstable angina; 86 male, age 65+/-12 years) and 40 matched patients with stable CAD and 40 healthy controls (HC) in a cross-sectional analysis. Plasma vWf, TF and IL-6 levels were measured by ELISA. CECs were quantified using epifluorescence microscope after immunomagnetic separation with CD146. Brachial artery FMD was assessed in a subset of 39 ACS patients. RESULTS: ACS patients had significantly higher CECs, vWf, TF and IL-6 levels, but lower FMD, when compared to stable CAD and HC (all p<0.001) and all were inter-correlated significantly. In ACS, CECs was strongly correlated with FMD (r=-0.64, p<0.001) and TF (r=0.7, p<0.001). In stable CAD, significant correlations were again found between many indices, but on multivariate analysis, IL-6 and vWf were both independently related to FMD. CONCLUSIONS: Increased CECs in ACS patients are closely associated with endothelial damage/dysfunction (vWf and FMD), coagulation (TF) and inflammation (IL-6). These inter-relationships support the concept of a central role of endothelial damage/injury in the activation of vascular and coagulation abnormalities in ACS.

Plasma angiopoietin-1, angiopoietin-2, angiopoietin receptor tie-2, and vascular endothelial growth factor levels in acute coronary syndromes.

BACKGROUND: Angiopoietin (Ang) -1 and -2, their receptor Tie-2, and vascular endothelial growth factor (VEGF) regulate angiogenesis and may be important in myocardial collateral development. Elevated levels of growth factors and their receptors are reported in myocardial infarction (MI), but changes after an acute coronary event are unknown. METHODS AND RESULTS: Plasma Ang-1, Ang-2, Tie-2, and VEGF levels were measured on admission (baseline) and at 48 hours (acute stage) in 126 patients with acute coronary syndrome (82 MI, 44 unstable angina pectoris). Baseline levels were compared with those of 40 patients with stable angina and 40 healthy controls. Measurements were repeated in 38 MI patients at 6 and 18 weeks (chronic stage). Baseline Ang-2 and Tie-2 levels were highest in MI patients (P<0.001). Patients with MI and unstable angina pectoris had higher VEGF levels compared with stable angina patients and healthy control subjects (P<0.001). In patients with acute MI, serial changes in all indexes from baseline to 18 weeks were observed (all P<0.001). Ang-1 levels were unchanged from baseline to 6 weeks but were elevated at 18 weeks. Ang-2 changes followed a biphasic pattern, being higher at baseline and 6 weeks but lower at 48 hours and 18 weeks. Tie-2 levels increased from baseline and remained elevated in the chronic phase. VEGF peaked at 6 weeks and then decreased toward baseline at 18 weeks. CONCLUSIONS: Plasma Ang-2, Tie-2, and VEGF levels but not Ang-1 levels were increased in patients with acute coronary syndrome. Serial changes in the plasma levels and interrelationships among Ang-1, Ang-2, Tie-2, and VEGF levels from the acute to the chronic stages in MI may reflect the progressive stages of angiogenesis activity in the ischemic-necrotic myocardium in vivo.

Impaired tissue Doppler diastolic function in patients with coronary artery disease: relationship to endothelial damage/dysfunction and platelet activation.

BACKGROUND: Pulsed tissue Doppler imaging (TDI) allows direct measurement of systolic and diastolic function of the left ventricle. In patients with coronary artery disease (CAD), myocardial ischemia-related impaired diastolic function may be linked to systemic endothelial damage/dysfunction and increased thrombogenesis. We hypothesized relationships between TDI-defined diastolic dysfunction and plasma von Willebrand factor (vWf, marking endothelial damage/dysfunction), soluble P-selectin (sP-sel, reflecting platelet activation), fibrin D dimer (an index of fibrin turnover and thrombogenesis), fibrinogen, and plasma viscosity (PV) in CAD. METHODS: Conventional 2-dimensional Doppler echocardiography and TDI were performed in 75 stable CAD patients (55 men, 59 +/- 11 years) and 40 age- and sex-matched healthy controls. Peak systolic (Sm), peak early (Em), and late (Am) diastolic mitral annular velocities measured at 4 sites (septal, lateral, inferior, and anterior) were averaged as global systolic and diastolic left ventricular function, respectively. The mean TDI velocities were dichotomized into low and high (below/above median) groups. Plasma vWf, sP-sel, D dimer (enzyme-linked immunosorbent assay), fibrinogen (modified Clauss), and PV levels were measured. RESULTS: CAD patients had significantly lower Sm, Em, Em/Am ratio, and a higher ratio of early transmitral flow E-velocity over Em (E/Em) when compared with controls (all P < .05). On multivariate analysis, adjusted for age, ejection fraction, and clinical variables, the differences in the group means of vWf, sP-sel, and fibrinogen remained significantly different between the low and high TDI indexes. D-dimer levels were unrelated to any TDI indexes. None of the transmitral flow indexes were independently related to the research indexes. CONCLUSIONS: In patients with CAD, diastolic dysfunction was closely associated with increased platelet activation and endothelial damage/dysfunction independent of systolic function. TDI-derived indexes are more sensitively related to plasma hemostatic markers than transmitral indexes in middle-aged patients with CAD.

Plasma markers of endothelial damage/dysfunction, inflammation and thrombogenesis in relation to TIMI risk stratification in acute coronary syndromes.

Risk stratification at presentation with acute coronary syndromes (ACS) on the basis of the TIMI risk score for unstable angina and non-ST-elevation myocardial infarction (UAP/NSTEMI) identifies patients at high risk of recurrent cardiac events and those who benefit from more aggressive treatment strategy. We hypothesised the following: (a) that a high TIMI risk score brings a greater degree of acute changes in endothelial damage/dysfunction (circulating endothelial cells [CECs], von Willebrand factor [vWf]), inflammation (interleukin-6, IL-6) and blood thrombogenicity (plasma tissue factor, TF); and (b) that these indices are higher in those with high TIMI risk score who experienced recurrent cardiac event at day 14 and day 30. TIMI risk scores were determined at admission and 48 hours later in 88 ACS patients (60 male, age 67+/-12 yrs) with UAP or NSTEMI. CECs, IL-6 and TF levels were measured at both time points and the acute change (delta) calculated. Patients were split into high (score > or =4) or low (<4) TIMI score groups. The composite end point of death, myocardial infarction, and refractory angina requiring revascularisation following 14 and 30 days' follow-up was ascertained. Fifty-eight patients with high TIMI risk score (mean 4.7) had significantly higher baseline and 48 h CEC, vWf, IL-6,TF and deltaTF levels, compared to low TIMI risk score (mean 2.4) patients (all p<0.05). Multivariate Cox regression analysis adjusted for clinical variables and TIMI risk score expressed as either continuous or categorical variable identified baseline CECs and deltavWf levels (both p< or =0.01) as independent predictors of subsequent cardiac events at both 14 days and 30 days. TIMI risk score for UA/NSTEMI identifies those patients with more profound vascular insult, inflammation and thrombogenicity that, in the 'high risk' patient group, predicts short-term outcomes, although vascular damage was the more sensitive predictor. These indices may further refine global risk stratification for short-term adverse cardiac events in these patients.

Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease.

Normal adults have very few circulating endothelial cells (CECs) in their blood, but increased levels have been shown in association with conditions associated with endothelial damage such as myocardial infarction and stroke. As atrial fibrillation (AF) is associated with a hypercoagulable state and abnormalities of plasma indices of endothelial damage/dysfunction, we hypothesised that CECs would also be raised in this condition, and would correlate with these plasma markers. We measured CECs (by immunofluoresence) as an indicator of frank endothelial damage, alongside 3 plasma indices of endothelial perturbation: von Willebrand factor (vWf), soluble E-selectin and soluble thrombomodulin (sTM) (all ELISA) in 28 patients with chronic 'stable' AF, 63 patients with AF plus an acute cardiovascular or cerebrovascular event as positive controls, and 20 healthy subjects in sinus rhythm as negative controls. Chronic 'stable' AF patients had significantly higher levels of plasma vWf (p<0.001 ), but comparable numbers of CECs (p=0.1638) in comparison to healthy controls. In patients with AF associated with an acute cardiovascular or cerebrovascular event, levels of CECs (p<0.0001) and sTM (p=0.004), but not vWf or sEsel, were significantly increased in comparison to chronic 'stable' AF patients. Patients with uncomplicated AF have abnormal systemic endothelial damage/dysfunction, as evident by increased plasma vWf levels, but normal numbers of CECs, compared to subjects in sinus rhythm. However, following clinical complications, such as stroke or significant haemodynamic compromise, further endothelial disturbance (as indicated by high levels of sTM and CECs) suggests additional endothelial damage.

Circulating endothelial cells in acute ischaemic stroke.

Increased numbers of CD146-bearing circulating endothelial cells (CECs) in the peripheral blood probably represent the most direct evidence of endothelial cell damage. As acute ischaemic strokes are associated with endothelial abnormalities, we hypothesised that these CECs are raised in acute stroke, and that they would correlate with the other indices of endothelial perturbation, i.e. plasma von Willebrand factor (vWf) and soluble E-selectin. We studied 29 hypertensive patients (19 male; mean age 63 years) who presented with an acute stroke and compared them with 30 high risk hypertensive patients (21 male; mean age 62 years) and 30 normotensive controls (16 male; mean age 58 years). CECs were estimated by CD146 immunobead capture, vWf and soluble E-selectin by ELISA. Patients with an acute ischaemic stroke had significantly higher numbers of CECs/ml of blood (p<0.001) plasma vWf (p=0.008) soluble E-selectin (p=0.002) and higher systolic blood pressure (SBP) as compared to the other groups. The number of CECs significantly correlated with soluble E-selectin (r=0.432, p<0.001) and vWf (r=0.349, p=0.001) but not with SBP (r=0.198, p=0.069). However, in multivariate analysis, only disease group (i.e. health, hypertension or stroke) was associated with increased CECs. Acute ischaemic stroke is associated with increased numbers of CECs. The latter correlate well with established plasma markers of endothelial dysfunction or damage, thus unequivocally confirming severe vasculopathy in this condition. However, the greatest influence on CECs numbers was clinical group.

High pulse pressure and nondipping circadian blood pressure in patients with coronary artery disease: Relationship to thrombogenesis and endothelial damage/dysfunction.

BACKGROUND: Patients with high ambulatory pulse pressure (APP) or nondipping pattern of circadian BP (nondippers) are at increased risk of cardiovascular disease that may be due to abnormalities in coagulopathy and vascular function. We hypothesized that patients with high APP or nondipper status have an adverse hemostasis profile. Accordingly, we assessed hemorheology (by plasma viscosity and fibrinogen levels), endothelial damage/dysfunction (von Willebrand factor [vWf] and flow-mediated dilatation [FMD]), thrombogenesis (D-dimer), and platelet activation (soluble P-selectin). METHODS: Seventy-three patients (58 men, 59 +/- 11 years) with stable coronary artery disease completed 24-h ambulatory BP monitoring. Plasma viscosity was assessed on a Coulter viscometer, fibrinogen by Clauss, vWf, D-dimer and soluble P selectin by ELISA, and FMD by reactive hyperemia. RESULTS: High APP (median APP >/=51 mm Hg) and nondipping was associated with significantly higher levels of vWf, D-dimer, fibrinogen, and soluble P-selectin compared to patients with low APP and dippers, respectively (all P < .05), even after adjustment for ages, 24-h mean systolic, mean diastolic, and mean arterial BPs. After the same adjustments, as well as for dipping status, white coat effects, and left ventricular mass, patients with high APP also had more impaired FMD and still significantly higher levels of vWf and D-dimer, compared to patients with low APP (all P < .05). However, the highest levels of vWf, fibrinogen, and soluble P-selectin and the most impaired FMD were found in those nondipper patients with concurrent high APP. CONCLUSIONS: High ambulatory pulse pressure or nondipping pattern of circadian BP per se are important pathophysiologic factors that may influence cardiovascular risk by altering hemostasis or endothelial function.

Recruitment of ethnic minority patients to a cardiac rehabilitation trial: the Birmingham Rehabilitation Uptake Maximisation (BRUM) study [ISRCTN72884263].

BACKGROUND: Concerns have been raised about low participation rates of people from minority ethnic groups in clinical trials. However, the evidence is unclear as many studies do not report the ethnicity of participants and there is insufficient information about the reasons for ineligibility by ethnic group. Where there are data, there remains the key question as to whether ethnic minorities more likely to be ineligible (e.g. due to language) or decline to participate. We have addressed these questions in relation to the Birmingham Rehabilitation Uptake Maximisation (BRUM) study, a randomized controlled trial (RCT) comparing a home-based with a hospital-based cardiac rehabilitation programme in a multi-ethnic population in the UK. METHODS: Analysis of the ethnicity, age and sex of presenting and recruited subjects for a trial of cardiac rehabilitation in the West-Midlands, UK. PARTICIPANTS: 1997 patients presenting post-myocardial infarction, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. DATA COLLECTED: Exclusion rates, reasons for exclusion and reasons for declining to participate in the trial by ethnic group. RESULTS: Significantly more patients of South Asian ethnicity were excluded (52% of 'South Asian' v 36% 'White European' and 36% 'Other', p < 0.001). This difference in eligibility was primarily due to exclusion on the basis of language (i.e. the inability to speak English or Punjabi). Of those eligible, similar proportions were recruited from the different ethnic groups (white, South Asian and other). There was a marked difference in eligibility between people of Indian, Pakistani or Bangladeshi origin. CONCLUSION: Once eligible for this trial, people from different ethnic groups were recruited in similar proportions. The reason for ineligibility in the BRUM study was the inability to support the range of minority languages.

Are there ethnic differences in the circadian variation in onset of acute myocardial infarction? A comparison of 3 ethnic groups in Birmingham, UK and Alicante, Spain.

We hypothesised that ethnicity may influence the circadian pattern in acute myocardial infarction (MI), in view of the potential differences in genetic background, cardiovascular risk factors and cultural habits. To test our hypothesis, we studied 340 consecutive acute MI patients (268 males; mean age 61.6+/-12.3 years) from two different city-centre teaching hospitals in Birmingham (United Kingdom) and Alicante (Spain). A different circadian rhythm in MI onset was observed between the ethnic groups (p=0.001), with a significantly higher number of acute MI onset occurring between midnight and noon in British Caucasians and Indo-Asians. In contrast, Mediterranean Caucasians showed the converse circadian pattern, with most of the acute MI events happened between noon and midnight. Indo-Asian patients were the youngest patient group and showed the highest prevalence of diabetes and increased body mass index. Mediterranean patients had the highest prevalence of smokers but their mean serum cholesterol was the lowest. No differences in sex, blood pressure, height and weight were observed. In conclusion, this study has shown a different circadian rhythm in acute MI onset between 3 ethnic groups from two different city-centre teaching hospitals in Birmingham (United Kingdom) and Alicante (Spain) and, for the first time, provide data in the Indo-Asian population. Further studies are required to determine the pathophysiological mechanism(s) underlying these differences.

Effects of lifestyle on hemostasis, fibrinolysis, and platelet reactivity: a systematic review.

The pathophysiology of atherothrombosis in cardiovascular disease is complex and multifactorial. No doubt, lifestyle habits such as exercise, smoking, diet, and alcohol consumption may have significant influence on cardiovascular disease. As the hemostatic system is assuming an increasingly prominent role in the pathogenesis and progression of atherovascular diseases, this review evaluates the effects of lifestyle habits (or lifestyle modifications) on blood coagulation, fibrinolysis, and platelet reactivity.

Acute coronary syndromes: Virchow's triad revisited.

The acute coronary syndromes (ACS), which include unstable angina, non-ST-segment and ST-segment elevation acute myocardial infarction, all share common pathophysiology processes that are characterized by coronary plaque disruption with superimposed thrombus formation, leading to myocardial ischaemia. A greater understanding of these processes has enable us to correlate the abnormalities in arterial vessel wall substrates ('vessel abnormalities'), rheologic and biomechanical conditions ('abnormal flow'), and blood thrombogenicity ('abnormal blood constituents') to the contribution of coronary plaque disruption and subsequent thrombosis, with the basic concepts of Virchow's triad for thrombus formation (thrombogenesis) described about 150 years ago. This improved understanding has led to the identification of newer therapeutic targets and, hence, novel pharmacological agents targeting different components of Virchow's triad, particularly in altering thrombus formation and plaque vulnerability.

Management of 'no-reflow' complicating reperfusion therapy.

No-reflow phenomenon, defined as inadequate myocardial perfusion of the adequately dilated target vessel without evidence of angiographic mechanical obstruction. It is a multifactorial, well-recognised, secondary phenomenon following reperfusion therapy such as thrombolysis or percutaneous coronary interventions (PCI). The pathophysiological mechanisms leading to the no-reflow state are incompletely understood. Embolization of the atheromatous material to the distal vasculature and intense arteriole vasospasm caused by microembolization of platelet-rich thrombi that release vasoactive agents resulting in microvascular obstructions are likely mechanisms. Current prophylaxis and management strategies are derived from limited clinical data. Intracoronary verapamil, adenosine and nitroprusside have been most frequently studied and administered for angiographic no-reflow during PCI for acute myocardial infarction or saphenous vein graft (SVG) lesions and have been shown to improve epicardial flow and microvascular perfusion. The use of distal embolic protection devices in SVG interventions also provide microvascular protection and improve clinical outcomes. However, by far the most important measures are prevention and anticipation during PCI as once no-reflow established, complete reversal of the situation may not be possible.

Cardiogenic shock complicating myocardial infarction and outcome following percutaneous coronary intervention.

Cardiogenic shock is the commonest cause of death in acute myocardial infarction (AMI). Although the syndrome of cardiogenic shock complicating AMI is common to all, the spectrum of underlying pathology is broad. While thrombolysis can be attempted with inotropic support or augmentation of blood pressure with an intra-aortic balloon pump, the greatest mortality benefit is seen after urgent coronary angiography and early revascularization. The long-term SHOCK Trial six-year follow-up results confirm durability of early revascularization over medical stabilization in shock patients. Indeed, cardiogenic shock is a catheter laboratory emergency. Percutaneous left ventricular assist devices may provide an advance in the management of patients with left ventricular dysfunction and cardiogenic shock.

Effects of omega-3 polyunsaturated fatty acids on metabolically active hormones in patients post-myocardial infarction.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids (PUFA) supplementation is used as a therapeutic secondary prevention strategy among post-myocardial infarction (MI) patients. The effects of omega-3 PUFA on markers of energy homeostasis among post-MI patients are unclear. METHODS: We investigated the effects of Omacor (a pharmaceutical capsule formulation of highly refined, concentrated omega-3 PUFA; Solvay Healthcare, Southampton, UK; 1 g/day) in addition to usual care (cardiovascular therapy) in a pilot randomised study of 35 post-MI men. Following randomisation to Omacor (n=16), or 'usual care' controls (n=19), fasting levels of insulin, non-esterified fatty acids (NEFA), triglycerides, glucose and adipocytokines (adiponectin, leptin and tumour necrosis factor (TNF)-alpha), as indices of markers of energy homeostasis, were measured at baseline and after 3-month treatment. RESULTS: There were no baseline differences in age, body mass index, blood pressure, fasting triglycerides, plasma glucose, NEFA and adipocytokines between the two treatment arms (P=0.07). There were no significant changes in metabolically active hormones within groups after 3-month treatment. Across arms, the direction of baseline to follow-up changes in insulin levels were significantly different (P= 0.03), with a mean increase with Omacor (+3.39 mU/ml) and a decrease among controls (-17.6 mU/ml), without associated deteriorating changes in triglycerides, NEFA or plasma glucose. CONCLUSION: This pilot study suggests that Omacor had little effect on glycaemic control among male post-MI patients. However, Omacor was associated with raised insulin levels, compared to usual care; thus, a metabolic basis for the cardioprotective action of Omacor, outside of its lipid lowering effects, merits further investigation.

Circulating endothelial cells, von Willebrand factor, interleukin-6, and prognosis in patients with acute coronary syndromes.

Markers of inflammation (eg, interleukin-6 [IL-6]), and endothelial perturbation (von Willebrand factor [VWF], circulating endothelial cells [CECs]) are altered in acute coronary syndromes (ACS). We hypothesized that CECs and IL-6 levels during the first 48 hours of ACS would predict 30-day and 1-year major cardiovascular end points (MACE). A total of 156 patients with ACS were included. Blood was drawn on admission (baseline) and 48 hours later for plasma VWF, IL-6 (both enzyme-linked immunosorbent assay [ELISA]), and CECs (CD146 immunomagnetic separation). CEC phenotyping was performed by indirect immunoperoxidase staining. At 30 days, 48 patients had a MACE, a predicted by baseline and 48-hour CECs and IL-6 levels, 48-hour VWF levels, and by the "admission-48 hour change" (Delta) in CECs, VWF, and IL-6 (all P = .002). On multivariate analysis, 48-hour CECs (P < .001) were the strongest predictor of MACE, followed by DeltaIL-6 (P = .01) and DeltaVWF (P = .048); 48-hour CECs were the only predictor of death (P = .007). At 1 year, 65 patients had MACE, predicted by 48-hour CECs and DeltaIL-6 levels (P < .001); age (P = .046) and 48-hour CECs (P < .001) were the only predictors of death. CECs stained 93% positive for endothelial nitric oxide synthase (eNOS) but were less than 1% positive for CD34, CD36, and CD45 and less than 3% for CD31. Like raised VWF, abnormal CECs and IL-6 levels during the first 48 hours of ACS were strongly associated with 30-day MACE. CECs at 48 hours were the only independent predictor of both death and MACE at 30 days and 1 year, indicating the crucial role of endothelial/vascular damage in ACS pathophysiology.