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Background: TSP-1 is a vasoconstrictive protein, which is released from both endothelium and cardiomyocytes during ischemia and promotes platelet aggregation and adhesion to subendothelial layers in atherosclerotic lesions. During myocardial ischemia and reperfusion, TSP-1 disturbs local microcirculation by disrupting both NO-signaling as well as VEGF-pathways by activation of CD47 and CD36. Furthermore, activation of TGF-ß might induce excessive fibrosis after infarction. It was assumed that TSP-1 is washed out after successful coronary reperfusion. In this study, we examined circulating TSP-1 post emergency PCI as a risk factor for major adverse cardiac events after STEMI with and without ventricular fibrillation., Methods: TSP-1 levels in platelet poor plasma were measured in 54 patients after ST-elevation myocardial infarction. Major adverse cardiac events were monitored for 426 days., Results: Patients with decreased TSP levels after coronary stenting showed a significantly higher risk for MACE than patient with higher TSP levels (TSP-1[d0]: n = 46, no MACE = 16.38 ± 1.98 ug/mL vs. MACE 7.11 ± 1.54 ug/mL; p = 0.003). Kaplan-Meyer-analysis for MACE showed a better outcome above 10 ug/mL (p = 0.02). For MACE later than 3 months post-STEMI, the corresponding Kaplan-Meier-analysis yielded a p-value of 0.01. The number needed to diagnose for late MACE was 2.158., Conclusion: Low plasma levels of TSP1 after PCI are associated with MACE. Due to its procoagulant effects and dysregulation of microvascular tone, adequately powered prospective studies are warranted to test the impact of TSP-1 on cardiac microcirculation, endothelial function and remodeling. TSP-1 might serve as a new diagnostic and therapeutic approach in cardiovascular disease.

Patients with Takotsubo cardiomyopathy (TC) often present with symptoms similar to those of myocardial infarction (MI). We analyzed blood concentrations of mediators of inflammation and platelet- and monocyte-activity markers in patients with TC and MI for significant differences. Clinical data of patients with TC (n = 16) and acute MI (n = 16) were obtained. Serial blood samples were taken at the time of hospital admission (t(0)), after 2-4 days (t(1)) and after 4-7 weeks (t(2)), respectively. Plasma concentrations of interleukin (IL)-6, IL-7, soluble CD40 ligand (sCD40L), and monocyte chemotactic protein 1 (MCP-1) were determined with an ELISA. Tissue factor binding on monocytes, platelet-activation marker CD62P, platelet CD40-ligand (CD40L), and platelet-monocyte aggregates were measured using flow cytometry. Expression of CD62P on platelets and IL-6 plasma levels were significantly lower in patients with TC compared to MI at the time of hospital admission. IL-7 plasma levels were significantly elevated in patients with TC compared to patients with MI at 2-4 days after hospital admission. No significant differences were observed concerning sCD40L and MCP-1 plasma levels, tissue factor binding on monocytes, CD40L expression on platelets, and platelet-monocyte aggregates at any point in time. Our results indicate that inflammatory mediators and platelet-activity markers contribute to the differences in the pathogenesis of MI and TC.

Background: In a recently published genome-wide association study (GWAS), three single nucleotide polymorphisms (SNPs) (rs2824292, rs1353342, rs12090554) were significantly associated with increased susceptibility for ventricular fibrillation (VF) during acute myocardial infarction (AMI). The association of rs2824292 could be confirmed in a second cohort. Both cohorts were from the Netherlands. We aimed to replicate this association in a German cohort of AMI patients with or without VF., Methods: We included a German cohort of 90 individuals with AMI and VF (cases) and 167 AMI individuals without VF and used Taqman assays for SNP typing., Results: None of the loci showed evidence for a statistically significant association with VF. The observed genotype frequencies of the three loci were in Hardy-Weinberg equilibrium, which essentially excludes genotyping errors., Conclusions: In contrast to the data from the Netherlands, we could not detect a significant association of the rs2824292 locus and risk of VF during AMI in our German cohort. Differences in recruitment and clinical phenotypes between the Dutch and German cohorts may underlie different genotype associations.

Unlabelled: The P-Selectin Gene Polymorphism Val168Met., Aims: Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death (SCD). Family history of SCD is described as risk factor for primary VF during acute AMI. Genetic factors may be associated with primary VF. We examined polymorphisms in genes related to the activation and adhesion of blood platelets in patients with and without VF in the setting of AMI and among healthy controls., Methods: Two hundred and forty patients with a history of AMI and 475 healthy controls were studied. Seventy-three patients (30%) had primary VF during AMI. By using PCR techniques with sequence-specific primers (PCR-SSP), we genotyped 5 single nucleotide polymorphisms (SNPs) in P-selectin (SELP) (V168M, S290N, N592D, V599L, T715P), 2 SNPs (M62I, S273F) in P-selectin glycoprotein ligand-1 (SELPLG), 5 SNPs in CD40LG (-3459A>G, -122A>C, -123A>C, 148T>C, intr4-13T>C), the H558R SNP in SCN5A, and rs2106261 in ZFHX3. In addition, length polymorphisms in SELPLG (36bp-tandem repeat) and CD40LG (CA-repeat) were genotyped by PCR methods. Results were evaluated by 2-sided t-tests, chi-square tests, and logistic regression analysis., Results: None of the gene polymorphisms showed significant differences between AMI patients and healthy controls. Among patients with a history of VF, however, the SELP 168M variant showed a significantly higher prevalence (14/73 patients; 19.2%) as compared with patients without VF (13/167 patients; 7.8%; P < 0.01). This association remained significant in a logistic regression analysis after adjustment for age and gender (P = 0.013; odds ratio 2.8; 95% confidence interval 1.2-6.3)., Conclusions: This is the first description of an association of the SELP gene variant 168M with primary VF during acute MI. This variant may be a candidate polymorphism for evaluating the susceptibility for VF in the setting of acute MI., (© 2010 Wiley Periodicals, Inc.)

Background: The widespread use of primary coronary intervention (PCI) has significantly improved the prognosis of men presenting with acute coronary syndromes, but the cardiovascular event rate among women has either levelled off or increased. The purpose of the present prospective study was to compare the clinical outcome of women and men presenting with ST-elevation myocardial infarction (STEMI) undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors., Methods: Between January 2006 and December 2007, 297 consecutive patients presenting with STEMI were prospectively included in this single center investigation. Overall, 82 (27.6%) women and 215 (72.4%) men were treated by PCI with additional bare metal stent implantation and a GP IIb/IIIa inhibitor., Results: Women were significantly older (65 ± 10 vs 60 ± 12 years, p = 0.04), presented with a smaller reference luminal diameter (2.83 ± 0.51 vs 2.94 ± 0.43, p = 0.03) and had a higher prevalence of hypertension (68% vs 53%, p = 0.025) and obesity (30% vs 18%, p = 0.03). The incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularization and coronary artery bypass graft) during long-term follow-up was similar in women and men (20% vs 26%, p = 0.29). Age, C-reactive protein, platelet count and cardiogenic shock were identified as independent predictors for MACE, whereas gender was not predictive., Conclusions: In this study, female gender did not emerge as an independent predictor for MACE, but women presenting with STEMI had a higher cardiovascular risk profile; this emphasizes the need for a more extensive therapeutic strategy. Combination therapy with primary PCI and GP IIb/IIIa inhibitors might mitigate gender-related differences in clinical outcomes.

Background: Percutaneous coronary intervention (PCI) with stent implantation is considered to be the standard treatment in patients presenting with ST-elevation myocardial infarction (STEMI). According to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for STEMI, there is a class IIa recommendation (treatment reasonable) for platelet glycoprotein (GP) IIb/IIIa inhibitors. This study aims to compare the clinical outcome of patients with and without diabetes, presenting with STEMI undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors in real clinical practice., Methods: Over the course of three years (2004-2006) 394 consecutive patients presenting with STEMI were included in this single centre experience. There were 95 patients (24%) with, and 299 patients (76%) without, diabetes. A GP IIb/IIIa inhibitor was administered to all patients without contraindications (316 patients, 80%)., Results: Patients with diabetes were significantly older, more often suffered from hypertension and had a higher incidence of obesity. The rate of administration of GP IIb/IIIa inhibitors was similar in both groups (74% vs. 82%, p = 0.14). The in-hospital incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularisation and coronary artery bypass graft) was similar in both patient groups (18 [19%] diabetics vs. 51 [17%] non-diabetics, p = 0.65). Hypertension, age and obesity were identified as predictors for MACE, whereas diabetes was not predictive., Conclusions: In this single centre experience, in diabetic and non-diabetic patients presenting with STEMI, combination therapy with primary PCI and GP IIb/IIIa inhibitors might have contributed to a similar clinical outcome.

Background: An important role in the acceleration of vascular disease has been previously suggested for advanced glycation end products. N(epsilon)-(carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined non-enzymatic glycation and glycoxidation reactions. CML reacts with the receptor of advanced glycation end products inducing impairment of endothelium dependent relaxation and is a marker of oxidative stress., Methods: A total of 40 patients with acute myocardial infarction (17 patients with ST-elevation myocardial infarction, 23 patients with non-ST-elevation myocardial infarction) and 40 patients with stable coronary artery disease were included consecutively in this study. During coronary angiography, peripheral venous blood sample was taken for measuring CML., Results: Serum levels of CML were significantly increased in patients with acute myocardial infarction [17.9+/-10.7 vs. 6.6+/-3.1 arbitrary units (AU)/mg protein, p<0.001]. A cut-off value of CML>9.5 AU/mg protein was associated with an odds ratio of acute myocardial infarction of 39.7 [95% confidence interval (CI): 11.1-142, p<0.001], a sensitivity of 0.85 (95% CI: 0.70-0.94) and a specificity of 0.88 (95% CI: 0.73-0.96)., Conclusions: CML levels are significantly elevated in patients presenting with acute myocardial infarction. These results suggest the involvement of endothelial dysfunction (through receptor interaction) and oxidative stress in acute myocardial infarction.

Aims: Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death. A potential role of intrinsic, subclinical inflammatory states in patients suffering from ischemia-related VF has not been investigated yet. The aim of the present study was (i) to examine serum levels of proinflammatory markers in VF survivors and (ii) to evaluate basal and lipopolysaccharide (LPS)-stimulated interleukin-8-mRNA (IL-8-mRNA) levels in patients with and without VF complicating AMI., Methods: Twenty-five patients with a history of VF during AMI and a control group of 25 AMI patients without VF were included. Blood samples were taken remote from AMI with a mean of 590 days. Circulating serum levels of IL-8, IL-6, soluble E-selectin (sE-selectin), tissue factor activity (TFA), tissue inhibitor of matrix-metalloproteinase-1 (TIMP-1) and matrix-metalloproteinase-9 (MMP-9) were measured. Mononuclear cells were isolated by density gradient centrifugation. The cells were stimulated with lipopolysaccharide (LPS) from Escherichia coli (700 ng/mL). IL-8-mRNA levels in mononuclear cells were determined by a colorimetric mRNA quantification assay., Results: Serum levels (median; range) of IL-8 (VF: 2.24 pg/mL; <0.10-19.3 pg/mL versus controls: 0.10 pg/mL; <0.10-7.7 pg/mL; p=0.014), IL-6 (VF: 0.68 pg/mL; <0.05-2.9 pg/mL versus controls: 0.23 pg/mL; <0.05-1.8 pg/mL; p=0.042) and TIMP-1 (VF: 229 ng/mL; 144-348 ng/mL versus controls: 186 ng/mL; 126-263 ng/mL; p=0.014) were significantly higher among patients with VF as compared to controls. Baseline IL-8-mRNA concentrations of blood mononuclear cells were significantly higher among patients with VF (257 amol/mL; 52-2672 amol/mL) as compared to patients without VF (37 amol/mL, 3.2-770 amol/mL; p<0.01). IL-8-mRNA levels after LPS-challenge were significantly higher among patients with VF (3503 amol/mL; 215-13,573 amol/mL) than in patients without VF (1003 amol/mL; 208-3386 amol/mL; p<0.01)., Conclusions: Circulating IL-8, IL-6, and TIMP-1 concentrations as well as IL-8-mRNA expression in mononuclear cells at baseline and after LPS-challenge are increased among patients with a history of VF in the setting of AMI as compared to patients without VF. These findings indicate an enhanced inflammatory response to a proinflammatory stimulus in VF survivors. The magnitude of this increased acute phase reactants may indicate a novel pathway of arrhythmogenesis in patients with AMI.

Introduction: Acute myocardial infarction, often occurring postprandially, can be complicated by ventricular fibrillation. The role of acute alimentary lipemia and inflammation in the occurrence of ventricular arrhythmias in acute myocardial infarction has not been described yet., Methods and Results: Before and 2 h after consumption of a defined fatty meal, blood samples of 27 patients with a history of acute myocardial infarction (AMI) were incubated with lipopolysaccharide (LPS). In 10 patients, AMI was complicated by ventricular fibrillation (VF), in 17 patients, AMI occurred without VF. CD40-ligand and CD62P expression on platelets, tissue-factor binding on monocytes and platelet-monocyte aggregates were measured with flow cytometry. Soluble CD40-ligand plasma levels were measured with an ELISA. With the meal, serum triglyceride levels increased from 211.85+/-94.60 mg/dl to 273.59+/-122.52 mg/dl (p=0.0002). LPS stimulation before the meal showed a non-significant tendency to increase platelet-monocyte aggregates and tissue factor on monocytes in both patient groups. LPS stimulation in acute alimentary lipemia significantly increased tissue-factor expression on monocytes in both patient groups and platelet-monocyte aggregates in patients with VF. Baseline plasma levels of soluble CD40L did not differ significantly between both groups. Acute alimentary lipemia significantly decreased total plasma levels of sCD40L, leading to a significantly lower level of sCD40L in patients with a history of VF., Conclusions: Alimentary lipemia enhances procoagulatory effects of inflammatory stimulation in patients with a history of AMI complicated by ventricular fibrillation. These observations might reveal a mechanism for an increased risk of VF in acute coronary syndromes in a postprandial state.

Background: Atherosclerotic plaques prone to cause thrombotic complications and plaque rupture account for the majority of fatal myocardial infarctions (MI), which may be complicated by ventricular fibrillation (VF). Matrix-degrading metalloproteinases (MMPs) and their inhibitors (TIMPs) are expressed in atherosclerotic lesions and contribute to plaque vulnerability. Interleukin-8 (IL-8) is one of the predominant chemokines interacting with MMPs and TIMPs and the coagulation system. The aim of the present study was to assess potential differences of levels of MMP-9, TIMP-1 and IL-8 in postmyocardial infarction patients with or without VF complicating acute MI., Methods: Blood samples were taken from 45 patients with VF complicating acute MI and from 88 patients without VF. All samples were collected during a symptom-free interval remote from the acute ischemic event with a median of 556 days. The markers of interest were TIMP-1, MMP-9 and IL-8., Results: IL-8 and TIMP-1 levels were significantly higher among patients with VF than among patients without VF (p<0.001). In a logistic regression approach IL-8 was an independent indicator of patients prone to VF during MI (p=0.03). High levels of TIMP-1 (p=0.05), MMP-9 (p=0.03), the MMP-9/TIMP-1 ratio (p=0.049) and hypertension (p=0.02) were found to be indicators in patients with reinfarction or unstable angina pectoris during follow-up. Hypertension (p=0.02) and MMP-9 (p=0.03) were the only significant indicators characterizing patients undergoing coronary reinterventions, such as percutaneous coronary interventions and coronary bypass surgery., Conclusions: Higher TIMP-1 and IL-8 levels are present in patients with VF complicating MI. High TIMP-levels may be related to the degree of fibrosis which is a substrate for electrical instability and may contribute to the occurrence of VF. Patients prone to develop VF during MI seem to have an increased proinflammatory condition compared to patients without VF.

Background: Acute myocardial infarction can be complicated by ventricular arrhythmias due to electrophysiological changes in the ischemic myocardium, but the exact predisposing factors causing ventricular fibrillation during myocardial infarction still remain unclear. A role of inflammatory stimulation on platelets as a potential risk factor for ventricular fibrillation during acute myocardial infarction has not been described yet., Methods and Results: Whole blood samples of 21 patients with a history of acute myocardial infarction (AMI) and ventricular fibrillation (VF) were incubated with lipopolysaccharide (LPS). As a control group, we studied 19 patients without VF during AMI. CD40-ligand and CD62P expression on platelets and tissue factor binding on monocytes were measured by flow cytometry. Platelet-monocyte aggregates were measured by CD41 expression on platelets adherent to monocytes. Soluble CD40-ligand plasma levels were measured with an ELISA. Without LPS, no significant difference between the patient groups concerning CD40L expression on platelets was observed, but plasma levels of soluble CD40L were significantly higher in patients with a history of AMI with VF. After LPS stimulation, patients with a history of VF showed a significantly increased expression of CD40L in comparison to the patients without ventricular fibrillation, based on a significantly higher increase of CD40L expression. CD62P expression on platelets was significantly increased in patients with a history of VF., Conclusions: Patients with a history of VF complicating AMI show an enhanced expression of CD40L on platelets after in vitro lipopolysaccharide-challenge with an enhanced platelet activation.

Background: Indicators of coagulation and inflammation are elevated in patients with coronary heart disease. A role of coagulation activation in ventricular fibrillation during acute myocardial infarction has not been described., Methods and Results: Whole blood samples of 21 patients with a history of acute myocardial infarction complicated by ventricular fibrillation and whole blood samples of 18 patients without ventricular fibrillation were incubated with lipopolysaccharide (LPS). In both groups, the in vitro blood coagulation time was measured with the ReoRox, a viscometric whole blood coagulometer. CD62P expression on platelets, tissue-factor binding on monocytes, and platelet-monocyte aggregates were measured with flow cytometry. Without LPS, no difference in the coagulation times were observed in both patient groups. After incubation with LPS, patients with a history of ventricular fibrillation showed a significantly decreased coagulation time compared to patients without ventricular fibrillation. The decrease of coagulation time after incubation with LPS also differed significantly in both groups. Expression of CD62P on platelets was significantly higher in patients with a history of ventricular fibrillation after incubation with LPS. Although in each patient group incubation with LPS induced a significantly increased amount of tissue factor on monocytes and a significantly increased the number of platelet-monocyte aggregates, the two groups did not differ significantly concerning tissue factor binding on monocytes and the amount of platelet-monocyte aggregates., Conclusions: After in vitro LPS challenge, patients with a history of ventricular fibrillation during myocardial infarction show an enhanced coagulation activation, which may partly be due to an enhanced platelet activation.

Abstract: Background: Retinal microvascular changes predict cardiovascular morbidity and mortality independent of classical risk factors. However, it is unclear which retinal changes characterize patients with established coronary artery disease (CAD), and in particular, with acute coronary syndromes (ACS). The aim of the present preliminary study was to assess retinopathy in these patients. Methods: 43 consecutive patients with ACS and 19 consecutive patients with stable CAD were investigated. Among the patient group with ACS, 20 patients presented with ST-Elevation Myocardial Infarction (STEMI) and 23 patients presented with Non-STEMI (NSTEMI). Standardized protocols were used and retinal fundus photography was taken within 48 h post-coronary angiography to assess retinopathy and general arteriolar narrowing as arterio-venous ratio (AVR). Clinical and laboratory cardiovascular risk factors were recorded. Results: Despite comparable age and comparable frequency of diabetes and hypertension, patients with ACS had a much higher likelihood for retinal microaneurysms and dot bleedings than patients with stable CAD (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43–96.59; p=0.006). Performing multivariate analysis, this association remains significant (OR 20.5, 95%CI 1.6–255, p=0.019). CAD patients presented more often with focal signs of arteriovenous nicking / focal vasoconstriction (10 (53%) vs. 9 (21%) patients, OR 4.2; 95%CI 1.31–13.4; p=0.018), however after multivariate analysis this association lost significance. The AVR was comparably low in both groups. Conclusion: Patients with ACS present more often with dot bleedings and microaneurysms. These findings provide preliminary evidence that retinal fundus examination may be useful to contribute to the risk profile of patients, enabling a more intensive survey and care. [Copyright &y& Elsevier]