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SummaryNovel strategies for a tailored risk prediction in chronic heart failure (CHF) are crucial to identify patients at very high risk for an improved patient management and to specify treatment regimens. Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism with the ability to counteract endothelial injury and the possibility of new vessel formation. We hypothesised that exhaustion of circulating EPCs may be a suitable prognostic biomarker in patients with CHF. EPCs, defined as CD34+CD45dimKDR+ cells, were analysed using fluorescence-activated cell sorting. EPCs were measured in 185 patients with CHF including 87 (47%) patients with ischaemic aetiology and 98 (53%) patients with non-ischaemic CHF and followed for a median time of 2.7 years. During this period, 34.7% of patients experienced the primary study endpoint all-cause mortality. EPC count was a significant and independent inverse predictor of mortality with an hazard ratio hazard ratio (HR) per increase of one standard deviation (1-SD) of 0.47 (95% confidence interval [CI]: 0.35–0.61; pSupplementary Material to this article is available online at www.thrombosis-online.com.

SummaryWe aimed to assess whether the CRUSADE risk score represents a robust instrument for stratification of bleeding risk in elderly myocardial infarction (MI) patients (≥80 years) and further aimed to identify age-specific predictors of major bleeding events. Binary logistic regression models were applied to assess the effect of variables on the occurrence of bleeding events during hospital stay. Receiver operating characteristic (ROC) analysis was used to evaluate the discriminatory power. Out of 387 patients in the final study cohort, 74 patients (19.1 %) experienced a major bleeding event according to the definition of the International Society on Thrombosis and Haemostasis. The CRUSADE risk score demonstrated only a weak discriminatory power to predict bleeding in this group of patients (area under the ROC curve: 0.57 [0.51–0.65]; p=0.05). In the multivariate regression analysis, history of bleeding with an adjusted hazard ratio (HR) of 3.21(95 % confidence interval: 1.29–8.03, p=0.01) and C-reactive protein with an adjusted HR per increase of 10 mg/l of 1.05 (1.01–1.10) were independent predictors of major bleeding. Integration of both variables into the CRUSADE score demonstrated a significantly improved performance for bleeding as indicated by a significant increase in the ROC analysis (area under the curve: 0.64 vs 0.57; for comparison p

SummaryCellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00–5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 % CI 1.45–4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

SummaryOxidative stress affects clinical outcome in patients with ST-elevation acute coronary syndrome (STE-ACS). Although high-density lipoprotein (HDL) particles are generally considered protective, deleterious properties of HDL have been observed in patients with acute myocardial infarction. Here, we analysed the association between pro oxidant HDL and all-cause mortality in STE-ACS patients. We determined the antioxidant function of HDL in 247 prospectively enrolled patients undergoing primary percutaneous coronary intervention for STE-ACS. Patients were stratified as by a pro-oxidant serum HDL oxidant index (HOI 1) or with an antioxidant serum HOI (HOL< 1) capacity. Multivariate regression analysis was used to relate HOI to survival. The median follow-up time was 23 months (IQR 14.4–40.0 months). Pro-oxidant HDL was observed in 44.1 % of STE-ACS patients and was independently associated with all-cause mortality with a hazard ratio of 3.30(95 %CI 1.50–7.27, p = 0.003). Mortality rates were higher in patients with baseline pro-oxidant HDL compared to patients with preserved HDL function at 30 days (11.9 % vs 2.2 %, p=0.002), and at 4 years (22.9 % vs 8.7 %, p=0.002). Elevated neutrophil counts were a strong and independent predictor for pro-oxidant HDL with an odds ratio per standard deviation of 1.50 (95 %CI 1.11–2.03, p=0.008), as was history of prior acute myocardial infarction, elevated triglycerides levels and reduced glomerular filtration rate. In conclusion, pro-oxidant HDL represents a strong and independent predictor of long-term as well as short-term all-cause mortality in STE-ACS patients. Elevated neutrophil counts predicted the presence of serum pro-oxidant HDL. The maintenance of HDL functions might be a promising therapeutic target in STE-ACS patients.

SummaryThe single nucleotide polymorphism (SNP) rs342293 has been shown to influence platelet number and mean platelet volume (MPV). We investigated the association between the rs342293 polymorphism and cardiovascular outcome in a prospective cohort study. The rs342293 polymorphism was analysed in 404 patients with coronary artery disease undergoing percutaneous coronary intervention. The rates of cardiac adverse events were recorded during two years of follow-up. The polymorphism was associated with MPV (median 10.1 fL, interquartile range [IQR]: 9.6 to 10.6 in patients with the CC-allele vs 10.4 fL, IQR: 9.9 to 11.1 in G>C SNP carriers; p

Purpose: Transtemporal sonothrombolysis is a tool for a more effective treatment in acute stroke patients. However, some reports revealed side effects, which might be potentially connected to temperature elevation. To gain better insight into cerebral temperature changes during transtemporal sonication, diagnostic and therapeutic ultrasound (US) applications were evaluated using an anthropomorphic skull model. Materials and Methods: The impact of diagnostic (PW-Doppler, 1.8-MHz, 0.11 W/cm², TIC 1.2) and therapeutic (1-MHz and 3-MHz, 0.07 – 0.71 W/cm², continuous and pulsed mode) US application on temperature changes was evaluated at the level of muscle/temporal bone (TB), TB/brain, brain and at the middle cerebral artery (MCA) using 4 miniature thermocouples along the US beam. Sonication lasted 120 minutes. Results: Diagnostic ultrasound revealed a maximum temperature increase of 1.45°/0.60°/0.39°/0.41°C (muscle/TB, TB/brain, brain, MCA) after 120 minutes. Therapeutic-1-MHz ultrasound raised temperature by 4.33°/2.02°/1.05 °C/0.81°C (pulsed 1:20) and by 10.38°/4.95°/2.43°/2.08°C (pulsed 1:5) over 120 minutes. Therapeutic-3-MHz US raised temperature by 4.89°/2.56°/1.24/1.25°C (pulsed 1:20) and by 14.77°/6.59°/3.56°/2.86°C (pulsed 1:5) over 120 minutes, respectively. Continuous application of therapeutic US (1-MHz and 3-MHz) led to a temperature increase of 13.86°/3.63°/1.66°/1.48°C and 17.09°/4.28°/1.38/0.99°C within 3 minutes. Conclusion: Diagnostic PW-Doppler showed only a moderate temperature increase and can be considered as safe. Therapeutic sonication is very powerful in delivering energy so that even pulsed application modes resulted in significant and potentially harmful temperature increases.

Summary Aim: We compared and delineated possible differences of model-based analysis of ECGgated SPECT using 99mTc-sestamibi (Tc- SPECT) with ECG-gated 18F-fluorodeoxyglucose- PET (FDG-PET) for determination of enddiastolic (EDV) and end-systolic (ESV) cardiac volumes, left ventricular ejection fraction (LVEF), and myocardial mass (LVMM). Patients, methods: 24 patients (21 men; age: 54 ± 12years) with coronary artery disease underwent Tc-SPECT and FDG-PET imaging for evaluation of myocardial perfusion and viability. By using model-based analysis EDV, ESV, LVEF and LVMM were calculated from short axis images of both Tc-SPECT and FDGPET. Results: Left ventricular volumes by Tc- SPECT and FDG-PET were 176 ± 60 ml and 181 ± 59 ml for EDV, and 97 ± 44 ml and 103 ± 45 ml for ESV respectively, LVEF was 47 ± 8% by Tc-SPECT and 45 ± 9% by FDG-PET. The LVMM was 214 ± 40 g (Tc-SPECT) and 202 ± 43 g (FDG-PET) (all p = NS, paired t-test). A significant correlation was observed between Tc-SPECT and FDG-PET imaging for calculation of EDV (r = 0.93), ESV (r = 0.93), LVEF (r = 0.83) and LVMM (r = 0.72). Conclusion: ECG-gated Tc-SPECT and FDG-PET using two tracers with different characteristics (perfusion versus metabolism) showed close agreement concerning measurements of left ventricular volumes, contractile function and myocardial mass by using a model-based analysis.

SummaryAcute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a logadditive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45–0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3–0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).

SummaryThe aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30–45% received BM-MNC by intramyocardial followed by intracoronary injection 68 ± 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 ± 10.7% to 24.1 ± 11.5%, pClinical Trials Gov Nr: NCT00384982.

SummaryAcute coronary syndrome is characterized by compromised blood flow at the epicardial and microvascular levels. We have previously shown that thrombectomy in ST-elevation myocardial infarction (STEMI) accelerates ST-segment resolution, possibly by preventing distal embolization. We hypothesized that thrombus constituents contribute to microcirculatory dysfunction. Therefore, we analyzed the molecular and cellular composition of acute coronary thrombi, and correlated vasoconstrictive mediators with the magnitude of ST-segment resolution within one hour of percutaneous coronary intervention (PCI). Fresh coronary thrombi were retrieved in 35 consecutive STEMI patients who were treated with the X-Sizer thrombectomy catheter, and thrombus cell counts and vasoconstrictor concentrations were assessed. Twelve-lead ECG recordings were analyzed prior to and one hour after PCI. Concentration of endothelin (ET) was 20.0 (7.9–52.2) fmol/ml in thrombus compared with 0.1 (0.1–0.3) fmol/ml in corresponding peripheral plasma (p

SummaryIn most studies showing cardio- and vasculoprotective effects of estrogens, 17β-estradiol was used and little information on possible effects of different estrogen metabolites is yet available. We investigated whether particular estrogen metabolites are effective in counteracting inflammatory activation of human endothelium. Human endothelial cells were incubated with 17α-dihydroequilenin, 17β-dihydroequilenin, δ-8,9-dehydroestrone, estrone and 17β-estradiol and stimulated with interleukin (IL)-1α.The expression of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) was determined. 17β-dihydroequilenin and 17β-estradiol at a concentration of 1µM reduced IL-1α-induced up regulation of IL-6, IL-8 and MCP-1 close to control levels. When both compounds were used in combination an additive effect was observed. 17α-dihydroequilenin and δ-8,9-dehydroestrone showed a similar anti-inflammatory effect only when used at 10µM whereas estrone had no effect. The effect of 17β-dihydroequilenin on IL-1α-induced production of IL-6, IL-8 and MCP-1 was reversed by the estrogen receptor antagonist ICI 182,780. 17β-dihydroequilenin also inhibited IL-1α-induced translocation of p50 and p65 to the nucleus of the cells. We have identified the estrogen metabolite 17β-dihydroequilenin, as an inhibitor of inflammatory activation of human endothelial cells. Characterization of specific estrogens – as shown in our study – could provide the basis for tailored therapies, which might be able to achieve vasoprotection without adverse side effects.

SummaryThe chemokine fractalkine (FKN) recruits leukocytes into lesions of the arterial wall, which may lead to restenosis after stenting. FKN also regulates proliferation of smooth muscle cells, another mechanism pivotal to neointimal thickening. We assessed the hypothesis that functionally important polymorphisms of the FKN receptor CX3CR1 influence restenosis after coronary stenting. Three hundred and sixty-five patients undergoing coronary stenting were genotyped for the CX3CR1 polymorphisms V249I and T280M. Restenosis occurred in 25% of patients, and recurrent (> 1) restenosis at the target lesion in 8%.The allele I249 was associated with an increased risk of restenosis (adjusted odds ratio 2.4, 95% confidence interval: 1.3–4.2,P = 0.003) and recurrent restenosis (odds ratio 2.7,95% confidence interval:1.3–5.9,P = 0.011).Particularly, patients with I249 lacking the allele M280 were at an elevated risk of restenosis (P = 0.006) and, accordingly, the haplotype containing I249 but not M280 was more frequent in patients with restenosis (P = 0.001). In conclusion, the CX3CR1 I249 allele is associated with an increased risk of restenosis while the CX3CR1 M280 allele might counteract the harmful influence of I249.These findings show the importance of the chemokine FKN and genetic variations of its receptor for restenosis after coronary stenting. Recognition of these inherited risk modifiers may help to individualize treatment of coronary stenosis.

SummarySeveral lines of evidence suggest that the chemokine fractalkine (FKN) and its receptor CX3CR1 contribute to the accumulation of leukocytes in the atherosclerotic plaque. The M280 allele of the CX3CR1T280M polymorphism modulates leukocyte recruitment and is associated with lower prevalence of cardiovascular disease. The influence of V249I, another CX3CR1 poly-morphism, is discussed controversially. We investigated the association of the alleles M280 and I249 of CX3CR1 with coronary artery disease (CAD) and with acute coronary syndrome (ACS). Additionally, we assessed their association with the soluble ligand FKN and inflammatory activation measured by high-sensitivity C-reactive protein (hsCRP). The genotypes of the V249I and T280M polymorphisms were determined in 1152 patients with suspected CAD. 720 (62.5%) individuals showed significant CAD with an ACS prevalence of 59.3%. Using multivariate regression, we found a harmful influence of I249 (adjusted OR=1.8, P

SummaryUltrasound of 2 MHz frequency and 1.2 W/cm2 acoustic intensity was applied to examine the effect of sonication on recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis as well as on the distribution of plasminogen and t-PA within whole blood clots in vitro. Thrombolysis was evaluated quantitatively by measuring clot weight reduction and the level of fibrin degradation product D-dimer (FDP-DD) in the supernatant. Weight reduction in the group of clots treated both with ultrasound and rt-PA was 35.2% ± 6.9% which is significantly higher (p

ZusammenfassungDie Thrombolysetherapie stellt wegen ihrer ubiquitären Zugänglichkeit und einfachen Applikationsweise einen Meilenstein in der Behandlung des akuten Myokardinfarktes dar. Mit dem natürlichen Gewebeplasminogenaktivator (t-PA) und seinen biochemisch modifizierten Varianten, die zumindest theoretisch bessere Eigenschaften aufweisen als die Muttersubstanz, stehen uns heute äußerst potente Fibrinolytika zur Verfügung. Andere neue Präparate wie z.B. Staphylokinase, Pro-Urokinase, oder der Vampir-Fledermaus-Plasminogen-Aktivator DSPA-alpha-1 stehen an der Schwelle zur kommerziellen klinischen Nutzung. Im vorliegenden Artikel wird besonders auf weitere Verbesserungsmöglichkeiten der Thrombolysetherapie, wie z. B. die Verkürzung der Zeitdauer Infarktbeginn - Lysebeginn, die Verbesserung der TIMI-Grad-3-Flußrate und die Optimierung der antithrombotischen Begleittherapie, eingegangen.

SummaryChronic thromboembolic pulmonary hypertension (CTEPH) is a disease resulting from the thromboembolic obstruction of the segmental and/or large size pulmonary arteries, subsequently leading to pulmonary arterial hypertension. Incomplete resolution of acute pulmonary emboli and thrombus organization are believed to be important for the development of the disease. Primary pulmonary hypertension (PPH) is a further disease that at present is poorly understood but shows a clinical picture similar to CTEPH. Since lipoprotein(a) [Lp(a)], a genetically determined risk factor for atherosclerosis and thrombosis, has been found increased in plasma of patients with deep vein thrombosis and pulmonary embolism, we measured plasma Lp(a) levels in 40 patients with CTEPH and 50 patients with PPH and compared them to 50 matched controls. The median for Lp(a) plasma levels was significantly higher in CTEPH patients (26.6 mg/dl) than in PPH patients (9.6 mg/dl) and controls (7.2 mg/dl). Increased plasma Lp(a) could, therefore, play a significant role in the mechanisms of ongoing thrombosis and thrombus organization in CTEPH, while its possible role in PPH can be limited to a small number of patients.