Enoxaparin injection for the treatment of high-risk patients with non-ST elevation acute coronary syndrome

Non-ST elevation acute coronary syndrome (NSTE-ACS) refers to a cardiovascular disorder characterized by intracoronary thrombus formation on a disrupted atherosclerotic plaque with partial or transient occlusion. Generation of thrombin resulting from exposure of collagen leads to activation of platelets and conversion of fibrinogen to fibrin, thus forming a platelet-rich thrombus. The main therapeutic objective is to protect the patient from thrombotic complications, independent of the choice of antithrombotic agents. The management of NSTE myocardial infarction (MI) is constantly evolving. For primarily conservative strategy, enoxaparin has been proven superior to unfractioned heparin (UFH). With early invasive strategy providing better clinical outcome compared with conservative strategy, the effectiveness of enoxaparin in reducing death and MI rates is now being reconsidered in the era of poly-pharmacotherapy, early percutaneous coronary interventions and drug eluting stents. Bleeding complications can be minimized by avoiding cross-over from UFH to enoxaparin or vice versa, or by reducing the dosage of enoxaparin. We review the studies of enoxaparin and discuss its current role in the contemporary treatment of NSTE-ACS

Platelet activation and thrombus formation relates to the presence of myocardial inflammation in patients with cardiomyopathy

AbstractBackgroundPatients with cardiomyopathy show a significantly increased risk for thromboembolic events due to a hypercoagulable state and platelet dysfunction. The pathophysiologic mechanism underlying the increasing platelet activity in patients with cardiomyopathy remains unclear. We performed a clinical study to elucidate the link between myocardial tissue alterations and platelet activation in patients with cardiomyopathy.MethodsA total of 30 patients with suspected cardiomyopathy and 10 healthy control patients were included in our study. Hemodynamic parameters were measured by catheterization and echocardiography. Endomyocardial biopsies were taken to determine myocardial inflammation. Flow cytometry was performed to examine the platelet activation by quantification of p-selectin and thrombospondin expression on platelets.ResultsThe p-selectin (8.46±3.67AU) and thrombospondin (26.56±23.21AU) expression was significantly correlated with the amount of CD3+ T cells (p-selectin: r=0.573, p<0.05; thrombospondin: r=0.488, p<0.05) and the endothelial/interstitial activation (p-selectin: r=0.521, p<0.05; thrombospondin: r=0.39, p<0.05). This was found to be independent of hemodynamic parameters, age, and gender. The platelet activation of patients (n=3) with echocardiographically documented ventricular thrombi was significantly increased (p-selectin: 12.57±5.5AU vs. 8.1±3.2AU, p<0.05) and this was associated with elevated myocardial inflammation scores.ConclusionMyocardial inflammation is associated with a significant increase in platelet activation and ventricular thrombus formation independently of the hemodynamic conditions

Quantification of Circulating Endothelial Progenitor Cells Using the Modified ISHAGE Protocol

Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data.In 25 control subjects, 65 patients with coronary artery disease (CAD; 40 stable CAD, 25 acute coronary syndrome/acute myocardial infarction (ACS)), EPC were quantified using the following approach: Whole blood was incubated with CD45, KDR, and CD34. The ISHAGE sequential strategy was used, and finally, CD45(dim)CD34(+) cells were quantified for KDR. A minimum of 100 CD34(+) events were collected. For comparison, CD45(+)CD34(+) and CD45(-)CD34(+) were analysed simultaneously. The number of CD45(dim)CD34(+)KDR(+) cells only were significantly higher in healthy controls compared to patients with CAD or ACS (p = 0.005 each, p<0.001 for trend). An inverse correlation of CD45(dim)CD34(+)KDR(+) with disease activity (r = -0.475, p<0.001) was confirmed. Only CD45(dim)CD34(+)KDR(+) correlated inversely with the number of diseased coronaries (r = -0.344; p<0.005). In a second study, a 4-week de-novo treatment of atorvastatin in stable CAD evoked an increase only of CD45(dim)CD34(+)KDR(+) EPC (p<0.05). CD45(+)CD34(+)KDR(+) and CD45(-)CD34(+)KDR(+) were indifferent between the three groups.Our newly established protocol adopted from the standardised ISHAGE protocol achieved higher accuracy in EPC enumeration confirming previous findings with respect to the correlation of EPC with disease activity and the increase of EPC during statin therapy. The data of this study show the CD45(dim) fraction to harbour EPC

Circulating Progenitor Cell Count for Cardiovascular Risk Stratification: A Pooled Analysis

Background: Circulating progenitor cells (CPC) contribute to the homeostasis of the vessel wall, and a reduced CPC count predicts cardiovascular morbidity and mortality. We tested the hypothesis that CPC count improves cardiovascular risk stratification and that this is modulated by low-grade inflammation. Methodology/Principal Findings: We pooled data from 4 longitudinal studies, including a total of 1,057 patients having CPC determined and major adverse cardiovascular events (MACE) collected. We recorded cardiovascular risk factors and high-sensitive C-reactive protein (hsCRP) level. Risk estimates were derived from Cox proportional hazard analyses. CPC count and/or hsCRP level were added to a reference model including age, sex, cardiovascular risk factors, prevalent CVD, chronic renal failure (CRF) and medications. The sample was composed of high-risk individuals, as 76.3% had prevalent CVD and 31.6% had CRF. There were 331 (31.3%) incident MACE during an average 1.7±1.1 year follow-up time. CPC count was independently associated with incident MACE even after correction for hsCRP. According to C-statistics, models including CPC yielded a non-significant improvement in accuracy of MACE prediction. However, the integrated discrimination improvement index (IDI) showed better performance of models including CPC compared to the reference model and models including hsCRP in identifying MACE. CPC count also yielded significant net reclassification improvements (NRI) for CV death, non-fatal AMI and other CV events. The effect of CPC was independent of hsCRP, but there was a significant more-than-additive interaction between low CPC count and raised hsCRP level in predicting incident MACE. Conclusions/Significance: In high risk individuals, a reduced CPC count helps identifying more patients at higher risk of MACE over the short term, especially in combination with a raised hsCRP level

investigations of humorla and cellular factors of endothelial damage and regeneration

In der vorgelegten Arbeit werden Ergebnisse zu dem Forschungsschwerpunkt der endothelialen Schädigung und Regeneration beim Menschen vorgelegt. Das Verständnis über den Einfluss von Faktoren auf das Endothel hat sich im Laufe der Jahre, in dem diese Arbeit entstand, stark gewandelt. Anfänglich herrschte die Vorstellung, dass lediglich so genannte „klassische Risikofaktoren“, wie Rauchen, Diabetes mellitus, Bluthochdruck, genetische Belastung und erhöhte Blutfette einen Einfluss auf das Endothel haben. Beim Menschen werden zur Messung der Endothelfunktion, deren Störung ein essentieller Schritt in der Pathogenese der Atherosklerose ist, Surrogatparameter wie die endothelabhängige Dilatation oder humorale und zelluläre Messgrößen herangezogen. Unmittelbare, lokale Flussverhältnisse schalten Gene in der Zelle an- oder aus und regulieren hierüber Funktionalität, programmierten Zelltod – die Apoptose-, das Zytoskelett, entzündliche Aktivierung oder Sekretion bestimmter endothelialer Faktoren. Dies beeinflusst entscheidend die Konzentration löslicher humoraler Faktoren wie VEGF und lösliches VCAM. Die Konzentration des löslichen Flt-1 im Blut, dem Antagonisten von VEGF, scheint keinen direkten Einfluss auf die Endotheldysfunktion zu haben. Für die Integrität des Endothels sind sowohl endotheliale Schädigung, wie auch das Ausmaß der endothelialen Regeneration entscheidend. Eine niedrige Anzahl zirkulierender Progenitorzellen, ein Surrogatparameter für die endotheliale Regeneration, hat einen wichtigen Einfluss auf, und ist prädiktiv, für das Auftreten zukünftiger kardiovaskulärer Komplikationen. Die endotheliale Regeneration einerseits und das Ausmaß der Endothelzellapotose andererseits lassen sich medikamentös durch Statine beeinflussen. Im Gegensatz hierzu hat die alleinige potente Lipidreduktion durch Ezetimibe keinen Einfluss auf die endotheliale Schädigung und Regeneration gehabt. Hierdurch wurde ein weiterer pleiotroper Effekt der Statine belegt. Das Endothel interagiert mit immunkompetenten Zellen. Hier kommt ihm eine Schlüsselrolle bei der chronischen subklinischen Transplantatabtoßung mit Entwicklung der Transplantatvaskulopathie zu. Es konnte gezeigt werden, dass die Zusammensetzung zirkulierender Lymphozyten nach Passage durch ein Transplantat beeinflusst wird, und dass es zu einer Migration von tolerogenen Zellen in das humane Transplantat kommt. Virale Infekte führen nicht nur unspezifisch zu einer vorübergehenden Schädigung und Aktivierung des Endothels. Durch Infektion mit dem humanen Parvovirus B19 ließen sich spezifisch Schädigung von reifen Endothelzellen, wie auch Beeinflussung der Zellen der endothelialen Regeneration nachweisen. Zusammmenfassend werden in dieser Arbeit Untersuchungen zu humoralen und zellulären Faktoren der endothelialen Schädigung und Regeneration bei Patienten mit atherosklerotischer und immunologisch bedingter endothelialer und kardialer Schädigung vorgestellt.In the provided paper results focussing on endothelial damage and regeneration in humans are presented. In humans surrogates such as measuring endothelial function, humoral or cellular factors give insight into the apthogenesis of atherosclerotic disease. As response to local or systemic damage, apoptosis and function of endothelial cells is altered, inflammatory activation occurs, as well as secretion of endothelial-specific factors. Thus, concentrations of soluble VCAM-1 or VEGF are modified according to physiological alterations of perfusion. Soluble flt-1, the antagonist of VEGF seems to be unrelated to endothelial dysfunction. Integrity of the endothelium is a result of endothelial damage and regeneration through circulating progenitor cells. Number of these cells have a direct prognostic effect on clinical outcome in ahterosclerosis. Endothelial regeneration is improved through statin therapy in patients with coronary artery disease. Transplant vasculopathy is a limiting step in long-term outcome after heart transplantation and tolerogenic cells are influenced after passage through the cardiac allograft. Finally, infection with parvovirus B19 has been shown to affect endothelial cell apoptosis and regeneration

Persistent weight loss with a non-invasive novel medical device to change eating behaviour in obese individuals with high-risk cardiovascular risk profile.

In evidence-based weight-loss programs weight regain is common after an initial weight reduction. Eating slowly significantly lowers meal energy intake and hunger ratings. Despite this knowledge, obese individuals do not implement this behaviour. We, thus tested the hypothesis of changing eating behaviour with an intra-oral medical device leading to constant weight reduction in overweight and obesity. Six obese patients (6 men, age 56 ± 14, BMI 29 ± 2 kg / m2) with increased CVRF profile were included in this prospective study. All patients had been treated for obesity during the last 10 years in a single centre and had at least 3 frustrate evidence-based diets. Patients received a novel non-invasive intra-oral medical device to slow eating time. Further advice included not to count calories, to avoid any other form of diet, to take their time with their meals, and to eat whatever they liked. This device was used only during meals for the first 4 to 8 weeks for a total of 88 [20-160] hours. Follow-up period was 23 [15-38] months. During this period, patients lost 11% [5-20%] (p5%, and 67% (4/6) achieved a >10% bodyweight loss. In the course of the study, altered eating patterns were observed. There were no complications with the medical device. Of note, all patients continued to lose weight after the initial intervention period (p<0.001) and none of them had weight regain. With this medical device, overweight and obese patients with a history of previously frustrating attempts to lose weight achieved a significant and sustained weight loss over two years. These results warrant the ongoing prospective randomised controlled trial to prove concept and mechanism of action.German Clinical Trials Register DRKS00011357

Telbivudine Reduces Parvovirus B19-Induced Apoptosis in Circulating Angiogenic Cells

Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (−39% and −40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease.Peer Reviewe

Interferon Beta Modulates Endothelial Damage in Patients with Cardiac Persistence of Human Parvovirus B19 Infection

Background: In a phase 1 study, we investigated whether interferon beta reduced endothelial damage in patients with cardiac persistence of human parvovirus B19 (B19V) infection. Methods and results: In vitro, B19V infected cultivated endothelial cells (ECs), which led to a reduction in their viability (Pp.007). Interferon beta suppressed B19V replication by 63% (Pp.008) in ECs and increased their viability (Pp.021). Circulating mature apoptotic ECs (CMAECs [CD45-CD146+ cells expressing von Willebrand factor and annexin V]) and circulating progenitor cells (CPCs [CD34+KDR+ cells]) were quantified by flow cytometry in 9 symptomatic patients with cardiac B19V infection before and after 6 months of interferon beta therapy (16 MU) and were compared to levels in 9 healthy control subjects. Endothelial dysfunction was measured using flow-mediated dilatation of the forearm. Patients with B19V persistence had significantly higher (Pp.004) levels of CMAECs than did control subjects, which normalized after treatment (mean standard deviation, 0.06%-0.08% vs 0.01%-0.006%; Pp.008). Similar improvement was shown for flow-mediated dilatation (Pp.04) in the treatment group only (Pp.017 for the comparison with untreated patients with B19V persistence [np5]). There were significantly higher numbers of CPCs in patients with B19V persistence before therapy (mean standard deviation, 0.04%-0.05% vs 0.01%-0.004%; Pp.02) than in control subjects, which normalized after treatment (Pp.03). Conclusion: Thus, we present (for the first time, to our knowledge) a modulation of virally induced chronic endothelial damage specifically, EC apoptosis and endothelial regeneration