Thomas W. Weiss

Catecholamines potentiate LPS-induced expression of MMP-1 and MMP-9 in human monocytes and in the human monocytic cell line U937: possible implications for peri-operative plaque instability

Plaque destabilization leading to myocardial infarction is observed after surgery even if the intervention is of noncardiovascular nature. Mediators of peri‐ or postoperative stress responsible for such events could include catecholamines and lipopolysaccharide (LPS). Monocytes may be involved in destabilization of atherosclerotic plaques by production of matrix metalloproteinases (MMP). We examined whether catecholamines could affect the expression of MMPs in human monocytes/macrophages and whether catecholamines could modulate LPS‐stimulated expression of particular MMPs in these cells. Epinephrine and norepinephrine up‐regulated MMP‐1 and potentiated LPS‐induced expression of MMP‐1 in peripheral blood monocytes and monocyte‐ derived macrophages. We further characterized this effect employing the monocytic cell line U937 and showed that catecholamines potentiate LPS‐induced effects on MMP‐1 and MMP‐9 antigen and activity. mRNA levels of the respective MMPs also increased. These effects did not result from higher mRNA stability but rather from increased transcription possibly induced by enhanced DNA binding of AP‐1 and were mediated by either β1‐ or β2‐receptors. If this mechanism is also effective in vivo, our findings might, at least in part, help to explain the observation that cardiac events are important causes of morbidity and mortality after noncardiac surgery and support the findings that peri‐operative β‐blockade has been shown to reduce postoperative mortality from cardiac events.

Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis

Contemporary medicine is shifting towards person rather than disease-oriented care.1 With increasing life expectancy and the ageing of baby boomers, the proportion over 60 years is growing faster than the overall population, with worldwide estimates reaching 2 billion by 2050 (http://www.un.org/esa/population/publications/worldageing19502050).2 In parallel, acute coronary syndromes (ACS) and atrial fibrillation (AF)—the most frequent indications for dual platelet inhibition or anticoagulation—occur mostly in older patients.2–6 There is general agreement that people ≥75 years can be defined ‘elderly’; however, cutoffs as low as 65 years have been applied to important clinical datasets and risk scores.3,7–10 Moreover, ageing is a continuous process and life-span expansion is deflating (http://www.nber.org/papers/w18407). For these reasons, a threshold to define ‘elderly’ has been intentionally avoided in this document. Of note, over one third of patients admitted with acute myocardial infarction (MI) and two thirds dying from MI are over 75 years, but <7% of patients in ACS trials are reported ≥75 years.11 Older patients have multi-organ changes, increased risk of both bleeding and ischaemic events,3,5,12 frequent comorbidities/comedication, and reduced adherence to prescriptions. Given the challenges of antithrombotic treatment in the elderly, the European Society of Cardiology (ESC) Working Group on Thrombosis gathered a task group to address the topic.nnAntiplatelet, anticoagulant, and fibrinolytic drugs can prevent, postpone, or attenuate the severity of thrombotic events—namely stroke, transient ischaemic attack (TIA), MI, systemic embolism (SE), deep vein thrombosis (DVT), or pulmonary embolism (PE)—and retard cardiovascular and all-cause death, but at the cost of increased bleeding. The critical conundrum is whether, in the older patient, the benefits outweigh the …

The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-κB activation

Summary.u2002 Background: Atherosclerosis is considered to be a chronic inflammatory disorder. Activation of the complement cascade is a major aspect of chronic inflammatory diseases. Complement components were identified in atherosclerotic plaques, and a correlation between adverse events and C5a plasma levels was found. These findings support the notion that complement activation contributes to development and progression of atherosclerotic lesions. Objectives: We investigated whether complement components C3a and C5a regulate plasminogen activator inhibitor (PAI‐1) in human macrophages. Methods: Human monocyte‐derived macrophages (MDM) and human plaque macrophages were cultured and incubated with the complement component C5a. Results: C5a increased PAI‐1 up to 11‐fold in human MDM and up to 2.7‐fold in human plaque macrophages. These results were confirmed at the mRNA level using real time‐polymerase chain reaction. Pertussis toxin or anti‐C5aR/CD88 antibody completely abolished the effect of recombinant human C5a on PAI‐1 production, suggesting a role of the C5a receptor. Experiments with antitumor necrosis factor (TNF)‐α antibodies and tiron showed that the effect of C5a was not mediated by TNF‐α or oxidative burst. Furthermore C5a induced NF‐κB binding to the cis element in human macrophages and the C5a‐induced increase in PAI‐1 was completely abolished by an NF‐κB inhibitor. Conclusions: We conclude that C5a upregulates PAI‐1 in macrophages via NF‐κB activation. We hypothesize that – if operative in vivo– this effect could favor thrombus development and thrombus stabilization in the lesion area. On the other hand one could speculate that C5a‐induced upregulation of PAI‐1 in plaque macrophages could act as a defense mechanism against plaque destabilization and rupture.

Components of the Interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness

OBJECTIVEnThe metabolic syndrome (MetS) is an increasing epidemiologic challenge and cardiovascular risk factor. Interleukin-6 (IL-6) is a cytokine that exerts its biological function via a complex orchestration of soluble and membrane bound receptors. We have investigated associations between IL-6 and its soluble receptors, soluble IL-6 receptor (sIL-6r) and soluble glycoprotein 130 (sGP130) and the metabolic syndrome. Furthermore, we have investigated possible associations with endothelial dysfunction and arterial stiffness.nnnMETHODSnA total of 563 subjects were included in this study. The Adult Treatment Panel III criteria of the National Cholesterol Education Program were used for the definition of MetS. We used commercially available ELISA to analyse circulating levels of the markers. Pulse wave propagation time (PWP) was determined to assess arterial stiffness.nnnRESULTSnThe criteria for having MetS were filled by 221 subjects. sGP130, sIL-6r and IL-6 levels were elevated in subjects with MetS (p<0.05 for all markers), and are associated with increasing components of MetS. Particularly hypertriglyceridaemia, hypertension and fasting plasma glucose (FPG) seem to carry this association. sGP130 (p<0.01), IL-6 (p<0.05) and partially sIL-6r (p<0.05) correlated with markers of endothelial function (E-selectin, I-CAM-1, V-CAM-1) and inversely with PWP after adjustment for relevant covariates.nnnCONCLUSIONnsGP130, sIL-6r and IL-6 were significantly elevated in subjects with MetS. In addition, sGP130, IL-6 and partially sIL-6r were associated with markers of endothelial function and arterial stiffness. This finding sheds new light on the role of these inflammatory cytokines in subjects with MetS and the development and progression of clinically silent atherosclerosis.

Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis

Bleeding is a frequent complication of the management of patients with coronary artery disease (CAD), especially those presenting with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI), and of patients with atrial fibrillation (AF). Randomized trials have shown a risk of major bleeding of 1–8% at 30 days in ACS patients,1–5 and of 2–5% per year in patients with AF treated with oral anticoagulants (OACs).6 Observational studies suggest that bleeding risk is even higher.7 Major bleeding is associated with a subsequent increase in both short- and long-term mortality.7–13 Even minimal bleeding may have prognostic importance because it frequently leads to disruption of antithrombotic therapy.14,15nnSeveral mechanisms have been put forward to explain the relationship between major bleeding and increased mortality ( Figure 1 ). The overlap in risk factors for bleeding and ischaemic events means that patients who are more likely to suffer from bleeding complications of antithrombotic therapy also tend to be at higher risk of thrombotic events.16 Discontinuation of antithrombotic drugs may lead to an increased rate of thrombotic events due to the progressive recovery of platelet function and coagulation activity.17–19 In addition, bleeding may provoke prothrombotic responses beyond those related to discontinuation of antithrombotic drugs.20,21 Clearly, balancing the risks of further bleeding vs. potentially fatal thrombotic events is critical for decisions about if and when to restart antithrombotic therapy after bleeding. nnnnFigure 1 nHypothetical mechanisms linking bleeding to thrombotic events and death. Numerous risk factors for bleeding are also risk factors for myocardial infarction, stroke and death (large arrows).nnVTE, venous thromboembolism.nnnnAlthough several recommendations have been published dealing with the acute management of bleeding in patients treated with antithrombotic drugs,22–24 there is an unmet need for guidance on how to manage antithrombotic therapy after bleeding …

Myocarditis in a juvenile patient with influenza A virus infection

A 19-year-old previously healthy male was admitted with acute chest pain and electrocardiographic ST-elevation ( Panel A ). He reported headaches and dry coughs but no fever during the last week before admission. No other relevant medical history or drug intake was reported. Coronary angiography demonstrated open arteries. Left ventriculography showed slight …

The honey man — Second degree heart block after honey intoxication

In October 2007, a 70-year-old Turkish patient presented to the emergency department of a Viennese state hospital with syncope. The electrocardiogram showed a second degree heart block type Wenckebach with intermittent 2:1 conduction and preterminal negative T waves. There was no biochemical evidence of an acute ischemic cardiac event or any electrolyte imbalance. A coronary angiogram showed no evidence for coronary artery disease. During the first day of hospital admission, a jar of home made honey from the Black Sea region of Turkey is brought to the hospital by relatives of the patient. A commonly used household remedy in the eastern Black Sea region of Turkey, bitter honey or mad honey contains grayanotoxin from the nectar of Rhododendron luteum and Rhododendron ponticum. This is the first documented case of honey poisoning in the European Union where structural and ischemic causes have been excluded as possible reasons for the temporary AV-block. This case serves as a poignant reminder that physicians must demonstrate awareness of the cultural, social, and in this case toxicological, particularities of patients within immigrant populations.

IL-6 signalling in patients with acute ST-elevation myocardial infarction

Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI. In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state. In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated.

Genetic variation, gene-expression and circulating levels of matrix metalloproteinase-9 in patients with stable coronary artery disease.

BACKGROUNDnMediators involved in atherosclerosis and plaque rupture may have importance as risk markers for coronary artery disease (CAD). We have investigated the influence of matrix metalloproteinase (MMP)-9 genetic variations on gene- and protein expression in stable CAD patients.nnnMETHODSnThe promoter -1562C/T and exon 6 R279Q A/G polymorphisms were determined in 1001 patients with angiographically verified stable CAD and in 204 healthy controls. Genotype and gene-expression were determined by real-time PCR. Serum levels of MMP-9 and its inhibitor TIMP-1were measured immunologically and by zymography (MMP-9 activity).nnnRESULTSnNone of the polymorphisms associated with the presence of CAD, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p=0.015). The T- and G alleles associated with lower and higher mRNA levels, respectively (p<0.005 both), also shown in an experimental ex-vivo LPS stimulated model. T-allele carriers had higher concentrations of MMP-9 (adjusted p=0.032) and the GG genotype induced lower MMP-9 gelatinolytic activity (p=0.01). Higher MMP-9 gene-expression and TIMP-1 levels were observed in patients with previous myocardial infarction, the latter also was elevated in diabetics (<0.05, all).nnnCONCLUSIONnThe investigated MMP-9 polymorphisms influenced gene- and protein expression differently and the R279Q polymorphism associated significantly with hypertension.

Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes

BackgroundTissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population.MethodsPatients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5upstream region and the TFPI -33T/C in intron 7.ResultsNo significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type-2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both).The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both).ConclusionGenetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.