Activated protein C levels and outcome in patients with cardiogenic shock complicating acute myocardial infarction.

INTRODUCTION: In patients with severe sepsis, low levels of activated protein C are associated with high morbidity and mortality. In an observational study we investigated whether patients with cardiogenic shock have decreased circulatory levels of activated protein C, and if these are associated with increased mortality. METHODS: We measured serum activated protein C and interleukin-6 levels in 43 patients with cardiogenic shock following acute myocardial infarction and in 15 control patients with uncomplicated myocardial infarction at days 0-5 and 7 after the onset of shock/myocardial infarction. RESULTS: Activated protein C levels were significantly lower in patients with cardiogenic shock compared to controls. In cardiogenic shock patients, there was no difference in activated protein C levels at baseline, whereas activated protein C levels significantly declined in 28-day non-survivors at day 2, compared with 28-day survivors. Lower levels of activated protein C were associated with a higher degree of vasopressor need, whereas there was no significant association with multiple organ failure in the first days. Regarding the inflammatory response, a strong inverse correlation was observed between interleukin-6 and activated protein C levels. CONCLUSION: Patients with cardiogenic shock who did not survive up to 28 days showed a decline in activated protein C levels during the course of the disease, which was inversely correlated with interleukin-6. This study underlines sustained inflammatory mechanisms in the development and persistence of cardiogenic shock, highlighting a potential effect of anti-inflammatory interventions early during cardiogenic shock.

G-CSF Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease.

Granulocyte-colony-stimulating-factor (G-CSF) induces mobilization of progenitor cells but may also exert pro-inflammatory and pro-thrombotic effects. Treatment with recombinant G-CSF after acute myocardial infarction is currently under examination and has been associated with in-stent restenosis. However, it is not known whether plasma levels of endogenous G-CSF are also associated with an increased cardiovascular risk. Therefore we included 280 patients with angiographically proven stable coronary artery disease. G-CSF was measured by specific ELISA and patients were followed for a median of 30 months for the occurrence of major adverse cardiovascular events (MACE: death, myocardial infarction, re-hospitalization). Those with cardiac events during follow-up showed significant higher G-CSF levels (32.3 pg/mL IQR 21.4-40.5 pg/mL vs. 24.6 pg/mL IQR 16.4-34.9 pg/mL; p<0.05) at baseline. Patients with G-CSF plasma levels above the median had a 2-fold increased risk for MACE (p<0.05). This was independent from established cardiovascular risk factors. In addition, G-CSF above the median was a predictor of clinical in-stent restenosis after implantation of bare-metal stents (6.6% vs. 19.4%; p<0.05) but not of drug-eluting stents (7.7% vs. 7.6%; p = 0.98). This data suggests that endogenous plasma levels of G-CSF predict cardiovascular events independently from established cardiac risk factors and are associated with increased in-stent restenosis rates after implantation of bare metal stents.

An increase of VEGF plasma levels is associated with restenosis of drug-eluting stents.

AIMS: Drug-eluting stents (DES) reduce late lumen loss compared to bare metal stents but were not able to eradicate in-stent restenosis (ISR) fully. Vascular endothelial growth factor (VEGF) may inhibit late lumen loss through accelerated reendothelialisation, but may also promote neointima formation by proinflammatory effects. The aim of this study was to evaluate whether endogenous plasma levels of VEGF are associated with development of ISR after implantation of DES. METHODS AND RESULTS: We studied 85 patients who were treated with 159 DES. VEGF plasma levels were determined before and 24 hours after PCI. During the eight-month follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (14.5% of patients, 7.6% of stents) developed angiographic ISR. Basal VEGF plasma levels were not different in patients with and without ISR at follow-up. In contrast to patients without ISR, VEGF increased significantly upon PCI in patients with ISR (p<0.005). Patients with a decrease of VEGF after PCI had a restenosis rate of 2.4% compared to a restenosis rate of 26.2% in patients with an increase of VEGF after the procedure (p<0.05). This was independent from clinical and angiographic risk factors. CONCLUSIONS: Basal plasma levels of VEGF are not associated with the development of ISR. However, an increase of VEGF after PCI is associated with a dramatically increased ISR rate after implantation of DES.

CD4+ CD28(null) cells are an independent predictor of mortality in patients with heart failure.

AIMS: Immune activation and subsequent release of proinflammatory cytokines plays a central role in the pathophysiology of chronic heart failure (CHF). Cytotoxic CD4(+)CD28(null) cells are generated under inflammatory conditions and implicated in a variety of pathological processes like atherosclerosis and autoimmune diseases. The study aim was to assess the impact of CD4(+)CD28(null) cells on survival in CHF patients. METHODS AND RESULTS: Circulating lymphocytes from 107 CHF patients were analyzed for the distribution of CD4 subsets by flow cytometry. During a median follow-up of 23 months, 22 (20%) persons died. CD4(+)CD28(null) cells independently predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.88 per 1-standard deviation increase (95% confidence interval (CI): 1.26-2.79, P = 0.002) and with a HR of 1.83 for cardiovascular mortality (95% CI: 1.18-2.86, P = 0.008), respectively. Further, we found a significant association with NT-proBNP (r = 0.23). CONCLUSION: Circulating CD4(+)CD28(null) cells are associated with CHF severity and are a strong and independent predictor of mortality in CHF fostering the implication of the immune system in CHF pathophysiology.

A multi-biomarker risk score improves prediction of long-term mortality in patients with advanced heart failure.

BACKGROUND: Accurate risk prediction is important for an adequate management of heart failure (HF) patients. We assessed the incremental prognostic ability of a multi-biomarker approach in advanced HF. METHODS: In 349 patients with advanced HF (median 75 years, 66% male) we investigated the incremental prognostic value of 12 novel biomarkers involved in different pathophysiological pathways including inflammation, immunological activation, oxidative stress, cell growth, remodeling, angiogenesis and apoptosis. RESULTS: During a median follow-up of 4.9 years 55.9% of patients died. Using multivariable Cox regression and bootstrap variable-selection age, chronic obstructive pulmonary disease, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the following 5 novel biomarkers were retained in the best mortality prediction model: the chemokine fractalkine, the angiogenic and mitogenic hepatocyte growth factor (HGF), the growth differentiation factor 15 (GDF-15) influencing cardiac remodeling and apoptosis, and the 2 pro-apoptotic molecules soluble apoptosis-stimulating fragment (sFAS) and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). This multi-biomarker score had strong discriminatory power for 5-year mortality (area under the Receiver Operating Characteristic curve [AUC]=0.81) and improved risk prediction beyond the prognostic power of a comprehensive conventional risk score including known clinical predictors and NT-proBNP (AUC=0.77). Net reclassification confirmed a significant improvement of individual risk prediction (p=0.003). CONCLUSIONS: Risk prediction by a multi-biomarker score is superior to a conventional risk score including clinical parameters and NT-proBNP. Additional predictive information from different biological pathways reflects the multisystemic character of HF.

Fractalkine is an independent predictor of mortality in patients with advanced heart failure.

Immunological processes are implicated in the multifactorial pathophysiology of heart failure (HF). The multifunctional chemokine fractalkine (CX3CL1) promotes the extravasation of cytotoxic lymphocytes into tissues. We aimed to assess the prognostic value of fractalkine in HF. Fractalkine plasma levels were determined in 349 patients with advanced systolic HF (median 75 years, 66% male). During a median follow-up of 4.9 years (interquartile range: 4.6-5.2), 55.9% of patients died. Fractalkine was a significant predictor of all-cause mortality (p<0.001) with a hazard ratio of 2.78 (95% confidence interval: 1.95-3.95) for the third compared to the first tertile. This association remained significant after multivariable adjustment for demographics, clinical predictive variables and N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.008). The predictive value of fractalkine did not significantly differ between patients with ischaemic and non-ischaemic HF aetiology (p=0.79). The predictive value of fractalkine tertiles was not significantly modified by tertiles of NT-proBNP (p=0.18) but was more pronounced in the first and third tertile of NT-proBNP. Fractalkine was also an independent predictor of cardiovascular mortality (p=0.015). Fractalkine levels were significantly lower in patients on angiotensin-converting enzyme inhibitor therapy (p<0.001). In conclusion, circulating fractalkine with its pro-inflammatory and immunomodulatory effects is an independent predictor of mortality in advanced HF patients. Fractalkine improves risk prediction beyond NT-proBNP and might therefore help to identify high risk patients who need special care. Our data indicate the implication of immune modulation in HF pathology.

Markers of oxidative stress after ablation of atrial fibrillation are associated with inflammation, delivered radiofrequency energy and early recurrence of atrial fibrillation.

BACKGROUND: The role of oxidative stress after radiofrequency ablation of atrial fibrillation (AF) has not yet been well characterized. We sought to evaluate the time course of biomarkers of oxidative stress and inflammation after AF ablation and their association with clinical variables. METHODS: Thirty consecutive patients (57.9 ± 1.7 years, 63% males) with paroxysmal AF underwent pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Biomarkers were determined in blood samples before ablation and 6 h, 1, 2, 7, 30, 90 and 180 days post-ablation. RESULTS: The pro-oxidant enzyme myeloperoxidase and oxidized low-density lipoprotein reflecting oxidant damage of lipoproteins increased 2.9 ± 0.2-fold and 1.2 ± 0.1-fold, respectively, and were significantly up-regulated until day 2 post-ablation. The anti-oxidant enzyme copper/zinc superoxide dismutase did not change significantly. Inflammatory markers significantly increased (high-sensitivity C-reactive protein (hs-CRP): 41 ± 8-fold; interleukin-6: 4.4 ± 0.7-fold) for 7 and 2 days, respectively. The increase of myeloperoxidase and hs-CRP was interrelated and both predicted early recurrence of AF within the first post-ablation week (both p < 0.05). The increase of both markers was associated with the amount of delivered radiofrequency energy (p < 0.05). The up-regulation of hs-CRP correlated with troponin T (p = 0.008), while myeloperoxidase and troponin T were borderline associated (p = 0.054). However, the oxidative and inflammatory responses did not predict long-term ablation outcome (p > 0.05). CONCLUSIONS: Markers of oxidative stress showed a significant up-regulation during the first 2 days after AF ablation. Their up-regulation was linked to inflammation, delivered radiofrequency energy, and early recurrence of AF, but did not predict long-term ablation outcome.

The prognostic impact of soluble apoptosis-stimulating fragment on mortality in patients with carotid atherosclerosis.

BACKGROUND AND PURPOSE: Markers of apoptosis are associated with cardiovascular disease. The soluble apoptosis-stimulating fragment (sFAS) was found to be a predictor for outcome in patients with heart failure, but its importance in patients with atherosclerotic disease has not been fully understood as yet. The aim of the present study was to investigate the impact of sFAS on all-cause and cardiovascular mortality in patients with atherosclerosis in the carotid arteries. METHODS: We studied 981 of 1286 consecutive patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex Doppler sonography. Patients were prospectively followed for long-term all-cause and cardiovascular mortality. RESULTS: During a median follow-up of 6.2 years (interquartile range, 5.9 to 6.6 years), a total of 250 deaths (25.5%), including 165 (66%) cardiovascular deaths, were recorded. The risk for all-cause and for cardiovascular mortality, respectively, increased significantly with sFAS concentrations (P<0.001). The hazard ratio for all-cause death was elevated by 2.3-fold (P<0.001) and for cardiovascular death by 2.4-fold (P<0.001) in patients within the highest quintile of sFAS compared with patients within the lowest quintile, respectively. Results remained significant after adjustment for potential confounders and established cardiovascular risk factors, including high-sensitivity C-reactive protein. Patients with high sFAS but low high-sensitivity C-reactive protein had a comparable survival rate with those with elevated high-sensitivity C-reactive protein only (P=0.50). CONCLUSIONS: Markers of apoptosis, as measured by sFAS, were found to be independent risk predictors for death in patients with atherosclerotic disease in the carotid arteries.

Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure.

OBJECTIVE: To assess the prognostic value of the mitogenic, antiapoptotic, angiogenic and antifibrotic hepatocyte growth factor (HGF) in heart failure (HF). DESIGN: Prospective cohort study. SETTING/PATIENTS: Assessment of HGF levels at inclusion in 351 patients with advanced HF (median 75 years, interquartile range (IQR) 63-82, 66% male). MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular mortality. RESULTS: During a median follow-up of 16 months, 26% of patients died. HGF tertiles were associated with an increasing risk for all-cause mortality (p < 0.001) with a hazard ratio (HR) of 3.06 (95% confidence interval (CI) 1.69 to 5.53) for the third compared with the first tertile. This association remained significant after multivariable adjustment for B-type natriuretic peptide (BNP) and other risk factors (p = 0.002). Subgroup analysis revealed that HGF was a strong predictor of the secondary end point cardiovascular mortality in ischaemic HF (p = 0.009) with an adjusted HR of 6.2 (95% CI 1.76 to 21.8) comparing the third with the first tertile but not in non-ischaemic HF (HR = 1.47, 95% CI 0.48 to 4.49, p = 0.5). Patients with high HGF but low BNP had a comparable survival rate to those with elevated BNP but low HGF (p=0.66). Of note, the dose of angiotensin converting enzyme (ACE) inhibitors inversely correlated with HGF concentrations (r = -0.25, p < 0.001). CONCLUSIONS: HGF is a strong and independent predictor of mortality in advanced HF and, in particular, in ischaemic HF. These results indicate that HGF with its multiple effects on myocardial function exerts an overall deleterious effect in advanced HF. HGF may be of special interest for risk prediction and tailoring of HF treatment.

Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome.

BACKGROUND: Radiofrequency ablation of atrial fibrillation (AF) creates left atrial (LA) tissue damage with a subsequent healing process. We sought to prospectively assess the time course of biomarkers of tissue repair after ablation and to evaluate their association with clinical variables. METHODS: 30 consecutive patients (57.9 ± 1.7 yrs, 63% males) with paroxysmal AF underwent a CARTO-guided LA circumferential ablation, Lasso-guided segmental pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1), both key regulators of tissue repair, and the aminoterminal propeptide of type III procollagen (PIIINP), reflecting collagen synthesis, were determined in blood samples before and 6h, 1, 2, 7, 30, 90 and 180 days post-ablation. RESULTS: All markers showed a significant ablation-induced up-regulation (MMP-9: 1.8 ± 0.1-fold, TGF-ß1: 2.4 ± 0.4-fold, PIIINP: 1.3 ± 0.1-fold). MMP-9 was significantly up-regulated until day 90, TGF-ß1 only on day 2. PIIINP increased from day 2 to 7. The area under the curve (AUC) of MMP-9 and TGF-ß1 correlated with the ablation-induced reduction of LA volume (both p<0.05). The AUC of MMP-9 was additionally associated with the amount of radiofrequency energy delivered during ablation (p < 0.05). At 12 months of follow-up 57% of patients were free of AF off antiarrhythmic drugs. The AUC of PIIINP independently predicted recurrent AF (p < 0.05). CONCLUSIONS: Markers of healing showed a significant up-regulation after AF ablation detectable for up to 90 days. A more pronounced up-regulation of MMP-9 or TGF-ß1 is associated with a greater reduction of LA size. High PIIINP levels after ablation predict a poor ablation outcome.

Differences in the predictive value of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in advanced ischemic and non-ischemic heart failure.

OBJECTIVE: To assess the prognostic value of the pro-apoptotic, but also cell growth-inducing molecule soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in heart failure (HF). METHODS: We assayed sTWEAK levels in 351 patients with advanced HF (non-ischemic: 130, ischemic: 221). During a median follow-up of 4.9 years, 195 patients (56%) died. RESULTS: sTWEAK concentrations were associated with extended survival in patients with non-ischemic (P=0.022), but not with ischemic HF (P=0.82). The inverse association in non-ischemic HF remained significant in a multivariable Cox regression model (P=0.025) with a hazard ratio of 0.40 (95% confidence interval: 0.21-0.77) comparing the third to the first tertile (P=0.007). CONCLUSION: Low sTWEAK levels independently predict mortality in advanced non-ischemic HF. sTWEAK-induced proliferation of cardiomyocytes may explain its impact on suvival. The different prognostic value of sTWEAK in ischemic and non-ischemic HF may point towards distinct pathogenic pathways determining the course of disease.

Prognostic value of pigment epithelium-derived factor in patients with advanced heart failure.

OBJECTIVE: Whereas angiogenesis, the formation of new blood vessels from preexisting vessels, may be beneficial in restoring failing myocardium, apoptosis may contribute to the progression of heart failure (HF). We investigated the role of pigment epithelium-derived factor (PEDF), a recently discovered antiangiogenic factor with additional proapoptotic effects, in patients with advanced HF. METHODS: We assayed PEDF levels in 351 patients with advanced HF at baseline. During the median follow-up time of 16 months, 50% of patients experienced the composite end point of rehospitalization and/or death. RESULTS: The risk of a clinical event increased with concentrations of the antiangiogenic marker PEDF, with a 1.94-fold higher risk in the third tertile compared with the first tertile (95% CI, 1.33-2.84). This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = .015). Experimental data revealed that PEDF may contribute to the progression of HF by inducing apoptosis in human cardiac myocytes and fibroblasts via activation of caspase 3. CONCLUSIONS: We suggest a role of PEDF in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts. Our clinical data suggest that PEDF concentrations may have the potential to become a valuable marker of the prognosis of HF, in addition to BNP.

Increased restenosis rate after implantation of drug-eluting stents in patients with elevated serum activity of matrix metalloproteinase-2 and -9.

OBJECTIVES: Our aim was to test whether serum levels of matrix metalloproteinase (MMP)-2 and -9 are associated with the development of in-stent restenosis (ISR) after implantation of drug-eluting stents (DES). BACKGROUND: With the introduction of DES coronary ISR could be reduced dramatically. However, it still plays a significant role, particularly after treatment of multiple, complex lesions. METHODS: We studied 85 patients who were treated with 159 DES. Blood samples for measurement of MMP-2 and -9 antigen and activity were taken directly before and 24 h after percutaneous coronary intervention (PCI). Restenosis was evaluated at 6 to 8 months by coronary angiography. RESULTS: During the follow-up period, 2 patients (2.4%) died of cardiovascular causes, and 12 patients developed angiographic ISR. Patients with ISR showed significantly higher serum activity of MMP-9 at baseline (p = 0.017) and of MMP-2 (p < 0.0001) and MMP-9 (p < 0.0001) after the procedure. The PCI increased serum activity of MMP-2 (p = 0.005) and MMP-9 (p = 0.008) only in patients with ISR. The restenosis rates of patients in the highest quartile of MMP-2 after and MMP-9 before and after PCI were 40.0%, 38.9%, and 42.9% compared with 6.3%, 7.7%, and 4.0% in the lower quartiles, respectively. This was independent of clinical and procedural characteristics. CONCLUSIONS: Elevated serum activities of MMP-2 and -9 are associated with dramatically increased restenosis rates after PCI with implantation of DES. Determination of MMP levels might be useful for identification of patients who are at high risk for ISR despite implantation of DES.

Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a.

OBJECTIVE: Drug eluting stents (DES) reduce recurrent luminal narrowing through anti-migratory and anti-proliferative effects. However, recent concerns arose that DES may also induce significant chronic inflammatory responses that may impair vascular healing and lead to in-stent restenosis (ISR). As the complement components C3a and C5a exert particularly strong chemotactic and proinflammatory effects, we examined the association of serum levels of C3a and C5a and ISR after implantation of DES. METHODS: We included 82 patients that were treated with 151 DES. Blood samples were taken directly before and 24h after PCI. Serum levels of C3a and C5a were measured by specific ELISA and restenosis was evaluated at 6-8 months by coronary angiography. RESULTS: C5a but not C3a increased after implantation of DES (p<0.05). During the follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (7.9% of stents, 15% of patients) developed ISR. Serum levels of C3a before and 24h after PCI as well as C5a levels at baseline were significantly higher in patients that developed ISR at follow-up. C3a and C5a at baseline were significantly associated to angiographic late lumen loss independent from clinical and procedural risk factors. CONCLUSION: Increased complement activation as measured by higher levels of C3a and C5a before PCI is significantly associated with late lumen loss. Inhibition of the complement cascade to prevent ISR warrants further investigation.

Non-conventional markers of atherosclerosis before and after gastric banding surgery.

AIMS: Obesity and type 2 diabetes are associated with increased cardiovascular risk and elevation of traditional and non-traditional risk markers. As bariatric surgery reduces overweight and improves metabolic derangement, we examined a cluster of established and emerging cardiovascular risk factors, such as soluble CD40 ligand (sCD40L) and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), which might improve prediction of future cardiovascular events because of their more direct involvement in plaque destabilization. METHODS AND RESULTS: Obese patients [n = 32, body mass index (BMI) 46.1 +/- 5.9 kg/m(2)] underwent clinical examinations and blood sampling for measurement of glucose and lipid parameters as well as non-traditional cardiovascular risk markers, i.e. high-sensitivity C-reactive protein, plasminogen activator inhibitor-1 (PAI-1), soluble cellular adhesion molecules (CAM), MMP-2, MMP-9, CD40L, and Lp-PLA(2) before and after 1 year following laparoscopic adjustable gastric banding (LAGB), respectively. In patients undergoing LAGB, blood pressure (P < 0.0001) and blood glucose (P = 0.02) were significantly lowered by approximately 16% as well as triglyceride levels by approximately 29% (P = 0.002). In addition to a decrease of the inflammatory and pro-thrombotic marker PAI-1 (P = 0.001), CAMs, and MMP-9 (P = 0.004) were reduced, whereas no change was observed for plasma levels of MMP-2, sCD40L, and Lp-PLA(2) after LAGB, respectively. Individual changes in (ICAM-1) intercellular adhesion molecule-1 (DeltaICAM-1) were related to changes in insulin (Deltafasting insulin) before and after LAGB (r = 0.36 and r = 0.38; both P = 0.04). E-selectin correlated positively with changes in BMI (r = 0.38; P = 0.04 and r = 0.36; P = 0.05), while Lp-PLA(2) concentration was negatively correlated with BMI (r =-0.41; P = 0.02) after 1 year. Changes were comparable in both overweight diabetic and non-diabetic subjects. CONCLUSION: LAGB not only induced weight loss but also an improvement in the subclinical pro-inflammatory state. However, concentrations of most of the non-traditional risk factors for plaque instability, i.e. MMP-9, sCD40L, and Lp-PLA(2) remained unchanged.

Prognostic value of apoptosis markers in advanced heart failure patients.

AIMS: Apoptosis plays an important role in the progression of heart failure (HF). The purpose of this study was to assess whether the pro-apoptotic molecules apoptosis-stimulating fragment (FAS, CD95/APO-1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) predict event-free survival of HF patients. METHODS AND RESULTS: We assayed soluble (s)FAS and sTRAIL levels in 351 patients with advanced HF. During the median follow-up time of 16 months, 175 patients (50%) experienced the composite endpoints: rehospitalization and death. The hazard increased with sFAS concentrations, with a hazard ratio of 2.3 comparing fourth and first quartiles. This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = 0.014). Patients with high sFAS but low BNP had a comparable event-free survival rate with those with elevated BNP only (P = 0.78). Conversely, high sTRAIL concentrations were related to a better prognosis. Particularly, the risk of mortality dropped by 70% in the fourth quartile of sTRAIL (P = 0.001, multivariable Cox regression model). CONCLUSION: sFAS is an independent risk predictor in advanced HF patients. It may be of particular value for the identification of high-risk patients in addition to BNP. Conversely, sTRAIL appears to be protective and could be an interesting therapeutic agent.

Clopidogrel pretreatment abolishes increase of PAI-1 after coronary stent implantation.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been shown to increase after percutaneous coronary intervention (PCI). Whether activated platelets, local trauma with activation of resident vascular cells or the acute phase response is the source of this PAI-1 increase is not well defined. Therefore we examined whether intensive platelet inhibition may modulate PAI-1 levels or whether the PAI-1 increase is associated with the acute phase protein C-reactive protein (CRP). METHODS: We included 51 patients with stable angina who underwent elective PCI with stent implantation. At the time of study, routine pretreatment with clopidogrel before PCI was not standard of care, but left to the discretion of the referring cardiologist. We matched 17 patients with stable angina that were not pretreated with clopidogrel but received a loading dose of 300 mg immediately after stent implantation according age, sex and smoking with 34 patients that received clopidogrel at least 12 to 24 hours before PCI. Blood samples for measurement of PAI-1, t-PA and CRP were taken directly before and 24 hours after the procedure. RESULTS: PAI-1 and t-PA active antigen plasma levels before PCI were not different in patients with and without clopidogrel pretreatment. Whereas PCI induced a significant increase of PAI-1 levels in patients without pretreatment (p<0.05), the procedure had no effect on PAI-1 active antigen in patients pretreated with clopidogrel. This resulted in significant lower PAI-1 plasma levels 24 hours after PCI in patients with pretreatment (p<0.05). CRP was not associated with pre- or postprocedural PAI-1 levels. CONCLUSION: Clopidogrel pretreatment completely abolishes the increase of PAI-1 active antigen after coronary stent implantation. This suggests that peri-procedural platelet activation might play a major role for the increase of PAI-1 after PCI thus increasing the risk of acute and subacute thrombus formation based on a reduced endogenous fibrinolytic system.

Time course of prothrombotic and proinflammatory substance release after intracoronary stent implantation.

We hypothesized that restenosis after coronary stenting is predicted by elevated levels of markers of thrombus formation and inflammation. Plasma levels of representative markers of inflammation, the thrombin and plasmin activation systems and adhesion molecules were measured in 59 patients with stable angina pectoris before, immediately after and 6 hours (h), 12 h, 24 h, one month and six months after elective stent implantation (radioactive phosphorus-32 stents/RSs/ n = 16, bare-metal stents/BMSs/ n = 43). All patients underwent clinical and angiographic follow-up (FUP) six months after stenting. RSs had significantly higher angiographic severity of restenosis than BMSs (47.1 +/- 20.1% vs. 27.6 +/- 22.0%, p = 0.003). Repeated measures ANOVA revealed significant differences between the BMS and RS groups as regards the increases in plasma levels of vascular cell adhesion molecule-1 (VCAM-1, p = 0.022), plasminogen activator inhibitor-1 (PAI-1, p = 0.047), tissue-type plasminogen activator (tPA, p = 0.047) and CD40 ligand (CD40L, p = 0.038). tPA levels tended to increase immediately after stenting in both groups, whereas the PAI-1 level one month after stenting was elevated significantly only in the RS group. In the RS group, the plasma levels of CD40L were increased at 24 h and six months after stenting, and the VCAM-1 level rose immediately after stenting and remained high during the FUP. Multivariate analysis on pooled laboratory data of both groups revealed elevated levels of VCAM-1 at 12 h and at six months as significant predictors of the severity of stent restenosis. In conclusion, the process of inflammation and thrombosis occurring after coronary interventions seems to be prolonged and enhanced in patients with high-grade restenosis at the follow up.

Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty.

PURPOSE: To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. METHODS: C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. RESULTS: Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p<0.001) 8 hours post intervention. During the follow-up period, 70 (53%) patients developed restenosis. Increasing levels of C5a (quartiles) at baseline were significantly associated with an increased risk for restenosis (p=0.0092). Adjusted hazard ratios (95% confidence intervals) for restenosis with increasing quartiles of baseline serum C5a levels were 1.24 (0.60 to 2.58), 1.93 (0.95 to 3.93), and 2.08 (1.02 to 4.21), respectively, compared to the lowest quartile. This effect was independent of nonspecific inflammation as reflected by plasma levels of C-reactive protein. CONCLUSION: Inflammatory mechanisms play a major role in the development of restenosis after angioplasty. The complement component C5a exerts strong chemotactic and proinflammatory effects. Enhanced complement activation prior to PTA, as measured by higher levels of C5a, was significantly associated with restenosis after SFA balloon angioplasty. Pathways of complement inhibition thus may be worth investigating with respect to improving patency rates.