Chemokine ligand 18 predicts all-cause mortality in patients hospitalized with chest pain of suspected coronary origin.

Introduction: Chemokines mediate recruitment and activation of leucocytes. Chemokine ligand 18 (CCL18) is mainly expressed by monocytes/macrophages and dendritic cells. It is highly expressed in chronic inflammatory diseases, and locally in atherosclerotic plaques, particularly at sites of reduced stability, and systemically in acute coronary syndrome patients. Reports on its prognostic utility in the latter condition, including myocardial infarction (MI), are scarce. Aim: To assess the utility of CCL18 as a prognostic marker of recurrent cardiovascular events in patients hospitalized with chest pain of suspected coronary origin. Methods: The population consisted of 871 consecutive chest-pain patients, of whom 386 were diagnosed with acute myocardial infarction (AMI) based on Troponin-T (TnT) levels >50 ng/L. Stepwise Cox regression models, applying normalized continuous loge/SD values, were fitted for the biomarkers with cardiac mortality within 2 years and total mortality within 2 and 7 years as the dependent variables. Results: Plasma samples from 849 patients were available. By 2 years follow-up, 138 (15.8%) patients had died, of which 86 were cardiac deaths. Univariate analysis showed a positive, significant association between CCL18 and total death [HR 1.55 (95% 1.30-1.83), p < 0.001], and for cardiac death [HR 1.32 (95% 1.06-1.64), p = 0.013]. Associations after adjustment were non-significant. By 7 years follow-up, 332 (38.1%) patients had died. CLL18 was independently associated with all-cause mortality [HR 1.14 (95% CI, 1.01-1.29), p = 0.030], but not with MI (n = 203) or stroke (n = 55). Conclusion: CCL18 independently predicts long-term all-cause mortality but had no independent prognostic bearing on short-term cardiac death and CVD events.

α1-antichymotrypsin complex (SERPINA3) is an independent predictor of all-cause but not cardiovascular mortality in patients hospitalized for chest pain of suspected coronary origin.

INTRODUCTION: SERPINA3 is an acute phase protein triggered by inflammation. It is upregulated after an acute myocardial infarction (AMI). Data on its long-term prognostic value in MI patients are scarce. We aimed to assess the utility of SERPINA3 as a prognostic marker in patients hospitalized for chest pain of suspected coronary origin. METHODS: A total of 871 consecutive patients, 386 diagnosed with AMI, were included. Stepwise Cox regression models, applying continuous loge-transformed values, were fitted for the biomarker with all-cause mortality and cardiac death within 2-years or all-cause mortality within median 7 years as dependent variables. An analysis of MI and stroke, and combined endpoints, respectively, was added. The hazard ratio (HR) (95% CI) was assessed in a univariate and multivariable model. RESULTS: Plasma samples from 847 patients were available. By 2 years follow-up, 138 (15.8%) patients had died, of which 86 were cardiac deaths. The univariate analysis showed a significant association between SERPINA3 and all-cause mortality [HR 1.41 (95% 1.19-1.68), p<0.001], but not for cardiac death. Associations after adjustment were non-significant. By 7 years follow-up, 332 (38.1%) patients had died. SERPINA3 was independently associated with all-cause mortality from the third year onwards. The HR was 1.14 (95% CI, 1.02-1.28), p=0.022. Similar results applied to combined endpoints, but not for MI and stroke, respectively. The prognostic value of SERPINA3 was limited to non-AMI patients. No independent associations were noted among AMI patients. CONCLUSIONS: SERPINA3 predicts long-term all-cause mortality, but failed to predict outcome in AMI patients.

Angiopoietin-2 and angiopoietin-like 4 protein provide prognostic information in patients with suspected acute coronary syndrome.

BACKGROUND: Plasma levels of angiopoietin-2 (ANGPT2) and angiopoietin-like 4 protein (ANGPTL4) reflect different pathophysiological aspects of cardiovascular disease. We evaluated their association with outcome in a hospitalized Norwegian patient cohort (n = 871) with suspected acute coronary syndrome (ACS) and validated our results in a similar Argentinean cohort (n = 982). METHODS: A cox regression model, adjusting for traditional cardiovascular risk factors, was fitted for ANGPT2 and ANGPTL4, respectively, with all-cause mortality and cardiac death within 24 months and all-cause mortality within 60 months as the dependent variables. RESULTS: At 24 months follow-up, 138 (15.8%) of the Norwegian and 119 (12.1%) of the Argentinian cohort had died, of which 86 and 66 deaths, respectively, were classified as cardiac. At 60 months, a total of 259 (29.7%) and 173 (17.6%) patients, respectively, had died. ANGPT2 was independently associated with all-cause mortality in both cohorts at 24 months [hazard ratio (HR) 1.27 (95% confidence interval (CI), 1.08-1.50) for Norway, and HR 1.57 (95% CI, 1.27-1.95) for Argentina], with similar results at 60 months [HR 1.19 (95% CI, 1.05-1.35) (Norway), and HR 1.56 (95% CI, 1.30-1.88) (Argentina)], and was also significantly associated with cardiac death [HR 1.51 (95% CI, 1.14-2.00)], in the Argentinean population. ANGPTL4 was significantly associated with all-cause mortality in the Argentinean cohort at 24 months [HR 1.39 (95% CI, 1.15-1.68)] and at 60 months [HR 1.43 (95% CI, 1.23-1.67)], enforcing trends in the Norwegian population. CONCLUSIONS: ANGPT2 and ANGPTL4 were significantly associated with outcome in similar ACS patient cohorts recruited on two continents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00521976. ClinicalTrials.gov Identifier: NCT01377402.

The prognostic utility of dihomo-gamma-linolenic acid (DGLA) in patients with acute coronary heart disease.

BACKGROUND: We previously investigated the prognostic utility of red blood cell (RBC) n-3 fatty acids (FAs) in survivors of an acute myocardial syndrome (ACS) but found no relationship with all-cause mortality and cardiac death or MI after two years. Here we extend our follow-up to 7years, focusing on the potential predictive power of RBC n-6 FAs. METHODS: We included 398 ACS patients presenting with increased troponin-T (TnT) levels for whom baseline RBC FA data were available. Cox regression analysis was used to relate the risk of future events to RBC n-6 FA levels, both continuously and by quartile. RESULTS: At 7-year follow-up, 183 (46.0%) had died, 128 (32.2%) had experienced another MI and 24 (6.0%) had had a stroke. Death or MI occurred in 227 patients (57.0%); and death, MI or stroke in 235 patients (59.0%). In a multivariable Cox regression model for total death, the hazard ratio (HR) in the highest as compared to the lowest quartile of dihomo-γ-linolenic acid (DGLA) was 0.55 [95% confidence interval (CI), 0.35-0.88, p=0.012, for death or MI [HR 0.62 (95% CI, 0.41-0.94), p=0.025], and for the fully combined endpoint [HR 0.57 (95% CI, 0.38-0.86), p=0.006]. Similar results were found in the per 1-SD analysis. No other RBC n-6 FAs significantly predicted these outcomes in multivariable models. CONCLUSION: RBC DGLA levels had significant independent prognostic value in post-ACS patients. These findings need confirmation, and the possible biochemical pathways by which higher DGLA membrane levels may be cardioprotective should be explored.

Suggested Cut-Off Values for Vitamin D as a Risk Marker for Total and Cardiac Death in Patients with Suspected Acute Coronary Syndrome.

BACKGROUND: Several studies have demonstrated an association between low vitamin D levels and cardiovascular risk. Vitamin D cut-off levels are still under debate. OBJECTIVES: To assess two cut-off levels, 40 and 70 nmol/L, respectively, for vitamin D measured as 25-hydroxyvitamin D in chest pain patients with suspected acute coronary syndrome. METHODS: We investigated 1853 patients from coastal-Norway and inland Northern-Argentina. A similar database was used for pooling of data. Two-year follow-up data including all-cause mortality, cardiac death, and sudden cardiac death in the total patient population were analyzed, applying univariate and multivariable analysis. RESULTS: Two hundred fifty-five patients with known vitamin D concentrations died. In the multivariable analysis, there was a decrease in total mortality above a cut-off level of 40 nmol/L and a decrease in cardiac death above a cut-off level of 70 nmol/L [HRs of 0.66 (95% CI, 0.50-0.88), p = 0.004 and 0.46 (95% CI, 0.22-0.94), p = 0.034, respectively]. CONCLUSION: Vitamin D cut-off levels of 40 and 70 nmol/L were related to total mortality and cardiac death, respectively.

Long-term prognostic utility of pentraxin 3 and D-dimer as compared to high-sensitivity C-reactive protein and B-type natriuretic peptide in suspected acute coronary syndrome.

BACKGROUND: Vascular inflammation plays a key role in the development of atherosclerosis and acute coronary syndrome (ACS), and pentraxin 3 (PTX3) is one of several novel, promising markers of inflammation. In addition, D-dimer might serve as a marker of thrombogenesis and a hypercoagulable state following plaque rupture. The present study assesses the prognostic utility of these two biomarkers as compared to high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP), in addition to conventional clinical risk factors for coronary heart disease in patients with suspected ACS. METHODS: Chest pain patients with suspected ACS (n = 871) were consecutively included in a prospective, observational study with a follow-up time of 84 months. RESULTS: At 7-year follow-up, 332 patients had died and 203 had suffered an adverse troponin T-positive, non-fatal cardiac event. In the multivariate analysis, levels of PTX3 above 5.88 ng/mL (median) and D-dimer above 436 µg/L (lower limit upper quartile) independently predicted mortality (HR 1.60 [95% CI 1.10-2.33]; p = 0.014 and HR 1.83 [95% CI 1.20-2.78]; p = 0.005, respectively). Also, BNP levels above 310.75 pg/mL (lower limit upper quartile) (HR 2.16 [95% CI 1.37-3.42]; p = 0.001), but not hsCRP, independently predicted mortality. Only hsCRP and BNP also predicted future myocardial infarction (HR 1.59 [95% CI 1.05-2.40]; p = 0.029 and HR 1.91 [95% CI 1.10-3.31]; p = 0.021, respectively). CONCLUSION: High levels of PTX3, D-dimer and BNP were found to be independent, long-term predictors of all-cause mortality in chest pain patients with a suspected ACS. hsCRP and BNP also predicted future myocardial infarction.

Borderline Values of Troponin-T and High Sensitivity C-Reactive Protein Did Not Predict 2-Year Mortality in TnT Positive Chest-Pain Patients, Whereas Brain Natriuretic Peptide Did.

BACKGROUND: Troponin-T (TnT), high-sensitive C-reactive protein (hsCRP), and Brain Natriuretic Peptide (BNP) have been shown to be independent prognostic indicators of total and cardiac death during short- and long-term follow-up. METHODS: We investigated prospectively the prognostic value of admission samples of TnT, hsCRP, and BNP in 871 chest-pain patients from South-Western Norway and 982 patients from Northern Argentina, based on a similar protocol and database setup. Follow-up was 2 years for the pooled population. The prognostic value of the selected biomarkers was investigated in quartiles of 239 patients with TnT values greater than 0.01 and up to and including 0.1 ng/mL, with continuous TnT as a potential confounder. RESULTS: After 24 months, 69 patients had died, of whom 38 died from cardiac causes. In the selected range of TnT, this biomarker was not significantly different between patients who died and survived (mean 0.0452 and 0.0457, p = 0.887). The BNP levels were significantly higher among patients dying than in long-term survivors [340 (142-656) versus 157 (58-367) pg/mL (median, 25 and 75% percentiles), p < 0.001]. In a multivariable Cox regression model for death within 2 years, the hazard ratio (HR) for BNP in the highest quartile (Q4) as compared to the lowest (Q1) was significantly related to total mortality [HR 2.84 (95% confidence interval (CI), 1.13-7.17)], p = 0.027, in addition to age (p ≤ 0.001) and hypercholesterolemia (p = 0.043). For cardiac death, the HR for BNP was 5.18 (95% CI, 1.06-25.3), p = 0.042. Several other variables (age, congestive heart failure, ST elevation myocardial infarction, and study country) were also significantly related to cardiac death. In a multivariable Cox regression model, hsCRP rendered no significant prognostic information for all-cause mortality (p = 0.089) or for cardiac mortality (p = 0.524). CONCLUSION: In patients with borderline TnT values (greater than 0.01 and up to and including 0.1 ng/mL), this biomarker as well as hsCRP did not render prognostic information, whereas BNP was found to be a strong prognostic indicator of 2-year total and cardiac mortality.

Prognostic utility of vitamin D in acute coronary syndrome patients in coastal Norway.

BACKGROUND: An inverse relationship between cardiovascular risk and levels of vitamin D and omega-3 index may exist. OBJECTIVES: To evaluate the prognostic utility of serum 25-hydroxyvitamin D [25(OH)D] in 871 patients with suspected acute coronary syndrome (ACS) and to assess the seasonal correlation between 25(OH)D and the omega-3 index in 456 ACS patients from southwestern Norway. RESULTS: In the univariate analysis the hazard ratio (HR) at 2-year follow-up for all-cause mortality in the highest as compared to the lowest quartile of 25(OH)D in the total population was 0.61 (95% confidence interval (CI), 0.37-1.00), P = 0.050. At 7-year follow-up, the corresponding HR for all-cause mortality was 0.66 (95% CI, 0.49-0.90), P = 0.008, and for females alone 0.51 (95% CI, 0.32-0.83), P = 0.006. Quartile survival did not differ in the multivariable analysis, whereas 25(OH)D < 40 nM (<16 ng/mL) was found to be independently related to mortality. Seasonal differences in 25(OH)D, but not for the omega-3 index, were noted, and the two biomarkers were positively correlated, especially during winter-spring; Pearson's correlation coefficient was 0.358, P < 0.001. CONCLUSION: Vitamin D levels are related to survival, especially in females, and correlate with the omega-3 index.

Long-term prognostic utility of PAPP-A and calprotectin in suspected acute coronary syndrome.

BACKGROUND: Vascular inflammation plays a key role in the development of acute coronary syndrome (ACS). Pregnancy-associated plasma protein A (PAPP-A) and calprotectin are two of several novel promising markers of inflammation. The present study evaluates the prognostic utility of these two biomarkers in patients with suspected ACS. METHODS: Chest pain patients with suspected ACS (N = 871) were consecutively included in a prospective, observational study with a mean follow-up time of 84 months. Blood samples were drawn at admission, prior to treatment with heparin. RESULTS: Total mortality was 38.9%. In univariate analyses, high PAPP-A levels were associated with significant increased mortality. The hazard ratio [HR] in quartile (Q) 3 and Q4 were 1.57 (95% confidence interval (CI), 1.14-2.18), p = 0.006, and 1.41 [95% CI 1.02-1.97], p = 0.040, respectively, as compared to Q1. Calprotectin in the upper quartile (Q4) was associated with total mortality [HR1.94 (95% CI 1.42-2.66)], p = < 0.001, the combined endpoint of death or recurrent myocardial infarction (MI) [HR 1.68 (95% CI 1.26-2.24), p = < 0.001], and recurrent MI [HR 1.60 (95% CI 1.06-2.41); p = 0.024]. However, neither PAPP-A nor calprotectin was found to be an independent predictor of future adverse events. CONCLUSION: In this study, high levels of PAPP-A and calprotectin were associated with adverse clinical outcome in chest pain patients with clinically suspected ACS. However, neither of the two biomarkers was an independent predictor of long-term prognosis.

A history of late and very late stent thrombosis is not associated with increased activation of the contact system, a case control study.

BACKGROUND: The pathophysiological pathways resulting in Late Stent Thrombosis (LST) remain uncertain. Findings from animal studies indicate a role of the intrinsic coagulation pathway in arterial thrombus formation, while clinical studies support an association with ischemic cardiovascular disease. It is currently unknown whether differences in the state of the contact system might contribute to the risk of LST or Very Late Stent Thrombosis (VLST). We assessed the relation between levels of several components involved in the contact system and a history of LST and VLST, termed (V)LST in a cohort of 20 patients as compared to a matched control group treated with PCI. METHODS AND RESULTS: Activated factor XII (FXIIa), FXII zymogen (FXII), FXIIa-C1-esterase inhibitor (C1-inhibitor), Kallikrein-C1-inhibitor, FXIa-C1-inhibitor and FXIa-alpha1-antitrypsin (AT-inhibitor) complexes were measured by Enzyme-linked immunosorbent assy (ELISA) methodology.Cases and controls showed similar distributions in sex, age, baseline medications and stent type. Patients with a history of (V)LST had a significantly greater stent burden and a higher number of previous myocardial infarctions than the control patients.There were no significant between-group differences in the plasma levels of the components of the contact system. CONCLUSION: In a cohort of patients with a history of (V)LST, we did not observe differences in the activation state of the intrinsic coagulation system as compared to patients with a history of percutaneous coronary intervention without stent thrombosis.

The activity of pregnancy-associated plasma protein A (PAPP-A) as expressed by immunohistochemistry in atherothrombotic plaques obtained by aspiration thrombectomy in patients presenting with a ST-elevation myocardial infarction: a brief communication.

BACKGROUND: The expression of pregnancy-associated plasma protein A (PAPP-A) was identified by immunohistochemistry (IHC) in culprit atherothrombotic plaque specimens harvested from patients admitted with ST-segment elevation myocardial infarction (STEMI). METHODS: The atherothrombotic samples were collected from a consecutive cohort consisting of 20 individuals admitted with STEMI to Stavanger University Hospital, Norway, from 2005-2006, presenting angiographically with an acute thrombotic occlusion of a coronary artery characterized by TIMI flow 0. The atherothrombotic plaques were obtained by aspiration thrombectomy during percutaneous coronary intervention within 12 hours from the onset of symptoms and prepared for IHC analysis. RESULTS: In the IHC analysis staining for PAPP-A occurred in the extracellular matrix of the plaques and no evidence of staining for PAPP-A was found in the thrombi. CONCLUSION: Our results indicate that in vivo PAPP-A is strongly expressed in atherothrombotic plaques harvested from patients admitted with STEMI, as documented by IHC. TRIAL REGISTRATION: biobankregisteret@fhi.no1846.

Activated factor XII type A and B-type natriuretic peptide are complementary and incremental predictors of mortality in patients following admission with acute coronary syndrome.

The aim of this analysis was to assess the predictive value of activated factor XII type A (XIIaA) and B-type natriuretic peptide (BNP) in acute coronary syndrome patients stratified according to troponin release and to evaluate their complementary utility as predictors of all-cause mortality and recurrent troponin T (TnT)-positive events. Multivariable analysis in 870 patients admitted with suspected myocardial infarction was performed using the Cox proportional hazard ratio model. Variables in the model included XIIaA and BNP as well as conventional risk factors for mortality. Although both XIIaA and BNP were identified as independent predictors for all-cause mortality in the total group of patients, only BNP was found to be an independent predictor for all-cause mortality in patients with a confirmed myocardial infarction (TnT > 0.05 ng/ml) at admission (hazard ratio 4.24, 95% confidence interval 1.28-14.07), whereas only XIIaA was an independent predictor for all-cause mortality in patients with low TnT release (0.01 < TnT < or = 0.05 ng/ml) at admission (hazard ratio 10.37, 95% confidence interval 2.89-37.21). The combination of these two biomarkers provided complementary prognostic information for all-cause mortality as compared with each of the biomarkers alone in the total patient material. XIIaA is particularly useful in predicting mortality in acute coronary syndrome patients with low troponin release, whereas BNP is effective in predicting mortality in patients with confirmed myocardial infarction and more substantial troponin release. The combination of these two biomarkers improves outcome prediction in unselected patients with chest pain and acute coronary syndrome.

The long pentraxin 3 (PTX3): a novel prognostic inflammatory marker for mortality in acute chest pain.

The long pentraxin 3 (PTX3) is a recently identified member of the pentraxin protein family that includes C-reactive protein. PTX3 is produced by the major cell types involved in atherosclerotic lesions in response to inflammatory stimuli, and elevated plasma levels are found in several conditions including acute coronary syndromes (ACS). The aim of this study was to assess the value of PTX3 as a prognostic marker of mortality and recurrent ischaemic events in a consecutive series of patients admitted with acute chest pain and potential ACS. The patients received follow-up for 24 months. Blood samples were taken on admission for measurement of PTX3, high sensitive C-reactive protein (hsCRP), B-type natriuretic peptide (BNP), and troponin T. All-cause mortality at 24 months in the study cohort was 15.2%. Patients in the upper PTX3 quartiles had a significantly higher death risk than those in the lowest quartile (Q3: hazard ratio [HR] 2.36; 95% CI 1.12-4.99; p = 0.024, and Q4: HR 3.60; 95% CI 1.68-7.72; p = 0.001). Elevated BNP levels were also significantly associated with a fatal outcome (Q3: HR 3.05; 95% CI 1.16-7.99; p = 0.024; and Q4: HR 3.90; 95% CI 1.48-10.26; p = 0.006). Elevation in hsCRP was not associated with increased death risk. As PTX3 predicted mortality independently of BNP, the combination of these two biomarkers showed an incremental prognostic value. PTX3 is a new biomarker related to inflammation that, independently of BNP, strongly predicts long-term all-cause mortality in patients with acute chest pain. The combination of these two biomarkers enhances the prognostic value over either marker alone.

Moderate alcohol consumption is associated with reduced long-term cardiovascular risk in patients following a complicated acute myocardial infarction.

BACKGROUND: The impact on prognosis of alcohol use in patients with coronary artery disease remains uncertain. We related alcohol use to all-cause mortality, cardiovascular (CV)-mortality and hospitalization in patients following a complicated myocardial infarction (MI). METHODS: In the OPTIMAAL trial, 5477 patients from 7 Western European countries with heart failure and/or evidence of left ventricular dysfunction following MI were recruited. Following randomization median 3 days, patients were asked to assess their average alcohol consumption prior to the index infarction. Patients were stratified by the frequency of the use of alcohol into either non-users (n = 2160), moderate users (1-7 drinks/week, n = 2753) and heavy users (> 7 drinks/week, n = 545) and related to prespecified clinical outcomes in the groups. RESULTS: A total of 5477 patients were included in the trial. During the follow-up period of 2.7 years 946 deaths were reported. Adjusted for age and smoking status, patients with moderate use of alcohol had 24% lower risk of all-cause death (p < 0.001), 26% lower risk of CV-death (p < 0.000) and 8% lower risk for hospitalization (p = 0.030) than abstainers. There was no significant difference between non-drinkers and heavy drinkers with regard to survival following adjustment for age and smoking status. CONCLUSION: Our results demonstrate a strong positive association between moderate alcohol use and survival in a cohort of patients following complicated MI. Both heavy drinkers and abstainers had poorer prognosis, with no significance difference between those 2 groups.

B-type natriuretic peptide is a long-term predictor of all-cause mortality, whereas high-sensitive C-reactive protein predicts recurrent short-term troponin T positive cardiac events in chest pain patients: a prognostic study.

BACKGROUND: Few studies have addressed whether the combined use of B-type natriuretic peptide (BNP) and high-sensitive C-reactive protein (hsCRP) improves risk stratification for mortality and cardiovascular events in a population with chest pain and suspected acute coronary syndromes (ACS). Therefore, we wanted to assess the incremental prognostic value of these biomarkers with respect to long-term all-cause mortality and recurrent troponin T (TnT) positive cardiac events in 871 patients admitted to the emergency department. METHODS: Blood samples were obtained immediately following admission. RESULTS: After a follow-up period of 24 months, 129 patients had died. The BNP levels were significantly higher among patients dying than in long-term survivors (401 (145-736) versus 75 (29-235) pq/mL [median, 25 and 75% percentiles], p = 0.000). In a multivariable Cox regression model for death within 2 years, the hazard ratio (HR) for BNP in the highest quartile (Q4) was 5.13 (95% confidence interval (CI), 1.97-13.38) compared to the lowest quartile (Q1) and was associated with all-cause mortality above and beyond age, congestive heart failure and the index diagnosis ST-segment elevation myocardial infarction. HsCRP rendered no prognostic information for all-cause mortality. However, within 30 days, the adjusted HR for patients with recurrent TnT cardiac positive events hsCRP in Q4 was 14.79 (95% CI, 1.89-115.63) compared with Q1 and was associated with recurrent ischemic events above and beyond age, hypercholesterolemia and TnT values at admission. CONCLUSION: BNP may act as a clinically useful biomarker when obtained at admission in an unselected patient population following hospitalization with chest pain and potential ACS, and may provide complementary prognostic information to established risk determinants at long-term follow-up. Our data do not support the hypothesis that the additional assessment of hsCRP will lead to better risk stratification for survival than BNP alone.

The prognostic utility of D-dimer and fibrin monomer at long-term follow-up after hospitalization with coronary chest pain.

D-dimer and fibrin monomer both reflect a prothrombotic potential. There are limited data available comparing these two markers of activated coagulation in a prospective manner in an unselected patient population presenting to the emergency department with chest pain. In addition, their role in risk stratification in patients with acute coronary syndrome is still under evaluation. Therefore, we wanted to assess the prognostic value of these markers with respect to long-term all-cause mortality in 871 patients admitted to the emergency department. Blood samples were obtained immediately following admission. After a follow-up period of 24 months, 123 patients had died. In the univariate analysis, both D-dimer and fibrin monomer predicted all-cause mortality within 2 years with an odds ratio of 7.78 (95% confidence interval, 3.95-15.33) and 4.19 (95% confidence interval, 2.42-7.28), respectively, in the highest quartile (Q4) compared with the lowest quartile (Q1). However, in the multivariable logistic regression model for death within 2 years, the odds ratio of D-dimer and fibrin monomer was 1.80 (95% confidence interval, 0.81 to 3.97) and 1.04 (95% confidence interval, 0.53 to 2.04) in Q4 compared with Q1, respectively, and added no prognostic information above and beyond age, known coronary heart disease, B-type natriuretic peptide and the index diagnoses of ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction and unstable angina pectoris. In an unselected patient population hospitalized with chest pain and potential acute coronary syndrome, neither D-dimer nor fibrin monomer provided complementary prognostic information to established risk determinants during long-term follow-up.

The long-term prognostic value of multiple biomarkers following a myocardial infarction.

INTRODUCTION: We assessed the long-term prognostic value of multiple cardiac biomarkers after an acute myocardial infarction (MI) in order to evaluate a multimarker approach to risk stratification. MATERIAL AND METHODS: Blood samples from 298 patients hospitalized with a myocardial infarction were subsequently tested for NT-proBNP, hsCRP, MMP-9, PAPP-A, MPO, sCD40L and FM. RESULTS: During the median follow-up period of 45 months, 83 patients suffered at least one TnT- positive event. In the unadjusted analysis NT-proBNP predicted future ACS or cardiac death with a hazard ratio (HR) of 1.83 (95% confidence interval (CI), 1.17-2.87, p=0.009) in Q4 as compared to the three lower quartiles (Q1-3). However, NT-proBNP was dependent on chronic heart failure and HDL-cholesterol in the stepwise multivariable model, with a hazard ratio (HR) in Q4 of 1.38 (95% CI, 0.82-2.33, p=0.229). The other biomarkers were not found to be related to the primary event following the index MI. CONCLUSION: In a patient population consisting of 298 subjects hospitalized with a MI, a multimarker approach with NT-proBNP, hsCRP, MMP-9, PAPP-A, MPO, sCD40L and FM rendered no additional prognostic information beyond conventionally used stratification tools in the acute phase. However, this does not preclude clinical valuable prognostic information by a biomarker such as NT-proBNP.

The effect of primary percutaneous coronary intervention as compared to tenecteplase on myeloperoxidase, pregnancy-associated plasma protein A, soluble fibrin and D-dimer in acute myocardial infarction.

INTRODUCTION: Acute coronary reperfusion is accomplished pharmacologically with intravenous thrombolytic therapy or mechanically with primary percutaneous coronary intervention (PCI). METHODS: We have determined the immediate effects of the main coronary reperfusion procedures on the plasma concentrations of myeloperoxidase (MPO), pregnancy-associated plasma protein A (PAPP-A), fibrin monomer (FM) and D-dimer (DD). We studied a total of 38 patients admitted for ST-segment elevation infarct (STEMI). 18 patients were given thrombolytic therapy with tenecteplase and 20 were treated with primary PCI. RESULTS: The plasma concentrations of PAPP-A increased by a factor of six to eight times (p<0.001) following both reperfusion therapies. No significant increase was observed for MPO by either procedure. DD and FM concentrations both increased significantly following thrombolytic therapy, p=0.000, whereas only minor increases, although statistically significant for FM (p=0.013), were noted after PCI. DD and FM were highly correlated prior to the two treatment regimens (R=0.91), and were still highly correlated after PCI (R=0.94) and thrombolytic therapy (R=0.86). No correlation was demonstrated between PAPP-A and markers of activated coagulation. CONCLUSIONS: This is the first report of a significant rise in the plasma concentration of PAPP-A after PCI as compared to thrombolytic treatment (p=0.002) and may indicate a greater impact of PCI than that of thrombolytic therapy on target coronary plaques.

Long term influence of regular intake of high dose n-3 fatty acids on CD40-ligand, pregnancy-associated plasma protein A and matrix metalloproteinase-9 following acute myocardial infarction.

Pregnancy-associated plasma protein A (PAPP-A) and matrix metalloproteinase 9 (MMP-9), both zinc-binding endopeptidases, are abundantly expressed in ruptured and eroded plaques in patients with acute coronary syndromes (ACS). The adhesion molecule CD-40 ligand (CD40L), expressed on activated platelets and T-lymphocytes, can activate metalloproteinases and thereby promote plaque-rupture. N-3 fatty acids, through their anti-inflammatory and anti-thrombotic properties, might reduce the levels of these proatherosclerotic markers and thereby the development of ACS. 300 patients were randomized on day 4 to 6 following an acute myocardial infarction (MI) to receive either 4 g of n-3 fatty acids or a similar daily dose of corn oil for at least one year. We compared levels of PAPP-A, MMP-9 and sCD-40 L at baseline and 12 months in each group, and also looked for inter-group changes. In the omega-3 group, the median level of PAPP-A rose from 0.47 mU/l to 0.56 mU/l (p < 0.001). In the same group, sCD-40 L decreased from a mean baseline value of 5.19 ng/ml to 2.45 ng/ml (p < 0.001) and MMP-9 decreased nonsignificantly from 360.50 ng/ml to 308.00 ng/ml. Corresponding values for the corn oil group were 0.54 mU/l to 0.59 mU/l for PAPP-A (p = 0.007), 5.27 ng/ml to 2.84 ng/ml for sCD-40 L (p < 0.001) and 430.00 ng/ml to 324.00 ng/ml for MMP-9 (p = ns), respectively. In conclusion; both interventions resulted in a significant rise in PAPP-A, a significant decrease in sCD40L and a non-significant decrease in MMP-9 after 12 months of treatment in MI survivors. No inter-group differences were noted.

[A 34-year-old man with hemorrhagic cystitis]. / En 34 år gammel mann med hemoragisk cystitt.

BACKGROUND: A 34-year-old male presented with macroscopic haematuria, abdominal pain and dysuria while being treated with penicillin for bacterial endocarditis. All blood cultures yielded Streptococcus mutans. After four weeks of treatment he developed haemorrhagic cystitis, thrombophlebitis and eosinophilia. The symptoms disappeared when he was taken off penicillin. After change of medication to ceftriaxone, the patient developed reversible neutropenia and recovered completely. INTERPRETATION: Haemorrhagic cystitis caused by penicillin can be potentially fatal; two cases have earlier been described. Because of cross reaction this patient also developed reversible neutropenia. It is well known that beta-lactam antibiotics can induce severe neutropenia.