Dirk Peetz

Sensitive Troponin I Assay in Early Diagnosis of Acute Myocardial Infarction

BACKGROUND Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. METHODS In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. RESULTS For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003). CONCLUSIONS The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset.

Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina

Background—Interleukin (IL)-18 plays a central role in orchestrating the cytokine cascade and accelerates atherosclerosis and plaque vulnerability in animal models. However, epidemiological data evaluating the role of IL-18 levels in atherosclerosis are lacking. Methods and Results—In a prospective study of 1229 patients with documented coronary artery disease, we measured baseline serum concentrations of IL-18 and other markers of inflammation. During the follow-up period (median, 3.9 years), 95 patients died of cardiovascular causes. Median serum concentrations of IL-18 were significantly higher among patients who had a fatal cardiovascular event than among those who did not (68.4 versus 58.7 pg/mL;P <0.0001). The hazard risk ratio of future cardiovascular death increased with increasing quartiles of IL-18 (hazard risk ratio, 1.46; 95% CI 1.21 to 1.76;P for trend <0.0001). After adjustment for most potential confounders, including the strong predictor ejection fraction as well as the inflammatory variables IL-6, high-sensitive C-reactive protein, and fibrinogen, this relation remained almost unchanged, such that patients within the highest quartile of IL-18 had a 3.3-fold increase in hazard risk compared with those in the first quartile (95% CI, 1.3 to 8.4, P =0.01). This relation was observed in patients with stable angina and patients with unstable angina at baseline. Conclusions—Serum IL-18 level was identified as a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of the clinical status at admission. This result strongly supports recent experimental evidence of IL-18–mediated inflammation leading to acceleration and vulnerability of atherosclerotic plaques.

Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease: Results from the AtheroGene Study

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 &mgr;mol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.

Serial Changes in Highly Sensitive Troponin I Assay and Early Diagnosis of Myocardial Infarction

CONTEXT Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. OBJECTIVE To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI). DESIGN, SETTING, AND PATIENTS A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours. MAIN OUTCOME MEASURES Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department. RESULTS Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours. CONCLUSIONS Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI.

Copeptin Improves Early Diagnosis of Acute Myocardial Infarction

OBJECTIVES Early identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation. BACKGROUND The aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction. METHODS Between January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h. RESULTS Of 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%. CONCLUSIONS In triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.

Multiple marker approach to risk stratification in patients with stable coronary artery disease

AIMS multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. METHODS AND RESULTS we investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C-terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid-regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic peptide (Nt-proBNP)] in 1781 stable angina patients in relation to non-fatal myocardial infarction and cardiovascular death (n = 137) over 3.6 years. Using Cox proportional hazards models and C-indices, the strongest association with outcome for log-transformed biomarkers in multivariable-adjusted analyses was observed for Nt-proBNP [hazard ratio (HR) for one standard deviation increase 1.65, 95% confidence interval (CI) 1.28-2.13, C-index 0.686], GDF-15 (HR 1.59, 95% CI 1.25-2.02, C-index 0.681), MR-proANP (HR 1.46, 95% CI 1.14-1.87, C-index 0.673), cystatin C (HR 1.39, 95% CI 1.10-1.75, C-index 0.671), and MR-proADM (HR 1.63, 95% CI 1.21-2.20, C-index 0.668). Each of these top single markers and their combination (C-index 0.690) added predictive information beyond the baseline model consisting of the classical risk factors assessed by C-index and led to substantial reclassification (P-integrated discrimination improvement <0.05). CONCLUSION comparative analysis of 12 biomarkers revealed Nt-proBNP, GDF-15, MR-proANP, cystatin C, and MR-proADM as the strongest predictors of cardiovascular outcome in stable angina. All five biomarkers taken separately offered incremental predictive ability over established risk factors. Combination of the single markers slightly improved model fit but did not enhance risk prediction from a clinical perspective.

Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study

AIMS Chronic kidney disease is associated with increased risk of cardiovascular disease. Cystatin C is a promising marker to reliably mirror renal function. The role of cystatin C in patients with coronary artery disease (CAD) and normal or mildly reduced kidney function is the subject of current investigation. METHODS AND RESULTS In 2162 patients, over the whole spectrum of CAD, baseline cystatin C concentrations were measured. Patients with an estimated glomerular filtration rate of < or =60 mL/min per 1.73 m(2) (n = 295) were excluded. In patients with complete follow-up information (n = 1827), 66 cardiovascular deaths were registered during a median follow-up of 3.65 years. Logarithmically transformed, standardized cystatin C was associated with cardiovascular death [hazard ratio: 1.94, 95% confidence interval (CI): 1.59-2.37, P < 0.001]. A potential threshold effect was observed; patients in the upper quartile had a 3.87-fold (95% CI: 2.33-6.42; P < 0.001) risk of mortality compared with the pooled lower quartiles. This risk association remained robust after adjustment for potential confounders including classical risk factors and N-terminal pro B-type natriuretic peptide. Serum creatinine was not associated with the outcome in this group of patients with normal renal function. CONCLUSION Results of this prospective study show that cystatin C is a potent predictor of cardiovascular mortality beyond classical risk factors in patients with CAD and normal or mildly reduced kidney function.

Retinal vascular occlusion and deficiencies in the protein C pathway

PURPOSE To report abnormalities in the protein C pathway and other vascular occlusion risk factors in patients with retinal vascular occlusion. METHODS In a study, we investigated 76 consecutive patients who had in-patient evaluation of venous or arterial retinal vascular occlusion. All patients underwent comprehensive tests for coagulation disorders including determinations of protein C, protein S, lupus anticoagulants, and resistance to activated protein C and were screened for vascular disease risk factors. Resistance to activated protein C was confirmed by a polymerase chain reaction method to detect the specific factor V R506Q mutation. For comparative purposes, we also screened 209 consecutive inpatients with deep vein thrombosis from the same geographic region for resistance to activated protein C as well as protein C and protein S deficiencies. RESULTS Ten (29%) of 35 patients with central retinal vein occlusion (CRVO) had factor V R506Q mutation. The factor V R506Q mutation was detected in four (19%) of 21 patients with branch retinal vein occlusion. The higher frequency in factor V R506Q mutation compared with the expected 9% mutation prevalence in a white population was highly significant for the central retinal vein occlusion group but not for the branch retinal vein occlusion group. In all patients with resistance to activated protein C, the factor V R506Q mutation was detected; 16 were heterozygous, one homozygous. No cases of lupus anticoagulants, protein C, or protein S deficiencies were detected. Forty (19%) of 209 patients with deep vein thrombosis were carriers of the factor V R506Q mutation. CONCLUSIONS The prevalence of the factor V R506Q mutation is similar in patients with central retinal vein occlusion and patients with deep vein thrombosis and represents a relevant risk factor. Screening for this mutation is therefore recommended in all patients with central retinal vein occlusion.

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C <or=45 mg/dl. P=0.047). The present findings indicate that ER-niacin treatment improves endothelial dysfunction in patients with CAD and low HDL-C, but not with normal HDL-C.

Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study

Background: Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process. Objectives: To compare plasma levels of soluble TF (sTF) and free‐TFPI (f‐TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long‐term prognosis. Patients/methods: Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f‐TFPI levels, but not on sTF levels, patients having received UFH before blood drawing were excluded from the analyses on f‐TFPI (n = 226). Results: On admission, no significant differences in sTF levels were observed between SAP and ACS patients. By comparison to patients with stable angina, f‐TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non‐ST‐elevation myocardial infarction and ST‐elevation myocardial infarction (P < 10−4). Among the 1669 individuals with a coronary artery disease, 56 died from a cardiovascular cause. In prospective analyses, high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS (fully adjusted hazard ratio associated with one quartile increase = 2.06; 95% confidence interval 1.24–3.45; P = 0.006) but not in those with SAP (hazard ratio = 1.07; 95% confidence interval 0.78–1.46; P = 0.67). In SAP and ACS patients, high f‐TFPI levels were not independently associated with an increased risk of cardiovascular death. Conclusions: Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS, whereas f‐TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome.