Kavsak, Peter A.

Abstract Background: The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population. Methods: In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: <5.00, 5.00–9.99, 10.00–40.00, and >40.00 ng/L. Kaplan–Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation. Results: There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P < 0.05). At 6 months, patients with hs-cTnI ≥10.00 ng/L were at higher risk for death/MI (hazard ratio >3.7; P < 0.05) compared with those having hs-cTnI <5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65–0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L. Conclusions: This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.

Abstract Background: Improvements in cardiac troponin (cTn) assays have increased the rapidity with which clinicians can identify patients with changing cTn concentrations (rise or fall) indicative of acute myocardial injury. The aim of the present study was to characterize a new, high-sensitivity cTnI (hs-cTnI) assay and examine whether increased sensitivity can result in still earlier detection of evolving injury. Methods: We determined the limit of detection, precision profiles, and preliminary estimates of the 99th percentile for the Beckman Coulter hs-cTnI assay in 125 healthy individuals (age <55 years, 54% male). We compared AccuTnI® and hs-cTnI to assess whether change criteria for early concentration changes (i.e., ≥3SD for low concentrations and 20% difference for concentrations >0.10 μg/L) were exceeded in the first 2 specimens (median time between specimens, 1 h; 25th–75th percentile, 1–3 h) from subjects with symptoms suggestive of cardiac ischemia (n = 290). Results: The limit of detection for the hs-cTnI assay was 2.06 ng/L, and the 20% CV and 10% CV concentrations were 2.95 and 8.66 ng/L, respectively. The preliminary 99th percentile estimates in lithium heparin, serum, and EDTA plasma were 9.20, 8.00, and 8.60 ng/L, respectively. In 108 patients with myocardial injury based on the peak AccuTnI concentration, applying the change criteria on the 2 earliest specimens identified 81% (95% CI 73%–88%) of patients using the hs-cTnI assay compared to 62% (53%–71%) using the AccuTnI assay (P < 0.001). Conclusions: Although more extensive validation studies are required, this Beckman Coulter hs-cTnI assay appears to detect patients with evolving myocardial injury earlier.

Abstract Background: Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations. Methods: We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2–4 hours, and a later second specimen obtained at 9 hours, IQR 9–9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) ≥1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years. Results: In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P ≥0.15). Conclusions: A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.

Abstract Background: Inflammation in acute coronary syndrome (ACS) can identify those at greater long-term risks for heart failure (HF) and death. The present study assessed the performance of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) (cytokines involved in the activation and recruitment of leukocytes) in addition to known biomarkers [e.g., N-terminal pro-brain natriuretic peptide (NT-proBNP)] for predicting HF and death in an ACS population. Methods: In a cohort of 216 ACS patients, NT-proBNP (Elecsys®; Roche) and IL-6, IL-8, and MCP-1 (evidence investigator™; Randox) were measured in serial specimens collected early after symptom onset (n = 723). We collected at least 2 specimens from each participant: an early specimen (median 2 h; interquartile range 2–4 h) and a later specimen (9 h; 9–9 h), and used the later specimens’ biomarker concentrations for risk stratification. Results: An increase in both IL-6 and NT-proBNP was observed but not for IL-8 or MCP-1 early after pain onset. Kaplan–Meier analysis demonstrated that individuals with increased NT-proBNP (>183 ng/L) or cytokines (IL-6 > 6.4 ng/L; above upper limit of normal for IL-8 or MCP-1) had a greater probability of death or HF in the following 8 years (P <0.05). In a Cox proportional hazard model adjusted for both CRP and troponin I, increased IL-6, MCP-1, and NT-proBNP remained significant risk factors. Combining all 3 biomarkers resulted in a higher likelihood ratio for death or HF than models restricted to any 2 of these biomarkers. Conclusion: IL-6, MCP-1, and NT-proBNP are independent predictors of long-term risk of death or HF, highlighting the importance of identifying leukocyte activation and recruitment in ACS patients.

Abstract Background: Recent data suggest that older men with detectable cardiac troponin I (cTnI) concentrations that remain below the 99th percentile concentration cutoff are at increased risk for subsequent cardiovascular events. We designed this study to extend this observation by examining risk prediction in both men and women presenting to an emergency department with chest discomfort. Methods: We obtained data for all-cause mortality and hospital discharges associated with either acute myocardial infarction (AMI) or congestive heart failure (CHF) for up to 8 years after the initial presentation in 448 patients who originally presented in 1996 with acute coronary syndrome (ACS). We performed retrospective analysis for cTnI (AccuTnI™; Beckman Coulter) in frozen plasma samples based on the patients’ reported time from onset of symptoms. Peak cTnI concentration was used for risk assessment. Results: Patients with cTnI concentrations ≥0.02 μg/L (i.e., limit of detection), including those whose peak values remained below the 99th percentile (0.04 μg/L), were at greater risk for death and AMI/CHF readmissions at 2, 5, and 8 years of follow-up compared with those with peak cTnI <0.02 μg/L. All results were statistically significant (P <0.05) except for death within 2 years among patients with normal but detectable cTnI (0.02 to 0.03 μg/L), relative to the group with values <0.02 μg/L. Kaplan–Meier analyses indicated that both men and women with cTnI ≥0.02 μg/L had worse outcomes (P <0.001). Conclusion: Both men and women who present with possible ACS with detectable cTnI concentrations that remain below the 99th percentile are at a greater risk for future adverse events.

Abstract Background: In a population originally classified for acute myocardial infarction (AMI) by the World Health Organization (WHO) definition, we compared the health outcomes after retrospectively reclassifying with the European Society of Cardiology and the American College of Cardiology (ESC/ACC) AMI definition, using the peak cardiac troponin I (cTnI) concentrations. The health outcomes were based on the WHO definition and occurred in an era that preceded the use of cardiac troponin biomarkers. Methods: For 448 patients who presented to the emergency department with symptoms suggestive of cardiac ischemia in 1996, we obtained data for all-cause mortality and recurrent AMI for up to 1 year after the initial presentation. We performed retrospective analysis of the patients’ frozen plasma samples to measure cTnI (AccuTnI®, Beckman Coulter). Results: At 30, 120, and 360 days, the risk for AMI/death in patients positive for AMI by only the ESC/ACC criteria was significantly lower than the risk in patients positive by both ESC/ACC and WHO criteria, and significantly higher than in patients negative according to both criteria. In a separate analysis, patients with a peak cTnI >0.10 μg/L were at greater risk for AMI/death than patients with cTnI concentrations of 0.04–0.10 μg/L. Patients negative by both definitions or with peak cTnI concentrations <0.04 μg/L had the highest event-free survival rates (92% and 94%, respectively) at 1 year. Conclusion: In a troponin-naïve population, patients classified as positive for AMI by only the ESC/ACC criteria have a prognosis that appears to be intermediate between those classified positive by both the WHO and ESC/ACC definitions and those who meet neither criteria.