Fred S. Apple

Myocardial infarction redefined - A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee f or the redefinition of myocardial infarction

This document was developed by a consensus conference initiated by Kristian Thygesen, MD, and Joseph S. Alpert, MD, after formal approval by Lars Rydén, MD, President of the European Society of Cardiology (ESC), and Arthur Garson, MD, President of the American College of Cardiology (ACC). All of the participants were selected for their expertise in the field they represented, with approximately one-half of the participants selected from each organization. Participants were instructed to review the scientific evidence in their area of expertise and to attend the consensus conference with prepared remarks. The first draft of the document was prepared during the consensus conference itself. Sources of funding appear in Appendix A. The recommendations made in this document represent the attitudes and opinions of the participants at the time of the conference, and these recommendations were revised subsequently. The conclusions reached will undoubtedly need to be revised as new scientific evidence becomes available. This document has been reviewed by members of the ESC Committee for Scientific and Clinical Initiatives and by members of the Board of the ESC who approved the document on April 15, 2000.*

Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery

BACKGROUND The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. METHODS We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. RESULTS A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. CONCLUSIONS A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032.).

Cardiac Troponin and Outcome in Acute Heart Failure

BACKGROUND Cardiac troponin provides diagnostic and prognostic information in acute coronary syndromes, but its role in acute decompensated heart failure is unclear. The purpose of our study was to describe the association between elevated cardiac troponin levels and adverse events in hospitalized patients with acute decompensated heart failure. METHODS We analyzed hospitalizations for acute decompensated heart failure between October 2001 and January 2004 that were recorded in the Acute Decompensated Heart Failure National Registry (ADHERE). Entry criteria included a troponin level that was obtained at the time of hospitalization in patients with a serum creatinine level of less than 2.0 mg per deciliter (177 micromol per liter). A positive troponin test was defined as a cardiac troponin I level of 1.0 microg per liter or higher or a cardiac troponin T level of 0.1 microg per liter or higher. RESULTS Troponin was measured at the time of admission in 84,872 of 105,388 patients (80.5%) who were hospitalized for acute decompensated heart failure. Of these patients, 67,924 had a creatinine level of less than 2.0 mg per deciliter. Cardiac troponin I was measured in 61,379 patients, and cardiac troponin T in 7880 patients (both proteins were measured in 1335 patients). Overall, 4240 patients (6.2%) were positive for troponin. Patients who were positive for troponin had lower systolic blood pressure on admission, a lower ejection fraction, and higher in-hospital mortality (8.0% vs. 2.7%, P<0.001) than those who were negative for troponin. The adjusted odds ratio for death in the group of patients with a positive troponin test was 2.55 (95% confidence interval, 2.24 to 2.89; P<0.001 by the Wald test). CONCLUSIONS In patients with acute decompensated heart failure, a positive cardiac troponin test is associated with higher in-hospital mortality, independently of other predictive variables. (ClinicalTrials.gov number, NCT00366639 [ClinicalTrials.gov].).

It's time for a change to a troponin standard.

Recently, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) convened a conference to discuss refinements in the diagnosis of acute myocardial infarction. The panel on biochemistry considered issues related to the use of marker proteins. We were guided predominantly by the science of the area. We were also cognizant of the impact that changes in the standards would have on epidemiology, clinical trials, education of physicians, and patient care. Our recommendations will be incorporated, with the recommendations of the other panels, into a position paper for the ESC and the ACC. However, the members of the biochemistry group decided to express the opinions we felt were important in this area independently. Our thinking does not represent the position of the ESC, the ACC, or of the conjoint task force. Many modifications of the original World Health Organization criteria for acute myocardial infarction1 have been accepted and incorporated into the ESC/ACC criteria; some deletions have also occurred. Until recently, most markers were detected using enzymatic activity; detection of the protein concentration now is preferred. Thus, it is more appropriate to refer to molecules released into the circulation as a consequence of cardiac injury as biochemical diagnostic markers or biomarkers. In this editorial, we emphasize issues related to the biochemical diagnosis of acute myocardial infarction. New and improved plasma biomarkers (troponins) with better sensitivity and specificity will be emphasized in preference to markers such as total creatine kinase (CK), CK-MB, lactate dehydrogenase, and aspartate aminotransferase. Rapid assays for the early detection of infarction that may be helpful will be delineated, and the use of the troponin markers to aid in the risk stratification of patients with acute coronary syndromes will be recommended. ### Biomarker Increases Detectable increases in the biomarkers of cardiac injury are indicative of injury to the …

Predictive Value of Cardiac Troponin I and T for Subsequent Death in End-Stage Renal Disease

Background—This study determined the prevalence of increased cardiac troponin I (cTnI) and T (cTnT) in end-stage renal disease (ESRD) patients and whether an increased troponin was predictive of death. Methods and Results—Serum was obtained from 733 ESRD patients and measured for cTnI and cTnT. Relative risks were estimated using Cox proportional hazards regressions univariately and adjusted for age, time on dialysis, and coronary artery disease. Kaplan-Meier curves compared time to event data between groups. Greater percentages of patients had an increased cTnT versus cTnI at each cutoff, as follows: 99th percentile, 82% versus 6%; 10% coefficient of variation, 53% versus 1.0%; and receiver operator characteristic, 20% versus 0.4%. Increased versus normal cTnT was predictive of increased mortality using all cutoffs and only above the 99th percentile for cTnI. Two-year cumulative mortality rates increased (P <0.001) with changes in cTnT from normal (<0.01 &mgr;g/L, 8.4%) to small (≥0.01 to <0.04 &mgr;g/L, 26%), moderate (≥0.04 to <0.1 &mgr;g/L, 39%), and large (≥0.1 &mgr;g/L, 47%) increases. Two-year mortalities were 30% for cTnI <0.1 &mgr;g/L and 52% if ≥0.1 &mgr;g/L. Univariate and adjusted relative risks of death associated with elevated (>99th percentile) cTnT were 5.0 (CI, 2.5 to 10;P <0.001) and 3.9 (CI, 1.9 to7.9;P <0.001) and cTnI were 2.0 (CI, 1.3 to 3.3;P =0.008) and 2.1 (CI, 1.3 to 3.3;P =0.007). Age, coronary artery disease, and time on dialysis were also independent predictors of mortality. Conclusions—Increases in cTnT and cTnI in ESRD patients show a 2- to 5-fold increase in mortality, with a greater number of patients having an increased cTnT.

Analytical characteristics of high-sensitivity cardiac troponin assays.

BACKGROUND Cardiac troponins I (cTnI) and T (cTnT) have received international endorsement as the standard biomarkers for detection of myocardial injury, for risk stratification in patients suspected of acute coronary syndrome, and for the diagnosis of myocardial infarction. An evidence-based clinical database is growing rapidly for high-sensitivity (hs) troponin assays. Thus, clarifications of the analytical principles for the immunoassays used in clinical practice are important. CONTENT The purpose of this mini-review is (a) to provide a background for the biochemistry of cTnT and cTnI and (b) to address the following analytical questions for both hs cTnI and cTnT assays: (i) How does an assay become designated hs? (ii) How does one realistically define healthy (normal) reference populations for determining the 99th percentile? (iii) What is the usual biological variation of these analytes? (iv) What assay imprecision characteristics are acceptable? (v) Will standardization of cardiac troponin assays be attainable? SUMMARY This review raises important points regarding cTnI and cTnT assays and their reference limits and specifically addresses hs assays used to measure low concentrations (nanograms per liter or picograms per milliliter). Recommendations are made to help clarify the nomenclature. The review also identifies further challenges for the evolving science of cardiac troponin measurement. It is hoped that with the introduction of these concepts, both laboratorians and clinicians can develop a more unified view of how these assays are used worldwide in clinical practice.

Biochemical Mechanisms for Oxygen Free Radical Formation During Exercise

SummaryThe biochemical mechanisms behind skeletal muscle soreness and damage with muscular overuse have remained unclear. Recently, however, a growing amount of evidence indicates that free radicals play an important role as mediators of skeletal muscle damage and inflammation. During exercise, two of the potentially harmful free radical generating sources are semiquinone in the mitochondria and xanthine oxidase in the capillary endothelial cells. During high intensity exercise the flow of oxygen through the skeletal muscle cells is greatly increased at the same time as the rate of ATP utilisation exceeds the rate of ATP generation. The metabolic stress in the cells causes several biochemical changes to occur, resulting in a markedly enhanced rate of production of oxygen free radicals from semiquinone and xanthine oxidase. During normal conditions free radicals are generated at a low rate and subsequently taken care of by the well developed scavenger and antioxidant systems. However, a greatly increased rate of free radical production may exceed the capacity of the cellular defence system. Consequently, a substantial attack of free radicals on the cell membranes may lead to a loss of cell viability and to cell necrosis and could initiate the skeletal muscle damage and inflammation caused by exhaustive exercise.

Determination of 19 Cardiac Troponin I and T Assay 99th Percentile Values from a Common Presumably Healthy Population

BACKGROUND Between-assay comparability of 99th percentiles for cardiac troponin concentrations has not been assessed systematically in a single population for a large number of assays. METHODS We determined 99th percentiles for 19 cardiac troponin assays in heparin plasma samples from a population of 272 and 252 presumably healthy males and females, respectively. The assays evaluated included 1 cardiac troponin T (cTnT) assay from Roche and 18 cTnI assays from Abbott, Alere, Beckman, bioMerieux, Instrumentation Laboratory, Ortho-Clinical Diagnostics, Singulex, Siemens, and Roche. Five of these assays were categorized as high-sensitivity, 9 as sensitive-contemporary, and 5 as point-of-care (POC) assays. RESULTS For high-sensitivity cTnI (hs-cTnI) assays 99th percentiles varied from 23 to 58 ng/L. At least 80% of individuals had measurable hs-cTnI, whereas only 25% had measurable high-sensitivity cTnT. All high-sensitivity cardic troponin assays had 99th percentiles that were 1.2-2.4-fold higher in males than females. For the 9 sensitive-contemporary cTnI assays, 99th percentiles varied from 12 to 392 ng/L, and only the Beckman assay gave measurable concentrations in a substantial portion of the population (35% vs ≤6% for the others). Seven of these 9 assays had 1.3-5.0-fold higher 99th percentiles for males than females. For 5 cTnI POC assays, 99th percentiles varied from <10 to 40 ng/L. The Instrumentation Laboratory assay gave measurable results in 27.8% of study participants vs ≤6% for the others. Correlations were generally poor among assays. CONCLUSIONS Among cardiac troponin assays 99th percentile concentrations appear to differ. High-sensitivity assays provide measurable cardiac troponin results in a substantially greater fraction of presumably healthy individuals.

A New Season for Cardiac Troponin Assays: It’s Time to Keep a Scorecard

Advancements in cardiac troponin (cTn)1 assay technology have created a conundrum for clinicians and laboratory scientists, who must determine which assays are best for optimal patient care. Unfortunately, few resources are available to guide the medical and scientific communities in this regard. International guidelines (1)(2)(3) have defined an increased cTn above the 99th percentile limit as an abnormal result; what is lacking, unfortunately, is an approach to define this limit across the heterogeneity of the assays. In spite of the evidence-based literature demonstrating that cTn concentrations tend to increase in individuals >60 years old (4), 99th percentile reference limits are often determined across wide age ranges using subjects as old as 70 years (convenience samples). Further frustrating the problem of selecting relevant reference subjects, in clinically defined “normal” individuals without known cardiovascular disease, increased cTn concentrations are indicative of a significantly higher risk of death (4)(5). The occurrence of such individuals in reference populations may reflect inadequate screening for comorbidities at the time of sample acquisition. Given such problems, a majority of laboratories either accept the manufacturer’s reference limit from the US Food and Drug Administration (FDA)-cleared package insert, perform an underpowered normal range study to establish a reference limit, or accept a reference limit published in the literature. To validate cTn assays, however—to level the playing field for all users—is necessary for the best patient care. cTnI and cTnT are established as the standard biomarkers for the detection of myocardial injury and prognostic evaluation of patients with acute coronary syndrome (ACS) and without (1)(2)(3). The consensus guidelines from the Global Task Force for the Universal Definition of Myocardial Infarction (1) and the National Academy of Clinical Biochemistry (2), plus the updated American College of Cardiology/American Heart Association guidelines …

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure

### A. Context of Biochemical Marker Testing in Heart Failure Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting. The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled “ National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure ”, …