There are important differences in the 99th percentile upper reference limit (URL) for high-sensitivity (hs) troponin assays by age and sex but no significant differences by race or ethnicity, according to a new analysis of NHANES data. The study, published online Monday and in the May 23 issue of the Journal of the American College of Cardiology, the noted that the 2018 Universal Definition of Myocardial Infarction requires evidence of both acute myocardial ischemia and acute myocardial injury for diagnosis of myocardial infarction – adding that a cardiac troponin concentration above the 99th percentile of a healthy reference population URL is defined as myocardial injury. “This 99th percentile URL threshold is the common benchmark of abnormality for all troponin assays,” said the authors, led by John W. McEvoy, MB, BCh, MHS, PhD, from the University of Galway, Ireland; Johns Hopkins University, Baltimore; and the Johns Hopkins Bloomberg School of Public Health, Baltimore. McEvoy and colleagues noted, however, that recent developments of hs cardiac troponin assays – which allow for earlier diagnosis of myocardial infarction – may lead to potential issues in the diagnosis of MI, due to variability in the approach used to define the 99th percentile URL for hs-troponin assays and the fact that the various hs-troponin assays are not standardized or harmonized. “The URLs in current clinical use are typically those reported by manufacturers and were derived from convenience samples using inconsistent approaches,” said the team. “Therefore, hs-troponin concentrations at 99th percentiles do not align across assays, and the generalizability of manufacturer-reported URLs for hs-troponin assays to the U.S. adult population is unknown,” they said. Study setup McEvoy and colleagues analyzed data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to estimate hs troponin URLs in a representative sample of the U.S. adult population: overall and by sex, race/ethnicity, and age group. The team measured hs-troponin T using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens and Ortho) in a subset of 2,746 NHANES participants who met criteria for the healthy subgroup (mean age 37 years, 50% men). “In a strictly defined healthy reference subgroup, we estimated 99th percentile URLs for each assay using the recommended nonparametric method,” explained the team. Key findings According to McEvoy and colleagues the NHANES 99th percentile URL for hs-troponin T (19 ng/L) matched the manufacturer-reported URL (19 ng/L). Meanwhile, NHANES URLs were 13 ng/L (95% confidence interval [CI]: 10-15 ng/L) for Abbott hs-troponin I (manufacturer: 28 ng/L), 5 ng/L (95% CI: 4-7 ng/L) for Ortho hs-troponin I (manufacturer: 11 ng/L), and 37 ng/L (95% CI: 27-66 ng/L) for Siemens hs-troponin I (manufacturer: 46.5 ng/L). “For both the Abbott and Ortho hs-troponin I assays, the 99th percentile URL in our healthy reference sample was less than one-half of that reported by manufacturers; and the 95% CIs for our estimates did not overlap with the manufacturer-reported 99th percentile URL,” the team said, adding that although the Siemens 99th percentile URL was also numerically lower than the manufacturer-reported URL, the 95% CI estimate overlapped with the manufacturer-reported URL. Furthermore, the researchers reported significant differences in URLs by age and sex but none by race/ethnicity. These sex differences were statistically significant (all P values <0.001) “Comparing the youngest with the oldest age groups among men and women separately, the 95% CIs for these 99th percentile URLs did not overlap for the hs-troponin T assay but did overlap for the 3 hs-troponin I assays. However, the sex- and age-specific 75th percentiles for all 4 hs-troponin assays differed (with nonoverlapping 95% CIs) according to age and sex,” said the team, adding that they also observed “clear differences” according to age and sex when comparing the full distributions of hs-troponin concentrations in the healthy reference subsample. The team concluded that while myocardial injury is just one of the factors to consider in the diagnosis of myocardial infarction, further studies are needed to assess the impact of employing both sex- and age-specific hs-troponin thresholds for defining myocardial injury during diagnostic evaluations. “Our results support the reporting of sex-specific hs-troponin URLs in defining myocardial injury, which is recommended in the Fourth Universal Definition of Myocardial Infarction but is often not deployed in current clinical practice,” they said.What Is a Normal Troponin, Anyway?Writing in an accompanying editorial, Cian P. McCarthy, MB, BCh, BAO; Austin Vyas, BS; and James L. Januzzi Jr., MD, all from the Massachusetts General Hospital, Boston, noted that cardiac troponin (cTn) has been the favored biomarker for this application for the past 20 years but conceded that “what exactly constitutes an abnormal cTn concentration has been somewhat of a moving target.” “These findings from this study have implications on how we define and interpret normal and abnormal troponin values and highlight the importance of using a standardized process for deriving the URL for these widely used assays,” they said. “Clinically, the results emphasize importance of age and sex in hs-troponin test interpretation. And finally, the results resolve the question about whether race influences hs-troponin thresholds: it does not.” The editorialists noted that troponin measurements remain one of the most commonly utilized blood tests in hospital-based settings, “yet important questions remain about what exactly is a normal value for this test.” They added the new findings reveal an urgency for large, adequately powered studies derived from healthy cohorts, as defined by the International Federation of Clinical Chemistry and Laboratory Medicine/American Association for Clinical Chemistry, to answer the question of in a definitive fashion and derive precise age- and sex- specific 99th percentile URLs. Sources: McEvoy JQ, Tang O, Wang D, et al. Myocardial Injury Thresholds for 4 High-Sensitivity Troponin Assays in U.S. Adults. J Am Coll Cardiol 2023;81:2028-2039. McCarthy CP, Vyas A, Januzzi JL, Jr. What Is a Normal Troponin, Anyway? J Am Coll Cardiol 2023;81:2040-2042. Image Credit: Arif Biswas – stock.adobe.com