Variability of cardiac troponin levels in normal subjects and in patients with cardiovascular diseases: analytical considerations and clinical relevance

Abstract

In accordance with all the most recent international guidelines, the variation of circulating levels of cardiac troponins I and T, measured with high-sensitivity methods (hs-cTnI and hs-cTnT), should be used for the detection of acute myocardial injury. Recent experimental and clinical evidences have demonstrated that the evaluation of hs-cTnI and hs-cTnT variations is particularly relevant: a) for the differential diagnosis of Acute Coronary Syndromes (ACS) in patients admitted to the Emergency Department (ED); b) for the evaluation of cardiovascular risk in patients undergoing major cardiac or non-cardiac surgery, and in asymptomatic subjects of the general population aged >55 years and with co-morbidities; c) for the evaluation of cardiotoxicity caused by administration of some chemotherapy drugs in patients with malignant tumors. The aim of this document is to discuss the fundamental statistical and biological considerations on the intraindividual variability of hs-cTnI and hs-cTnT over time in the same individual. Firstly, it will be discussed in detail as the variations of circulating levels strictly depend not only on the analytical error of the method used but also on the intra-individual variability of the biomarker. Afterwards, the pathophysiological interpretation and the clinical relevance of the determination of the variability of the hs-cTnI and hs-cTnT values ​​ in patients with specific clinical conditions are discussed. Finally, the evaluation over time of the variation in circulating levels of hs-cTnI and hs-cTnT is proposed for a more accurate estimation of cardiovascular risk in asymptomatic subjects from the general population.

The Clinical Validation of a Common Analytical Change Criteria for Cardiac Troponin for Ruling in an Acute Cardiovascular Outcome in Patients Presenting with Ischemic Chest Pain Symptoms

“…Fifth, it is important to reiterate that the >20% criterion is recommended to distinguish acute from chronic myocardial injury, and the data from this study indicate that the application of this percent change across all concentration levels leads to lower specificity. However, the analytical change used in the 3C method finds support from recent studies assessing reference change values (RCV) for hs-cTn assays, where an RCV of 30% around the 99th percentile may be more suitable [ 34 , 35 ].…”

Circulating Cardiovascular Biomarkers in Cancer Therapeutics‐Related Cardiotoxicity: Review of Critical Challenges, Solutions, and Future Directions

“…Troponins have a low index of individuality when measured using hs methods (≤0.3), reflective of analytical, within‐subject, and between‐subject coefficients of variation. 62 , 63 , 64 This indicates good correlation with physiological characteristics such as age, sex, and body mass, such that changes over time that are biologically significant for a patient may not exceed reference thresholds for a population. Additionally, studies designed to evaluate reference change values for both hsTnI and hsTnT assays have demonstrated an reference change value of approximately 32% (95% probability, minimum 26%, maximum 45%, range 5–40 ng/L) and overall similar imprecision.…”

“…Additionally, studies designed to evaluate reference change values for both hsTnI and hsTnT assays have demonstrated an reference change value of approximately 32% (95% probability, minimum 26%, maximum 45%, range 5–40 ng/L) and overall similar imprecision. 64 Within‐subject interval changes (delta values) exceeding this range may thus be preferred to absolute cutoffs, emphasizing the importance of procurement of baseline/pretreatment biomarker values as well as analyses incorporating novel decision limits (eg, different high‐ and low‐risk thresholds, delta values, and values derived using machine learning techniques).…”

“…More recently, research involving hsTn assays has reawakened interest in circulating biomarkers for prediction of cardiotoxicity. 64 , 66 A panel of biomarkers including hsTnI was assessed in 78 patients with early‐stage HER2+ breast cancer in 1 study; changes in TnI and myeloperoxidase (MPO) predicted CTRCD (Cardiac Review and Evaluation Committee definition; 26 cases). 41 When delta values of both MPO and TnI were elevated (>90th percentile) by 15 months, the probability of cardiotoxicity approached ~50%.…”

Contemporary Management of Cardiomyopathy and Heart Failure in Pregnancy

“…Adverse maternal cardiac events have been associated with high concentrations (> 128 pg/mL) [ 26 ], and NT-proBNP levels > 200 pg/mL should raise concern for HF and/or pre-eclampsia [ 27 ]. Cardiac troponin (cTn) assays using high-sensitivity methods can also provide a key role in the diagnosis of acute or chronic cardiac injury in pregnant women with cardiomyopathy, and in some cases may signal early cardiac injury prior to detection on imaging [ 28 ]. An elevated troponin level is never normal in pregnancy and should prompt further evaluation for myocardial injury [ 27 , 29 – 31 ].…”