Longitudinal Studies of Cardiac Troponin-I Concentrations in Serum from                Male Sprague Dawley Rats: Baseline Reference Ranges and Effects of Handling and                Placebo Dosing on Biological Variability

Serum cardiac troponin-I has been validated as a biomarker for cardiotoxicity in numerous animal models; however, baseline reference ranges for cTnI concentration in a healthy population of laboratory rats, as well as an investigation of biological cTnI variability in rats with respect to time, handling, and placebo dosing methods, have not been reported. In this study, we used an ultrasensitive cTnI immunoassay to quantify hourly concentrations of cTnI in live rats handled under standard laboratory conditions using 15 μL of serum per determination. The baseline reference range (mean 4.94 pg/mL, range 1–15 pg/mL, 99% confidence interval [CI]) of cTnI concentration in rats was consistent with previously reported reference ranges for cTnI in humans (1–12 pg/mL) and with preliminary studies in dogs (1–4 pg/mL) and monkeys (4–5 pg/mL) using the same cTnI assay method. In addition, cTnI concentrations in individual rat serum samples show minimal biological variability over a twenty-four-hour interval when compared to a meaningful reference change value of 193% to 206%. Furthermore, measurements of cTnI concentration were consistent within the reference limits in individual rats over long periods and under three different standard laboratory handling conditions. Thus, using this new method, rats can be followed longitudinally at hourly intervals, and a doubling of cTnI concentration would be significant above biological variability. This is a new paradigm for preclinical testing, which allows transient changes in cTnI concentration to be accurately quantified. This understanding of baseline and biological variability in rats will be fundamental for designing and analyzing future studies that assess potential cardiotoxicity in drug development.

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Biological variation of cardiac troponins in chronic kidney disease

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563220906431 ◽

2020 ◽

Vol 57 (2) ◽

pp. 162-169

Author(s):

RA Jones ◽

J Barratt ◽

EA Brettell ◽

P Cockwell ◽

RN Dalton ◽

...

Keyword(s):

Myocardial Infarction ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Cardiac Troponin ◽

Troponin I ◽

Troponin T ◽

Biological Variation ◽

Cardiac Troponin I ◽

Cardiac Troponin T ◽

Reference Change Value

Background Patients with chronic kidney disease often have increased plasma cardiac troponin concentration in the absence of myocardial infarction. Incidence of myocardial infarction is high in this population, and diagnosis, particularly of non ST-segment elevation myocardial infarction (NSTEMI), is challenging. Knowledge of biological variation aids understanding of serial cardiac troponin measurements and could improve interpretation in clinical practice. The National Academy of Clinical Biochemistry (NACB) recommended the use of a 20% reference change value in patients with kidney failure. The aim of this study was to calculate the biological variation of cardiac troponin I and cardiac troponin T in patients with moderate chronic kidney disease (glomerular filtration rate [GFR] 30–59 mL/min/1.73 m2). Methods and results Plasma samples were obtained from 20 patients (median GFR 43.0 mL/min/1.73 m2) once a week for four consecutive weeks. Cardiac troponin I (Abbott ARCHITECT® i2000SR, median 4.3 ng/L, upper 99th percentile of reference population 26.2 ng/L) and cardiac troponin T (Roche Cobas® e601, median 11.8 ng/L, upper 99th percentile of reference population 14 ng/L) were measured in duplicate using high-sensitivity assays. After outlier removal and log transformation, 18 patients’ data were subject to ANOVA, and within-subject (CVI), between-subject (CVG) and analytical (CVA) variation calculated. Variation for cardiac troponin I was 15.0%, 105.6%, 8.3%, respectively, and for cardiac troponin T 7.4%, 78.4%, 3.1%, respectively. Reference change values for increasing and decreasing troponin concentrations were +60%/–38% for cardiac troponin I and +25%/–20% for cardiac troponin T. Conclusions The observed reference change value for cardiac troponin T is broadly compatible with the NACB recommendation, but for cardiac troponin I, larger changes are required to define significant change. The incorporation of separate RCVs for cardiac troponin I and cardiac troponin T, and separate RCVs for rising and falling concentrations of cardiac troponin, should be considered when developing guidance for interpretation of sequential cardiac troponin measurements.

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Prognostic Value of Serial Changes in High-Sensitivity Cardiac Troponin I and T over 3 Months Using Reference Change Values in Hemodialysis Patients

Clinical Chemistry ◽

10.1373/clinchem.2015.251835 ◽

2016 ◽

Vol 62 (4) ◽

pp. 631-638 ◽

Cited By ~ 26

Author(s):

Yader Sandoval ◽

Charles A Herzog ◽

Sara A Love ◽

Jing Cao ◽

Yan Hu ◽

...

Keyword(s):

Cardiac Troponin ◽

Prognostic Value ◽

Troponin I ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Adverse Outcomes ◽

Cox Models ◽

Reference Change Value ◽

Hazard Ratios ◽

All Cause Mortality

Abstract INTRODUCTION Serial changes in cardiac troponin in hemodialysis (HD) patients have uncertain clinical implications. We evaluated associations of adverse outcomes in HD patients with reference change value (RCV) data and tertile concentrations for cardiac troponin I (cTnI) and cTnT measured by high-sensitivity (hs) assays. METHODS RCV data and tertiles for hs-cTnI and hs-cTnT were determined from plasma samples collected 3 months apart in 677 stable outpatient HD patients and assessed for their associations with adverse outcomes using adjusted Cox models. Primary outcomes were all-cause mortality and sudden cardiac death (SCD). RESULTS During a median follow-up of 23 months, 18.6% of patients died. RCVs were: hs-cTnI +37% and −30%; hs-cTnT +25% and −20%. Patients with serial hs-cTnI and hs-cTnT changes >RCV (increase or decrease) had all-cause mortality of 25.2% and 23.8% respectively, compared to 15.0% and 16.5% with changes ≤RCV [adjusted hazard ratios (aHRs): 1.9, P = 0.0003 and 1.7, P = 0.0066), respectively]. Only hs-cTnI changes >RCV were predictive of SCD (aHR 2.6, P = 0.005). hs–Cardiac troponin changes >RCV improved all-cause mortality prognostication compared to changes ≤RCV in tertile 2: hs-cTnI aHR, 2.70 (P = 0.003); hs-cTnT aHR, 1.98 (P = 0.043). The aHR of changes in hs-cTnI in tertile 2 >RCV for SCD was 5.62 (P = 0.039). CONCLUSIONS Changes over 3 months in hs-cTnI and hs-cTnT of >RCV identified patients at greater risk of all-cause mortality, and for hs-cTnI were also predictive of SCD. Among patients with middle tertile cardiac troponin concentrations, hs-cTnI changes >RCV provided additive prognostic value for both SCD and all-cause mortality, whereas those for hs-cTnT provided additive prognostic value only for all-cause mortality.

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086 Biological Variability of Cardiac Troponin I in Healthy Individuals, Patients with Renal Failure Requiring Haemodialysis and Patients With Cardiomyopathy

Heart Lung and Circulation ◽

10.1016/j.hlc.2020.09.093 ◽

2020 ◽

Vol 29 ◽

pp. S75-S76

Author(s):

N. Lan ◽

L. Nguyen ◽

S. Vasikaran ◽

C. Wilson ◽

J. Jonsson ◽

...

Keyword(s):

Renal Failure ◽

Cardiac Troponin ◽

Troponin I ◽

Cardiac Troponin I ◽

Biological Variability ◽

Healthy Individuals

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Interpretation of high sensitivity cardiac troponin I results: Reference to biological variability in patients who present to the emergency room with chest pain: Case report series

Clinica Chimica Acta ◽

10.1016/j.cca.2008.12.004 ◽

2009 ◽

Vol 401 (1-2) ◽

pp. 170-174 ◽

Cited By ~ 27

Author(s):

Alan H.B. Wu

Keyword(s):

Case Report ◽

Chest Pain ◽

Emergency Room ◽

Cardiac Troponin ◽

Troponin I ◽

High Sensitivity ◽

Cardiac Troponin I ◽

Biological Variability

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Clinical Performance of Two Highly Sensitive Cardiac Troponin I Assays

Clinical Chemistry ◽

10.1373/clinchem.2008.106500 ◽

2009 ◽

Vol 55 (1) ◽

pp. 109-116 ◽

Cited By ~ 51

Author(s):

Per Venge ◽

Stefan James ◽

Leif Jansson ◽

Bertil Lindahl

Keyword(s):

At Risk ◽

Cardiac Troponin ◽

Troponin I ◽

Clinical Performance ◽

Composite Endpoint ◽

Outcome Data ◽

Cardiac Troponin I ◽

Healthy Population ◽

Reference Limit ◽

Patients At Risk

Abstract Background: The aim of this study was to compare the clinical performance of 2 sensitive cTnI assays with 10% CV imprecision below the 99th percentile upper reference limit. Methods: We measured cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations in a random sample of the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) IV cohort (n = 1251). Outcome data of 1-year mortality and the composite endpoint DMI [death and/or myocardial infarction (MI) within 30 days] were available in all patients. The 99th percentile of a healthy population was estimated from the Sweden Women and Men and Ischemic Heart Disease (SWISCH) cohort (n = 442). We measured cardiac troponin I (cTnI) using the Access AccuTnI (Beckman Coulter) and Centaur TnI Ultra (Siemens Healthcare Diagnostics) and NT-proBNP using the Elecsys 2010 (Roche Diagnostics). Results: Applying the 10% CV cutoff, the sensitivity of the Access AccuTnI assay in identifying DMI and death was higher than that of the Centaur TnI Ultra (P = 0.02 and P < 0.001), and the AccuTnI assay also identified more patients at risk (P < 0.001) and with poor outcome. Applying the 99th percentile cutoffs, AccuTnI identified more patients at risk than the Centaur TnI (P < 0.001) and with significant differences in outcome. Significantly more patients with cardiac troponins below the cutoffs as measured by Centaur TnI had increased NT-proBNP concentrations (P < 0.001) compared with AccuTnI. Conclusions: The AccuTnI assay identified more patients at risk than the Centaur cTnI Ultra assay. Our results demonstrate the clinical potential of high-sensitivity cardiac troponin assays for the identification of patients at risk of dying from cardiovascular disease.

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Establishing the 99th percentile for high sensitivity cardiac troponin I in healthy blood donors from Southern Italy

Biochemia Medica ◽

10.11613/bm.2019.020901 ◽

2019 ◽

Vol 29 (2) ◽

pp. 402-406 ◽

Cited By ~ 9

Author(s):

Luisa Agnello ◽

Giulia Bivona ◽

Marcello Ciaccio ◽

Bruna Lo Sasso ◽

Maddalena Muratore ◽

...

Keyword(s):

Single Molecule ◽

Cardiac Troponin ◽

Blood Donors ◽

Troponin I ◽

Parametric Method ◽

High Sensitivity ◽

Reference Population ◽

Cardiac Troponin I ◽

Healthy Population ◽

Males And Females

Introduction: The knowledge of high sensitivity cardiac troponin I (hsTnI) distribution in a reference population is mandatory for its introduction in clinical practice. The aim of this study was to define the Upper Reference Limit (URL) of hsTnI measured by Single Molecule Counting technology (SMC) in an accurately selected reference population. Materials and methods: In the study 1140 blood donors were included and selected on the basis of medical history and biomarkers. High sensitivity cardiac troponin I was measured by SMC technology (Clarity, Singulex, Alamed, USA). The 99th percentile was calculated by the non-parametric method according to the Clinical and Laboratory Standard Institute - CLSI C28-A3. Results: The median age was 41 years (IQR: 28 - 50) and 69% were males. The overall 99th percentile was 5 ng/L (90% CI: 4.2 - 5.6). When considering sex-related differences, we found slight differences between the 99th percentile in males and females. Moreover, the 99th percentile trended with age, especially in females. Conclusions: We defined the 99th percentile of hs-cTnI measured by SMC technology in a highly selected healthy population, with only minor differences between males and females. Our findings provide the basic criteria for the reliable interpretation of hsTnI concentrations measured by the SMC technology in clinical settings.

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Short-term increases of plasma cardiac troponin I are better evaluated by comparison with the reference change value

Biochemia Medica ◽

10.11613/bm.2010.042 ◽

2010 ◽

pp. 327-333 ◽

Cited By ~ 2

Author(s):

Giovanni Introcaso ◽

Monica Raggi ◽

Tiziana D'Errico ◽

Annalisa Cavallero

Keyword(s):

Cardiac Troponin ◽

Troponin I ◽

Cardiac Troponin I ◽

Short Term ◽

Reference Change Value

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Longitudinal Studies of Cardiac Troponin I in a Large Cohort of Healthy Children

Clinical Chemistry ◽

10.1373/clinchem.2012.192054 ◽

2012 ◽

Vol 58 (12) ◽

pp. 1665-1672 ◽

Cited By ~ 24

Author(s):

Gus Koerbin ◽

Julia M Potter ◽

Walter P Abhayaratna ◽

Richard D Telford ◽

Tony Badrick ◽

...

Keyword(s):

Cardiac Troponin ◽

Troponin I ◽

Limit Of Detection ◽

High Sensitivity ◽

Biological Variation ◽

Cardiac Troponin I ◽

Community Dwelling ◽

Low Grade ◽

Healthy Children ◽

Reference Change Value

BACKGROUND There is little information available on cardiac troponin concentrations in healthy young children. METHODS Using a precommercial high-sensitivity assay from Abbott Diagnostics, we measured cardiac troponin I (cTnI) in longitudinal blood samples collected at ages 8, 10, and 12 years from a cohort of healthy, community-dwelling children. The 99th percentile values were calculated and estimates of the long-term biological variation were made. RESULTS cTnI concentrations were above the limit of detection in 87%, 90%, and 98% of the children at ages 8, 10, and 12 years. The 99th percentiles were lower compared to a healthy adult population in both male and female children at all ages studied. At the 3 periods of study assessment, different children had cTnI concentrations above the 99th percentile. The calculated 99th percentile varied markedly depending upon whether the lowest or highest cTnI measurement for an individual child was included in the calculation. Biological variation varied markedly between 0% and 136%, the index of individuality was low at 0.36, and the reference change value was an increase of 147% or a decrease of 59%. CONCLUSIONS In this longitudinal study of cTnI concentrations in healthy children as determined by a high-sensitivity assay, different children had concentrations of cTnI above the 99th percentile at the 3 episodes of assessment. These results suggest that in children the 99th percentile may not be a reliable index of silent cardiac disease, but rather may be indicating low-grade intercurrent illness.

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