To the Editor:
Limited data exist on early cardiac troponin (cTn) increases above the sex-specific 99th percentile upper reference limits (URL) in relation to symptom onset in myocardial infarction (MI). Studies that report kinetics are predicated on timing of specimen acquisition in the laboratory or based on presentation, not symptom onset (1). Illustrations published often are simulated without real patient data. High-sensitivity (hs) cTnI and cTnT assays have the ability to measure low concentrations and follow absolute changes within hours of presentation to derive kinetics of early cTn release (2–5). We evaluated serial hs-cTnI and hs-cTnT concentrations in the initial 6-hour time period ‘following symptom onset’ in patients presenting to the emergency department with non-ST-segment elevation MI (NSTEMI).
Pooled data from 7 international cohorts (2) (UTROPIA, High-STEACS, RING, ROMI, EDACS, ADAPT-CH, SPACE) for patients presenting with ischemic symptoms with ‘NSTEMI and serial concentrations measured within 6 hours of onset of systems’, with plasma hs-cTnI (n = 514, Abbott: 99th percentile URLs: male 34 ng/L, female 16 ng/L) and one cohort with hs-cTnT (n = 183; Roche: URLs: male 15 ng/L, female 10 ng/L) were included. hs-cTn concentrations were plotted against time from symptom onset and proportion greater than the sex-specific URLs at each blood-draw. Medians were compared with Kruskal-Wallis test. Logistic regression was used to analyze the association of sex and increased first blood draw with adjustment for log of symptom time.
In the hs-cTnI group, mean age was 67 (SD 13) years, with 514 MIs (333 males, 181 females). For hs-cTnT, mean age was 67 (SD 11) years, with 183 MIs (137 males, 46 females). For hs-cTnI and hs-cTnT, median times from symptom onset to first draw were different (P = 0.05): 3.1 h (IQR 2.2–4.0) vs. 3.5 h (IQR 2.8–4.5). Time from symptom onset was longer for hs-cTnT than hs-cTnI in both men 3.6 h (IQR 2.8–4.7) vs. 3.0 h (IQR 2.2–4.0) and women hs-cTnT 3.3 h (IQR 2.4–4.2) vs. hs-cTnI 3.1 h (IQR 2.0–4.0) (both, P = 0.04). Figure 1 shows the relationship between time from onset and cTn result, using a smoothed regression line with splines and 95% confidence bands (no significant differences between regressions); hs-cTnI (panels A and B) and hs-cTnT (panels C and D) concentrations were stratified by sex. Time to first increased concentration >99th URL was higher in males than females using hs-cTnI, 3.7 h vs. 3.3 h (P = 0.07), but not observed with hs-cTnT, 3.7 h vs. 3.4 h (P = 0.60). Females, after adjustment for time since symptom onset, were less likely than males to cross the sex-specific URLs on first blood draw, with an odds ratio of 0.51 (95%CI: 0.34, 0.77) for hs-cTnI and an odds ratio of 0.33 (95%CI: 0.11, 0.99) for hs-cTnT. Maximum cTn concentrations within 6 h of symptom onset were higher in males than females for hs-cTnI with a median 99 ng/L (IQR 40–346) ng/L vs. 72 ng/L (IQR 26–289), P = 0.08), and reversed in hs-cTnT with a median 53 ng/L (IQR 17–134) vs. 80 ng/L (IQR 37–169ng/L), P = 0.08). Median increases >99th percentile were 1.5 fold (IQR 0–8.2) for hs-cTnI and 1.6 fold (0.3–5.7) for hs-cTnT.
Smoothed regression lines (95% CI) demonstrating changes in high-sensitivity cardiac troponin I (Panels A and B) and high-sensitivity troponin T (Panels C and D) concentrations stratified by sex and time after symptom onset in patients with myocardial infarction.
There are 3 principal findings from our international cohorts with NSTEMI evaluated using serial hs-cTnI and hs-cTnT. First, variations in hs-cTn concentrations between males and females exist, with females being less likely than males to be identified at presentation as having myocardial injury when using sex-specific URLs, possibly due to differences in time to presentation or medical assistance. We recognize females are underrepresented. Second, early hs-cTnI and hs-cTnT kinetics vary considerably from classic patterns shown in textbooks, in that 5–10-fold increases do occur in 43% for hs-cTnI and 32% of hs-cTnT patients with NSTEMIs within 6 h, compared to textbooks that imply substantial increases take up to 24 h. While graphic ‘peak’ concentrations are aesthetically appealing, educational schemes that demonstrate hypothetical curves are minimally relevant in clinical practice, since hs-cTn assays can rule out/in the majority of MIs and myocardial injury within 6 h of ischemic symptom onset, supporting the Fourth Universal Definition of Myocardial Infarction (3). Third, clinicians need to be aware that very early, substantially increased cTn concentrations do occur in patients with NSTEMI within 6 h of symptoms and are not always indicative of late presenters or reperfusion. Two study limitations were 1) we did not have data after 6 h from symptom onset and cannot comment on the release kinetics of late presenters, and 2) kinetics were not available in all cohorts to distinguish type 1 and type 2 MIs.
In conclusion, substantial increases in hs-cTn concentrations occur very early in both sexes following NSTEMI, corroborating the linear release of hs-cTn during the first hours of ischemic symptoms.
Author Contributions
All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.
N .L. Mills, financial support, administrative support, provision of study material or patients; P. Kavsak, provision of study material or patients; F. S. Apple, financial support, statistical analysis, administrative support, provision of study material or patients.
Authors’ Disclosures or Potential Conflicts of Interest
Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
Employment or Leadership
F. S. Apple, Clinical Chemistry, AACC, HyTest Ltd. F. S. Apple has served as an unsalaried research principal investigator through the Hennepin Healthcare Research Institute for Abbott Diagnostics, Abbott Point of Care, Roche Diagnostics, Siemens Healthineers, Quidel/Alere, Ortho Clinical Diagnostics, and Beckman Coulter.
Consultant or Advisory Role
Y. Sandoval, Abbott Diagnostics and Roche Diagnostics without personal financial compensation; M. Than, Abbott Point of Care, Abbott Diagnostics, Alere, Beckman Coulter, Roche Diagnostics; J. W. Pickering, consulting for Abbott Diagnostics outside the submitted work; P. Kavsak, Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics; F. S. Apple, HyTest, LumiraDx, Siemens Healthcare, Qorvo, Brava Dx.
Stock Ownership
None declared.
Honoraria
Y. Sandoval, speaker for Abbott without personal financial compensation; A. R. Chapman, Abbott Diagnostics, Siemens Diagnostics; N. L. Mills, Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, Singulex; M. Than, Abbott Point of Care, Abbott Diagnostics, Alere, Beckman Coulter, Roche Diagnostics; P. Kavsak, Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics; F. S. Apple, Instrumentation Laboratory, Abbott Diagnostics, Siemens Diagnostics.
Research Funding
Funded in part through the Hennepin Healthcare Research Institute. N. L. Mills, research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work; M. Than, grants/reagents from Abbott Point of Care, Abbott Diagnostics, Alere, Beckman Coulter, Roche Diagnostics; A. Worster, research grants from the Canadian Institutes of Health Research; P. Kavsak, grants/reagents from Abbott Laboratories, Abbott Point of Care, Abbott Diagnostics Division Canada, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics; F. S. Apple, funding from Abbott Diagnostics to institution.
Expert Testimony
M. Than, Abbott, Alere, Beckman, Roche.
Patents
McMaster University has filed patents with P. Kavsak listed as an inventor in the acute cardiovascular biomarker field.
