Sex and age specific differences in high-sensitivity cardiac troponin T and high-sensitivity cardiac troponin I among cardiac-healthy individuals

Introduction The clinical introduction of high sensitivity cardiac troponin (hs-cTn) assays has revolutionized myocardial infarction (MI) diagnosis, enabling earlier detection and better outcomes. The Fourth Universal Definition of MI (UDMI) sets the 99th percentile upper reference limit (URL) as a diagnostic threshold. Age as a possible confounder is ignored. Reported sex differences in the 99th percentile URL (hs-cTnT: 9 versus 16 ng/L; hs-cTnI: 16 versus 34 ng/L) suggest women have lower hs-cTn levels than men. Purpose We aimed to challenge the assumption of women having a significantly lower troponin level compared to men. Additionally, we hypothesized that the effect of age on troponin levels may be underestimated and could vary between sexes. Materials & Methods This secondary analysis included data from two large prospective diagnostic studies. Two independent cardiologists performed central adjudication based on extensive patient characterization including cardiac imaging and blinded measurements of hs-cTnT and hs-cTnI, to identify cardiac-healthy individuals. Further criteria included age under 75 years, no history of cardiovascular diseases, absence of relevant functional or structural abnormalities in cardiac imaging, no cardiovascular death or MI within two years of follow-up and exclusion of individuals with a N-terminal pro b-type natriuretic peptide (NT-proBNP) levels > 125 ng/L. The Dixon’s method was used to remove the hs-cTnT/I outliers. An adjusted quantile regression modeled the relation between hs-cTnT/I and the predictors age and sex. Results The cohort consists of 3’083 cardiac-healthy individuals, 1’154 women and 1’929 men. The difference in median hs-cTnT between women and men at age 60 was 1.9 ng/L, and at age 40, 1.1 ng/L. The difference in median hs-cTnI between women and men at age 60 and at age 40 was even smaller (0.6 ng/L vs. 0.8 ng/L). We observed similar findings for the 75th percentile for hs-cTnT and hs-cTnI. The confounding effect of age was larger than that of sex for both hs-cTnT and hs-cTnI. An independent external validation cohort confirmed these findings. Conclusion Sex-specific age-adjusted difference in median percentile for hs-cTn concentrations are considerably smaller than currently assumed, and much smaller than the effect of age. These important findings should inform future UDMI criteria and incorporate the effect of age.Median hs-cTnT (Age) Median hs-cTnI (Age)