Macrotroponin Complexes and Risk of Cardiovascular Events

Cardiac troponin is increasingly used for cardiovascular risk prediction. While abnormal values often reflect subclinical cardiovascular disease, they can be raised due to interference, where antibodies influence the assay or clearance of troponin from the circulation by forming macrotroponin complexes. The frequency of macrotroponins and its association with future risk are unknown.

In a general population cohort, participants with both cardiac troponin I and T measurements available (n=19 499, median 49 [25th-75th percentile, 36-58] years of age, 58.3% women) were categorized into 3 groups: no myocardial injury (neither cardiac troponin I or T was elevated), suspected macrotroponin (either cardiac troponin was elevated and discordant with a >3-fold difference in concentration), and myocardial injury (either cardiac troponin was elevated without discordance). Macrotroponin complex formation was verified in a subset of samples (n=203) using immunoglobulin depletion and ultracentrifugation. Associations with future myocardial infarction, ischemic stroke, or cardiovascular death were evaluated using Cox proportional hazards models adjusted for known cardiovascular risk factors. The generalizability of our findings was determined through replication in a second general population cohort study.

Elevated cardiac troponin I was present in 1% (193 of 19 499) of participants and elevated cardiac troponin T in 6% (1159 of 19 499). Among those, 48% and 57% were discordant, respectively. Biochemical testing attributed 92.5% of discordant troponin I and 15.4% of discordant troponin T to macrotroponin complexes. Participants with myocardial injury were at increased risk of future cardiovascular events compared with those without (cardiac troponin I: adjusted hazard ratio [HR], 2.90 [95% CI, 1.99-4.22]; cardiac troponin T: adjusted HR, 1.99 [95% CI, 1.63-2.42]), whereas those with suspected macrotroponin had similar risk as those without elevated values for suspected macrotroponin I (adjusted HR, 1.59 [95% CI, 0.94-2.70]) and T (adjusted HR, 1.27 [95% CI, 1.00-1.61]). Findings were similar in the replication cohort.

Assay interference due to macrotroponin complex formation is common in individuals with elevated cardiac troponin concentrations in the general population, particularly for cardiac troponin I. This has important implications for the use of cardiac troponin testing for cardiovascular risk assessment in the general population.