The cTnI/cTnT Ratio in Myocardial Injury: A Multicohort and Experimental Synthesis.

Abstract

Background: Cardiac troponin (cTn) I and cTnT are used interchangeably in clinical practice, despite emerging evidence from pilot studies that the cTnI/cTnT ratio may differ in acute necrotic vs chronic or non-necrotic myocardial injury.

Objectives: The purpose of this study was to challenge the interchangeability of cTnI and cTnT and to test the cTnI/cTnT ratio as a biologically meaningful construct of the type and severity of myocardial injury across a large, adjudicated multicohort population, validate the signal across multiple assays and external data sets, and pair clinical observations with experimental models that replicate the directional signal.

Methods: Participants from 3 prospective clinical studies with centrally adjudicated diagnoses were grouped as having no known, chronic, or acute cardiac disease. Circulating concentrations of hs-cTnI (Architect) and hs-cTnT (Elecsys) were measured, and regression models were used to examine how the cTnI/cTnT ratio relates to these diagnostic categories and its diagnostic utility. Findings were validated both internally and externally, and the cTnI/cTnT ratio was further explored in 4 experimental cardiomyocyte models simulating mild nonlethal and lethal injury.

Results: Among 9,704 individuals, the cTnI/cTnT ratio was highest in acute cardiac disease (2.06; 95% CI: 1.89-2.26), approximately 4-fold greater than in chronic (0.66; 95% CI: 0.60-0.72) and no known cardiac disease (0.50; 95% CI: 0.43-0.59). Findings were consistent across alternative hs-cTnI assays and external validation cohorts. In experimental models, mild nonlethal injury yielded cTnT-dominant release (cTnI/cTnT ratio ∼0.5), whereas lethal injury produced cTnI-dominant release (cTnI/cTnT ratio >1). Incorporating the cTnI/cTnT ratio as a predictor in a statistical model alongside cTnI and cTnT improved discrimination between type 1 and 2 acute myocardial infarction (AUC 0.73; 95% CI: 0.70-0.76 vs 0.70; 95% CI: 0.67-0.73; P < 0.01).

Conclusions: The cTnI/cTnT ratio distinguishes acute necrotic from chronic/non-necrotic myocardial injury in clinical and experimental studies, and improves type 1 vs type 2 AMI discrimination, offering potential diagnostic value and challenging the interchangeability of cTnI and cTnT.