Clinical and experimental evidence for differences between cardiac troponin I and T in acute and chronic cardiovascular conditions

Abstract Background Clinical and scientific practice operate under the assumption that systemic levels of cardiac troponin I (cTnI) and troponin T (cTnT) are indicative of the same underlying pathophysiological mechanisms and can be utilized interchangeably. Purpose To assess cTnI and cTnT levels and their ratio for differences in various cardiovascular conditions. Methods Individuals from three prospective clinical studies with a centrally adjudicated diagnosis were categorized into three groups: no known cardiac disease, chronic cardiac disease, and acute cardiac disease. Circulating cTnI and cTnT concentrations were measured using high-sensitivity assays (hs-cTnI-Architect, hs-cTnT-Elecsys) and the cTnI/cTnT ratio was calculated. Findings were validated using a second hs-cTnI assay (hs-cTnI-Clarity) and externally validated in independent cohorts. The cTnI/cTnT ratio was also assessed in five different non-lethal and lethal experimental models of cardiomyocyte injury. Results Of the 9704 included individuals, 9% had no known cardiac disease, 69% chronic cardiac disease, and 22% acute cardiac disease. No known cardiac disease and chronic cardiac disease were associated with a disproportional increase in cTnT compared to cTnI (cTnI/cTnT ratio, median 0.50, IQR 0.38-0.69 and 0.53, IQR 0.37-0.80). In contrast, cTnI concentrations were increased compared to cTnT in patients with acute cardiac disease, resulting in a cTnI/cTnT ratio of 1.62 (IQR 0.77-4.31). Findings were consistent using an alternative cTnI assay and in external validation cohorts (n=2776) where the cTnI/cTnT ratio was lower in those without cardiac disease (0.33 (IQR 0.25-0.50), 0.64 (IQR 0.40-1.05)) and with chronic cardiac disease (0.50 (IQR 0.32-0.75), 0.60 (IQR 0.38-1.00)), compared to those with acute cardiac disease (2.22 (IQR 1.08-5.27), 2.28 (IQR 1.01-5.67)). Non-lethal cardiomyocyte injury models showed a predominant release of cTnT with cTnI/cTnT ratios <0.5, and lethal injury models a predominant release of cTnI with cTnI/cTnT ratios >1. Conclusion Differences in cTnI and cTnT levels were observed in individuals with chronic and acute cardiac conditions, leading to distinct cTnI/cTnT ratios in both clinical and experimental settings. As a result, the interchangeability of cTnI and cTnT in present-day clinical and scientific settings needs to be reevaluated.Central illustration