Physiological circadian rhythm of cardiac myosin-binding protein C (cMyC) and cardiac troponin

Abstract

Abstract Introduction Cardiac myosin-binding protein C (cMyC) is a novel protein biomarker of myocardial injury, with a promising role in the triage and risk stratification of patients with cardiac disease. Understanding the physiological diurnal oscillation of cMyC and cardiac troponin is important for the interpretation of single and serial measurements within the biomarker-assisted triage and risk stratification algorithms. Purpose In this study, we aim to assess and compare the physiological diurnal oscillation of cMyC and cardiac troponin cTnT and cTnI. Method Twenty-six consecutive hourly blood samples were drawn between 08.30 am and 09.30 am (+1 day) from normotensive 24 individuals without a recent history of acute myocardial infarction, for the measurement of cMyC, cardiac troponin T (Roche hs-cTnT) and I (Abbott hs-cTnI). Fitted cosinor sine regression model (with R, version 3.6.1) was used to assess the presence and significance of circadian oscillation of the biomarker, and to estimate the respective amplitude and acrophase (the time of peak activity). Amplitude and acrophase were compared across the biomarkers that exhibited significant circadian rhythm. Results Mean age was 72±7. 79% of participants (n=19) were men. All participants were free from renal disease. On population-mean cosinor analysis, hs-cTnI exhibited random diurnal oscillation, whereas significant circadian rhythm was detected for cMyC and hs-cTnT (p=0.015 and <0.001, respectively) (Figure 1). The circadian rhythm of cMyC is characterised by gradually increasing concentrations from early afternoon until early morning (acrophase 03:03 am, 95% CI 01:54–04:26 am) compared to hs-cTnT concentrations which exhibits delayed increase and a later peak (acrophase, 08:01, 95% CI 07:10–08:51 am), p=0.028 for acrophase difference (Figure 1). Diurnal rhythm remained significant after correction for possible posture-induced changes in plasma volume. To allow direct comparison between amplitudes, the measurements of cMyC and hs-TnT were normalised to the respective 08:30 am value, re-fitted cosinor model did not show significant difference between the amplitudes (amplitude ng/L, 0.12, 95% CI 0.07–0.15 vs 0.11, 95% CI 0.08–0.12, for normalised cMyC vs hs-cTnT, respectively; p=0.67). Conclusion Significant circadian rhythm exists for cMyC and hs-cTnT, with 5-hours phase difference between the two biomarkers (cMyC ahead of hs-cTnT). The cause of this rhythmic variation is unknown, but the phase difference is consistent with the previously described disparity in the release of cMyC and cTnT after iatrogenic myocardial injury, raising the possibility of an underlying diurnal variation in myocardial vulnerability. Studies are required to assess the impact of this physiological phenomenon on the performance of the biomarkers within unadjused diagnostic algorithms Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart FoundationStichting de Weijerhorst