Direct Comparison of the Circadian Rhythm of Cardiac Myosin-Binding Protein C (cMyC) and Cardiac Troponin

To the Editor:

We have previously shown that significant circadian oscillations exist for cardiac troponin T (cTnT) but not for cardiac troponin I (cTnI) (1).

Cardiac myosin-binding protein C (cMyC) is a novel protein biomarker of myocardial injury with a promising role in the diagnosis and risk stratification of acute myocardial injury.

In this study, we examine and compare the diurnal variation of cMyC with cTnT/I.

Study design, population and methods are described by Klinkenberg et al. (1).

Briefly, 26 consecutive hourly blood samples were drawn between 8.30 Am and 09.30 Am (+ 1 day) from 24 individuals without active cardiac disease, uncontrolled hypertension, anemia, renal dysfunction, or a history of acute myocardial infarction or stroke within 12 months. Seven percent had type 2 diabetes (all on oral blood glucose lowering medications) and 42% were on antihypertensive medication.

cMyC was measured by Millipore Sigma (2). Limit of detection 0.4 ng/L, limit of quantitation (20% analytical coefficient of variation) of 1.2 ng/L; intra-series precision (CV, 11 +/− 3%), and inter-series precision (CV, 13 +/− 3%), 99th percentile is 87 ng/L. cTnT (Roche hs-cTnT) and cTnI (Abbott hs-cTnI) were measured previously by Klinkenberg et al. (1), but data were reanalyzed and are represented here to enable direct comparisons with cMyC.

Fitted population mean and single cosinor sine regression models were used to assess the presence and significance of circadian oscillation of each biomarker and to estimate the respective mesor (the average value around which the variable oscillates), amplitude (the difference between the peak and trough), and acrophase (the time of peak concentration) for the group (population mean) and individuals.

hs-cTnI exhibited random diurnal oscillation (P = 0.867), whereas significant circadian rhythms were detected for cMyC and hs-cTnT (P = 0.015 and <0.001, respectively) (Fig. 1).

Fig 1.

Circadian oscillation of hs-cTnI (Abbott), hs-cTnT (Roche), and cMyC. Median concentration (1st, 3rd quartile) (first row) and fitted cosinor model (second row). Dashed-line: cosinor fit estimate, continuous line: actual.

The circadian oscillation of cMyC is characterized by gradually increasing concentration from early afternoon to early morning (acrophase 3:03 Am; 95% CI, 1:54–4:26 Am) compared to hs-cTnT, which exhibits a later rise in concentration from early evening with a later peak (acrophase 8:01 Am; 95% CI, 7:10–8:51 Am), P = 0.028 for acrophase difference.

Time distributed measurements of cMyC oscillated around a mesor of 11.5 ng/L (95% CI, 8.1–14 ng/L), spanning an amplitude of 1.1 ng/L (95% CI, 0.4–1.8).

hs-cTnT values oscillated around a mesor of 13.7 ng/L (95% CI, 11.7–15.6 ng/L) with an amplitude of 1.8 ng/L (95% CI, 1.3–2.2 ng/L).

After normalizing to the individual’s 8:30 Am concentration, there was no significant difference between the amplitudes (amplitude 0.12; 95% CI, 0.07–0.15 vs 0.11; 95% CI, 0.08–0.12, for normalized cMyC vs hs-cTnT values, respectively; P = 0.67).

In summary, we observed a significant diurnal rhythm in the concentrations of both cMyC and hs-cTnT but not hs-cTnI with a 5-hour phase difference between cMyC and cTnT.

It is unknown why cTnI did not exhibit a diurnal rhythm, while both cTnT and cMyC exhibit strong rhythmicity. Unlike cTnI, cMyC has a location within the sarcomere that is distinct from cTnT, and it does not form part of the ternary troponin complex that enters the blood. The cause for the significant phase difference in the circadian oscillation of cTnT and cMyC is a matter of speculation.

Diurnal rhythm remained significant after correcting for hemoglobin and hematocrit, excluding posture-related changes in plasma volume. We have previously measured cortisol, thyroid-stimulating hormone, and testosterone (1); we found no indication of a clear correlation with cTn. However, this comparison has not been performed for cMyC.

Epidemiological studies have shown a circadian rhythm for cardiovascular events. Myocardial infarct size measured by creatine kinase and imaging and the resulting degree of left ventricular impairment have a circadian rhythm with maximal injury following acute myocardial infarctions that begin around midnight (3). This might reflect a circadian pattern of myocardial vulnerability to ischemia and/or a peak in atherosclerotic plaque vulnerability (1, 2).

The amplitude of the variation in the concentration of cMyC and cTnT in our study is approximately 30% of the magnitude of the 0/1 h deltas used to differentiate acute from chronic myocardial injury and might, therefore, impact the triage accuracy using serial or single measurements. However, the strong diurnal rhythmicity of cTnT and random fluctuation of cTnI did not appear to impact on the diagnostic accuracy in limited studies (4).

Our cohort is not entirely healthy; however, age of participants and presence of cardiac risk factors might make the results more applicable to people at risk of myocardial infarction.

Finally, it is unknown if diurnal variations for cTn and cMyC exist during stable chronic disease such as heart failure or if the diurnal rhythm is affected by changes in day/night cycles such as in night-shift workers.

Nonstandard Abbreviations: cTn, cardiac troponin; cTnI, cardiac troponin I; cMyC, cardiac myosin-binding protein C.

Statement of Human Ethics Review: The study was approved by the institutional review board and the ethics committee at Maastricht University Medical Center, the Netherlands, study number NCT02091427. The study was approved requiring volunteer consent.

Author Contributions:The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.

Bashir Alaour (Conceptualization-Lead, Data curation-Lead, Formal analysis-Lead, Funding acquisition-Lead, Investigation-Lead, Methodology-Lead, Project administration-Lead, Resources-Lead, Software-Lead, Supervision-Lead, Validation-Lead, Visualization-Lead, Writing—original), draft-Lead, Writing—review & editing-Lead), Thomas E. Kaier (Conceptualization-Supporting, Data curation-Supporting, Formal analysis-Supporting, Methodology-Supporting, Writing—original draft-Equal, Writing—review & editing-Supporting), Rasmus Bo Hasselbalch (Conceptualization-Supporting, Data curation-Supporting, Formal analysis-Supporting, Visualization-Supporting, Writing—original draft-Supporting, Writing—review & editing-Supporting), William Doorn (Conceptualization-Supporting, Formal analysis-Supporting, Investigation-Supporting, Methodology-Supporting, Project administration-Supporting, Writing—original draft-Supporting, Writing—review & editing-Supporting), Steven Meex (Conceptualization-Lead, Data curation-Lead, Formal analysis-Lead, Funding acquisition-Supporting, Investigation-Lead, Methodology-Lead, Supervision-Lead, Writing—original draft-Lead, Writing—review & editing-Lead), Michael Marber (Conceptualization-Lead, Data curation-Lead, Formal analysis-Lead, Funding acquisition-Lead, Investigation-Lead, Methodology-Lead, Project administration-Lead, Resources-Lead, Supervision-Lead, Validation-Lead, Visualization-Lead, Writing—original draft-Lead,), and Writing—review & editing-Lead)

Authors’ Disclosures or Potential Conflicts of Interest:Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:Employment or Leadership: S. Meex is an unpaid member of International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Applications of Cardiac Bio-Markers. Consultant or Advisory Role: M. Marber received consulting fees from Roche Diagnostics Advisory Board and Psyros Diagnostics Advisory Board. S. Meex received consulting fees (payment to institution) from Roche Diagnostics and participated on an advisory board for Roche Diagnostics (payment to institution). Stock Ownership: None declared. Honoraria: None declared. Research Funding: M. Marber received research grant FS/18/78/33902 (to institution) from British Heart Foundation. Expert Testimony: None declared. Patents: M. Marber is named as an inventor on a patent held by King's College London for the detection of cardiac myosin-binding protein C as a biomarker of myocardial injury (WO 2010/130985). Other Remuneration: S. Meex received support for attending meetings from Roche Diagnostics.

Author notes

Previous presentation: This research was previously presented at the 2021 ESC Congress, August 27–30, 2021.