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Cardiac Myosin-binding Protein C

Introduction

Cardiac Myosin-binding Protein C is a novel biomarker of myocardial ischaemia. Cardiac Troponins T & I have emerged as the gold standard necrosis biomarker for patients presenting with the chest pain and are incorporated into the universal definition of Acute Myocardial Infarction (AMI). A slow release profile means that Troponins reach peak concentrations many hours after symptom onset. The development of high-sensitivity Troponin assays has facilitated the routine detection of ever-smaller concentrations - to allow an earlier triage of patients with chest pain.

What’s the problem?

Nowadays, Troponin concentrations close to the Limit of Detection (LoD) are used as a tool for early rule-out of myocardial infarction. This is at odds with specificity, as chronic or subacute Troponin elevation is common - we frequently detect Troponin values above the LoD in patients with chronic obstructive pulmonary disease (COPD), renal dysfunction and - particularly common - congestive cardiac failure. This has prompted the European Society of Cardiology (ESC) to publish guidance incorporating a 3-tiered risk system for patients presenting with chest pain and no diagnostic ECG changes (bearing in mind this is only validated with onset of chest pain >3 hours ago). ESC 0 h/1 h rule-in and rule-out algorithm using high-sensitivity troponins

A recent audit at our institution has demonstrated that just over 50% of patients have a Troponin value which falls into the intermediate risk category - an observational ‘grey zone’ with no clear guidance attached. And even the best rule-out and rule-in algorithms rely on repeat measurements 1-3 hours following initial blood draws to optimise sensitivity and specificity, further prolonging hospital stays and psychological burden on patients.

Previous Work

We are actively evaluating cMyC as a novel biomarker of cardiac ischaemia - to improve rule-out ability and to reduce the size of the aforementioned grey zone, and have - thus far - published the following papers:

Jacquet S, Yin X, Sicard P, Clark J, Kanaganayagam GS, Mayr M, et al. Identification of cardiac myosin-binding protein C as a candidate biomarker of myocardial infarction by proteomics analysis. Mol Cell Proteomics. American Society for Biochemistry and Molecular Biology; 2009 Dec;8(12):2687–99.

The discovery paper: cMyC was found in the coronary effluent after myocardial infarction of the isolated, buffer-perfused heart and increased markedly with even trivial infarction.

Baker JO, Tyther R, Liebetrau C, Clark J, Howarth R, Patterson T, et al. Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury. Basic Research in Cardiology. Springer Berlin Heidelberg; 2015 Apr 13;:1–14.

This is the manuscript using our in-house assay that shows cMyC rises faster than cardiac Troponin T after iatrogenic MI (in patients undergoing alcohol septal ablation) and falls faster after Coronary Artery Bypass surgery.

Marjot J, Liebetrau C, Goodson RJ, Kaier T, Weber E, Heseltine P, et al. The development and application of a high-sensitivity immunoassay for cardiac myosin-binding protein C. Translational Research. Elsevier Inc; 2015 Dec 21;:1–14.

In this paper we establish the analytic performance of a sensitive assay for cMyC and then its application to ambulatory patients, comparing cMyC with hs-cTnT and hs-cTnI (invasive coronary angiograms showed no significant atherosclerosis). Here we demonstrate that the cMyC assay is very sensitive and cMyC concentration is closely related to hs-cTnT and hs-cTnI and seems perturbed by the same sorts of things (renal dysfunction, age, poor LV function).

Kaier TE, Anand A, Shah ASV, Mills NL, Marber M. Temporal Relationship between Cardiac Myosin Binding Protein C and Cardiac Troponin I in Type 1 Myocardial Infarction. Clinical Chemistry. 2016 Jun 20;:1–3.

This is a brief communication of a highly selected cohort of patients presenting within 3 hours of symptom onset with adjudicated type 1 AMI. Main message is that in these early presenters cMyC is relatively higher than cTnI on presentation and then cTnI catches up.