Conclusion
Cardiac myosin-binding protein C is a novel biomarker of myocardial injury with great potential for assisting in the early rule-out of AMI—other groups have investigated the use of cMyC in the diagnosis of myocardial infarction with confirmatory findings, but were limited by poor assay sensitivity. Despite careful selection of monoclonal antibodies and initially promising results on our electrochemiluminescence platform, cMyC sensitivity was outperformed by the increasingly available high-sensitivity Troponin assays. Kuster et al. independently reached a comparable LoD on the same device (MesoScale Discovery), making the translation of the assay onto a platform with greater sensitivity the natural next step. Given the binding sites of the two monoclonal antibodies are only affected by a single known mutation causing a non-pathogenic polymorphism of HCM, the risk of false-negative results appears diminishingly small.
Our work in migrating onto the Singulex Erenna enabled—for the first time—reliable cMyC quantification in stable outpatients. As demonstrated, this assay enabled two leaps in the translational phase: (1) quantify the cMyC level in all but one of 360 individuals without acute cardiovascular disease, thus allowing (2) the derivation of a 99th centile (87 ng/L). The assay, performed by a contract research organisation, achieved a LoD 200 times lower than our in-house assay and laid the foundation for clinical studies as described.
Favourable release kinetics and a higher sensitivity than hs-cTn assays are likely responsible for the better performance in patients presenting early after chest pain onset. The greater analytic bandwidth of the assay could, in turn, be responsible for a better calibration against acute myocardial injury versus the chronic release of myocardial necrosis markers often observed in clinical practice. This would explain the net reclassification benefit observed in the largest cohort study testing cMyC to date—both in all-comers and early presenters. As demonstrated in a single-centre prospective cohort study investigating the use of hs-cTnT in the emergency department at our institution, 52% of patients are assigned to an ‘observe’ zone after the first blood draw (~ 4000 patients annually; triage modelled on the 2015 ESC NTEMI guidelines). These patients—quasi-automatically—require repeat blood testing and therefore ongoing observation until a level of diagnostic certainty can be reached. Any admission avoided, employing more dynamic but equally specific cardiac necrosis markers, should be in the best interest of healthcare providers and patients alike. Extrapolating from findings to date, the gains might not be marginal!
Our work in migrating onto the Singulex Erenna enabled—for the first time—reliable cMyC quantification in stable outpatients. As demonstrated, this assay enabled two leaps in the translational phase: (1) quantify the cMyC level in all but one of 360 individuals without acute cardiovascular disease, thus allowing (2) the derivation of a 99th centile (87 ng/L). The assay, performed by a contract research organisation, achieved a LoD 200 times lower than our in-house assay and laid the foundation for clinical studies as described.
Favourable release kinetics and a higher sensitivity than hs-cTn assays are likely responsible for the better performance in patients presenting early after chest pain onset. The greater analytic bandwidth of the assay could, in turn, be responsible for a better calibration against acute myocardial injury versus the chronic release of myocardial necrosis markers often observed in clinical practice. This would explain the net reclassification benefit observed in the largest cohort study testing cMyC to date—both in all-comers and early presenters. As demonstrated in a single-centre prospective cohort study investigating the use of hs-cTnT in the emergency department at our institution, 52% of patients are assigned to an ‘observe’ zone after the first blood draw (~ 4000 patients annually; triage modelled on the 2015 ESC NTEMI guidelines). These patients—quasi-automatically—require repeat blood testing and therefore ongoing observation until a level of diagnostic certainty can be reached. Any admission avoided, employing more dynamic but equally specific cardiac necrosis markers, should be in the best interest of healthcare providers and patients alike. Extrapolating from findings to date, the gains might not be marginal!
