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Abstract
Background We identified cardiac myosin-binding protein C (cMyC) in coronary venous effluent and developed a high-sensitivity assay by producing an array of monoclonal antibodies and choosing an ideal pair based on affinity and epitope maps. Compared to high-sensitivity cardiac Troponin (hs-cTn), we demonstrated that cMyC appears earlier and rises faster following myocardial necrosis and is also more abundant. Contemporarily, we investigated 1) analytic sensitivity, 2) whether cMyC can aid in the diagnosis of Acute Myocardial Infarction (AMI) (a) amongst unselected patients presenting to the emergency department (ED) and (b) presenting in a pre-hospital setting.
Methods We compared abundance of cMyC to hs-cTn by spiking cardiomyocytes/cardiac tissue into aliquots of human serum. We evaluated the clinical utility of cMyC by calculating the area under the receiver-operating characteristics curve (AUC) in 1954 patients (17% AMI), for presentation and 1h-change values. Net Reclassification Improvement (NRI) determined triage effectiveness. In 776 patients (22% AMI) sensitivity and specificity were calculated from in-ambulance blood draws using a real and feasible Limit of Detection (LoD) on a point-of-care testing (POCT) device for cTnT and cMyC, respectively.
Results cTnT, cTnI, and cMyC increased by 3.9 ng/L (3.6–4.3), 4.3 ng/L (3.8–4.7), and 41.0 ng/L (38.0–44.0) per µg of human myocardium. In the ED, the diagnostic accuracy for AMI was comparable between the three biomarkers in baseline blood samples. cMyC increased the diagnostic performance of hs-cTnI but not hs-cTnT 0 and 1 hour samples. NRI was up to 30% better when comparing cMyC to hs-cTnT/I, translating into a more effective triage into rule-out and rule-in of AMI using a single blood test at presentation. In the pre-hospital setting, the diagnostic accuracy of cMyC was significantly higher than hs-cTnT (0.84 vs 0.80, p<0.001). The POCT threshold of cTnT (50 ng/L, 10-fold LoD of laboratory assay) achieved a sensitivity of 39.9% [32.6–48.1%]; cMyC (12 ng/L, 30-fold LoD) achieved a sensitivity of 94.9% [91.1–97.7%]. Risk prediction was better for cMyC at the POCT-detection limit.
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Conclusions hs-cTnT/I and cMyC are exquisitely sensitive biological signals, facilitating the detection of myocardial necrosis in tissue volumes too small to be detected by non-invasive imaging. cMyC is more abundant than cTnT/I and provides discriminatory power comparable to hs-cTnT/I for the diagnosis of AMI in all-comers, but identifies a greater proportion of patients with AMI in very early presenters. A standout feature is cMyC’s ability to more effectively triage patients. This distinction is likely related to the documented greater abundance and more rapid release profile of cMyC. If used on a POCT platform, cMyC could significantly improve the early triage of patients with suspected AMI.