Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction

Abstract

Background: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI.

Methods: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality.

Results: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (P<0.0001) and 0.926 (P=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (P<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (P<0.05 for both) and similar to hs-cTnT at predicting death at 3 years.

Conclusions: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Keywords: cMyC; cardiac myosin-binding protein C; myocardial infarction, APACE; troponin I; troponin T.

Figure 1.

Depiction of cardiac troponin and cardiac myosin-binding protein C release during myocardial injury. Structure of cardiac myosin-binding protein C and cardiac troponins in (A) healthy cardiomyocytes and (B) ischemia-induced cardiomyocyte damage. The highlighted N-terminal domain C0C1 is the binding site for the previously developed monoclonal antibodies used for detection of the cardiac-specific isoform of cMyC. cMyC indicates cardiac myosin-binding protein C; cTnI, cardiac troponin I; and cTnT, cardiac troponin T.

Figure 2.

Baseline distribution of cMyC levels at presentation to the emergency department in all patients based on adjudicated final diagnosis. Boxes represent interquartile ranges (IQR). Whiskers extend to 1.5*IQR from the hinges (y axis capped at 1500 ng/L, outliers represented by light gray bullets); 87 ng/L represents the 99th percentile based on a previous study and 120 ng/L the cutoff threshold for diagnostic rule-in of AMI at presentation. AMI, median, 237 ng/L (IQR 71, 876 ng/L); unstable angina, median, 21 ng/L (IQR 13, 43 ng/L); cardiac symptoms of origin other than coronary artery disease, median, 33 ng/L (IQR 12, 96 ng/L); noncardiac symptoms, median, 10 ng/L (IQR 6, 19 ng/L; symptoms of unknown origin, median, 11 ng/L (IQR 7, 16 ng/L) (P<0.001 for all comparisons with patients with AMI). AMI indicates acute myocardial infarction; cMyC, cardiac myosin-binding protein C; and UA, unstable angina.

Figure 3.

Receiver operating characteristic (ROC) curves for individual biomarkers. Diagnostic performance of cMyC, hs-cTnT, hs-cTnI, and s-cTnI in the early diagnosis of acute myocardial infarction (AMI) based on presentation blood sample and adjudicated AMI diagnosis. ROC curves describing the performance of cMyC (orange line; area under the curve [AUC], 0.924), hs-cTnT (light gray line; AUC, 0.927), hs-cTnI (dark gray line; AUC, 0.922), and s-cTnI (black line; AUC, 0.909*) (*P<0.05). cMyC indicates cardiac myosin-binding protein C; hs-cTnI, high-sensitivity cardiac troponin I; hs-cTnT, high-sensitivity cardiac troponin T; and s-cTnI, standard-sensitivity cardiac troponin I.

Figure 4.

Distribution of patients in different risk categories after presentation blood tests. Data are based on European Society of Cardiology guideline 2015 for hs-cTnT and hs-cTnI and newly developed cutoff thresholds for cMyC at ≤10 ng/L for rule-out and >120 ng/L for rule-in of myocardial infarction. AMI indicates acute myocardial infarction; cMyC, cardiac myosin-binding protein C; hs-cTnI, high-sensitivity cardiac troponin I; and hs-cTnT, high-sensitivity cardiac troponin T.