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Cardiac Myosin-Binding Protein C-From Bench to Improved Diagnosis of Acute Myocardial Infarction.

ABSTRACT: Chest pain is responsible for 6-10% of all presentations to acute healthcare providers. Triage is inherently difficult and heavily reliant on the quantification of cardiac Troponin (cTn), as a minority of patients with an ultimate diagnosis of acute myocardial infarction (AMI) present with clear diagnostic features such as ST-elevation on the electrocardiogram. Owing to slow release and disappearance of cTn, many patients require repeat blood testing or present with stable but elevated concentrations of the best available biomarker and are thus caught at the interplay of sensitivity and specificity.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. In this review, we discuss discovery and structure of cMyC, as well as the migration from a comparably insensitive to a high-sensitivity assay facilitating first clinical studies. This assay was subsequently used to describe relative abundance of the protein, compare sensitivity to two high-sensitivity cTn assays and test diagnostic performance in over 1900 patients presenting with chest pain and suspected AMI. A standout feature was cMyC's ability to more effectively triage patients. This distinction is likely related to the documented greater abundance and more rapid release profile, which could significantly improve the early triage of patients with suspected AMI.

SUBMITTER: Kaier TE

PROVIDER: S-EPMC6509074 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Cardiac Myosin-Binding Protein C-From Bench to Improved Diagnosis of Acute Myocardial Infarction.

Kaier Thomas E TE Alaour Bashir B Marber Michael M

Cardiovascular drugs and therapy 20190401 2

Chest pain is responsible for 6-10% of all presentations to acute healthcare providers. Triage is inherently difficult and heavily reliant on the quantification of cardiac Troponin (cTn), as a minority of patients with an ultimate diagnosis of acute myocardial infarction (AMI) present with clear diagnostic features such as ST-elevation on the electrocardiogram. Owing to slow release and disappearance of cTn, many patients require repeat blood testing or present with stable but elevated concentra ...[more]

PMID: 30617437

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Project description: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.

Project description:Glucose is a universally available inexpensive biomarker, which is increased as part of the physiological stress response to acute myocardial infarction (AMI) and may therefore help in its early diagnosis. To test this hypothesis, glucose, high-sensitivity cardiac troponin (hs-cTn) T, and hs-cTnI were measured in consecutive patients presenting with acute chest discomfort to the emergency department (ED) and enrolled in a large international diagnostic study (NCT00470587). Two independent cardiologists centrally adjudicated the final diagnosis using all clinical data, including serial hs-cTnT measurements, cardiac imaging and clinical follow-up. The primary diagnostic endpoint was index non-ST-segment elevation MI (NSTEMI). Prognostic endpoints were all-cause death, and cardiovascular (CV) death or future AMI, all within 730-days. Among 5639 eligible patients, NSTEMI was the adjudicated final diagnosis in 1051 (18.6%) patients. Diagnostic accuracy quantified using the area under the receiver-operating characteristics curve (AUC) for the combination of glucose with hs-cTnT and glucose with hs-cTnI was very high, but not higher versus that of hs-cTn alone (glucose/hs-cTnT 0.930 [95% CI 0.922-0.937] versus hs-cTnT 0.929 [95% CI 0.922-0.937]; glucose/hs-cTnI 0.944 [95% CI 0.937-0.951] versus hs-cTnI 0.944 [95% CI 0.937-0.951]). In early-presenters, a dual-marker strategy (glucose < 7 mmol/L and hs-cTnT < 5/hs-cTnI < 4 ng/L) provided very high and comparable sensitivity to slightly lower hs-cTn concentrations (cTnT/I < 4/3 ng/L) alone, and possibly even higher efficacy. Glucose was an independent predictor of 730-days endpoints. Our results showed that a dual marker strategy of glucose and hs-cTn did not increase the diagnostic accuracy when used continuously. However, a cutoff approach combining glucose and hs-cTn may provide diagnostic utility for patients presenting ≤ 3 h after onset of symptoms, also providing important prognostic information.

Dataset Information

Cardiac Myosin-Binding Protein C-From Bench to Improved Diagnosis of Acute Myocardial Infarction.

Publications

Cardiac Myosin-Binding Protein C-From Bench to Improved Diagnosis of Acute Myocardial Infarction.

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