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Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction.

ABSTRACT: Cardiac myosin binding protein-C (cMyBP-C) is a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function; however, the profile of cMyBP-C degradation after myocardial infarction (MI) is unknown. We hypothesized that cMyBP-C is sensitive to proteolysis and is specifically increased in the bloodstream post-MI in rats and humans. Under these circumstances, elevated levels of degraded cMyBP-C could be used as a diagnostic tool to confirm MI. To test this hypothesis, we first established that cMyBP-C dephosphorylation is directly associated with increased degradation of this myofilament protein, leading to its release in vitro. Using neonatal rat ventricular cardiomyocytes in vitro, we were able to correlate the induction of hypoxic stress with increased cMyBP-C dephosphorylation, degradation, and the specific release of N'-fragments. Next, to define the proteolytic pattern of cMyBP-C post-MI, the left anterior descending coronary artery was ligated in adult male rats. Degradation of cMyBP-C was confirmed by a reduction in total cMyBP-C and the presence of degradation products in the infarct tissue. Phosphorylation levels of cMyBP-C were greatly reduced in ischemic areas of the MI heart compared to non-ischemic regions and sham control hearts. Post-MI plasma samples from these rats, as well as humans, were assayed for cMyBP-C and its fragments by sandwich ELISA and immunoprecipitation analyses. Results showed significantly elevated levels of cMyBP-C in the plasma of all post-MI samples. Overall, this study suggests that cMyBP-C is an easily releasable myofilament protein that is dephosphorylated, degraded and released into the circulation post-MI. The presence of elevated levels of cMyBP-C in the blood provides a promising novel biomarker able to accurately rule in MI, thus aiding in the further assessment of ischemic heart disease.

SUBMITTER: Govindan S

PROVIDER: S-EPMC3246118 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction.

Govindan Suresh S McElligott Andrew A Muthusamy Saminathan S Nair Nandini N Barefield David D Martin Jody L JL Gongora Enrique E Greis Kenneth D KD Luther Pradeep K PK Winegrad Saul S Henderson Kyle K KK Sadayappan Sakthivel S

Journal of molecular and cellular cardiology 20110919 1

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function; however, the profile of cMyBP-C degradation after myocardial infarction (MI) is unknown. We hypothesized that cMyBP-C is sensitive to proteolysis and is specifically increased in the bloodstream post-MI in rats and humans. Under these circumstances, elevated levels of degraded cMyBP-C could be used as a diagnostic tool to confirm MI. To test this hy ...[more]

PMID: 21971072

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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:Background Cardiovascular magnetic resonance imaging is considered the reference methodology for cardiac morphology and function but requires manual postprocessing. Whether novel artificial intelligence-based automated analyses deliver similar information for risk stratification is unknown. Therefore, this study aimed to investigate feasibility and prognostic implications of artificial intelligence-based, commercially available software analyses. Methods and Results Cardiovascular magnetic resonance data (n=1017 patients) from 2 myocardial infarction multicenter trials were included. Analyses of biventricular parameters including ejection fraction (EF) were manually and automatically assessed using conventional and artificial intelligence-based software. Obtained parameters entered regression analyses for prediction of major adverse cardiac events, defined as death, reinfarction, or congestive heart failure, within 1 year after the acute event. Both manual and uncorrected automated volumetric assessments showed similar impact on outcome in univariate analyses (left ventricular EF, manual: hazard ratio [HR], 0.93 [95% CI 0.91-0.95]; P<0.001; automated: HR, 0.94 [95% CI, 0.92-0.96]; P<0.001) and multivariable analyses (left ventricular EF, manual: HR, 0.95 [95% CI, 0.92-0.98]; P=0.001; automated: HR, 0.95 [95% CI, 0.92-0.98]; P=0.001). Manual correction of the automated contours did not lead to improved risk prediction (left ventricular EF, area under the curve: 0.67 automated versus 0.68 automated corrected; P=0.49). There was acceptable agreement (left ventricular EF: bias, 2.6%; 95% limits of agreement, -9.1% to 14.2%; intraclass correlation coefficient, 0.88 [95% CI, 0.77-0.93]) of manual and automated volumetric assessments. Conclusions User-independent volumetric analyses performed by fully automated software are feasible, and results are equally predictive of major adverse cardiac events compared with conventional analyses in patients following myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00712101 and NCT01612312.

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Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction.

Publications

Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction.

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