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Heart failure (HF) has high morbidity and mortality in children. This study aimed to investigate the value of cardiac myosin binding protein-C (cMyBP-C) as a diagnostic and prognostic biomarker in children with heart failure. This study was a prospective case-control study that involved 50 children with acute HF and 25 healthy children of matched age and sex as a control group. cMyBP-C plasma levels were measured in patients with HF at the time of admission and 1 month after treatment. Echocardiographic assessment was done for all children. All patients were followed up for a period of 3 months. There was a significant increase in plasma levels of cMyBP-C (ng/ml) in patients with HF at admission (122.44 ± 41.01) as compared to patients after treatment (71.38 ± 49.68) and to control group (24.40 ± 9.83). This increase was associated with increased severity of HF according to pediatric Ross classification of HF. Significant increase in plasma levels of cMyBP-C at admission and its persistent increase after treatment were associated with adverse outcome of mortality and readmission. Plasma levels of cMyBP-C were significantly correlated with echocardiographic and clinical assessment of heart failure. Plasma levels of cMyBP-C were a good biomarker for diagnosis of HF with sensitivity 100% and specificity 96% at cutoff point of 45 ng/ml. Its value in predicting adverse outcome in HF patients was obtained by ROC curve with sensitivity of 90% and specificity 93% at a cutoff point of 152 ng/ml cMyBP-C at admission. cMyBP-C may be a novel useful diagnostic and prognostic biomarker in children with heart failure and determination of severity of HF in these patients.

Background: Heart failure is one of the cardiovascular diseases that have high morbidity and mortality especially among children. It accounts for 2% of all pediatric inpatient admission. Cardiac Myosin Binding Protein-C (cMyBP-C) is cardiomyocyte specific sarcomeric protein that regulates sarcomeric structure and its function where it is released in circulation in response to cardiac injury. Objective: To explore the role of cMyBP-C as a biomarker in heart failure in children. Patients and Methods: This prospective cohort study was carried out during the period from October 2017 to October 2018 in Pediatric Cardiology Unit, Zagazig University Hospital. It included 26 selected patients with heart failure diagnosed clinically and by echocardiography. Results: The study revealed that the most common cause pf heart failure in our patients was VSD (30.8%) then DCM (26.9%). 57.7% of studied patients were grade III of ROSS classification while 30.8% were grade IV and 11.5% were grade II. In ECHO findings, mean EF% was 52.3% while mean FS% was 33 % with negative correlation between plasma level of cMyBP-C and EF% and FS%. There was high statistical significant difference in cMyBP-C plasma level at time of admission and after treatment (123.5 ng/ml and 78.8 ng/ml respectively). There was high statistical significant difference in level of cMyBP-C among improved cases before and after treatment. There was no statistical significant difference in level of cMyBP-C before and after treatment among cases with bad prognosis. Conclusion: cMyBP-C could be a prognostic biomarker in children with HF and may be used as a tool to help in HF diagnosis in children as a marker of disease severity. [ABSTRACT FROM AUTHOR]

Cardiac myosin binding protein-C (cMyBP-C) is a cardiac-specific thick filament assembly, accessory, and regulatory protein. Physiologically, it is a key regulator of cardiac contractility. With more than 200 mutations in the cMyBP-C gene directly linked to the development of cardiomyopathy and heart failure, cMyBP-C clearly plays a critical role in heart function. At baseline, cMyBP-C is highly phosphorylated, a condition required for normal cardiac function. However, the level of cMyBP-C phosphorylation is significantly decreased during heart failure, indicating that the level of cMyBP-C phosphorylation is directly linked to signaling and cardiac function. Early studies indicated that cMyBP-C interacts with myosin and titin, whereas studies now show that it also interacts with thin filament proteins. However, the exact role(s) of cMyBP-C in the heart remain(s) to be elucidated. As such, we invited experts in the field of cardiac muscle to identify and address key issues related to cMyBP-C by contributing a mini review on such topics as structure, function, regulation, cardiomyopathy, proteolysis, and gene therapy. Starting from this issue, Pflügers Archiv European Journal of Physiology will publish two invited mini review articles each month to discuss the most recent advances in the study of cMyBP-C. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Cardiac myosin binding protein-C (cMyBP-C) becomes dephosphorylated in the failing heart and reduced phosphorylation-dependent regulation of cMyBP-C has been implicated in contractile dysfunction. To date, several phosphorylation sites have been identified for human cMyBP-C; however, a comprehensive characterization of the cMyBP-C phosphoproteome is lacking. This study aimed to characterize the cMyBP-C phosphoproteome using two different proteomic-based methods in explanted donor and end-stage failing hearts. Methods: The first approach used to characterize the cMyBP-C phosphoproteome employed a strong-cation exchange chromatography (SCX) fractionation method (10 pooled samples, technical replicates=4) and the second employed a sodium dodecylsulfate polyacrylamide gel electrophoresis method (n =10; technical replicates=2). Each subsequently underwent titanium dioxide (TiO2) affinity chromatography to enrich for the tryptic phosphopeptides, which were analyzed using an LTQ-Orbitrap mass spectrometer. Moreover, recombinant C0–C2 fragment of mouse cMyBP-C incubated with PKA, PKC, CaMKII and CK2 was analyzed to identify the kinases involved with phosphorylation of cMyBP-C. Results: Seventeen phosphorylation sites on cMyBP-C were identified in vivo, with the majority localized in the N-terminal domains C0–C2. The three most abundant phosphorylated sites, Ser284, Ser286 and Thr290, are located in the regulatory M-domain of cMyBP-C. Ser284 showed a significant reduction in phosphorylation in HF. Conclusion: This study demonstrates that cMyBP-C harbors more phosphorylation sites than previously known, with a total of 17 (9 novel) identified phosphorylation sites in vivo. Most sites were primarily located within the N-terminal side of the protein. The most highly phosphorylated site on cMyBP-C was Ser284 and this site showed decreased phosphorylation in the failing heart, which implicates importance for fine-tuning contractility. To date, the functional importance of Ser286 and Thr290 is unknown. In addition, 16 sites were identified after in vitro kinase incubation. The data have been deposited to the ProteomeXchange with identifier PXD000158. [Copyright &y& Elsevier]

It is now generally accepted that phosphorylation of cMyBP-C is critically important in maintaining normal cardiac function. Although much of the work to date on phospho-regulation of cMyBP-C has focused on the role of protein kinase A (PKA, also known as cAMP-dependent protein kinase), recent evidence suggests that a number of non-PKA serine/threonine kinases, such as Ca/calmodulin-dependent protein kinase II, protein kinase C, protein kinase D and the 90-kDa ribosomal S6 kinase are also capable of targeting this key regulatory sarcomeric protein. This article reviews such evidence and proposes a hypothetical role for some of the pertinent signalling pathways in phospho-regulation of cMyBP-C in the setting of heart failure. [ABSTRACT FROM AUTHOR]