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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 221-225

Value of plasma levels of cardiac myosin-binding protein C as a diagnostic and prognostic biomarker in heart failure


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Pediatrics, Mansoura Insurance Hospital, Ministry of Health, El Mansoura, Egypt

Date of Submission07-Aug-2019
Date of Decision14-Oct-2019
Date of Acceptance20-Oct-2019
Date of Web Publication27-Mar-2021

Correspondence Address:
Mohamed G. F Abdel Ghani
Insurance Hospital, Ministry of Health, El Mansoura, Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_239_19

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  Abstract 


Objective
To study the value of measuring plasma levels of cardiac myosin-binding protein C (cMyBP-C) as a biomarker in the diagnosis and prognosis of heart failure (HF) in pediatric patients.
Background
Previous research studies have declared that cMyBP-C phosphorylation modulates cardiac contractility. It is a thick filament-associated protein which regulates actin–myosin interaction and thereby the systolic and diastolic function of the heart and regulates cardiac contractility. CMyBP-C has been reported in many studies as a specific early diagnostic biomarker of myocardial infarction.
Patients and methods
To reach the goal of this research, a case–control study was designed. The study sample included 35 Egyptian children from the hospitalized children at Menoufia University Hospital with HF as 'a patient group' and 30 apparently healthy children of similar age and sex matched as 'a control group.'
Results
We found a significant increase in cMyBP-C (P = 0.001) in the patients with HF. There was a statistically significant difference between cMyBP-C in the patients at admission and their ROSS classification, as higher level was noticed in class IV in relation to classes II and III (P = 0.001), and also higher in class III in relation to class II (P = 0.0.008).
Conclusion
Our study reveals that the plasma level of cMyBP-C is a significant biomarker, which can be used for diagnosis and prognosis of HF in pediatric patients.

Keywords: cardiac myosin-binding protein C, children, Egyptian, heart failure, plasma levels


How to cite this article:
Khatab AA, El-Gazzar BA, Rizk MS, Abdel Ghani MG. Value of plasma levels of cardiac myosin-binding protein C as a diagnostic and prognostic biomarker in heart failure. Menoufia Med J 2021;34:221-5

How to cite this URL:
Khatab AA, El-Gazzar BA, Rizk MS, Abdel Ghani MG. Value of plasma levels of cardiac myosin-binding protein C as a diagnostic and prognostic biomarker in heart failure. Menoufia Med J [serial online] 2021 [cited 2021 Dec 6];34:221-5. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/221/312027




  Introduction Top


Heart failure (HF) is defined as failure of the heart to supply the blood required for the metabolic demands of the body. It has a high morbidity and mortality rate in children [1]. So, it is very important to have a simple early biomarker that can help in the diagnosis and prognosis of adverse outcome. Recently, a number of novel HF biomarkers have evolved and have helped in assessing the severity of HF and predicting the course of the disease. The mechanism for the release of these markers seems to be variable from myocyte injury, ventricular remodeling to reduced coronary reserve [2]. Cardiac myosin-binding protein C (cMyBP-C) is a thick filament-associated protein and is a specific cardiomyocyte determinant of cardiac sarcomere structural integrity and function [3]. It regulates actin–myosin interaction and thereby the systolic and diastolic function of the heart [4]. It regulates cardiac contractility, and its phosphorylation by protein kinase contributes to increase in cardiac output in response to B adrenergic stimulation [5]. This phosphorylation decreases in HF cases, causing contractility dysfunction and decreases response to B adrenergic stimulation [6]. CMyBP-C has been reported in many studies as a specific early diagnostic biomarker of myocardial infarction in adult through proteolysis, dephosphorylation, and subsequent release into circulation. However, its clinical value in pediatric HF is not investigated yet [7]. The aim of the present study was to assess the value of measurement of plasma levels of cMyBP-C as a novel biomarker in the diagnosis and prognosis of HF in pediatric patients.


  Patients and methods Top


After approval of the Local Institutional Ethical Committee of Menoufia University Hospital and after taking a written consent from the participants, this case–control study was performed by selecting 35 Egyptian children from the hospitalized children at Menoufia University Hospital with HF, who were enrolled in this study as the 'patient group,' and another 30 apparently healthy children matched for age and sex as ' a control group' in the period between July 2017 and August 2018. The inclusion criteria included (a) age range from 3 days to 3 years, (b) both sexes, and (c) infants and children with manifestations of acute HF owing to either acquired or congenital heart disease. They were classified according to ROSS classification as follows: (a) no limitations or symptoms; (b) mild tachypnea or diaphoresis with feedings in infants, dyspnea at exertion in older children, and no growth failure; (c) marked tachypnea or diaphoresis with feedings or exertion and prolonged feeding times with growth failure from congestive HF; and (d) symptomatic at rest with tachypnea, retractions, grunting, or diaphoresis. Exclusion criteria were as follows: (a) age under 3 days or older than 3 years and (b) patients experiencing any cardiac diseases other than HF, or having malignancy, inflammatory, or autoimmune conditions. All patients were subjected to full history taking, general examination, and local examination of the chest and heart. Laboratory investigations including hemoglobin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were done for the patient group at admission and the control group. Plasma levels of cMyBP-C were assessed at the time of admission and after 1-month treatment in the patient group, but only once at admission in the control group. Automated analyzer (Robonik prietest touch; Robonik Ltd, Thane, Mumbai, India) was used for measurement of hemoglobin and CRP; the citrated samples were used for ESR. Plain chest radiography using portable stand radiograph machine (ALLENGER Medical Systems Limited, Punjab, India) and echocardiograph using Chison Eco3 Export Ultrasound (Chison Ltd, Jiangsu, China) were done for the patient group at admission. Measurement of serum cMyBP-C was done by specimen collection, with ∼2 ml of peripheral venous blood being withdrawn in plain tubes. Samples were left for clotting for 30 min and then centrifuged, and the separated serum samples were aliquoted and stored at −30°C for cMyBP-C assessment and assay. The kit (SUNRED Biotechnology Company, Shanghai, China) uses a double-antibody sandwich enzyme-linked immunosorbent assay. In the assay, myosin-binding protein C sample is added to the monoclonal antibody enzyme well, which is precoated with human myosin-binding protein C antibodies. Then it is incubated. Thereafter, myosin-binding protein C antibodies labeled with biotin are added, which combine with streptavidin-HRP to form an immune complex. Then incubation is carried out and washed again to remove the uncombined enzyme. Then chromogen solutions A, B are added. The color of the liquid changes into blue, and at the effect of acid, the color finally becomes yellow. The chroma of color and concentration of the human substance myosin-binding protein C of sample were positively correlated. The data were collected and entered to the computer using SPSS 20 (statistical package for social sciences) (SPSS Inc., Armonk, New York, USA) program for statistical analysis. Data were entered as numerical or categorical, as appropriate. Two types of statistics were done: (a) descriptive statistics, as mean, SD, and range, and (b) analytical studies, such as χ2 test to measure association between qualitative variables as appropriate, Student t test, which is a test of significance and was used for comparison between two groups having quantitative data, and Mann–Whitney test (nonparametric test), which is a test of significance and was used for comparison between two groups not normally distributed having quantitative variables. P value, probability of chance, indicates significance when P value less than or equal to 0.05. To define the optimal cutoff level of cMyBP-C measured in HF, the receiver operating characteristic (ROC) curve analysis was used.


  Results Top


A total of 65 Egyptian children were enrolled in this study. Of them, 35 were patients hospitalized with HF [22 (62.9%) males and 13 (37.1%) females] and 30 were apparently healthy children matched for age and sex [18 (60%) males and 12 (40%) females]. The mean age of the patients was 5.45 ± 9.63 months. For children with age less than 1.5 years, length was measured, whereas for children with age more than 1.5 years, height was measured. There was a significant decrease in the patient group in relation to control regarding the anthropometric measurements: body weight, with P value = 0.010; height/length, with P value = 0.012; and BMI, with P value = 0.026 [Table 1]. There was no significant difference in ESR result between the patients and control (P = 0.322). There was a significant decrease in hemoglobin of the patients in relation to control (P = 0.001) but significant increase in cMyBP-C (P = 0.001) and CRP (P = 0.017) [Table 2]. There was a significant difference between cMyBP-C in the patients at admission and their ROSS classification, as higher level was noticed in class IV in relation to classes II and III (P = 0.001) and also higher in class III in relation to class II (P = 0.001) [Table 3]. Follow-up of the patients showed that in died patients, there was no significant decrease in cMyBP-C level before and after treatment (P = 0.516), whereas in recovered patients, there was a significant decrease in its level after treatment (P = 0.017) [Table 4]. ROC curve for cMyBP-C revealed sensitivity of 69%, specificity of 83%, and area under the curve (AUC) of 0.792 [Figure 1].
Table 1: The sex, age distribution, and anthropometric measurements of the studied groups

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Table 2: Laboratory investigations in the patients at admission and controls

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Table 3: Plasma level of cardiac myosin-binding protein C in the patients at admission in relation to their ROSS classification

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Table 4: Plasma level of cardiac myosin-binding protein C in the patients at admission (before treatment) and after treatment in relation to prognosis

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Figure 1: ROC curve for cardiac myosin-binding protein C. ROC, receiver operating characteristic.

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  Discussion Top


HF is one of the cardiovascular diseases that have high mortality and morbidity. Early diagnosis of HF is crucial for early management [8]. Cardiac biomarkers are useful diagnostic and prognostic tools, especially in patients who have atypical signs and symptoms [9]. cMyBP-C is a cardiomyocyte-specific sarcomeric protein. Moreover, the large size of it and its release into the circulation in response to cardiac injury make it one of the promising cardiac biomarkers for detection of cardiac injury [10]. There are many causes for its plasma level elevation. Sadayappan [11] reported that the plasma level of it is significantly elevated in patients with MI compared with healthy controls. Moreover, Anand et al. [12] reported increased levels of it in aortic stenosis patients with hypertrophy compared with healthy controls. In our study, the age of the patient and the control group ranged from 3 days to 3 years, with a mean 5.45 months for the patient group, whereas the mean age of the control group was 7 months. Overall, 62.9% of the patients group were males and 37.1% were females, whereas 60% of the control group were males and 40% were females. Both the patient and the control groups were sex and age matched, with no statistically significant difference. This is in accordance with El Amrousy et al. [3], who reported that the mean age of the patient group was 16.92 months, whereas the mean age of the control group was 18.36 months. Overall, 44% of patient group were females and 56% were males, whereas 48% of the control group were females and 52% were males. Both patient and control groups were sex and age matched, with no statistically significant difference. Our study showed mean body weight in the patient group was 4.67 ± 2.73 kg, whereas in the control group was 6.57–3.04 kg, with a significant decrease in the weight of the patient group. This is in accordance with Hassan et al. [13], who reported that weight in the patient group was a median of 7.5 kg, whereas in the control group was a median of 10 kg, with significant decrease in the weight of the patient group. A study done by Batte et al. [14] showed 42.5% of the patient group were underweight with weight for age, which correlates with our results. We found mean height in the patient group was 55.8 ± 11.52 cm, whereas the mean in the control group was 63.20 ± 11.51 cm, with significant decrease in the height of the patient group. This is in accordance with Polat et al. [15], who reported that mean ± SD height for hemodynamically normal patient group was 0.24 ± 1.91, −0.65 ± 2.84 in hemodynamically impaired patient group and 0.61 ± 2.03 in control one, with significant decrease in the height of the hemodynamically impaired patient group. We found mean BMI in the patient group was 13.99 ± 2.35 kg/m2, whereas in the control group was 15.44 ± 2.79 kg/m2, with significant decrease in BMI of the patient group. A study done by Batte et al. [14] showed 27.3% of patients had BMI for age Z score less than or equal to −2 (thin) with a median BMI for age Z score of −0.72. Moreover, a study done by Polat et al. [15] showed mean BMI in hemodynamically normal patients was 16.8 ± 1.9 kg/m2, 15.6 ± 2.4 kg/m2 in hemodynamically impaired, and 17.01 ± 1.9 kg/m2 in control group, with significant decrease in the hemodynamically impaired one, which correlates with our study. We found that there was no significant difference in ESR result between the patients and control, but there was a significant increase in cMyBP-C and CRP. This is in accordance with Butts et al. [16], who reported that ESR in moderate–severe depressed ventricular function patient group ranged from 2 to 33 mm/h, whereas it ranged from 7 to 33 mm/h in mildly depressed to normal ventricular function one, with no significant difference between them. Moreover, they showed CRP in moderate–severe group ranged from 1 to 13 and 1.2 to 16.3 mg/dl in mildly depressed to normal ones, with no significant difference between them, and there was a significant increase in cMyBP-C. There was a significant decrease in hemoglobin of the patients in relation to the control. This is in accordance with Herrscher et al. [17], who reported that hemoglobin in the patient group ranged from 12.1 to 14.3 g/dl, whereas it ranged from 13.2 to 15.2 g/dl in the control, with significant decrease in the patient group. Moreover, in a study done by Parsonage et al. [18], hemoglobin in the patient group ranged from 12.3 to 15 g/dl, whereas it ranged from 13.1 to 15.1 g/dl in the control, with nonsignificant difference between them. We found that there was significantly low level of cMyBP-C in control group in relation to the patient before treatment. This is in accordance with El Amrousy et al. [3], who reported that there was significantly low level of cMyBP-C in control group in relation to the patient before treatment. We found that there was a significant difference between cMyBP-C in the patients at admission and their ROSS classification, as higher level noticed in class IV in relation to classes II and III, and also higher in class III in relation to class II. This is in accordance with Granström et al. [19], who reported that 23.3% of the patients were class II, 46.7% were class III, and 30% were class IV. Moreover, a study conducted by Guazzi and Arena [20] showed that the severity of HF symptoms based on ROSS classification correlates best with elevations in pulmonary capillary wedge pressure, as the worse ROSS classification was most strongly associated with pulmonary capillary wedge pressure more than 22 mmHg, which correlates with our study. We found after follow-up of the patients in died patients, there was no significant decrease in cMyBP-C before and after treatment, whereas in recovered patients, there was a significant decrease in its level after treatment. This is in accordance with El Amrousy et al. [3], who reported that mean plasma level of cMyBP-C in died patients before treatment was 213 ± 9.34 ng/ml and after treatment was 205.25 ± 12.44 ng/ml, with no significant decrease in its plasma level. Mean plasma level of cMyBP-C in recovered patients before treatment was 111.17 ± 31.54 ng/ml and after treatment was 52.78 ± 23.71 ng/ml, with a significant decrease in its level. Moreover, the study showed that before treatment there was significantly high level of cMyBP-C in died compared with recovered, and after treatment, there was a significantly high level of it in died patients compared with recovered, which correlates with our study. Compared with other biomarkers of important prognostic value, Dunlay et al. [21] reported that higher levels of CRP, BNP, and TnT were associated with a large increase in 1-year mortality in community patients with HF. Moreover, a study done by Emdin et al. [22] reported that measurement of BNP/NT-proBNP levels can add prognostic information for newly diagnosed patients, more quickly and effectively than echocardiography. In our study, ROC curve was generated according to data of studied groups. We found at cutoff point of plasma level of cMyBP-C higher than 70 ng/ml, sensitivity was 69%, specificity was 83%, and AUC was 0.792. A study done by El Amrousy et al. [3] showed at cutoff point higher than 45 ng/ml, sensitivity was 100%, specificity was 96%, and AUC was 0.999.


  Conclusion Top


The results obtained in our study revealed that plasma level of cMyBP-C is a significant biomarker which can be used for diagnosis and also prognosis for cases of HF in pediatric patients as its level increases in these cases before treatment and decreases after treatment. Moreover, we found that there would be bad prognosis if there was no significant decrease in its level after treatment. Further studies are required to establish this finding.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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