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. 2021 Jan 19;11(1):1755.
doi: 10.1038/s41598-020-80868-z.

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

Kristina Sonnenschein  1   2 , Jan Fiedler  1 , David de Gonzalo-Calvo  1   3   4 , Ke Xiao  1 , Angelika Pfanne  1 , Annette Just  1 , Carolin Zwadlo  2 , Samira Soltani  2 , Udo Bavendiek  2 , Theresia Kraft  5 , Cristobal Dos Remedios  6 , Serghei Cebotari  7 , Johann Bauersachs  2   8 , Thomas Thum  9   10   11
Affiliations

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

Kristina Sonnenschein et al. Sci Rep. .

Abstract

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.

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Conflict of interest statement

T.T. has filed patents in the field of non-coding RNAs and is founder and holds shares of Cardior Pharmaceuticals GmbH. Other authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Proteomic approach of cardiometabolic panel of proteins was performed in serum of patients in the study groups and subsequently validated by ELISA assay. (A) Proteomic measurement. n = 10 in each group. c-KIT is labeled in red. (B) ELISA assay for c-KIT. n = 27–33 in each group. p values describe the significance level of differences for each comparison. HCM hypertrophic cardiomyopathy, HNCM non-obstructive hypertrophic cardiomyopathy, HOCM obstructive hypertrophic cardiomyopathy.
Figure 2
Figure 2
ROC curve analyses in controls versus HCM patients. Data are presented as the area under the ROC curve (AUC) and 95% confidence intervals (CI). N = 27–33 in each group. HCM hypertrophic cardiomyopathy.
Figure 3
Figure 3
Correlations between c-KIT levels and echocardiographic parameters in patients with obstructive hypertrophic cardiomyopathy (HOCM). c-KIT vs LVEDD in patients with HOCM. n = 27–33 in each group. Correlations between variables were analyzed using Spearman’s rho coefficient. LVEDD: left ventricular end-diastolic diameter.
Figure 4
Figure 4
Measurement of c-KIT levels in human biopsies and correlation with pro-fibrotic markers in obstructive hypertrophic cardiomyopathy (HOCM) via quantitative Real-time PCR. (A) c-KIT levels in HOCM; (B–E) Marker of fibrosis in human biopsies of HOCM patients and healthy controls. n = 6–10.
Figure 5
Figure 5
RNA-Sequencing after c-KIT silencing in human cardiac fibroblasts (HCFs). (A) Heatmap of RNA Sequencing in human cardiac fibroblasts after treatment with control siRNA or siRNA c-KIT. n = 3 independent experiments. (B) Gene set enrichment analysis of 1043 regulated genes with p < 0.05 and absolute fold change > 1.5. Functional terms are annotated according to the KEGG molecular functions, (red up-regulated, blue downregulated).
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