Endomyocardial proteomic signature corresponding to the response of patients with dilated cardiomyopathy to immunoadsorption therapy.
Dilated cardiomyopathy (DCM) is a disease of the myocardium with reduced left ventricular ejection fraction (LVEF). Cardiac autoantibodies (AAbs) play a causal role in the development and progression of DCM. Removal of AAbs using immunoadsorption (IA/IgG) has been shown as a therapeutic option to improve cardiac function. However, the response to therapy differs significantly among patients. The reasons for this variability are not completely understood. Hitherto, no potential biomarker is available to predict improvement of cardiac function after therapy accurately. This shotgun proteome study aims to disclose the differences in the endomyocardial proteome between patients with improved LVEF after IA/IgG (responders) and those without improvement (non-responders) before therapy start. Comparative analysis revealed 54 differentially abundant proteins that were mostly confined to carbohydrate and lipid metabolism, energy and immune regulation, and cardioprotection. Selected proteins representing various functional categories were further confirmed by multiple reaction monitoring (MRM). Among those, protein S100-A8, perilipin-4, and kininogen-1 were found the most robust candidates differentiating responders and non-responders. Receiver operating characteristic curve (ROC) analysis of these proteins revealed highest potential for protein S100-A8 (AUC 0.92) with high sensitivity and specificity to be developed as a classifier for the prediction of cardiac improvement after IA/IgG therapy.



We evaluated the differences in the myocardial proteome of responder and non-responder DCM patients before immunoadsorption therapy and identified a number of differentially abundant proteins involved in energy and lipid metabolism, immune system, and cardioprotection. MRM was used for verification of results. Proteins S100-A8, perilipin-4, and kininogen-1 were found to display the largest differences. The results provide a lead for further studies to screen for protein biomarker candidates in plasma that might be helpful to stratify patients for immunoadsorption therapy treatment.
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Gourav
G
Bhardwaj
Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Marcus
M
Dörr
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.
Praveen Kumar
PK
Sappa
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Sabine
S
Ameling
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.
Vishnu
V
Dhople
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.
Leif
L
Steil
Department of Molecular Pathology, University Hospital Tübingen, Germany.
Karin
K
Klingel
Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Greifswald, Germany.
Klaus
K
Empen
Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Greifswald, Germany.
Daniel
D
Beug
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Uwe
U
Völker
Department of Internal Medicine B (Cardiology), University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. Electronic address: felix@uni-greifswald.de.
Stephan B
SB
Felix
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. Electronic address: hammer@uni-greifswald.de.
Elke
E
Hammer
D000328:Adult; D001323:Autoantibodies / Q000302:isolation & purification*; D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005260:Female; D006801:Humans; D007163:Immunosorbent Techniques; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D010865:Pilot Projects; D011379:Prognosis; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012189:Retrospective Studies; D016896:Treatment Outcome
D001323:Autoantibodies; D015415:Biomarkers; D020543:Proteome
Dilated cardiomyopathy; Endomyocardial biopsies; Label-free tandem mass spectrometry; Multiple reaction monitoring; Therapy response