Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis

2022 | journal article. A publication with affiliation to the University of Göttingen.

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​Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis​
Brandenburg, S. ; Drews, L.; Schönberger, H.-L.; Jacob, C. F.; Paulke, N. J.; Beuthner, B. E. & Topci, R. et al.​ (2022) 
Journal of Molecular and Cellular Cardiology173 pp. 1​-15​.​ DOI: 

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Brandenburg, Sören ; Drews, Lena; Schönberger, Hanne-Lea; Jacob, Christoph F.; Paulke, Nora Josefine; Beuthner, Bo E.; Topci, Rodi; Kohl, Tobias ; Neuenroth, Lisa; Kutschka, Ingo ; Lehnart, Stephan E. 
The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS.
Issue Date
Journal of Molecular and Cellular Cardiology 
EXC 2067: Multiscale Bioimaging 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | Z02: Massenspektrometrie-basierte Proteomanalyse 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion 
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur 
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse 
Klinik für Kardiologie und Pneumologie ; Herzforschungszentrum Göttingen ; Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. ; Institut für Klinische Chemie ; Klinik für Thorax-, Herz- und Gefäßchirurgie ; Max-Planck-Institut für Multidisziplinäre Naturwissenschaften ; Institut für Medizinische Statistik ; Klinik für Kardiologie und Pneumologie ; Universitätsmedizin Göttingen 
Working Group
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG Lehnart (Cellular Biophysics and Translational Cardiology Section) 
RG Toischer (Kardiales Remodeling) 
RG Urlaub (Bioanalytische Massenspektrometrie) 
RG Brandenburg 
RG Lenz 
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