Cellular and extracellular proteomic profiling of paradoxical low-flow low-gradient aortic stenosis myocardium

• Published in: Frontiers in cardiovascular medicine Vol. 11; p. 1398114
• Main Authors: Elkenani, Manar, Barallobre-Barreiro, Javier, Schnelle, Moritz, Mohamed, Belal A, Beuthner, Bo E, Jacob, Christoph Friedemann, Paul, Niels B, Yin, Xiaoke, Theofilatos, Konstantinos, Fischer, Andreas, Puls, Miriam, Zeisberg, Elisabeth M, Shah, Ajay M, Mayr, Manuel, Hasenfuß, Gerd, Toischer, Karl
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 16-09-2024
• Subjects: Cardiovascular Medicine; cellular and extracellular matrix proteomics; myocardial biopsies; normal ejection fraction high-gradient aortic stenosis; paradoxical low-flow low-gradient aortic stenosis; transcatheter aortic valve implantation (TAVI); transcatheter aortic valve implantation (TAVI); cellular and extracellular matrix proteomics; normal ejection fraction high-gradient aortic stenosis; paradoxical low-flow low-gradient aortic stenosis; myocardial biopsies
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2024.1398114

Patients with severe aortic stenosis (AS), low transvalvular flow (LF) and low gradient (LG) with normal ejection fraction (EF)-are referred to as paradoxical LF-LG AS (PLF-LG). PLF-LG patients develop more advanced heart failure symptoms and have a worse prognosis than patients with normal EF and high-gradient AS (NEF-HG). Despite its clinical relevance, the mechanisms underlying PLF-LG are still poorly understood.
Left ventricular (LV) myocardial biopsies of PLF-LG (
 = 5) and NEF-HG patients (
 = 6), obtained during transcatheter aortic valve implantation, were analyzed by LC-MS/MS after sequential extraction of cellular and extracellular matrix (ECM) proteins using a three-step extraction method. Proteomic data are available via ProteomeXchange with identifier PXD055391.
73 cellular proteins were differentially abundant between the 2 groups. Among these, a network of proteins related to muscle contraction and arrhythmogenic cardiomyopathy (e.g., cTnI, FKBP1A and CACNA2D1) was found in PLF-LG. Extracellularly, upregulated proteins in PLF-LG were related to ATP synthesis and oxidative phosphorylation (e.g., ATP5PF, COX5B and UQCRB). Interestingly, we observed a 1.3-fold increase in cyclophilin A (CyPA), proinflammatory cytokine, in the extracellular extracts of PLF-LG AS patients (
 < 0.05). Consistently, immunohistochemical analysis confirmed its extracellular localization in PLF-LG AS LV sections along with an increase in its receptor, CD147, compared to the NEF-HG AS patients. Levels of core ECM proteins, namely collagens and proteoglycans, were comparable between groups.
Our study pinpointed novel candidates and processes with potential relevance in the pathophysiology of PLF-LG. The role of CyPA in particular warrants further investigation.