AUTHOR=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 TITLE=Cellular and extracellular proteomic profiling of paradoxical low-flow low-gradient aortic stenosis myocardium JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=11 YEAR=2024 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1398114 DOI=10.3389/fcvm.2024.1398114 ISSN=2297-055X ABSTRACT=Aims

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.

Methods

Left ventricular (LV) myocardial biopsies of PLF-LG (n = 5) and NEF-HG patients (n = 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.

Results

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 (p < 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.

Conclusion

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.