Single-nucleus transcriptomics reveals adrenergic and STAT3 signaling in paradoxical low-flow low-gradient -specific cardiomyocyte subclusters: implications for aortic stenosis pathogenesis/treatment

Xingbo Xu (Göttingen)1, X. Tan (Göttingen)2, B. Cui (Göttingen)1, N. Paul (Göttingen)2, M. Elkenani (Göttingen)3, B. E. Beuthner (Göttingen)3, B. A. Mohamed (Göttingen)3, M. Schnelle (Göttingen)4, M. Puls (Göttingen)3, K. Toischer (Göttingen)3, G. Hasenfuß (Göttingen)3

1Universitätsmedizin Göttingen Cardiology, DZHK building Göttingen, Deutschland; 2Universitätsmedizin Göttingen Göttingen, Deutschland; 3Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; 4Universitätsmedizin Göttingen Institut für klinische Chemie Göttingen, Deutschland


Background: Paradoxical low-flow low-gradient (PLFLG) aortic stenosis (AS) is associated with poor prognosis and higher morbidity and mortality than normal ejection fraction high gradient (NEFHG) aortic stenosis. The molecular mechanistic differences between cardiomyocyte (CM) populations in PLFLG and NEFHG are not well understood.

Methods and Results: We performed single nuclei RNA sequencing on human heart biopsy tissue from PLFLG (n=4) and NEFHG (n=4) patients undergoing transcatheter aortic valve implantation (TAVI) procedure. Unsupervised clustering of 47,580 nuclei led to the identification of ten major cell types. Further clustering analysis on the CM population identified seven CM subtypes (Cm1 to Cm7). Cm1, Cm2, and Cm7 were almost exclusively represented in PLFLG, while Cm3 and Cm5 were mainly restricted to NEFHG.  Bulk RNA-seq  performed in biopsies from 63 AS patients, deconvolution analysis confirmed a higher percentage of Cm2 in PLFLG AS samples (22/24) compared to NEFHG AS samples (9/39), moreover Cm7 was present in PLFLG AS samples (7/24)  but absent in NEFHG AS samples. In the total CM population, adrenergic signaling was among the top enriched terms differentially expressed genes of PLFLG as compared with NEFHG. Expression of adrenergic receptor genes (alpha- and beta-receptors) showed a tendency to increase in PLFLG CM. The gene expression of all adrenergic signaling-related genes identified in the CM population were significantly changed in PLFLG versus NEFHG. RAPGEF4 (Rap guanine nucleotide exchange factor 4, regulated by cAMP) was expressed highest in PLFLG-specific CM2 and CM7. Transcription factor analysis identified STAT3 to predict 55/263 genes up-regulated in PLFLG, and STAT3 as well as its receptor JAK1 were up-regulated in PLFLG-specific CM1. Furthermore, STAT3 pathway receptors IL20RA and CNTFR were up-regulated in PLFLG-specific CM2 and CM7 respectively.

Conclusions: Our results provide insights into the transcriptional diversity of CM between NEFHG and PLFLG aortic stenosis, suggesting that the CM subclusters in PLFLG differ significantly from NEFHG. Specifically, these subclusters combine both adrenergic and STAT3 signaling, potentially contributing to the development of PLFLG pathology. Further, increased activity of these pathways within PLFLG-specific CM subclusters may offer new treatment strategies to adjuvant valve replacement.

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