Multi-omic approach identifies GDF15 as cardiac cell senescence marker that also differentiates permanent atrial fibrillation from paroxysmal atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affecting more than 40 million individuals globally. It causes stroke and heart failure leading to high mortality rate and life-long disability. According to the duration, clinical features, and outcomes, AF can be classified into first (newly) diagnosed AF, paroxysmal AF (PaAF), persistent AF (PsAF), and permanent AF (PnAF). All the non-PnAF types have the trend to progress into PnAF, which is associated with higher incidence of stroke, heart failure and other conditions. However, there are not effective methods to predict the progression risk as the mechanism still remains uncertain. Cellular senescence is a biological response to various stresses and may contribute to AF. This thesis investigated the discovery of blood biomarkers that could contribute to AF progression from the perspective of cellular senescence.

Human cardiac cellular senescence models were established by administrating doxorubicin and etoposide to human cardiac fibroblast (CF) and human iPSC-derived atrial cardiomyocyte (HCM). Then, multi-omic approaches including genome-wide transcriptome sequencing and proteomic profiling analysis were performed and I identified five common cardiac cellular senescence markers of GDF15, NRCAM, EDA2R, SCARB2, and TNFRSF10C. PaAF and PnAF participants were recruited and their blood samples were used to perform the cardiometabolic-specific proteomic profiling analysis, which identified 44 candidate biomarkers, and potential risk factors including advanced age, male gender, high body mass index (BMI), alcohol consumption and previous heart failure that could contribute to AF progression risk prediction. By overlapping all these results, GDF15 was obtained to be the common cardiac cellular senescence-associated biomarker. GDF15 independently or combined with the other two candidate biomarkers of NPPB and NT-proBNP, and the potential risk factors can be used to predict AF progression. GDF15 was then discovered to play a cardioprotective role from the cardiac cellular senescence stress. Further bioinformatic analysis revealed the mechanism of AF progression could be due to the deposition of ECM, which could be regulated by cardiac cellular senescence-mediated inflammation, angiotensin II-MAPK, TGF-β/Smad, and p53 signalling pathways. This thesis overall demonstrates the cardiac cellular senescence-associated biomarker GDF15 could contribute to the AF progression risk prediction. The multi-omic results also provide data atlases to the cardiovascular disease and senescence fields that can be utilized for further scientific research.

Date of Award	Oct 2023
Original language	English
Sponsors	Western Health & Social Care Trust, Part-financed by a grant awarded to Prof A. J. Bjourson (University of Ulster) under the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland & the Northern Ireland Public Health Agency (HSC R&D). & Public Health Agency NI (Research & Development Division)
Supervisor	Tony Bjourson (Supervisor), Taranjit Singh Rai (Supervisor), Victoria McGilligan (Supervisor), Shu-Dong Zhang (Supervisor) & Aaron Peace (Supervisor)