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Atrial fibrillation in the presence or absence of heart failure is associated with differential expression of genes involved in inflammation, hypertrophy, cardiomyocyte structure and fibrosis

Session Poster session 1

Speaker Mr Stef Zeemering

Event : EHRA 2019

  • Topic : basic science
  • Sub-topic : Arrhythmias
  • Session type : Poster Session

Authors : S Zeemering (Maastricht,NL), A Isaacs (Maastricht,NL), J Winters (Maastricht,NL), B Casadei (Oxford,GB), C Dimopoulou (Sophia-Antipolis,FR), L Fabritz (Birmingham,GB), E Guasch (Barcelona,ES), D Haase (Munster,DE), S Hatem (Paris,FR), S Kaab (Munich,DE), P Kirchhof (Birmingham,GB), L Mont (Barcelona,ES), MF Sinner (Munich,DE), M Stoll (Maastricht,NL), U Schotten (Maastricht,NL)

Authors:
S Zeemering1 , A Isaacs1 , J Winters1 , B Casadei2 , C Dimopoulou3 , L Fabritz4 , E Guasch5 , D Haase6 , S Hatem7 , S Kaab8 , P Kirchhof4 , L Mont5 , MF Sinner8 , M Stoll1 , U Schotten1 , 1Cardiovascular Research Institute Maastricht (CARIM), Physiology - Maastricht - Netherlands , 2University of Oxford, Radcliffe Department of Medicine, Division of Cardiovascular Medicine - Oxford - United Kingdom , 3European Society of Cardiology - Sophia-Antipolis - France , 4University of Birmingham, Institute of Cardiovascular Sciences - Birmingham - United Kingdom , 5Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic - Barcelona - Spain , 6Atrial Fibrillation NETwork (AFNET) - Munster - Germany , 7University Pierre & Marie Curie Paris VI - Paris - France , 8Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University - Munich - Germany ,

On behalf: the CATCH-ME consortium

Topic(s):
Basic Science - Cardiac Diseases: Arrhythmias

Background: Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF) and the effect of its common comorbidity, heart failure (HF). 

Purpose: We investigated differentially expressed (DE) genes between atrial tissue samples from well-characterized patients with and without AF.

Methods: Left and/or right atrial appendage tissue samples were collected from 227 patients during cardiac surgery from 5 centers participating in the CATCH-ME consortium. Samples were sequenced using next generation RNA sequencing and analyzed according to AF history: no history of AF (noAF; n=100), paroxysmal AF (PAF; n=64) and persistent AF (persAF; n=63). All analyses were performed adjusting for age, gender and atrial side. Genes were DE if they reached transcriptome-wide significance (false discovery rate < 0.05). 

Results: Patients with PAF or persAF differed significantly from noAF patients in age (noAF/PAF/persAF: 61±12 years/67±10/66±12, p<0.001) and gender (81% male/61%/67%, p<0.02), but were otherwise comparable (diabetes, hypertension, type of surgery). AF history was associated with 1338 DE genes, predominantly driven by expression differences between noAF and persAF patients. Principal component analysis of clinical characteristics revealed that HF patients (n=93) formed a clinically distinct subset (younger, less hypertension, different type of surgery) that was associated with a large number of DE genes (5475). Comparing persAF with noAF, stratified by HF status, 210 DE genes were identified in patients without HF and 302 DE genes in patients with HF. Out of these genes 54 were DE in both groups with a concordant direction of effect, consisting mostly of novel gene associations, antisense and non-coding RNAs. While many of these genes have no apparent link with cardiac rhythm, others show involvement in known pathways linking AF to inflammation, cardiac hypertrophy, fibrosis and conduction disturbance. There was little evidence for an additional effect of the combination of AF and HF on gene expression. Gene set enrichment analysis, a method that also takes non-significant expression differences into account, did however demonstrate marked differences between AF patients with and without HF for gene ontology terms relating to inflammatory responses, regulation of responses to external stimuli and cell adhesion, which were down-regulated in AF patients without HF and up-regulated in those with HF.

Conclusions: Analysis of gene expression profiles of atrial tissue samples using RNA sequencing identified several novel genes associated with persistent AF. Gene expression changes associated with AF were mostly similar in patients with and without heart failure. However, gene set enrichment analysis suggests more subtle genome-wide differences in functional enrichment.

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