Cardiac chamber-specific genetic alterations suggest candidate genes and pathways implicating the left ventricle in the pathogenesis of atrial fibrillation

It is believed that the atria play a predominant role in the initiation and maintenance of atrial fibrillation (AF), while the role of left ventricular dysfunction in the pathophysiology remains enigmatic. We sought to dissect chamber specificity of AF-associated transcriptional changes using RNA-sequencing. We performed intra- and inter-chamber differential expression analyses comparing AF against sinus rhythm to identify genes specifically dysregulated in human left atria, right atria, and left ventricle (LV), and integrated known AF genetic associations with expression quantitative trait loci datasets to inform the potential for disease causal contributions within each chamber. Inter-chamber patterns changed drastically. Vast AF-associated transcriptional changes specific to LV, enriched for biological pathway terms implicating mitochondrial function, developmental processes and immunity, were supported at the genetic level, but no major enrichments for candidate genes specific to the atria were found. Our observations suggest an active role of the LV in the pathogenesis of AF. •We performed chamber-specific transcriptional analyses in AF (and SR) hearts.•Inter-chamber differences were more prominent than within-chamber AF effects.•AF-associated transcriptional changes were more prominent in the LV.•AF-associated LV-specific differences largely showed an underlying genetic basis.•We discovered chamber-specific lncRNAs associated with AF.