Atrioventricular node dysfunction in pressure overload-induced heart failure-Involvement of the immune system and transcriptomic remodelling

Heart failure is associated with atrioventricular (AV) node dysfunction, and AV node dysfunction in the setting of heart failure is associated with an increased risk of mortality and heart failure hospitalisation. This study aims to understand the causes of AV node dysfunction in heart failure by studying changes in the whole nodal transcriptome. The mouse transverse aortic constriction model of pressure overload-induced heart failure was studied; functional changes were assessed using electrocardiography and echocardiography and the transcriptome of the AV node was quantified using RNAseq. Heart failure was associated with a significant increase in the PR interval, indicating a slowing of AV node conduction and AV node dysfunction, and significant changes in 3,077 transcripts (5.6% of the transcriptome). Many systems were affected: transcripts supporting AV node conduction were downregulated and there were changes in transcripts identified by GWAS as determinants of the PR interval. In addition, there was evidence of remodelling of the sarcomere, a shift from fatty acid to glucose metabolism, remodelling of the extracellular matrix, and remodelling of the transcription and translation machinery. There was evidence of the causes of this widespread remodelling of the AV node: evidence of dysregulation of multiple intracellular signalling pathways, dysregulation of 109 protein kinases and 148 transcription factors, and an immune response with a proliferation of neutrophils, monocytes, macrophages and B lymphocytes and a dysregulation of 40 cytokines. In conclusion, inflammation and a widespread transcriptional remodelling of the AV node underlies AV node dysfunction in heart failure.

Automated summary

Heart failure is associated with AV node dysfunction, and AV node dysfunction in heart failure is linked to increased mortality and hospitalization risk. This study investigated the causes of AV node dysfunction in heart failure by examining changes in the entire nodal transcriptome. The findings revealed that heart failure leads to AV node conduction slowing and dysfunction, as well as significant alterations in 3,077 transcripts (5.6% of the transcriptome). Various systems were affected, including downregulation of transcripts supporting AV node conduction and changes in transcripts related to the PR interval. Additionally, there was evidence of sarcomere remodeling, a shift from fatty acid to glucose metabolism, extracellular matrix remodeling, and dysregulation of transcription and translation machinery. The study also identified dysregulation of multiple intracellular signaling pathways, protein kinases, transcription factors, and immune response as potential causes of AV node remodeling. In conclusion, inflammation and extensive transcriptional remodeling underlie AV node dysfunction in heart failure.