Molecular Signatures of Human Chronic Atrial Fibrillation in Primary Mitral Regurgitation

Abstract

Objectives: Transcriptomics of atrial fibrillation (AFib) in the setting of chronic primary mitral regurgitation (MR) remains to be characterized. We aimed to compare the gene expression profiles of patients with degenerative MR in AFib and sinus rhythm (SR) for a clearer picture of AFib pathophysiology.

Methods: After transcriptomic analysis and bioinformatics (n = 59), differentially expressed genes were defined using 1.5-fold change as the threshold. Additionally, independent datasets from GEO were included as meta-analyses.

Results: QRT-PCR analysis confirmed that AFib persistence was associated with increased expression molecular changes underlying a transition to heart failure (NPPB, P = 0.002; ANGPTL2, P = 0.002; IGFBP2, P = 0.010), structural remodeling including changes in the extracellular matrix and cellular stress response (COLQ, P = 0.003; COMP, P = 0.028; DHRS9, P = 0.038; CHGB, P = 0.038), and cellular stress response (DNAJA4, P = 0.038). Furthermore, AFib persistence was associated with decreased expression of the targets of structural remodeling (BMP7, P = 0.021) and electrical remodeling (CACNB2, P = 0.035; MCOLN3, P = 0.035) in both left and right atrial samples. The transmission electron microscopic analysis confirmed ultrastructural atrial remodeling and autophagy in human AFib atrial samples.

Conclusions: Atrial cardiomyocyte remodeling in persistent AFib is closely linked to alterations in gene expression profiles compared to SR in patients with primary MR. Study findings may lead to novel therapeutic targets. This trial is registered with ClinicalTrials.gov identifier: NCT00970034.

Conflict of interest statement

The authors declare no competing interests.

Copyright © 2021 Günseli Çubukçuoğlu Deniz et al.

Figures

Figure 1

Flow diagram of experimental design.

Figure 2

Overview of study steps and schematic representation of the study findings.

Figure 3

Hierarchical cluster analysis of gene expression microarrays of right and left atrial biopsies from AFib patients with primary mitral regurgitation compared to controls (S.R.). Heatmap shows the clusters how 178 differentially expressed genes separate all samples using 1.5-fold change as the threshold. Consequential 178 differentially expressed genes outcome from comparing gene expression profiles between AFib vs. S.R. of all atria tissues and separate AFib samples from S.R. samples with 85% success. Columns represent samples, and rows represent differentially expressed genes. As can be seen on the color bar, red indicates increased gene expression, and green indicates decreased gene expression. Heat and intensity of red or green color appear according to the fold-change.

Figure 4

Electron micrograph of human atrial tissues. (a) Normal nucleus, typical striated myofilaments, and scattered mitochondria in a longitudinal section of the SR atrial sample. Scale bar: 2500 nm. (b) Lipofuscin accumulation, striated myofibrils, and mitochondria in the longitudinal section of the AFib atrial sample. Scale bar: 1000 nm. (c) Cross-section of the cardiac cell of SR atrial sample mitochondria and myofilaments is arranged around the nucleus. Scale bar: 2500 nm. (d) At the same magnification of the cardiac cell of AFib atrial sample in cross-section, shrinkage of the cell. Scale bar: 2500 nm. (e) Large vacuoles, myofilaments, and mitochondria clusters in condensed cytoplasm in AFib atrial sample. Scale bar: 1000 nm. (f) Lipofuscin accumulations gathered mitochondria and myofilaments in shrinkage cells in AFib atrial sample. Scale bar: 1000 nm. N: nucleus; nc: nucleolus; V: vacuole; lp: lipofuscin accumulations; m: mitochondria; mf: myofilaments.

Figure 5

Differentially expressed genes in LAA tissues of AFib vs. SR (fold change > 1.5; P < 0.05) and ultrastructural changes. As can be seen on the color bar, red indicates increased gene expression, and green indicates decreased gene expression.