Atrial Tissue Pro-Fibrotic M2 Macrophage Marker CD163+, Gene Expression of Procollagen and B-Type Natriuretic Peptide

Chris J Watson, Nadezhda Glezeva, Stephen Horgan, Joe Gallagher, Dermot Phelan, Ken McDonald, Michael Tolan, John Baugh, Patrick Collier, Mark Ledwidge, Chris J Watson, Nadezhda Glezeva, Stephen Horgan, Joe Gallagher, Dermot Phelan, Ken McDonald, Michael Tolan, John Baugh, Patrick Collier, Mark Ledwidge

Abstract

Background Atrial tissue fibrosis is linked to inflammatory cells, yet is incompletely understood. A growing body of literature associates peripheral blood levels of the antifibrotic hormone BNP (B-type natriuretic peptide) with atrial fibrillation (AF). We investigated the relationship between pro-fibrotic tissue M2 macrophage marker Cluster of Differentiation (CD)163+, atrial procollagen expression, and BNP gene expression in patients with and without AF. Methods and Results In a cross-sectional study design, right atrial tissue was procured from 37 consecutive, consenting, stable patients without heart failure or left ventricular systolic dysfunction, of whom 10 had AF and 27 were non-AF controls. Samples were analyzed for BNP and fibro-inflammatory gene expression, as well as fibrosis and CD163+. Primary analyses showed strong correlations (all P<0.008) between M2 macrophage CD163+ staining, procollagen gene expression, and myocardial BNP gene expression across the entire cohort. In secondary analyses without multiplicity adjustments, AF patients had greater left atrial volume index, more valve disease, higher serum BNP, and altered collagen turnover markers versus controls (all P<0.05). AF patients also showed higher atrial tissue M2 macrophage CD163+, collagen volume fraction, gene expression of procollagen 1 and 3, as well as reduced expression of the BNP clearance receptor NPRC (all P<0.05). Atrial procollagen 3 gene expression was correlated with fibrosis and BNP gene expression was correlated with serum BNP. Conclusions Elevated atrial tissue pro-fibrotic M2 macrophage CD163+ is associated with increased myocardial gene expression of procollagen and anti-fibrotic BNP and is higher in patients with AF. More work on modulation of BNP signaling for treatment and prevention of AF may be warranted.

Keywords: atrial fibrillation; fibrosis; gene expression; macrophage; natriuretic peptide.

Figures

Figure 1
Figure 1
Correlations between cardiac atrial tissue staining of M2‐macrophage marker CD163 and gene expression of BNP (A) and Collagen 1 (B).Furthermore, BNP gene expression in the atrial tissue correlates positively with Collagen 1 (C) and Collagen 3 (D) gene expression. BNP indicates B‐type natriuretic peptide; CD163, Cluster of differentiation 163; Col1, Collagen 1; and Col3, Collagen 3.
Figure 2
Figure 2
Cardiac atrial tissue staining for CD163 positivity (A) and collagen volume fraction (CVF, picrosirius red) (B). Also shown is typical staining of CD163‐positive macrophages (C) and collagen accumulation (D, picrosirius red) in cardiac interstitial (black arrowheads) and perivascular (red arrowheads) regions. AF indicates atrial fibrillation; CD163, cluster of differentiation 163; and CVF, collagen volume fraction.
Figure 3
Figure 3
Cardiac atrial tissue gene expression of Collagen 1 (A), Collagen 3 (B), BNP (C), GC‐A (D), and NPRC (E) with significant differences observed between AF and Controls in all except BNP and GC‐A. Higher serum BNP levels were observed in patients with AF compared with Controls (F). Serum BNP data are not normally distributed and are presented as medians (line), interquartile ranges (box) and ranges (whiskers). AF indicates atrial fibrillation; BNP, B‐type natriuretic peptide; GG‐A, Guanyl‐cyclase‐A, also known as natriuretic peptide receptor A; and NPRC, natriuretic peptide receptor C.

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