A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

Abstract

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress

“…CFs are also the predominant source of matrix metalloproteinases (MMPs), which are calcium-dependent zinc-containing endopeptidases responsible for matrix protein degradation. MMPs are involved in collagen deposition and pro-fibrotic signaling and are important for cardiovascular diseases [ 39 ]. MMPs are tightly regulated by an endogenous group of inhibitors known as tissue inhibitors of metalloproteinases (TIMPs) [ 40 ].…”

The Diagnostic and Therapeutic Potential of Galectin-3 in Cardiovascular Diseases

“…Particularly, atrial interstitial fibrosis seems to be the key factor contributing to AF development [45]. It is known that left atrial (LA) interstitial fibrosis plays a significant role in initiating and maintaining atrial fibrillation [45,46]. Galectin-3 enhances cardiac fibrosis and remodelling and is a well-documented cause of arrhythmia.…”

Circulating Concentrations of Nutrition-Related Factors Are Not Causally Associated With Atrial Fibrillation: A Mendelian Randomization Study

“…They enhance AF substrate formation and contribute to contractile dysfunction, atrial electrical, and structural remodeling in AF. 29 Clinical studies indicated that some nutrition-related factors were implicated in AF-related inflammation and oxidative stress. Group B vitamins, including vitamin B12, were shown to be linked with circulating levels of C-reactive protein, homocysteine (Hcy), and matrix metalloproteinases, which are important contributors to the development of AF.…”