Extracellular matrix remodeling in atrial fibrosis: Mechanisms and implications in atrial fibrillation

Abstract

Atrial fibrosis has been strongly associated with the presence of heart diseases/arrhythmias, including congestive heart failure (CHF) and atrial fibrillation (AF). Inducibility of AF as a result of atrial fibrosis has been the subject of intense recent investigation, since it is the most commonly encountered arrhythmia in adults and can substantially increase the risk of premature death. Rhythm and rate control drugs as well as surgical interventions are used as therapies for AF; however, increased attention has been diverted to mineralocorticoid receptor (MR) antagonists including spironolactone as potential therapies for human AF because of their positive effects on reducing atrial fibrosis and associated AF in animal models. Spironolactone has been shown to exert positive effects in human patients with heart failure; however, the mechanisms and effects in human atrial fibrosis and AF remain undetermined. This review will discuss and highlight developments on (i) the relationship between atrial fibrosis and AF, (ii) spironolactone, as a drug targeted to atrial fibrosis and AF, as well as (iii) the distinct and common mechanisms important for regulating atrial and ventricular fibrosis, inclusive of the key extracellular matrix regulatory proteins involved.

Predictors of early and late left atrial tachycardia and left atrial flutter after catheter ablation of atrial fibrillation: Long-term follow-up

“…Contractile remodeling is evidenced by a decrease in atrial contractility which leads to dilation of the atria [38]. Structural remodeling within atria is evidenced by interstitial fibrosis and atrial dilatation [39]. This expanded the space between cardiomyocytes, likely due to the loss of cells and fibrotic replacement and expansion of the extracellular matrix, may also cause conduction delays between cardiomyocytes themselves and allow for alternate pathways of conduction [39].…”

Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

“…The reason was that fibroblasts coupling reduced the Ca 2+ concentration and caused a reduction in T a . Due to the strong correlation between fibroblast proliferation and heart failure (John et al, 2004;Assomull et al, 2006;Pellman et al, 2010), it can be expected that once the number of fibroblasts increases, a significant reduction would occur in T a .…”

“…Once the percentage of fibroblasts in the heart increases up to 10%-35%, a remodeling of the cardiac structure occurs, increasing muscle stiffness and reducing the coupling between adjacent muscle fiber bundles (Rossi, 2001;ten Tusscher and Panfilov, 2007). This process is strongly correlated with atrial and ventricular tachyarrhythmias and sudden cardiac death (John et al, 2004;Assomull et al, 2006;Pellman et al, 2010). The elastic modulus rises from (18±2) kPa in the normal heart muscle of non-infarcted animals to (55±15) kPa in significant fibroblast proliferous muscle of infarcted animals, an almost three-fold increase (Berry et al, 2006).…”

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…Evidence is growing that the extracellular space, including fibroblasts, plays an important role in cardiac disease and related electrophysiological changes for review see Pellman et al (2010); Yue et al (2011);Weber et al (2013). This is also reflected in the use of bi-domain or multi-domain models for the simulation of cardiac impulse propagation, taking extracellular conductivity and fibroblasts into account (Jack et al, 1975;Peskoff, 1979;Geselowitz and Miller, 1983;Roberts et al, 2008;Sachse et al, 2009).…”