Age-related atrial fibrosis

Abstract

Many age-related diseases are associated with, and may be promoted by, cardiac fibrosis. Transforming growth factor (TGF)-beta, hypoxia-induced factor (HIF), and the matrix metalloproteinase (MMP) system have been implicated in fibrogenesis. Thus, we investigated whether age is related to these systems and to atrial fibrosis. Right atrial appendages (RAA) obtained during heart surgery (n = 115) were grouped according to patients' age (<50 years, 51-60 years, 61-70 years, or >70 years). Echocardiographic ejection fractions (EF) and fibrosis using Sirius-red-stained histological sections were determined. TGF-beta was determined by quantitative RT-PCR and hypoxia-related factors [HIF1 alpha, the vascular endothelial growth factor (VEGF)-receptor, CD34 (a surrogate marker for microvessel density), the factor inhibiting HIF (FIH), and prolyl hydroxylase 3 (PHD 3)] were detected by immunostaining. MMP-2 and -9 activity were determined zymographically, and mRNA levels of their common tissue inhibitor TIMP-1 were determined by RT-PCR. Younger patients (<50 years) had significantly less fibrosis (10.1% +/- 4.4% vs 16.6% +/- 8.3%) than older individuals (>70 years). While HIF1 alpha, FIH, the VEGF-receptor, and CD34 were significantly elevated in the young, TGF-beta and PHD3 were suppressed in these patients. MMP-2 and -9 activity was found to be higher while TIMP-1 levels were lower in older patients. Statistical analysis proved age to be the only factor influencing fibrogenesis. With increasing age, RAAs develop significantly more fibrosis. An increase of fibrotic and decrease of hypoxic signalling and microvessel density, coupled with differential expression of MMPs and TIMP-1 favouring fibrosis may have helped promote atrial fibrogenesis.

Relationship Between Connexin Expression and Gap–Junction Resistivity in Human Atrial Myocardium

“…Animal studies have confirmed that atrial fibrosis with advancing age is associated with conduction slowing and arrhythmogenesis, 35,36 and human studies have demonstrated a correlation between levels of atrial fibrosis and advancing age. 37,38 By contrast, and in keeping with the present study, other studies have refuted an association between atrial fibrosis and advancing age, 39 and these findings also accord with our previous finding that human atrial CV did not directly correlate with atrial connective tissue content. 9 Among the conflicting studies correlating human atrial connective tissue, the techniques for connective tissue quantification and the age ranges of the subjects varied, but it also remains possible that in the relationship with conduction velocities what is important is not connective tissue quantification, per se, but the extent to which it causes changes in GJ coupling by altering the topology of connectivity of the myocytes.…”

“…Animal studies have confirmed that atrial fibrosis with advancing age is associated with conduction slowing and arrhythmogenesis, 35,36 and human studies have demonstrated a correlation between levels of atrial fibrosis and advancing age. 37,38 By contrast, and in keeping with the present study, other studies have refuted an association between atrial fibrosis and advancing age, 39 and these findings also accord with our previous finding that human atrial CV did not directly correlate with atrial connective tissue content. …”

Atrial fibrosis and atrial fibrillation: The role of the TGF-β1 signaling pathway

“…Atrial fibrosis is thought to promote these changes. Previously, we found atrial fibrosis to increase with the duration of AF [5] and to be associated with increasing age [6]. Once atrial fibrosis is established, it is only partly reversible and therefore contributes to sustain AF7 [7].…”

Hypoxia and Myocardial Remodeling in Human Cardiac Allografts: A Time-course Study

“…22 Hypertension is a possible stimulus for myocardial fibrosis. 23 TGF-␤ is an established pro-fibrotic cytokine in cardiac fibrosis [23][24][25] and is closely related to the reninangiotensin system. 26,27 Inhibition of the renin-angiotensin system (and, thus, indirectly TGF-␤) has been shown to prevent CsA-induced fibrosis.…”