42Age-related deterioration of cardiac cell-to-cell coupling likely contributes to development of atrial fibrillation in old guinea pig

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Rationale and Purpose: Mechanisms underlying atrial fibrillation (AF) the most common cardiac arrhythmia in aged population are not fully elucidated. We have previously shown that unlike to young the aged guinea pig heart is much prone to develop AF upon repetitive burst stimulation. We hypothesize that in addition to atrial structural remodeling the alterations in cardiac cell-to-cell coupling due to the ageing may facilitate induction and persistence of AF.

Methods: Experiments were conducted on male and female 4-weeks-old and 24-weeks-old guinea pigs (GP). Heart atrial tissue was processed for ultrastructure examination using electron microscopy. Gap junction connexin-43 distribution was detected by in situ immunostaining while the level of Cx43 mRNA and expression of Cx43 protein were determined by real time PCR and western blotting. Expression of mRNA of extracellular matrix metalloproteinase-2 (MMP2) that is involved in myocardial remodeling was also analyzed.

Results: Subcellular examination revealed interstitial fibrosis, flattened adhesive junctions with widened extracellular spaces and lower number of gap junctions in old versus young GP heart atria. Cellular distribution of Cx43-positive gap junctions was not uniform and their density of was lower in atria of old comparing to young GPs. In parallel, the atrial tissue levels of Cx43 mRNA and Cx43 protein were decreased in old versus young GP. In contrast, mRNA expression of MMP2 was significantly higher in old versus young GP. The changes were more pronounced in old males comparing to females GP.

Conclusions: Findings indicate that age-related down-regulation of atrial Cx43, dehiscence of adhesive junctions and up-regulation of MMP-2 can facilitate development of AF in old heart.

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