Atrial fibrillation (AF) is a common and serious arrhythmia. Current treatments are of limited efficacy, and most do not treat the atrial structural remodeling (hypertrophy and fibrosis) that underlies most clinical AF. Our group has created an experimental dog model of atrial mechanical stretch called the simultaneous atrial and ventricular pacing (SAVP) model (which results in atrial fibrosis and susceptibility to AF) in order to study novel treatments for structural remodeling induced AF. Omega-3 polyunsaturated fatty acids (n3 PUFAs), particularly the marine derived forms eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to be effective in treating arrhythmias (including AF) in some animal studies and clinical trials. The mechanism for this effect of n3 PUFAs is not well understood. In this study we sought to characterize the n3 PUFA effect on AF vulnerability, atrial electrophysiology, histology, and gene expression, and determine relevant mechanisms.
Dogs were paced for 0, 2, 7 or 14 days and given n3 PUFAs, olive oil or nothing. Prophylactic n3 PUFAs significantly reduced both AF vulnerability and conduction slowing in SAVP dogs (%AF inducibility: 9.2±8.8 vs. 4.7±6.3; global atrial conduction time: 75±11ms vs. 65±6ms [SAVP 14 days vs. SAVP 14 days with n3 PUFAs, P<0.05 for both comparisons]). Prophylactic n3 PUFAs also reduced inflammation (mean CD18 grade: 2.1±0.8 vs. 1.3±0.6 [SAVP 2 days vs. SAVP 2 days with n3 PUFAs, P=0.055]), hypertrophy (myocyte cross-sectional area: 498±64µm2 vs. 322±111µm2 [SAVP 14 days vs. SAVP 14 days with n3 PUFAs, P<0.05]), and fibrosis (%collagen area vs. unpaced dogs: 178±58 vs. 127±37 [SAVP 14 days vs. SAVP 14 days with n3 PUFAs, P<0.05]). N3 PUFAs were also found to reduce the expression of structural remodeling related molecules such as TGF-β, EGF, ERK and Akt. N3 PUFAs given after some pacing had already occurred were found to be less effective at reducing AF vulnerability and structural remodeling.
The results of this study suggest that, in the SAVP model, n3 PUFAs reduce vulnerability to AF by attenuation of adverse structural remodeling at the genetic level.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/26318 |
| Date | 22 February 2011 |
| Creators | Ramadeen, Andrew |
| Contributors | Dorian, Paul |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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