Abstract 3497: N-3 Polyunsaturated Fatty Acids Alter Gene Expression Profile and Reduce Vulnerability to Atrial Fibrillation in a Dog Model of Cardiomyopathy
Omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to AF. We hypothesized that PUFAs mediate their antiarrhythmic effect by interfering with signaling mechanisms responsible for responding to cellular injury. A genome wide approach was used to identify gene expression profiles involved in AF vulnerability, and whether PUFA therapy altered expression of these candidate genes. Thirty-six dogs were randomized into 3 groups of 12. Two groups were paced using simultaneous atrial and ventricular pacing at 220 bpm for 14 days to induce atrial enlargement, fibrosis and susceptibility to AF. One of these groups was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (PACED-PUFAs); the other received no PUFAs (PACED-CTRL). The final group was unpaced, unsupplemented and served as controls. Atrial tissue was taken for analysis at the end of the protocol. Gene expression analysis was done in 4 dogs from each group (n=12) with Affymetrix GeneChip® technology. PACED-CTRL dogs had greater AF inducibility than PACED-PUFA dogs (20.4±14.2% vs. 5.5±7.4% burst attempts leading to AF, p<0.001) and a greater collagen area fraction than PACED-PUFA dogs (17.2 ± 3.2% vs. 9.8 ± 2.7%, arbitrary units, p<0.05). PACED-CTRL dogs had significantly increased mRNA levels of pro-fibrotic, pro-inflammatory and pro-hypertrophic ERK, Akt and EGF, as well as pro-inflammatory JAM3 and CD99, pro-hypertrophic A2M, and decreased expression of anti-inflammatory TSP1, and anti-fibrotic TIMP1, Smad6 and Smad7. PACED-PUFA dogs had higher tissue PUFA levels than unsupple-mented dogs (5.27±0.6% vs. 4.38±0.6% of total lipids, p<0.01). PUFA supplementation was associated with attenuation of pacing induced changes in mRNA levels for all 10 genes listed above. The mechanism of PUFA mediated prevention of AF may be due to attenuation of the development of cardiac fibrosis, inflammation and hypertrophy.