**1. Introduction**

[89] Kuwabara, M, Niwa, K, & Niinuma, H. Hyperuricemia is an independent risk factor of atrial fibrillation due to electrical remodeling through activation of uric acid

[90] Sakabe, M, Fujiki, A, Sakamoto, T, Nakatani, Y, Mizumaki, K, & Inoue, H. Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction. *J Cardiovasc Electrophysiol* (2012). Apr 16. [Epub ahead of

transporter. *J. Am. Coll. Cardiol* (2012). Suppl.A, A163.

print].

44 Atrial Fibrillation - Mechanisms and Treatment

#### **1.1. Review of the relationship between n-3 polyunsaturated fatty acids and the atrial fibrillation**

It is well established that the consumption of fish is associated with lower rates of cardiovas‐ cular death (Albert CM,et al.,2002; Hu FB, et al.,2002). Dietary fish oil supplementation has been shown to reduce mortality in high-risk groups through a reduction in sudden cardiac death and ventricular tachyarrhythmia. It has been recently reported that atrial fibrillation (AF) is associated with inflammation and inflammatory cytokines, and n-3 polyunsaturated fatty acids (PUFAs) might be of anti-inflammatory effects. Whether PUFAs has some antiar‐ rhythmic effect and can be used in the treatment of AF is still unknown.

#### **1.2. Dietary n-3 PUFA supplementation attenuates the inducibility and maintenance of AF**

We established canine sterile pericarditis model and evaluate the anti-inflammatory effect of PUFAs on AF(Zhong Zhang,et al.,2010). Twenty mongrel sex-matched adult dogs were ran‐ domly divided into two groups. In the n-3 PUFA group (n=10), oral administration ofeicosa‐ pentaenoic+docosahexaenoic acid (EPA+DHA), 2 g/day (Omacor, Solvay Pharmaceuticals GmbH, Hanover, Germany) was started 4 weeks before the baseline study, and was contin‐ ued until the end of the study. The dogs in the control group (n=10) did not receive n-3 PU‐ FAs or plant oil for 4 weeks. We examined the plasma concentration of the CRP, IL-6, and

TNF-α before the operation and on the second postoperative day in both groups. There were no significant differences in three biomarkers of inflammation between two groups before the operation, and these biomarkers were significantly increased in both groups on the sec‐ ond postoperative day. However, three proinflammatory cytokines were significantly lower in the PUFA group than in the control group respectively (CRP, 7.6±0.5 vs. 11.7± 1.3 mg/dl, Pb0.0001 Fig. 1; IL-6, 112.0±37.3 vs. 142.0±19.6 pg/ml, Pb0.0001 Fig. 2; TNF-α, 83.3±8.5 vs. 112.4±8.2 pg/ml, Pb0.0001 Fig. 3).

**Figure 2.** Comparison of IL-6 levels between the control and PUFA groups before and after operation. Before opera‐ tion, there were no significant differences in IL-6 levels between two groups. On the second postoperative day, IL-6 was significantly increased in both groups; however, it was significantly lower in the PUFA group than in the control.

Effect of CD3+ T-Lymphocyte and n-3 Polyunsaturated Fatty Acids on the Diagnosis or Treatment of Atrial Fibrillation

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**Figure 3.** Comparison of TNF-α levels between the control and PUFA groups before and after operation. Before the operation, there were no significant differences in TNF- α levels between two groups. On the second postoperative day, TNF- α was significantly increased in both groups; however, it was significantly lower in PUFA group than in the

control.

**Figure 1.** Comparison of CRP levels between the control and PUFA groups before and after operation. Before the op‐ eration, there were no significant differences in CRP levels between two groups. On the second postoperative day, CRP was significantly increased in both groups; however, it was significantly lower in the PUFA group than in the con‐ trol.

The main finding of this study is that EPA and DHA supplementation of the diet can de‐ crease plasma concentration of the CRP, IL-6 and TNF-α in acute inflammation of canine sterile pericarditis, suggesting depression of inflammatory cytokines by n-3 FUFAs may in‐ volve in the anti-atrial fibrillation process. The results also showed that the PUFA group had a less AF inducibility and maintenance than the control group (Table1).

Thus we may reasonably conclude that Dietary n-3 PUFA supplementation attenuates the inducibility and maintenance of AF in the sterile pericarditis model by reducing the produc‐ tion of proinflammatory cytokines.

Effect of CD3+ T-Lymphocyte and n-3 Polyunsaturated Fatty Acids on the Diagnosis or Treatment of Atrial Fibrillation http://dx.doi.org/10.5772/54167 47

TNF-α before the operation and on the second postoperative day in both groups. There were no significant differences in three biomarkers of inflammation between two groups before the operation, and these biomarkers were significantly increased in both groups on the sec‐ ond postoperative day. However, three proinflammatory cytokines were significantly lower in the PUFA group than in the control group respectively (CRP, 7.6±0.5 vs. 11.7± 1.3 mg/dl, Pb0.0001 Fig. 1; IL-6, 112.0±37.3 vs. 142.0±19.6 pg/ml, Pb0.0001 Fig. 2; TNF-α, 83.3±8.5 vs.

**Figure 1.** Comparison of CRP levels between the control and PUFA groups before and after operation. Before the op‐ eration, there were no significant differences in CRP levels between two groups. On the second postoperative day, CRP was significantly increased in both groups; however, it was significantly lower in the PUFA group than in the con‐

The main finding of this study is that EPA and DHA supplementation of the diet can de‐ crease plasma concentration of the CRP, IL-6 and TNF-α in acute inflammation of canine sterile pericarditis, suggesting depression of inflammatory cytokines by n-3 FUFAs may in‐ volve in the anti-atrial fibrillation process. The results also showed that the PUFA group had

Thus we may reasonably conclude that Dietary n-3 PUFA supplementation attenuates the inducibility and maintenance of AF in the sterile pericarditis model by reducing the produc‐

a less AF inducibility and maintenance than the control group (Table1).

tion of proinflammatory cytokines.

112.4±8.2 pg/ml, Pb0.0001 Fig. 3).

46 Atrial Fibrillation - Mechanisms and Treatment

trol.

**Figure 2.** Comparison of IL-6 levels between the control and PUFA groups before and after operation. Before opera‐ tion, there were no significant differences in IL-6 levels between two groups. On the second postoperative day, IL-6 was significantly increased in both groups; however, it was significantly lower in the PUFA group than in the control.

**Figure 3.** Comparison of TNF-α levels between the control and PUFA groups before and after operation. Before the operation, there were no significant differences in TNF- α levels between two groups. On the second postoperative day, TNF- α was significantly increased in both groups; however, it was significantly lower in PUFA group than in the control.


Other studies correlated leukocytosis to an increased incidence in AF in postoperative cardi‐ ovascular patients [16,17](Abdelhadi RH,et al.,2004;Lamm G,et al.,2006), and found that a more pronounced increase in postoperative WBC count will independently predict develop‐ ment of postoperative AF. Moreover, atrial inflammation of cardiac surgery effects on the electrical properties of atrial tissue, and the degree of atrial inflammation was associated with a proportional increase in the inhomogeneity of atrial conduction and AF duration [18] ( Ishii Y, et al.,2005). Administration of anti-inflammatory drugs (dexamethasone or corti‐ sone) significantly decreases the incidence of AF after cardiac surgery [19,20](Yred JP,et al.,

Effect of CD3+ T-Lymphocyte and n-3 Polyunsaturated Fatty Acids on the Diagnosis or Treatment of Atrial Fibrillation

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hypothesis. The canine sterile pericarditis model can perfectly simulate inflammatory cir‐ cumstances of the post cardiac operation, by which AF can be induced and also peaks on the 2nd postoperative day [10](Page PL,et al.,1986). In this model, the multiple unstable reen‐ trant circuits were showed during AF, and it was critical for maintaining AF [10] (Page PL,et al.,1986). According to the multiple-wavelet hypothesis, atrial wavelength determines the number of wavelets, and the atrial wavelength is the product of AERP and the intra-atrial conduction velocity. So, the AERP and the intra-atrial conduction velocity have been thought to be important for the perpetuation of AF. In this canine sterile pericarditis model, we have evaluated CRP, IL-6 and TNF-α level on the baseline and on the 2nd postoperative day, and found that they all significantly increased in both groups. We simultaneously eval‐ uated the role of inflammation on atrial electrophysiological properties, and found that in‐ flammation can shorten AERPs and prolong intra-atrial CT in the canine sterile pericarditis model, which increased the inducibility and stability of AF. Our results are concordant with the previous results. Thus, in this model, elevated CRP, IL-6 and TNF-α were associated with sustained AF, suggesting that electrophysiological changes resulting from inflamma‐

**1.4. Other potential mechanisms of antiarrhythmic action of n-3 PUFA administration**

The current hypotheses of n-3 PUFAs in preventing AF are based on their inhibiting ca‐ pacity of some ion channels. Previous studies have demonstrated that n-3 PUFAs have capacity to inhibit fast, voltage dependent sodium currents, L-type calcium currents, the Na /Ca2 exchanger, which might prevent delayed after-depolarizations and triggered ac‐ tivity, as well as their class III antiarrhythmic-like effect on Kv1.5 channel (IKUR current present in the atrium) [36,37](Xial YF,et al.,2004;Honore E,et al.,1994). Other studies found n-3 PUFAs can attenuate atrial structural remodeling not only by activating matrix metalloproteinase-9 mRNA expression and attenuating of collagen turnover [38](Laurent G,et al.,2008), but also by modulating of atrial gap junction protein CX40 and CX43 [39] (Sarrazin JF,et al.,2007). Otherwise, evidence suggests that n-3 fatty acids consumption at‐ tenuates oxidative stress in humans, and the underlying mechanisms may lead to sup‐ pressed production of reactive oxygen species by leukocytes, inhibition of the prooxidant enzyme phospholipase A2, and induction of antioxidant enzymes [40](Mori

2000;Halonen J,et al.,2007), which supports this inflammation-AF

tion perpetuate AF.

TA,et al.,2003).

CT=conduction time; RAA=right atrial appendage; LRA=low lateral right atrium; HRA=high lateral right atrium; ARA= anterior right atrium.

†p<0.05 compared with before the operation
