PRECLINICAL STUDY
Reduced Incidence of Vagally Induced Atrial Fibrillation and Expression Levels of Connexins by n-3 Polyunsaturated Fatty Acids in Dogs
Jean-Francois Sarrazin, MD*,
Genevieve Comeau, MSc*,
Pascal Daleau, PhD*, ,
John Kingma, PhD*, ,
Isabelle Plante, PhD*,
Dominique Fournier, MSc* and
Franck Molin, MD*,,*
* Institut Universitaire de Cardiologie et Pneumologie, Quebec, Canada
Faculty of Pharmacy, Laval University, Quebec, Canada
Faculty of Medicine, Laval University, Quebec, Canada.
Manuscript received February 14, 2007;
revised manuscript received April 30, 2007,
accepted May 1, 2007.
* Reprint requests and correspondence: Dr. Franck Molin, Institut Universitaire de Cardiologie et Pneumologie, 2725, Chemin Sainte Foy, Quebec, G1V 4G5 Canada. (Email: franck.molin{at}med.ulaval.ca).
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Abstract
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Objectives: This open-label canine study assessed whether n-3 polyunsaturated fatty acids (PUFAs) prevent vagally induced atrial fibrillation (AF) and influence atrial tissue expression levels of connexins (CXs).
Background: n-3 polyunsaturated fatty acids in fish oils protect against sudden cardiac death and reduce postoperative AF. Changes in spatial organization of gap junctions or cellular CX levels have been linked to arrhythmogenesis.
Methods: Vagally induced AF was studied. Eight dogs were given fish oil daily for 14 days. Eight control dogs had reproducibly induced AF and were re-evaluated after intravenous administration of fish oil. Atrial fibrillation was compared, and n-3 PUFA, CX40, and CX43 protein levels were assessed in atrial biopsies.
Results: Atrial tissue n-3 PUFA levels increased in oral treatment dogs (5.78 ± 0.71% vs. 2.49 ± 0.46% in control animals, p < 0.001). No difference was observed for atrial refractory periods or hemodynamic or electrocardiographic parameters. Incidence of AF in oral treatment dogs decreased 79% with the extra stimulus technique (10.5% vs. 48.9%, p = 0.003) and 42% with burst induction (22.5% vs. 38.8%, p = 0.038). Both CX40 and CX43 levels were lower in oral treatment dogs (60% [p = 0.019] and 42% [p = 0.038] lower, respectively); protection against AF was mostly related to reduced CX40 expression levels (p = 0.02). In dogs that were given intravenous n-3 PUFAs, AF inducibility by the extra stimulus technique was reduced from 75.0% to 28.6% (p = 0.002).
Conclusions: Oral treatment with fish oils increased atrial n-3 PUFA levels and reduced vulnerability to induction of AF in this dog model. Modulation of cardiac CX by n-3 PUFAs probably contributes to the antiarrhythmic effects of fish oils.
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Abbreviations and Acronyms
| | AF = atrial fibrillation | | BCL = basic cycle length | | CX = connexin | | DHA = docosahexaenoic acid | | EPA = eicosapentaenoic acid | | ERP = effective refractory period | | HR = heart rate | | PAC = premature atrial complex | | PUFA = polyunsaturated fatty acid |
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Atrial fibrillation (AF) is a common arrhythmia encountered in clinical practice. Pharmacotherapy to restore or maintain normal sinus rhythm is successful in 50% to 70% of patients; many of the drugs used induce important side effects and increase risk of ventricular proarrhythmias (1).
Atrial fibrillation is associated with altered electrophysiological properties, mainly reduced atrial effective refractory period (ERP) and slow conduction velocity. The latter depends on cell-to-cell communications via gap junction channels (2). Connexins (CXs) 40, 43, and 45 have been detected in cardiac tissues; CX40 and CX43 are primary components of atrial gap junctions. Changes in spatial organization of gap junctions or cellular levels of cardiac CX are associated with arrhythmogenesis (2–4); however, their role in AF remains controversial. Whether n-3 polyunsaturated fatty acids (PUFAs) influence atrial CX content has not been investigated. Experimental evidence documents antiarrhythmic effects of n-3 PUFAs (5–7); however, few studies have focused on treatment with fish oils for atrial arrhythmias. Increased consumption of fish in patients either lowers risk (8), or has no effect on AF (9); n-3 PUFAs reduce postoperative AF (10) and decrease AF burden in patients with a pacemaker (11).
The present canine study was designed to demonstrate that atrial tissue n-3 PUFA levels could be enhanced with dietary fish oil supplementation thereby leading to reduction in vagally induced AF. We also examined whether treatment with n-3 PUFAs affected expression levels of atrial CX40 and CX43 that could ultimately be associated with reduced incidence of AF.
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Methods
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Experimental design.
Adult mongrel dogs (17 male dogs, 11 female dogs; 18 to 30 kg) were assigned but not randomized to either oral treatment with n-3 PUFAs or a control group. Dogs were fed Purina Pro Plan chow (Nestlé Purina PetCare Company, St. Louis, Missouri) containing 25% crude protein, 15% crude fat, 3% crude fiber, 12% moisture, 1.4% linoleic acid, 1% calcium, 0.8% phosphorus, 0.30 mg/kg selenium, and 15,000 IU/kg vitamin A and given water ad libitum. Eight dogs were given 1.2 g orally of n-3 PUFAs (320 mg eicosapentaenoic acid [EPA] and 160 mg docosahexaenoic acid [DHA] per gram, MEG-3 brand omega-3 fish oil, Ocean Nutrition Canada Ltd., Darmouth, Nova Scotia, Canada) daily for 14 consecutive days. Three dogs were fed chow for 14 days and served as time control animals. Of 17 control dogs, AF was induced by 3 consecutive premature atrial complexes (PACs) and burst pacing in 8; these dogs were re-evaluated after intravenous treatment with fish oil (1.4 g suspended in carrier solution comprising 10 g of 30% human albumin [Sigma Chemical Co., St. Louis, Missouri] and saline) infused at 1 ml/min intravenously. This group served as its own control as experiments were performed before and immediately after fish oil administration.
Baseline hemodynamic parameters including left ventricular end-diastolic pressure and ERP were recorded before and during vagal stimulation. Blood was withdrawn for determination of serum phospholipid fatty acids levels; a second sample was withdrawn from the intravenous treatment group at the end of infusion of n-3 PUFAs (analyzed by high-performance liquid chromatography, Human Nutraceutical Research Unit, University of Guelph, Guelph, Canada). At the end of the experiment but before sacrifice, a large right atrial biopsy was removed for determination of tissue n-3 PUFA and CX40 and CX43 levels.
Animal preparation.
Experimental procedures conformed to guidelines of the Canadian Council on Animal Care (volumes 1 and 2) and were approved by the Laval University Animal Care Committee. Dogs were premedicated with fentanyl (0.02 µg/kg subcutaneous) and midazolam (0.1 mg/kg intramuscular) and anesthetized with thiopental (20 mg/kg intravenous). Fentanyl (5 to 7.5 mg/kg/min intravenous) was continuously infused during the experiment; anesthesia was maintained using isofluorane (1.5% to 3.5%). An endotracheal tube was inserted; dogs were ventilated with a positive-pressure respirator (Ohmeda 7800 ventilator, DRE Medical Inc., Louisville, Kentucky), and blood gases were maintained within the physiological range. Body temperature was kept at 38°C.
A pig-tail catheter was advanced into the left ventricle via the right femoral artery to measure end-diastolic pressure; the catheter was subsequently pulled back for measurement of arterial pressures. A decapolar catheter (DCDA 15S4C4-00.5, Cordis, Miami Lakes, Florida) was wedged in the upper right atrium under fluoroscopy and used for atrial pacing and recording of bipolar atrial electrograms. Heparin (150 U/kg intravenous bolus) was given after catheters were positioned; half-dose boluses were repeated hourly thereafter. Surface electrocardiogram, aortic blood pressure, and intra-atrial electrical activity were continuously recorded using AxoScope software (Axon Instruments, Union City, California). At the end of the experiment, dogs were given an overdose of thiopental and sacrificed using euthanyl (107 mg/kg intravenous).
Vagal stimulation and measurement of electrophysiological parameters.
Vagally induced AF was initiated as previously described (12,13). After a midline cervical incision, left and right vagal nerves were dissected, isolated, and ligated cranially. Teflon-coated stainless steel electrodes (noncoated distal ends) were inserted through an 18-gauge needle into each nerve and connected to a Grass stimulator (Astro-Med Inc., West Warwick, Rhode Island) for bilateral vagal stimulation (pulse width of 0.1 ms) that was initiated at amplitude of 5 V and frequency of 10 Hz. Amplitude and/or frequency were titrated to lower heart rate (HR) to 50% baseline values immediately before vagal stimulation (12).
The decapolar catheter was connected to a Ventrix Stimulator (Model HV0200, VENTRITEX, Sunnyvale, California), and pacing and sensing threshold were determined; pacing was performed at 4 times threshold. Atrial ERP (longest coupling interval between basic drive and premature impulse that failed to induce atrial depolarization) was measured using the S1-S2 extra stimulus technique at basic cycle lengths (BCLs) of 400 ms, 300 ms, 250 ms, and 200 ms (13–15). The mean of 3 ERP values at each BCL was used in the data analysis.
AF model.
Right atrial and vagal stimulations were used to produce sustained AF (12,13,15); extra stimulus (14) and burst pacing (13) were used. For the extra stimulus technique, a short train of 8 beats at 400 ms (S1) was followed by 1 (S2), 2 (S3), or 3 (S4) consecutive PACs (Fig. 1). Premature atrial complexes commenced at 10 ms above ERP and were then decreased until AF induction or failure to capture the signal. Three attempts were made to induce AF for each PAC (S2, S3, and S4). For burst pacing, 30 consecutive beats were provoked at 100-ms cycle length; 5 attempts to induce AF were made in each dog. Data were recorded independently as either: 1) no AF; 2) nonsustained AF (episodes >1 s but <1 min (15,16); or 3) sustained AF (episodes >1 min). After positive determination of AF, vagal stimulation was stopped. If AF persisted longer than 5 min, normal sinus rhythm was restored by electrical cardioversion. Frequency of AF was calculated as the quotient of the number of successful sustained AF inductions and the total number of attempts for each technique.
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Figure 1 Induction of AF
Induction of atrial fibrillation (AF) by the extra stimulus technique. A train of paced atrial beats, followed by 2 premature atrial complexes, converted sinus rhythm into AF. ECG = electrocardiogram.
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Protein isolation and Western blotting for CX40 and CX43.
Expression levels of CX40 and CX43 and their phosphorylated isoforms were measured by Western blotting in biopsies from control dogs (n = 8) and dogs treated orally with n-3 PUFAs (n = 7) using a modified technique from our laboratory (17).
Total protein content was determined using the Bio-Rad Protein Assay (Mississauga, Canada) with bovine albumin as standard and subsequently separated with an 8% denaturing–acrylamide gel. Proteins transferred to Immobilon PVDF membranes (Millipore Corp., Mississauga, Canada) were incubated (1 h at room temperature) with rabbit polyclonal antibodies for CX40 and CX43 (epitopes CXA-5 and -1, Chemicon International, Temecula, California). Antibodies were diluted in TBS-Tween 1:200 for anti-CX40 and -CX43. Membranes were incubated with a secondary antibody (anti-rabbit, Cedarlane, Hornby, Canada) conjugated with horseradish peroxidase. An enhanced chemiluminescence detection kit (Amersham Biosciences, Baie d’Urfé, Canada) was used to reveal the antigen-antibody complex on Biomax MS Kodak films (Chalon-sur-Saône, France). Images were analyzed using a scanning densitometer (ChemiGenius XE, Canberra Packard, Montreal, Canada). The average densitometric value from control dogs (n = 8) was taken as 100%.
Assessment of atrial omega-3 and -6 levels.
Total lipid extracts were prepared from atrial biopsies by the extraction method of Bligh and Dyer (18); lipids were separated by thin-layer chromatography. Fatty acid methyl esters were prepared from the phospholipids fraction (19) and analyzed by gas-liquid chromatography with a 60-m DB-23 capillary column (0.32-mm internal diameter).
Statistical analysis.
Hemodynamic parameters, electrocardiographic measurements, and ERP are reported as mean ± standard deviation. Densitometry values are expressed as mean ± standard error of the mean. A p value <0.05 was considered statistically significant. Between-group comparisons were performed using an unpaired Student t test for the n-3 PUFA oral treatment group and a paired Student t test for the intravenous treatment group; 2-tailed tests were used for individual statistical comparisons. Frequency of sustained AF was compared using Fisher exact test.
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Results
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Baseline characteristics.
Total n-3 PUFA serum levels increased from 2.08 ± 0.41% in control animals to 9.17 ± 0.72% (p < 0.001) in the oral treatment group; proportional increases in EPA (0.49% vs. 3.01%) and DHA (0.39% vs. 3.19%) were also observed (Fig. 2). There was no change in serum levels of n-3 PUFAs in the intravenous treatment group: EPA 0.50%, DHA 0.43%, and total n-3 PUFAs 2.13%. Atrial tissue n-3 PUFA levels increased in the oral treatment group (5.78 ± 0.71% vs. 2.49 ± 0.46% in control animals, p < 0.001); omega-6 levels decreased from 48.08 ± 3.15% in control animals to 44.55 ± 1.58% (p = 0.026) in the oral treatment group. For the time control group, total n-3 PUFA serum levels were 3.37 ± 0.34% and atrial tissue levels were 2.53 ± 0.34%.
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Figure 2 Serum and Atrial Tissue n-3 PUFA Levels
Oral treatment (PO) increased total atrial tissue n-3 polyunsaturated fatty acid (PUFA) levels, and serum levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and total n-3 PUFAs (p < 0.001).
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Electrophysiological parameters.
Pacing thresholds and sensing were similar for all groups. During vagal stimulation, HR decreased 46.2% in oral treatment dogs and 45.3% in control animals (p = NS). Average vagal stimulation required to achieve these levels was 11.4 Hz at 6.1 V in the oral treatment group and 12.9 Hz at 6.1 V in the control group (p = NS).
Hemodynamic and electrocardiographic variables were similar between control and oral treatment groups at baseline and during vagal stimulation (Table 1). Vagal stimulation decreased blood pressure, prolonged PR interval, and shortened QT interval (p < 0.020 for each parameter) in both groups. With intravenous treatment, blood pressure was lower, PR interval was shorter, and QT interval was longer at baseline; QRS was larger during vagal stimulation (Table 2).
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Table 1 Hemodynamic and Electrocardiographic Parameters, and Atrial ERPs at Baseline and During Vagal Stimulation (PO Protocol)
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Table 2 Hemodynamic and Electrocardiographic Parameters, and Atrial ERPs at Baseline and During Vagal Stimulation (IV Protocol)
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Vagal stimulation shortens atrial ERPs compared with baseline in all groups (p < 0.002), but ERPs were not affected by oral or intravenous treatment with n-3 PUFAs (Tables 1 and 2).
AF induction.
Induction of sustained AF (Fig. 3) using the extra stimulus technique had an incidence of AF after 1 PAC of 26.0% in control animals (13 of 50 attempts) and 4.2% in n-3 PUFA oral treatment dogs (1 of 24 attempts, p = 0.019). After 2 PACs, AF was induced in 38.0% of control animals (19 of 50 attempts) and 12.5% of oral treatment dogs (3 of 24 attempts, p = 0.017). After 3 PACs, AF was 48.9% in control animals (23 of 47 attempts) and 10.5% in oral treatment dogs (2 of 19 attempts, p = 0.003); these data show a 79% reduction in sustained AF after oral treatment with n-3 PUFAs. Combined data for the extra stimulus technique demonstrated a significantly lower incidence of AF in oral treatment dogs (37.4% in control animals vs. 8.9% with oral n-3 PUFAs, p < 0.001). With burst pacing, sustained AF occurred in 38.8% of control animals (26 of 67 attempts) and 22.5% of oral treatment dogs (9 of 40 attempts) (p = 0.038).
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Figure 3 Sustained AF Inducibility
Sustained atrial fibrillation (AF) was reduced from 26.0% to 4.2% with the extra stimulus technique by 1 premature atrial complex (PAC) in the oral treatment (PO) group (p = 0.019); AF decreased from 38.0% to 12.5% after 2 PACs in the PO group (p = 0.017); AF decreased from 48.9% to 10.5% after 3 PACs in the PO group (p = 0.003); and AF decreased from 38.8% to 22.5% by burst pacing technique in the PO group (p = 0.038).
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In the intravenous group, sustained AF with 1 PAC was 24.0% (6 of 25 attempts) versus 33.3% before the infusion (p = NS), 21.1% with 2 PACs (4 of 19 attempts) versus 56.0% in control animals (p = 0.017), and 28.6% with 3 PACs (6 of 21 attempts) versus 75.0% before the infusion (p = 0.002). With burst pacing, AF occurred in 42.1% of intravenous treatment dogs (16 of 38 attempts) and 45.0% before infusion of n-3 PUFAs (p = NS). In the time control animals, AF was induced in all dogs; 2 had sustained AFs, while the third had nonsustained AF.
Overall, 27 episodes of nonsustained AF (duration ±26 s) were induced in control animals; 23 episodes (duration ±21 s) were induced in oral treatment dogs (p = NS for episodes and duration); 5 episodes (duration ±11 s) were induced in intravenous treatment dogs (p = NS).
One control dog developed intractable ventricular tachycardia and was excluded from the data analysis.
Western blotting.
Connexin levels were initially analyzed according to treatment group. Atrial CX40 and CX43 levels are shown in Figure 4; in n-3 PUFA oral treatment dogs, CX40 and CX43 protein levels were 60% (p = 0.019) and 42% (p = 0.038) lower than those seen in control animals. In oral treatment dogs, expression levels of phosphorylated CX40 (P1) decreased by 63% (p = 0.024) while the phosphoisoforms of CX43 (P2 and P1) decreased by 49% (p = 0.047) and 33% (p = 0.153), respectively. Nonphosphorylated forms of CX40 and CX43 (P0) decreased by 55% (p = 0.020) and 43% (p = 0.024), respectively.
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Figure 4 Western Blots for CX in Atrial Tissues
Representative Western blots for connexin (CX)40 (A) and CX43 (B) in atrial tissues from control animals and n-3 PUFA PO dogs. All protein expression levels were tested in duplicate. (C and D) Mean ± standard error of the mean for CX40 and CX43 (n = 8 for control animals and n = 7 for n-3 PUFA PO dogs). *p < 0.05. Abbreviations as in Figure 2.
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The CX levels were also compared in control and oral treatment dogs for which sustained AF was not induced. The CX43 protein levels were significantly lower with oral treatment group with regard to the "P0" band (p = 0.005) and for the total amount of CX43 (p = 0.05). For CX40 protein levels, each of the 2 bands on the Western blot and the total amount of protein were lower for the oral treatment group (all p < 0.02).
Atrial CX levels were compared between dogs with (AF+) and without (AF–) inducible sustained AF. For CX43, a significant difference (p < 0.05) between AF+ and AF– dogs was only obtained in the oral treatment group; AF– was associated with lower expression levels of CX43. Pooling results for AF+ and AF– categories for CX43 in all treatment groups did not show any significant difference for phosphorylation state either separately or overall. Differences in CX40 expression levels were not significant between AF+ and AF– dogs for either treatment group when considered separately. However, overall differences were significant for each of the 2 phosphorylation (p = 0.02) states when all AF+ and AF– were respectively pooled together.
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Discussion
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Our findings document that oral treatment with n-3 PUFAs markedly increases atrial n-3 PUFA tissue levels and lowers AF inducibility in dogs. We also report that oral treatment with n-3 PUFAs decreased expression levels of both CX40 and CX43 in atrial tissues. These findings support recent data regarding the antiarrhythmic properties of n-3 PUFAs (8,10).
Tissue levels of n-3 PUFAs.
Blood and atrial tissue n-3 PUFA levels were significantly augmented in dogs given fish oils over 14 days. To evaluate the influence of the standard diet in the oral treatment group, 3 dogs were studied after 14 days of standard chow. Total serum n-3 PUFA levels were higher compared with those in control animals (3.37 ± 0.34% vs. 2.08 ± 0.41%) but were much lower than values for the oral treatment group. Nonetheless, atrial tissue levels of either n-3 or n-6 PUFAs were not different in time control group compared with those in the initial control group (2.53 ± 0.34% vs. 2.49 ± 0.46%, and 48.36 ± 0.75% vs. 48.08 ± 3.15%). The relation between blood and cardiac fatty acid composition needs further investigation, but recent clinical (20) and experimental (21) findings show that red cell EPA + DHA levels may be the preferred surrogate for cardiac omega-3 status. The dose of n-3 PUFAs (1.2 g daily of EPA + DHA) used in this study was comparable to recommendations of the American Heart Association (22), and was sufficient to reach therapeutic levels. Dietary intake and associated elevated blood levels of n-3 PUFAs have been associated with reduced risk of sudden cardiac death (23,24).
Electrophysiological properties.
Atrial refractoriness was not affected in fish oil-fed dogs compared with that seen in control dogs. These data are not consistent with findings from isolated rabbit hearts undergoing rapid burst pacing and increasing intra-atrial pressures (21). Differences could be due to different experimental models and variations of action potential characteristics in higher mammalian species. Electrophysiological findings in our study concord with recent reports of reduced AF after n-3 PUFA treatment (8,10,11). The mechanisms responsible for these antiarrhythmic effects remain unclear but are not related to cardiac hemodynamics or atrial ERP. The n-3 PUFA may prevent ventricular arrhythmias by inhibiting fast, voltage-dependent sodium channels and L-type calcium channels (21,25). QRS and QTc durations were not statistically different in oral treatment dogs suggesting that these channels are not altered in situ; however, the present study is underpowered to confirm this hypothesis. In comparison with the oral treatment group, PR interval was shorter and QT longer in the intravenous group, but the ERPs were not different. These findings are not consistent with a previous study (5) where there were no changes. Earlier animal and human studies using standard doses of n-3 PUFAs did not detect differences in electrocardiographic parameters (5,26). Modulation of conduction velocity or conduction heterogeneity was not addressed in the present study.
Cardiac CXs and n-3 PUFAs.
An association between AF, increased CX expression, and remodeling of gap junction distribution has been documented (3,27,28). Chronic atrial pacing increases CX43 expression in dogs (27) and is associated with depressed atrial conduction. This paradox may be reconciled by altered distribution patterns of gap junctions (i.e., changed anisotropy) that contribute to development of multiple wavelet re-entry. Increased CX40 expression has been associated with higher AF susceptibility in patients (4). However, no change or decreased CX40 and CX43 expression has been reported in a goat model of AF (29). In heterozygous CX43+/– knockout mice, no difference in atrial conduction was observed compared with that in wild type (30); during myocardial infarction, frequency of spontaneous or inducible arrhythmias compared with that in wild type did not increase, indicating that reduced CX43 expression is not related to arrhythmogenicity (31).
In the present study, lower cardiac CX40 and CX43 levels after oral n-3 PUFA treatment were associated with an increased AF triggering threshold. Connexin levels in control and oral treatment dogs were compared in only those animals in which sustained AF was not induced. Lower CX40 and CX43 levels were observed in treated dogs suggesting that AF, per se, did not impact on differences in CX expression levels. Comparison of CX levels between AF+ and AF– dogs indicated that AF– was associated with lower CX43 expression levels in only the oral treatment group. Differences in CX40 expression levels were significant overall and for both phosphorylation states when AF+ and AF– data were respectively pooled. As such, protection against AF was mostly related to reduced CX40 expression levels.
The CX phosphorylation is associated with either increased or decreased gap junction intercellular communications (32,33); poor correlation between cell-to-cell communication and changes in CX43 phosphorylation status has been reported (34). We did not observe major changes in the ratio of phosphorylated and nonphosphorylated forms of CX40 and CX43 in association with the lower CX40 and CX43 expression levels; further experiments are necessary to elucidate mechanisms involved in n-3 PUFA-induced down-regulation of these 2 cardiac CXs.
Potential limitations.
Atrial fibrillation is a progressive and slowly evolving condition in humans; therefore, data from short-term studies should be interpreted with caution. While vagal stimulation facilitates induction of prolonged AF (12–14,16), the latter was only induced in 50% of control animals. Further limitations include: 1) autonomic tone influences AF (35), but vagally mediated paroxysmal AF is uncommon in humans (36); 2) AF usually occurs in diseased atria; 3) AF induced by vagal stimulation in dogs differs significantly from that observed in humans; and 4) the present study lacks randomization and blinding.
Results for the intravenous treatment group are difficult to interpret. Absence of change in serum n-3 PUFA levels may be due to the rapid blood clearance of n-3 PUFAs (i.e., <10% to 15% by 5 min, dropping to 1% to 2% by 25 min) (37); it may also be related to the lower dose of n-3 PUFAs administered compared with dosages used in earlier studies (38). The lower incidence of AF in these dogs during 2 or 3 PACs might be due to indirect actions of n-3 PUFAs despite normal plasma levels or by unknown effects of albumin.
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Conclusions
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Oral treatment with fish oils markedly increased serum and atrial tissue n-3 PUFA levels and reduced vulnerability to induction of AF. Modulation of cardiac CX probably contributes to the antiarrhythmic effects of fish oil supplementation. These findings add further insight to mechanisms involved in atrial arrhythmogenic remodeling and support the rationale for continued clinical studies to examine cardioprotective effects of dietary fish oil supplementation in man.
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Acknowledgments
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The authors gratefully acknowledge the assistance of Guy Noel, Justin Robillard, Sebastien Poulin, Lynn Atton, and Line Dufort.
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Footnotes
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This study was funded by the QHI Foundation. Ocean Nutrition Canada Ltd. provided the fish oil used herein.
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