Effects of Chronic Omega-3 Polyunsaturated Fatty AcidSupplementation on Human Pulmonary Vein and Left Atrial
Electrophysiology in Paroxysmal Atrial Fibrillation
Saurabh Kumar, BSc(Med), MBBSa,b, Fiona Sutherland, RNa, Andrew W. Teh, MBBSa,b,Patrick M. Heck, MDa, Geoffrey Lee, MBChBa,b, Manohar L. Garg, PhDc, and
Omega-3 polyunsaturated fatty acids in fish oils haveconsistently been shown to have antifibrillatory effects inpreclinical studies.1–8 In humans, epidemiologic,9–11 obser-vational,12,13 and randomized14–16 studies on incident,9–11
paroxysmal,12,13,16 and postoperative14,15 atrial fibrillationAF) with acute14–16 or chronic10–13 fish oil exposure haveeen contradictory. Pulmonary vein (PV) ectopy is criticalor the initiation and maintenance of paroxysmal AFPAF).17 In addition, PVs of patients with PAF exhibitistinct electrophysiologic properties that may form thesubstrate” for re-entry.18,19 The effect of chronic fish oilupplementation on human PV electrophysiology re-ains unknown. Chronic fish oil supplementation pro-
aCardiology Department, The Royal Melbourne Hospital, Parkville,Victoria, Australia; bDepartment of Medicine, University of Melbourne,
arkville, Victoria, Australia; cSchool of Biomedical Sciences and Phar-macy, Faculty of Health, University of Newcastle, Callaghan, New SouthWales, Australia.
This study was funded in part by the National Heart Foundation and thePfizer Cardiovascular Lipid Research Grant. Dr. Kumar is the recipient ofa postgraduate research scholarship cofunded by the National Health andMedical Research Council and the National Heart Foundation of Australia(Scholarship ID 628996). Dr. Teh has a postgraduate research scholarshipfunded by the National Heart Foundation.
ongs right atrial and coronary sinus refractoriness andecreases vulnerability to inducible AF; however, this wasssessed in patients without structural heart disease or clin-cal AF.20 The aim of this study was to evaluate the effect
of chronic polyunsaturated fatty acid supplementation onpulmonary venous and left atrial electrophysiology in pa-tients with PAF.
Methods
Patients 18 to 75 years old with PAF scheduled to un-dergo PV isolation were recruited. Patients on amiodarone,fish intake �1 time/week, or previous fish oil supplemen-tation were excluded. A 7-day Holter monitor and AtrialTachyarrhythmia Symptom Severity Scale21 were per-formed before recruitment. At least 1 month before abla-tion, patients were randomized to active therapy with fish oil(fish oil group) or no therapy (control group). Fish oil 6g/day containing a total dose of docosahexaenoic acid(DHA) 1.5 g and eicosapentaenoic acid (EPA) 0.3 g wereprescribed (Nu-mega Ingredients Pty. Ltd., Victoria, Aus-tralia). A DHA-enriched preparation was chosen as it mayproduce more potent antifibrillatory effects than EPA.9,20
A minimum exposure of 30 days was mandatory becauseatrial enrichment with EPA and DHA reaches a maximumat this time.22 Patients had continuous electrocardiographic
onitoring for 4 hours before ablation; patients with AF �1
532 The American Journal of Cardiology (www.ajconline.org)
minute were excluded from the study to eliminate the pos-sible confounding effect of AF on atrial23 and pulmonaryenous24 refractoriness.
The operator and technical staff were blinded to patientgroups. Off-line analysis was performed at a later date by 2authors who were also blinded to patient group assignment.Compliance with fish oil therapy was monitored weeklyusing pill count and by plasma fatty acid profile on the dayof ablation. Written informed consent was obtained fromeach patient, and the Melbourne health research ethics com-mittee approved the protocol.
Blood samples were collected on the day of procedureand centrifuged to separate plasma from the erythrocytefraction and analyzed as described previously.25 Total ome-ga-3, omega-6, EPA, and DHA levels were expressed aspercent fraction of total fatty acids in the phospholipidfraction.
Our method of PV isolation using general anesthesia,double transseptal punctures, and a single circular mappingcatheter has been previously described in detail.26 Intracar-diac catheters were positioned as follows: (1) 10-pole cor-onary sinus catheter (2- � 5- � 2-mm interelectrode spac-ing) with the proximal bipole positioned at the coronarysinus ostium as determined in the best septal left anterioroblique projection (6Fr “Response” DEC CSL, St. JudeMedical, Minneapolis, Minnesota); (2) His-bundle electro-graphic catheter (6Fr “Supreme” Hex JSN, St. Jude Medi-cal), (3) mapping/ablation catheter (7Fr Therapy Cool PathM Curve, St. Jude Medical), and (4) multipolar circularmapping catheter (20-mm Lasso, 7Fr deflectable, BiosenseWebster, Diamond Bar, California). Selective pulmonaryangiography was used to define the PV antrum; this wasfollowed by creation of left atrial geometry using a 3-di-mensional electroanatomical mapping system (NavX, St.Jude Medical). The research protocol consisted of the fol-lowing items measured in the same sequence in every pa-tient: (1) RR intervals, (2) P-wave duration, (3) pacingthreshold, (4) effective refractory periods (ERPs) from theleft superior, right superior PVs, posterior left atrium, anddistal coronary sinus at 600- and 450-ms drive trains, (5) PVconduction at the same drive trains, and (6) left atrial con-duction.
P-wave duration in sinus rhythm was measured on lead IIof the surface electrocardiogram and averaged over 10 beatsas a surrogate marker of interatrial conduction time. Pacingthreshold was determined at each site at a 2-ms pulse width.The catheter was repositioned if a diastolic threshold �5mA could not be obtained. All measurements were per-formed at twice the diastolic threshold. ERPs were mea-sured using pacing drive train of 8 beats followed by asingle extrastimulus commencing at a coupling interval of150 ms and incrementing by 10 ms until local capture wasdemonstrated.20 For measurement of ERPs and conduction,the ablation catheter was positioned 1 to 2 cm distal to thePV ostium as defined by pulmonary venography and pacingwas performed at the floor of the vein as defined by veno-graphic landmarks and assisted with fluoroscopy. Disper-sion of refractoriness, an important marker of AF vulnera-bility, was evaluated using the coefficient of variation ofERP at the 2 cycle lengths (SD/mean � 100%).27 If AF �1
minute was induced during ERP testing, this was docu-
mented and no further assessment of ERP or conductionwas attempted.
During AF, the circular mapping catheter was positionedwithin the PVs for measurement of AF cycle length. Totalduration, mean AF cycle length, shortest AF cycle length,and longest AF cycle length in PVs were measured at asweep speed of 100 mm/s by averaging 30 consecutivecycles. Shortest and longest AF cycle lengths were mea-sured within a random 10-second window of induced AF of�1-minute duration. Only the first induction of AF wasused to compare the cycle length between groups.
PV conduction was measured as the conduction timefrom the pacing site within PVs (1 to 2 cm distal to the os,as described earlier) to the earliest atrial electrogram re-corded on the circular mapping catheter positioned at thejunction of the PV and left atrium. Left atrial activation timewas calculated by pacing the distal coronary sinus andmeasuring activation time to the atrial electrogram at theHis bundle region. Conduction was measured at cyclelengths of 600 and 450 ms after stable capture for �10seconds. Conduction time was determined 5 times at eachcycle length and averaged. Autonomic blockade was notadministered to not interfere with the treatment of the clin-ical arrhythmia.
The study intended to detect �10-ms difference (SD 10)in pulmonary venous ERPs with 80% power and an alphalevel of 5%, producing an estimate of 16 patients required ineach group. SPSS 15.0 for Windows (SPSS, Inc., Chicago,Illinois) was used for analysis. To test for associationsbetween categorical variables, chi-square test or Fisher’sexact test was used. Mean values were compared usingStudent’s t test. Mann–Whitney U or Kruskal-Wallis tests
Values expressed as mean � SD or percentage of patients.* Measured before randomization.
were used for continuous variables where normal distribu-
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533Arrhythmias and Conduction Disturbances/Fish Oils and Human PAF Electrophysiology
tion was not present. A 2-tailed p value �0.05 was consid-ered statistically significant.
Results
Forty-two patients were screened; 2 were excluded be-cause they were already on fish oil, 2 were taking amioda-rone, and another 2 had �1 minute of AF in the 4 hoursefore the procedure. There were no dropouts in the fish oilroup. Thirty-six patients (18 controls, 18 fish oil subjects)onstituted the study population (mean age 54 � 10 years,
72% men). Baseline characteristics were similar (Table 1).Mean duration of fish oil therapy was 40 � 13 days (range30 to 66 days). Plasma EPA, DHA, and total omega-3 levelswere 2.2-, 2.6-, and 2-fold higher in the fish oil group on theday of testing (Figure 1).
Mean RR interval of the 2 groups was similar beforeprotocol commencement (fish oil 879 � 290 ms vs control964 � 210 ms, p � 0.36). Pulmonary venous threshold wassimilar in the left superior (fish oil 2.4 � 0.7 V vs control2.1 � 0.4 V, p � 0.33) and right superior (fish oil 2.8 � 0.4
Figure 1. Eicosapentaenoic acid, docosahexaenoic acid, and total omega-3levels were significantly higher and total omega-6 significantly lower in thefish oil group (gray bars) compared to the control group (black bars).
Figure 2. Pulmonary venous effective refractory periods were significantlylonger in the fish oil group (gray bars) versus the control group (blackars). LSPV 450 � left superior pulmonary venous effective refractoryeriods at 450-ms drive train; LSPV 600 � left superior pulmonary venousffective refractory periods at 600-ms drive train; RSPV 450 � rightuperior pulmonary venous effective refractory periods at 450-ms driverain; RSPV 600 � right superior pulmonary venous effective refractoryeriods at 600-ms drive train.
vs control 2.9 � 0.3 V, p � 0.75) PVs, posterior left
trium (fish oil 4.2 � 0.7 V vs control 4.4 � 0.7 V, p �.63), and distal coronary sinus (fish oil 2.9 � 0.4 V vsontrol 2.9 � 0.3 V, p � 0.93). The fish oil group hadignificantly longer pulmonary venous and left atrial ERPst the 2 pacing cycle lengths compared to controls (Figuresand 3). There was less dispersion of refractoriness in the
Vs of fish oil patients compared to controls (600 ms 5.5 �.7% vs 18.9 � 11.3%, p � 0.001; 450 ms 9.7 � 9.8% vs8.2 � 10%, p � 0.07). In the control population, ERPs
recorded from the left superior and right superior PVs wereas short as 120 ms, whereas all patients in the fish oil grouphad an ERP �200 ms. P-wave duration and pulmonaryvenous and left atrial conduction times were not signifi-cantly different between groups (Table 2).
As a consequence of shorter pulmonary venous ERPs incontrols, AF was initiated at short coupling intervals duringERP testing in 70.6% of controls versus 33.3% of patientsusing fish oil (p � 0.02). Cycle length of first induced AF inPVs was significantly longer in patients using fish oil com-pared to controls (209 � 39 vs 133 � 38 ms, p � 0.002).The shortest AF cycle length and longest AF cycle length inPVs were longer in patients using fish oil compared tocontrols (shortest AF cycle length 164 � 55 vs 100 � 30ms, p � 0.009; longest AF cycle length 223 � 47 vs 170 �37 ms, p � 0.04).
Discussion
This main finding of this study was that patients withPAF chronically supplemented with fish oils exhibited pro-longed pulmonary venous and left atrial refractoriness and
Figure 3. Effective refractory periods in the posterior left atrium (Post LA)were significantly longer in the fish oil group (gray bars) versus the controlgroup (black bars) and similar in the distal coronary sinus (DCS). 450 �450-ms drive train; 600 � 600-ms drive train.
Table 2P-wave duration and pulmonary vein and left atrial conduction
600 msLeft superior 54 � 17 46 � 14 0.25Right superior 54 � 22 60 � 17 0.57
450 msLeft superior 49 � 18 46 � 15 0.69Right superior 56 � 27 61 � 18 0.63
Left atrial conduction600 ms 84 � 18 77 � 12 0.3450 ms 81 � 13 75 � 15 0.44
Values expressed as mean � SD.
less dispersion of pulmonary venous refractoriness com-
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534 The American Journal of Cardiology (www.ajconline.org)
pared to “control” patients with similar clinical characteris-tics but with a history of low fish intake and significantlylower serum omega-3 polyunsaturated fatty acid levels. Thelower ERPs of the controls exposed them to shorter cou-pling intervals during testing, resulting in higher incidenceof PV-initiated AF. As a direct consequence of higher PVrefractoriness, patients on fish oil had decreased suscepti-bility to PV-initiated AF and longer cycle length AF in PVs.Although these electrophysiologic changes suggest thatlong-term fish oil intake may have an antifibrillatory effectin human PAF in this mechanistic study, randomized clin-ical trials of long-term fish oil supplementation are neededto support our findings.
The arrhythmogenicity of PVs in PAF is created by adynamic interaction between triggered activity and abnor-mal electrophysiologic substrate composed of short ERPsand circuitous slowed pulmonary venous conduction.17–19,28
PVs are susceptible to rapid electrical remodeling with evenshort durations of AF.24 Nonuniform distribution of refrac-toriness (refractoriness dispersion) is critical in allowingpremature extrastimuli to induce re-entry in AF.27 The find-ing that patients using fish oil had longer mean and longershortest recorded ERPs than controls, less dispersion ofrefractoriness, and longer mean and shortest AF cyclelength suggests that fish oils may be able to attenuate ar-rhythmogenic substrate for AF in the PVs. However, it isunclear if the described electrical properties in patientstaking fish oil are due to suppression of arrhythmia fre-quency and subsequent reverse electrical remodeling of PVsin the preceding days or weeks before testing or an effect ofincorporated fish oil on pulmonary venous cellular mem-branes. We cannot exclude the former because continuousmonitoring was not performed in this period. Abnormalcalcium handling play an important role in the genesis oftransient inward currents and delayed afterdepolarizationsthat are responsible for pulmonary venous arrhythogenic-ity.28,29 Fish oils have demonstrable effects on cytosoliccalcium fluxes and this may explain their antiarrhythmiceffect on PVs in the present study.29
Despite extensive preclinical work, no previous animalor human study has examined the effect of chronic fish oilintake on pulmonary venous electrophysiology. Chronicfish oil supplementation leads to modulation of ion channelsand repolarization currents resulting in increased thresholdfor stimulation of arrhythmias,1,2 downregulation of profi-brillatory cardiac connexins,3 decreased expression of pro-inflammatory genes,4 profibrotic enzymes,5 and proinflam-matory cytokines implicated in AF perpetuation.6,7 Thesehanges have been shown to attenuate conduction abnor-alities5,6 and decrease susceptibility to AF in response to
agal stimulation,3 stretch,8 pacing-induced atrial cardio-myopathy,5 or in canine cardiac surgical models of inflam-
atory AF.6,7 Atlhough the present study focused on theffects of chronic fish oil supplementation on electrophysi-logic properties, the anti-inflammatory and antiremodelingffects in PAF need further examination.
Our data are consistent with studies showing that chronicmega-3 polyunsaturated fatty acid supplementation de-reases the frequency and burden of PAF in patients withmplanted pacemakers12 and decreases early and late AF
ecurrences after PV isolation.13 Some although not all
pidemiologic studies of chronic omega-3 polyunsaturatedatty acid intake on incident AF have shown a protectiveffect.9–11 Geographic variation in fish intake, changing
levels of fish intake during the study period, difference inmethods of AF detection, and nonuniform use of serumomega-3 polyunsaturated fatty acid levels to stratify patientsinto high or low level fish exposure may offer some expla-nation for the heterogeneity in results. For these reasons,testing of fish oil efficacy in homogenous patient groups(such as ours) has been suggested.30
In contrast to our findings, randomized studies of fish oilson incident AF after coronary artery bypass surgery14,15 andf recurrent AF in patients with PAF and persistent AF16
have failed to show benefit. These studies measured endpoints after short duration of supplementation with fish oil(up to 1 week), whereas we measured end points after aminimum of 1 month. The mechanism of acute versuschronic fish oil supplementation may differ vastly. Chronicintake results in membrane incorporation; indeed, atrialaccumulation of EPA and DHA is curvilinear with time andreaches a maximum at 30 days.22 Of note, most animaltudies have supplemented fish oils for �2 weeks beforeesting their antifibrillatory potential.3–8 Differences in du-
ration of supplementation, formulation of fish oil capsules(our DHA enriched content), and the observational mecha-nistic nature of our study performed in a small yet homog-enous patient population may be responsible for divergentresults.
A limitation of the present study was that autonomicblockade was not administered to not interfere with theidentification of PV–left atrial connections during ablation.However, the RR interval recorded at the commencement ofthe research protocol was not significantly different betweengroups and all patients were studied under general anesthe-sia. The control group was not supplemented with anequivalent amount of placebo capsules and therefore thestudy was not double blinded. The degree of bias isunlikely to have influenced the results because the pri-mary analysis was based on physiologic measurementsnot influenced by a patient’s knowledge of group assign-ment and the fact that operators and investigators wereblinded to group assignment.
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