n-3 (omega-3) polyunsaturated fatty acids prevent acute atrial electrophysiological remodeling.

BACKGROUND AND PURPOSE: Recent reports suggest that n-3 (omega-3) polyunsaturated fatty acids (PUFAs) may reduce atrial fibrillation (AF). Reduction of the atrial effective refractory period (ERP) is believed to be an important early remodeling event that favors the development and perpetuation of AF. We hypothesized that n-3 PUFAs would attenuate early atrial electrophysiolgical remodeling in a canine model of acute atrial tachypacing. EXPERIMENTAL APPROACH: Adult dogs of either sex received n-3 PUFAs (n=6), n-6 PUFAs (n=6), or saline (n=6) infused over 1 h. After a stable ERP was established, treatment was initiated concurrently with 6 h of rapid atrial pacing (400 b.p.m.). Serial right atrial ERPs were measured during rapid atrial pacing, and induction of atrial tachyarrhythmias was attempted at the conclusion of each study. KEY RESULTS: There was no change in P wave duration or in the PQ, QRS, QT or QTc intervals in any of the treatment groups. N-3 PUFA treatment significantly reduced the shortening of atrial ERP, compared to both control groups (P<0.05). In separate experiments, the same n-3 PUFA infusion was given to dogs remaining in normal sinus rhythm. During sinus rhythm, n-3 PUFA infusion did not alter any electrocardiogram (ECG) parameter or the atrial ERP. CONCLUSIONS AND IMPLICATIONS: We conclude that acute n-3 PUFA treatment prevents acute atrial electrophysiological remodeling during high rate activity, which may minimize the self-perpetuation of AF.

Membrane effects of the n-3 fish oil fatty acids, which prevent fatal ventricular arrhythmias.

Fish oil fatty acids are known to exert beneficial effects on the heart and vascular systems. We have studied the membrane effects on ion channel conductance by the n-3 fish oil fatty acids that account for these beneficial effects. We have confirmed that these fatty acids prevent fatal cardiac arrhythmias in a reliable dog model of sudden cardiac death. This finding was followed by experiments indicating that the n-3 fatty acids electrically stabilize heart cells and do so largely through modulation of the fast voltage-dependent Na(+) currents and the L-type Ca(2+) channels in a manner, which makes the heart cells resistant to arrhythmias. Others and we have demonstrated that these membrane effects on the heart can prevent fatal cardiac arrhythmias in humans.

The antiarrhythmic and anticonvulsant effects of dietary N-3 fatty acids.

It has been shown in animals and probably in humans, that n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We report recent studies on the antiarrhythmic actions of PUFAs. The PUFAs stabilize the electrical activity of isolated cardiac myocytes by modulating sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the refractory period is markedly prolonged. Inhibition of voltage-dependent sodium currents, which initiate action potentials in excitable tissues, and of the L-type calcium currents, which initiate release of sarcoplasmic calcium stores that increase cytosolic free calcium concentrations and activate the contractile proteins in myocytes, appear at present to be the probable major antiarrhythmic mechanism of the PUFAs.

n-3 fatty acids in the prevention of cardiac arrhythmias.

In animals and probably in humans n-3 polyunsaturated fatty acids (PUFA) are antiarrhythmic. A report follows on the recent studies of the antiarrhythmic actions of PUFA. The PUFA stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the relative refractory period is markedly prolonged. This appears at present to be the probable major antiarrhythmic mechanism of PUFA.

Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs.

BACKGROUND: Rat diets high in fish oil have been shown to be protective against ischemia-induced fatal ventricular arrhythmias. Increasing evidence suggests that this may also apply to humans. To confirm the evidence in animals, we tested a concentrate of the free fish-oil fatty acids and found them to be antiarrhythmic. In this study, we tested the pure free fatty acids of the 2 major dietary omega-3 polyunsaturated fatty acids in fish oil: cis-5,8,11,14, 17-eicosapentaenoic acid (C20:5omega-3) and cis-4,7,10,13,16, 19-docosahexaenoic acid (C22:6omega-3), and the parent omega-3 fatty acid in some vegetable oils, cis-9,12,15-alpha-linolenic acid (C18:3omega-3), administered intravenously on albumin or a phospholipid emulsion. METHODS AND RESULTS: The tests were performed in a dog model of cardiac sudden death. Dogs were prepared with a large anterior wall myocardial infarction produced surgically and an inflatable cuff placed around the left circumflex coronary artery. With the dogs running on a treadmill 1 month after the surgery, occlusion of the left circumflex artery regularly produced ventricular fibrillation in the control tests done 1 week before and after the test, with the omega-3 fatty acids administered intravenously as their pure free fatty acid. With infusion of the eicosapentaenoic acid, 5 of 7 dogs were protected from fatal ventricular arrhythmias (P<0.02). With docosahexaenoic acid, 6 of 8 dogs were protected, and with alpha-linolenic acid, 6 of 8 dogs were also protected (P<0.004 for each). The before and after control studies performed on the same animal all resulted in fatal ventricular arrhythmias, from which they were defibrillated. CONCLUSIONS: These results indicate that purified omega-3 fatty acids can prevent ischemia-induced ventricular fibrillation in this dog model of sudden cardiac death.

Dietary n-3 fatty acids in the prevention of cardiac arrhythmias.

It has been shown that in animals, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We discuss recent studies on the antiarrhythmic actions of polyunsaturated fatty acids. Polyunsaturated fatty acids stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels so that a stronger electrical stimulus is required to elicit an action potential and the relative refractory period is markedly prolonged. This appears at present to be the probable major antiarrhythmic mechanism of polyunsaturated fatty acids.

Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids in dogs.

The objective of this study was to obtain functional information associated with the prevention by n-3 polyunsaturated fatty acids (PUFA) of ischemia-induced fatal cardiac ventricular arrhythmias in the intact, conscious, exercising dog. Thirteen dogs susceptible to ischemia-induced ventricular fibrillation were prepared surgically by ligation of their anterior descending left coronary artery and placement of an inflatable cuff around their left circumflex artery. After 4 wk of recovery, exercise-plus-ischemia tests were performed without and then with an intravenous infusion of an emulsion of free n-3 PUFA just prior to occluding the left circumflex artery while the animals were running on a treadmill. One week later the exercise-plus-ischemia test was repeated but with a control infusion replacing the emulsion of n-3 PUFA. The infusion of the free n-3 PUFA in quantities of 1.0 to 10 g prevented ventricular fibrillation in 10 of the 13 dogs tested (P < 0.005), apparently without esterification of the PUFA into membrane phospholipids. The antiarrhythmic effect of the n-3 PUFA was associated with slowing of the heart rate, shortening of the QT-interval (electrical action potential duration), reduction of left ventricular systolic pressure, and prolongation of the electrocardiographic atrial-ventricular conduction time (P-R interval). These effects are comparable with those we have reported in studies with cultured neonatal rat cardiac myocytes.

Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids.

A specially prepared dog model of myocardial infarction was used to test the efficacy of the long-chain polyunsaturated fish oil omega 3 fatty acids eicosapentaenoic (20:5 n-3) and docosahexaenoic (22:6 n-3) acids to prevent ischemia-induced malignant cardiac arrhythmias. The dogs had sustained a prior experimental myocardial infarction from ligation of the left anterior descending coronary artery, and a hydraulic cuff was implanted around the left circumflex artery at that operation. After recovery from that procedure the animals were tested during a treadmill exercise test. With compression of the left circumflex artery sensitive animals will predictably develop ventricular fibrillation (VF). In such prepared dogs an emulsion of fish oil fatty acids was infused i.v. over a 50- to 60-min period just before the exercise-plus-ischemia test, and the effect on development of VF was recorded. The infusion was 100 ml of a 10% (vol/vol) emulsion of a fish oil concentrate containing 70% omega 3 fatty acids with free eicosapentaenoic acid and docosahexaenoic acid composing 33.9% and 25.0% of that total, respectively. Alternatively, some animals similarly received an emulsion containing 5 ml of the free fatty acid concentrate plus 5 ml of a triacylglyerol concentrate containing 65% omega 3 fatty acids with eicosapentaenoic acid and docosahexaenoic acid composing 34.0% and 23.6% of that total, respectively. In seven of eight animals the infusion of the fish oil emulsion completely prevented the acute occurrence of VF in the susceptible animals (P < 0.005). In five of five of these animals the subsequent exercise-plus-ischemia test after a similar infusion of an emulsion in which soy bean oil replaced the fish oil fatty acid concentrates resulted in prompt development of VF. Possible mechanisms for this protective effect of omega 3 fatty acids against exercise and ischemia-induced malignant arrhythmias are considered.

Effect of calcium channel antagonists on susceptibility to sudden cardiac death: protection from ventricular fibrillation.

The effects of calcium channel antagonists and an agonist on susceptibility to ventricular fibrillation were investigated using chronically instrumented dogs with a healed anterior wall myocardial infarction. Three to 4 weeks after the infarction, a 2-min coronary occlusion was initiated during the last minute of exercise and continued for 1 min after cessation of exercise. Twenty-two dogs developed ventricular fibrillation (susceptible) whereas the remaining 14 animals did not (resistant) during this exercise plus ischemia test. The exercise plus ischemia test was repeated in the susceptible dogs after the following treatments: verapamil (n = 17, 250 micrograms/kg), nifedipine (n = 9, 10 and 100 micrograms/kg) and magnesium sulfate (n = 9, 100 mg/kg). Verapamil prevented ventricular fibrillation in all dogs whereas the high dose of nifedipine protected eight of nine animals; the low dose of nifedipine protected one of nine animals and magnesium sulfate protected seven of nine dogs. Finally, the calcium channel agonist Bay K8644 (n = 9, 30 micrograms/kg) was given to resistant animals. All resistant dogs developed ventricular fibrillation when the exercise plus ischemia test was repeated after Bay K8644. These data suggest that calcium entry may play a critical role in the development of arrhythmias during ischemia, with increased calcium entry provoking arrhythmias and calcium entry blockade preventing the lethal events.