Dietary omega-3 fatty acids and susceptibility to ventricular fibrillation: lack of protection and a proarrhythmic effect

Abstract

Background: Recent clinical studies that evaluated the effects of supplemental omega-3 polyunsaturated fatty acids (n-3 PUFAs) on sudden cardiac death have yielded conflicting results. Our aim was to clarify this issue using an established and clinical relevant canine model of sudden cardiac death.

Methods and results: Susceptibility to ventricular fibrillation (VF) was evaluated using a 2-minute left circumflex artery occlusion during the last minute of an exercise test in 76 dogs (from 2 independent studies) with healed myocardial infarctions (MI); 44 developed VF (susceptible, VF+), whereas 32 did not (resistant, VF-). These dogs were then randomly assigned to either placebo (1 g/d, corn oil; 15 VF+, 11 VF-) or n-3 PUFA (1-4 g/d, docosahexaenoic acid+eicosapentaenoic acid ethyl esters, 29 VF+, 21 VF-) groups. Seven sham (no-MI) dogs were also treated with n-3 PUFA (4 g/d). After treatment (3 months), the exercise+ischemia test was repeated. Dietary n-3 PUFAs produced significant (P<0.01) increases in red blood cell and left ventricular n-3 PUFA levels. Nine post-MI (5 placebo versus 4 n-3 PUFA) and 2 sham dogs died suddenly during the 3-month treatment period. The n-3 PUFA treatment failed to prevent arrhythmias in VF+ dogs (decreased in 27% placebo versus 24% n-3 PUFA, P=0.5646) but induced VT/VF in VF- animals (n-3 PUFA 33% versus placebo 0%, P=0.0442).

Conclusions: Despite large increases in cardiac tissue n-3 PUFA content, dietary n-3 PUFAs did not prevent ischemia-induced VF and actually increased arrhythmia susceptibility in both noninfarcted and low-risk post-MI dogs.

Figure 1

A flow chart of the post-MI animals used in Study 2. The exercise + ischemia test could not be repeated at the end of treatment in some animals due to occluder failure [11 VF+ (5 placebo, 6 n-3 PUFA) and 5 VF− (2 placebo, 3 n-3 PUFA)] or spontaneous death (VF+: 5 placebo, 4 n-3 PUFA). VF = ventricular fibrillation; n-3 PUFA = omega-3 polyunsaturated fatty acids.

Figure 2

The response of each susceptible (VF+) dog before and at the end of a 3 month treatment period with either placebo (Fig 2a., 1 g/day corn oil, n=15) or n-3 PUFA (Fig 2b., 1-4 g/day, n=21). Only the results of the post-MI animals used in the Study 2 are shown. Note that 9 dogs died spontaneously (SD; 5 placebo, 4 n-3 PUFA) and could not receive a post-treatment exercise + ischemia test. The n-3 PUFA treatment did not prevent ventricular tachyarrhythmias for any n-3 PUFA dose (1 g/day P=0.7278; 2 g/day, P=0.4769; 4 g/day P=0.5159). VF = ventricular fibrillation; PVCs = premature ventricular complexes; Pre = before the onset of treatment; Post = after 3-months of treatment. Open circle = 1 g/day; open square = 2 g/day, and closed circle = 4 g/day.

Figure 2

The response of each susceptible (VF+) dog before and at the end of a 3 month treatment period with either placebo (Fig 2a., 1 g/day corn oil, n=15) or n-3 PUFA (Fig 2b., 1-4 g/day, n=21). Only the results of the post-MI animals used in the Study 2 are shown. Note that 9 dogs died spontaneously (SD; 5 placebo, 4 n-3 PUFA) and could not receive a post-treatment exercise + ischemia test. The n-3 PUFA treatment did not prevent ventricular tachyarrhythmias for any n-3 PUFA dose (1 g/day P=0.7278; 2 g/day, P=0.4769; 4 g/day P=0.5159). VF = ventricular fibrillation; PVCs = premature ventricular complexes; Pre = before the onset of treatment; Post = after 3-months of treatment. Open circle = 1 g/day; open square = 2 g/day, and closed circle = 4 g/day.

Figure 3

The response of each resistant (VF−) dog before and at the end of a 3 month treatment period with either placebo (Fig 3a., 1 g/day corn oil, n=10) or n-3 PUFA (Fig 3b., 1–4 g/day, n=21). Only the results of the post-MI animals used in the Study 2 are shown. Note that the n-3 PUFA treatment increased (P=0.442) the severity of arrhythmias in one third (7 of 21; 3 of 5 with 2 g/day & 4 of 15 with 4 g/day) of these dogs while the placebo treatment did not induce arrhythmias in any animal. * indicates an episode of ventricular fibrillation (VF). VT = ventricular tachycardia; PVCs = premature ventricular complexes; none = no arrhythmias; Pre = before the onset of treatment; Post = after 3-months of treatment. Open circle = 1 g/day; open square = 2 g/day, and closed circle = 4 g/day.

Figure 3

The response of each resistant (VF−) dog before and at the end of a 3 month treatment period with either placebo (Fig 3a., 1 g/day corn oil, n=10) or n-3 PUFA (Fig 3b., 1–4 g/day, n=21). Only the results of the post-MI animals used in the Study 2 are shown. Note that the n-3 PUFA treatment increased (P=0.442) the severity of arrhythmias in one third (7 of 21; 3 of 5 with 2 g/day & 4 of 15 with 4 g/day) of these dogs while the placebo treatment did not induce arrhythmias in any animal. * indicates an episode of ventricular fibrillation (VF). VT = ventricular tachycardia; PVCs = premature ventricular complexes; none = no arrhythmias; Pre = before the onset of treatment; Post = after 3-months of treatment. Open circle = 1 g/day; open square = 2 g/day, and closed circle = 4 g/day.