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We explored possible mechanisms by which recommended intakes of ω-3 fatty acids may decrease the risk for sudden cardiac death in patients with documented coronary heart disease. The cardioprotective effects of ω-3 fatty acids have been documented in epidemiologic and randomized controlled trials. These fatty acids are presumed to decrease susceptibility to fatal arrhythmias, but whether this is mediated by classic risk factors or direct cardiac mechanisms is not known. Eighteen white men with a history of myocardial infarction and ejection fractions <40% were randomized to placebo or ω-3 fatty acids (585 mg of docosahexaenoic acid and 225 mg of eicosapentaenoic acid) for two 4-month periods in a crossover design. At the end of each period, heart rate (HR), HR variability, and rate of HR recovery after exercise were determined, as were effects on arterial compliance, blood pressure, cardiac function, and fasting serum levels of lipids and inflammatory markers. Omega-3 fatty acids decreased HR at rest from 73 ± 13 to 68 ± 13 beats/min (p <0.0001) and improved 1-minute HR recovery after exercise (−27 ± 10 to −32 ± 12 beats/min, p <0.01). HR variability in the high-frequency band increased (p <0.02), but no change was noted in overall HR variability. There were no significant effects on blood pressure, arterial compliance, lipids, or inflammatory markers. These changes are consistent with an increase in vagal activity and may in part explain the observed decrease in risk for sudden cardiac death seen with ω-3 fatty acid supplementation.
Consistent data from animal models, epidemiologic studies, and randomized controlled trials have suggested that increased ω-3 fatty acids intakes from fish or supplements decrease risks of fatal coronary heart disease
Because these effects have been documented only in studies using higher doses (3 to 5 g/day) than can be practically achieved by diet, they may not account for the decreased risk seen with lower doses (∼1 g/day)
However, these end points have not been studied in the most clinically relevant setting, namely, patients with coronary heart disease who take low doses of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
This was a randomized, double-blind, placebo-controlled, crossover trial in which subjects were given placebo or ω-3 fatty acids for 2 sequential 4-month periods. All testing occurred at the final visit of each period. Inclusion criteria were a myocardial infarction that occurred 3 months to 5 years previously, left ventricular ejection fraction <40%, and a stable medical regimen. Patients who used ω-3 supplements and those with atrial fibrillation or >1 premature ventricular contraction on a screening 10-second electrocardiogram were excluded. Patients were asked to consume ≤1 fish meal per month during the study.
An ω-3 supplement that contained 75 mg of EPA and 195 mg of DHA per 500-mg capsule was used (Ocean Nutrition Canada, Ltd., Halifax, Nova Scotia, Canada). Three capsules per day provided 810 mg of EPA plus DHA. The placebo contained a 50:50 mix of corn and olive oils. Capsules with taken with meals.
HR was recorded with a digital Holter’s monitor (model RZ152R, Rozinn Electronics, Glendale, New York) over a 76-minute period with the patient in 3 postural positions: supine (8 minutes), standing (8 minutes), and sitting at rest (60 minutes). Custom software was used to calculate the following HR variability metrics: the SD of all normal RR intervals (a measurement of overall variability) and power in the low- and high-frequency spectral bands.
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology Heart rate variability standards of measurement, physiological interpretation, and clinical use.
) and cardiac output were estimated noninvasively using the CVProfilor DO-2020 (Hypertension Diagnostics, Eagan, Minnesota), which analyzes radial artery waveforms.
Patients underwent an exercise stress test using a standard Bruce’s protocol that concluded with a 2-minute cool-down phase. Patients on β blockers were instructed to discontinue these medications 48 hours before the test.
Fasting plasma was analyzed for lipids and lipoproteins.
Inflammatory markers (high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin-6) were measured according to the manufacturer’s instructions (R&D Systems, Minneapolis, Minnesota).
Data were analyzed with paired t test. HR variability data were analyzed after log-transformations by 2-way repeated measures analysis of variance using SAS 9.1 (SAS Institute, Cary, North Carolina). Differences between means were considered statistically significant at a p value <0.05. Results are presented as means ± SDs.
Eighteen patients completed the 2 phases of the study. All were Caucasian men, with an average age of 67.8 ± 6.5 years, waist circumference of 94 ± 8 cm, and body mass index of 29.7 ± 4.3 kg/m2. Fifteen patients were on lipid-lowering agents, and 14 were on β blockers. There were no clinically relevant side effects.
The minute-by-minute mean HRs averaged over 76 minutes (including supine, standing, and sitting positions) were 73 ± 13 beats/min during the placebo period and 68 ± 13 beats/min during the ω-3 period (p <0.0001; Figure 1). The decrease in HR was accompanied by appropriate increases in stroke volume and ejection times (Table 1). The decrease in HR from the first to the second minute after standing was greater with ω-3 supplementation than with placebo (−3.6 ± 3.7 vs −2.4 ± 3.5 beats/min, p <0.05).
Table 1Cardiac function parameters, arterial compliance, and heart rate variability in coronary heart disease patients during placebo and omega-3 fatty acid supplementation periods (n = 18)
Although there was no effect of treatment on peak exercise HR or test duration (ω-3, 12 ± 3, vs placebo, 11 ± 3 minutes, p = NS) in the 14 subjects who completed the 2 stress tests, the decrease in HR at 1 minute after exercise was 19% greater (p <0.01) after ω-3 treatment (Table 2). The only effect of supplementation on HR variability was a 48% increase (p <0.02) in power in the high-frequency band (Table 1).
Table 2Effects of omega-3 fatty acid supplementation on heart rate and blood pressure during an exercise stress test (n = 14)
This study was designed to explore some of the possible mechanisms by which relatively low doses of ω-3 fatty acids could decrease risk for sudden cardiac death. Our principal findings were that ω-3 fatty acids significantly decreased HR at rest, accelerated the return to a normal HR after standing and exercise, and increased HR variability in the high-frequency band. Together, these observations suggest altered vagal activity, but they do not rule out an additional direct effect on the myocardium itself. Leaf et al
found that ω-3 fatty acids can inhibit the fast, voltage-dependent sodium current and the l-type calcium currents in cultured myocardiocytes. Animal and preliminary human studies have also shown that intravenous infusion of ω-3 fatty acids results in immediate improvement in susceptibility to dysrhythmias in the settings of severe ischemia or cardiomyopathy.
Consequently, whether the improvements we observed with ω-3 fatty acids supplementation are due to altered autonomic balance, a modification of the kinetic properties of voltage-gated myocardial ion channels, or the 2 together remains the subject of future mechanistic research.
Although high-dose ω-3 supplementation has been shown to improve many other potentially important cardiovascular parameters, such as blood pressure,
the present study showed no significant improvement in these parameters. It is therefore possible that the most important effects of doses of ω-3 fatty acids as recommended by the American Heart Association in patients with coronary heart disease are on cardiac and/or autonomic nervous system physiology. These changes might explain the decreased risk for fatal dysrhythmias that is associated with low-dose ω-3 fatty acid supplementation.
The investigators acknowledge the significant contributions to this project made by Sheryl Windsor, MT, MBA, Amy Reinert, BS, Crystal Russel-Lopez, BS, Qing Lan Zhang, BS, Rebecca Peterson, BS, Kristine Whitson, BS, and Rick Lustig, MD.
Van Horn L.
Accumulated evidence on fish consumption and coronary heart disease mortality.