Advertisement

Effects of Omega-3 Fatty Acids on Resting Heart Rate, Heart Rate Recovery After Exercise, and Heart Rate Variability in Men With Healed Myocardial Infarctions and Depressed Ejection Fractions

      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
      • He K.
      • Song Y.
      • Daviglus M.L.
      • Liu K.
      • Van Horn L.
      • Dyer A.R.
      • Greenland P.
      Accumulated evidence on fish consumption and coronary heart disease mortality a meta-analysis of cohort studies.
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      and sudden cardiac death.
      GISSI-Prevenzione Investigators
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction results of the GISSI-Prevenzione trial.
      There are several possible mechanisms by which fatty acids may operate, including decreases in blood pressure,
      • Morris M.C.
      • Sacks F.M.
      • Rosner B.
      Does fish oil lower blood pressure? A meta-analysis of controlled trials.
      lipids,
      • Harris W.S.
      N-3 fatty acids and serum lipoproteins human studies.
      and platelet aggregation and inflammation.
      • Calder P.C.
      Dietary fatty acids and the immune system.
      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)
      • He K.
      • Song Y.
      • Daviglus M.L.
      • Liu K.
      • Van Horn L.
      • Dyer A.R.
      • Greenland P.
      Accumulated evidence on fish consumption and coronary heart disease mortality a meta-analysis of cohort studies.
      that are currently recommended by the American Heart Association.
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      Observational studies have linked diets high in fish to increased heart rate (HR) variability,
      • Christensen J.H.
      • Korup E.
      • Aarøe J.
      • Toft E.
      • Moller J.
      • Rasmussen K.
      • Dyerberg J.
      • Schmidt E.B.
      Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.
      decreased HR,
      • Mozaffarian D.
      • Geelen A.
      • Brouwer I.A.
      • Geleijnse J.M.
      • Zock P.L.
      • Katan M.B.
      Effect of fish oil on heart rate in humans a meta-analysis of randomized controlled trials.
      and improved endothelial function.
      • Nestel P.
      • Shige H.
      • Pomeroy S.
      • Cehun M.
      • Abbey M.
      • Raederstorff D.
      The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans.
      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.
      HR variability was determined using only data from the period of sitting at rest.
      Large and small artery compliance (a reflection of endothelial function
      • Nakamura M.
      • Sugawara S.
      • Arakawa N.
      • Nagano M.
      • Shizuka T.
      • Shimoda Y.
      • Sakai T.
      • Hiramori K.
      Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure.
      ) 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.
      • Bybee K.A.
      • O’Keefe Jr, J.H.
      • Harris W.S.
      • Garg S.
      • George S.J.
      • Bateman T.M.
      Lipid risk factor correlates of ischemic heart disease as diagnosed by myocardial perfusion scintigraphy.
      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).
      Figure thumbnail gr1
      Figure 1HR was monitored minute by minute in 18 patients with coronary heart disease after 4 months of treatment with placebo and ω-3 fatty acids (810 mg/day) in a randomized, crossover design. Patients were in the supine position for 8 minutes, followed by 8 minutes of standing and 60 minutes of sitting at rest. Mean HRs over the entire 76-minute period were 73.6 ± 4.1 beats/min during the placebo phase and 68.7 ± 3.7 beats/min during the ω-3 phase (p <0.0001).
      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)
      Placeboω-3 Fatty Acidsp Value
      Estimated cardiac ejection time (ms)318.9 ± 27.2328.9 ± 29.10.03
      Estimated stroke volume (ml/beat)79.8 ± 13.885.1 ± 14.60.002
      Estimated cardiac output (L/min)5.3 ± 1.05.3 ± 0.9NS
      Large artery elasticity index (ml/mm Hg × 10)15.6 ± 4.715.5 ± 3.8NS
      Small artery elasticity index (ml/mm Hg × 100)5.3 ± 2.35.3 ± 3.5NS
      SD of all normal RR intervals (ms)40.7 ± 18.843.8 ± 16.7NS
      Low-frequency power (ms2)330 ± 333255 ± 261NS
      High-frequency power (ms2)84 ± 78124 ± 990.02
      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)
      HR (beats/min)Blood Pressure (mm Hg)
      PlaceboFish OilSystolicDiastolic
      PlaceboFish OilPlaceboFish Oil
      Baseline78 ± 2074 ± 17128 ± 11126 ± 1374 ± 775 ± 7
      Peak135 ± 21133 ± 18164 ± 20164 ± 1676 ± 880 ± 6
      p <0.05;
      1-Minute after exercise108 ± 23101 ± 20
      p ≤0.01.
      Change27 ± 1032 ± 12
      p <0.05;
      — = Not done or no information available.
      low asterisk p <0.05;
      p ≤0.01.
      Neither large nor small artery compliance nor cardiac output was affected by ω-3 fatty acid supplementation (Table 1), nor were lipids or inflammatory markers (Table 3).
      Table 3Lipids and inflammatory markers
      No differences were statistically significant.
      (n = 18)
      PlaceboFish Oil
      Cholesterol (mg/dl)161 ± 31162 ± 31
      Triglycerides (mg/dl)180 ± 148161 ± 100
      High-density lipoprotein cholesterol (mg/dl)40 ± 1040 ± 10
      Low-density lipoprotein cholesterol (mg/dl)93 ± 2789 ± 32
      Very low-density lipoprotein cholesterol (mg/dl)33 ± 1932 ± 20
      C-reactive protein (mg/l)1.3 ± 1.21.6 ± 1.6
      Tumor necrosis factor-α (pg/ml)6.7 ± 7.45.7 ± 7.1
      Interleukin-6 (pg/ml)1.6 ± 1.72.4 ± 1.1
      low asterisk No differences were statistically significant.
      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
      • Leaf A.
      • Kang J.X.
      • Xiao Y.F.
      • Billman G.E.
      Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils.
      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.
      • Billman G.E.
      • Kang J.X.
      • Leaf A.
      Prevention of sudden cardiac death by dietary pure ω-3 polyunsaturated fatty acids in dogs.
      • Schrepf R.
      • Limmert T.
      • Claus W.P.
      • Theisen K.
      • Sellmayer A.
      Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia.
      A high HR at rest (especially in men) has been strongly linked to cardiovascular events, including mortality.
      • Hjalmarson A.
      Significance of reduction in heart rate in cardiovascular disease.
      The decrease in HR noted in the present study is in the same range as that observed with β-blocker therapy, another intervention that has been shown to decrease risk of sudden death
      • Dahlof B.
      • Devereux R.B.
      • Kjeldsen S.E.
      • Julius S.
      • Beevers G.
      • de Faire U.
      • Fyhrquist F.
      • Ibsen H.
      • Kristiansson K.
      • Lederballe-Pedersen O.
      • et al.
      Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) a randomised trial against atenolol.
      A recent meta-analysis has associated a small but significant decrease in HR with increased ω-3 fatty acids intakes.
      • Mozaffarian D.
      • Geelen A.
      • Brouwer I.A.
      • Geleijnse J.M.
      • Zock P.L.
      • Katan M.B.
      Effect of fish oil on heart rate in humans a meta-analysis of randomized controlled trials.
      Our observations extend these findings and suggest that modulation of HR can be achieved in patients with known coronary heart disease who consume recommended amounts of EPA plus DHA.
      To our knowledge, this is the first study to document an improved postexercise HR recovery with ω-3 supplementation. Multiple studies have shown HR recovery, which is mediated by vagal tone,
      • Imai K.
      • Sato H.
      • Hori M.
      • Kusuoka H.
      • Ozaki H.
      • Yokoyama H.
      • Takeda H.
      • Inoue M.
      • Kamada T.
      Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure.
      to be an important predictor of cardiovascular prognosis.
      • Smith L.L.
      • Kukielka M.
      • Billman G.E.
      Heart rate recovery after exercise a predictor of ventricular fibrillation susceptibility after myocardial infarction.
      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,
      • Morris M.C.
      • Sacks F.M.
      • Rosner B.
      Does fish oil lower blood pressure? A meta-analysis of controlled trials.
      arterial elasticity,
      • Nestel P.
      • Shige H.
      • Pomeroy S.
      • Cehun M.
      • Abbey M.
      • Raederstorff D.
      The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans.
      lipids,
      • Harris W.S.
      N-3 fatty acids and serum lipoproteins human studies.
      and inflammatory markers,
      • Calder P.C.
      Dietary fatty acids and the immune system.
      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.

      Acknowledgment

      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.

      References

        • He K.
        • Song Y.
        • Daviglus M.L.
        • Liu K.
        • Van Horn L.
        • Dyer A.R.
        • Greenland P.
        Accumulated evidence on fish consumption and coronary heart disease mortality.
        Circulation. 2004; 109: 2705-2711
        • Kris-Etherton P.M.
        • Harris W.S.
        • Appel L.J.
        Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
        Circulation. 2002; 106: 2747-2757
        • GISSI-Prevenzione Investigators
        Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction.
        Lancet. 1999; 354: 447-455
        • Morris M.C.
        • Sacks F.M.
        • Rosner B.
        Does fish oil lower blood pressure? A meta-analysis of controlled trials.
        Circulation. 1993; 88: 523-533
        • Harris W.S.
        N-3 fatty acids and serum lipoproteins.
        Am J Clin Nutr. 1997; 65: 1645S-1654S
        • Calder P.C.
        Dietary fatty acids and the immune system.
        Nutr Rev. 1998; 56: S70-S83
        • Christensen J.H.
        • Korup E.
        • Aarøe J.
        • Toft E.
        • Moller J.
        • Rasmussen K.
        • Dyerberg J.
        • Schmidt E.B.
        Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.
        Am J Cardiol. 1997; 79: 1670-1673
        • Mozaffarian D.
        • Geelen A.
        • Brouwer I.A.
        • Geleijnse J.M.
        • Zock P.L.
        • Katan M.B.
        Effect of fish oil on heart rate in humans.
        Circulation. 2005; 112: 1945-1952
        • Nestel P.
        • Shige H.
        • Pomeroy S.
        • Cehun M.
        • Abbey M.
        • Raederstorff D.
        The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans.
        Am J Clin Nutr. 2002; 76: 326-330
        • Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology
        Heart rate variability.
        Circulation. 1996; 93: 1043-1065
        • Nakamura M.
        • Sugawara S.
        • Arakawa N.
        • Nagano M.
        • Shizuka T.
        • Shimoda Y.
        • Sakai T.
        • Hiramori K.
        Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure.
        J Card Fail. 2004; 10: 36-42
        • Bybee K.A.
        • O’Keefe Jr, J.H.
        • Harris W.S.
        • Garg S.
        • George S.J.
        • Bateman T.M.
        Lipid risk factor correlates of ischemic heart disease as diagnosed by myocardial perfusion scintigraphy.
        Prev Cardiol. 2000; 3: 154-159
        • Leaf A.
        • Kang J.X.
        • Xiao Y.F.
        • Billman G.E.
        Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils.
        Circulation. 2003; 107: 2646-2652
        • Billman G.E.
        • Kang J.X.
        • Leaf A.
        Prevention of sudden cardiac death by dietary pure ω-3 polyunsaturated fatty acids in dogs.
        Circulation. 1999; 99: 2452-2457
        • Schrepf R.
        • Limmert T.
        • Claus W.P.
        • Theisen K.
        • Sellmayer A.
        Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia.
        Lancet. 2004; 363: 1441-1442
        • Hjalmarson A.
        Significance of reduction in heart rate in cardiovascular disease.
        Clin Cardiol. 1998; 21: II3-II7
        • Dahlof B.
        • Devereux R.B.
        • Kjeldsen S.E.
        • Julius S.
        • Beevers G.
        • de Faire U.
        • Fyhrquist F.
        • Ibsen H.
        • Kristiansson K.
        • Lederballe-Pedersen O.
        • et al.
        Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE).
        Lancet. 2002; 359: 995-1003
        • Imai K.
        • Sato H.
        • Hori M.
        • Kusuoka H.
        • Ozaki H.
        • Yokoyama H.
        • Takeda H.
        • Inoue M.
        • Kamada T.
        Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure.
        J Am Coll Cardiol. 1994; 24: 1529-1535
        • Smith L.L.
        • Kukielka M.
        • Billman G.E.
        Heart rate recovery after exercise.
        Am J Physiol Heart Circ Physiol. 2005; 288: H1763-H1769