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Kansas City, MO
New Orleans, LA
Dr. Abuissa is a Preventive Cardiology Fellow, Dr. O’Keefe is Professor of Medicine, and Dr. Harris is Professor of Medicine, Mid America Heart Institute. Dr. Lavie is Medical Co-Director, Cardiac Rehabilitation, and Director, Exercise Laboratories, Ochsner Clinic Foundation.
Correspondence to: Carl J. Lavie, MD, Medical Co-Director, Cardiac Rehabilitation, Director, Exercise Laboratories, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121-2483; e-mail: clavie{at}ochsner.org
The status of the autonomic nervous system, although ignored by many clinicians, is a major determinant of cardiovascular health and prognosis. Any therapy that chronically activates the sympathetic nervous system and/or diminishes parasympathetic (vagal) tone will increase the risk of cardiovascular events. In contrast, therapies that tip the autonomic balance toward parasympathetic dominance and decrease sympathetic tone will improve prognosis.1
Many studies23 have established an elevated resting heart rate as a risk factor for cardiovascular disease and mortality. What used to be considered a "normal" sinus rhythm of 90 beats/min is more worrisome compared with a reassuringly "abnormal" sinus bradycardia of 50 beats/min. An impaired chronotropic response to exercise, defined as a failure to achieve 85% of the age-predicted maximal heart rate, is another indicator of abnormal functioning of the autonomic system and is associated with increased mortality.4 Heart rate recovery after exercise, which is mediated primarily by vagal tone, has also been shown to be a significant prognostic factor.5
Intact heart rate variability (HRV) [beat-to-beat variability mediated by a dynamic autonomic nervous system, especially vagal tone] and baroreflex sensitivity (reflex-mediated changes in heart rate as a response to fluctuations in preload and venous return) are characteristics of a healthy autonomic system and are potent independent predictors of cardiovascular prognosis. Low HRV has been associated with increased risk of coronary heart disease (CHD) and mortality,6 as well as angiographic progression of coronary atherosclerosis7 and sudden cardiac death.8
Many interventions have been found to improve autonomic function. Although nonphysiologic stresses increase the risk of adverse cardiovascular events, normal physiologic sympathetic activation (eg, during exercise or sexual activity) improves physical conditioning, mood, and cardiovascular prognosis. Exercise transiently stimulates the sympathetic nervous system, but because it strongly augments background vagal activity, it is an effective and practical means to restore a healthy balance of autonomic tone.9
The Ochsner Clinic Foundation trial10 studied 40 patients following major CHD events, including 29 patients who underwent comprehensive phase II cardiac rehabilitation and exercise training programs and 11 control coronary patients who did not attend cardiac rehabilitation. The purpose of our study was to determine whether active training improves prognostic indexes of autonomic regulation of the sinoatrial node and whether the changes in baroreflex gain could be ascribed to the arterial or to the cardiopulmonary component of the overall arterial pressure/heart rate baroreflex. We determined that cardiac rehabilitation and exercise training were associated with significant improvements in autonomic markers of neuroregulation of the sinoatrial node, such as increases in R-R variance and the gain of the overall spontaneous baroreflex, with specific improvements in the cardiopulmonary component as opposed to the arterial baroreflex component of this system. These improvements may further explain the reductions in morbidity and mortality noted after formal cardiac rehabilitation and exercise training programs.10
Another intervention to improve autonomic function is the intake of marine omega-3 fatty acids (FA), principally docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Interest in the potential cardiovascular protective effects of increasing omega-3 fats began with studies of the Inuit. These Greenland Eskimos were found to have a low risk of ischemic heart disease despite a diet that was high in fat and cholesterol.11 Since the 1970s, the understanding of the important physiologic benefits of dietary omega-3 FA has continued to expand. There are several possible mechanisms whereby these dietary supplements may reduce the risk of CHD. They do appear to have a modest BP-lowering effect.1213 They also improve the lipid profile, through decreasing triglycerides and very-low-density lipoproteins and slightly raising the cardioprotective high-density lipoprotein cholesterol.14 Omega-3s also alter prostaglandin metabolism by inhibiting the production of thromboxane A2 and inflammatory cytokines, reducing the likelihood of acute coronary thrombosis.15 However, these effects of omega-3 fats have only been documented in studies using pharmacologic doses of EPA and DHA (3 to 5 g/d), and thus they may not be able to account for the major impact on the risk of fatal CHD seen with nutritional doses (< 1 g/d).161718
Evolving as the most important mechanism whereby omega-3s protect against a fatal heart attack is the reduction of serious cardiac arrhythmias, particularly during myocardial ischemia or infarction. Omega-3s have been shown to have a potent antiarrhythmic effect in animal studies.1920 In these experiments, intra-venous infusion of the major omega-3 fats DHA and EPA conferred almost immediate protection against ischemia-induced ventricular tachycardia and ventricular fibrillation.19 Similar studies have been performed in humans undergoing ventricular stimulation in the electrophysiology laboratory.21
Sudden death caused by sustained ventricular arrhythmias accounts for 50 to 60% of all deaths in persons with CHD.22 To date, the largest, prospective, randomized controlled trial on the effects of omega-3 FA is the GISSI-Prevenzione Trial.23 This study included 11,324 patients with known CHD who were randomized to receive either 300 mg of vitamin E, 850 mg of omega-3 FA, both, or neither. After 3.5 years, the group receiving omega-3 FA alone had a 45% reduction in sudden death and a 20% reduction in all-cause mortality. The former observation is consistent with an antiarrhythmic effect of fish oil omega-3 FA.
In humans, an increase in HRV following a myocardial infarction is associated with a decreased risk of fatal arrhythmias.24 Several studies suggest that omega-3 FA (especially DHA) may improve parameters of autonomic function, including HRV and baroreflex sensitivity. Hulguin et al, in this issue of CHEST (see page 1102), published a study addressing the effects of these FA on HRV. They administered fish oil (2 g/d providing 1.7 g of EPA plus DHA) or soy oil (2 g/d providing 0.13 g of the short-chain omega-3 FA, 
-linolenic acid [ALA]) to 52 residents of a Mexican nursing home. HRV was assessed with 6-min readings obtained every other day for a 2-month run-in period and a 6-month supplementation period. They reported that both supplements improved HRV, with the fish oil supplement having a somewhat greater impact than the soy capsules. These findings should be considered preliminary, however, because there was no true placebo arm in the study (although most researchers in the field would consider the 2 g of soy oil a placebo, given the very small amount of ALA it provided). There was no analysis of the differences in response between the groups; thus, the fish oil supplement may not have been statistically different from the soy supplement. In addition, the generalizability of the findings to the US dietary setting remains to be determined. Nevertheless, this study lends support to the hypothesis that omega-3 FA can improve autonomic function, and thus potentially decrease the risk for life-threatening cardiac arrhythmias.
Dallongeville et al25 conducted a cross-sectional analysis of 9,758 men 50 to 59 years old without CHD to assess heart rate and CHD risk factors in relation to the quantity and frequency of fish consumption. They found that increased fish consumption was associated with decreased heart rate in men. In a clinical trial26 at the Mid America Heart Institute, we used the "GISSI dose" of omega-3 (a daily supplement of purified fish oil to supply 1 g of EPA plus DHA) to assess changes in autonomic function. This study of 18 cardiac patients showed a significant decrease in resting pulse of 4 beats/min and a strong trend for an improvement in postexercise heart rate recovery after the omega-3 period as compared to the placebo period. Because heart rate is positively associated with risk of sudden death,23 the heart rate-lowering effect may also contribute toward the cardioprotection noted with marine omega-3 fats.
Omega-3 FA from fish are a natural, safe, and inexpensive therapy that provide a unique and potent protection against fatal dysrrhythmias that appears to be mediated, at least in part, by favorable changes in function of the autonomic nervous system. The American Heart Association has endorsed omega-3 fish oils as an important component of secondary prevention in patients with CHD.27 Although further work needs to be done to fully elucidate the optimal dose and mechanisms of action, there is little justification for not including omega-3 fish oils as part of the dietary recommendations for our patients with known or high risk of CHD. The availability of a new blood test for RBC omega-3 levels along with proposed cardioprotective cut points that we described28 now make it simpler for physicians to rationally prescribe omega-3 oils.
References
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