Fish Consumption Is Associated With Lower Heart Rates

In the last decade, the protective cardiovascular effect of fish consumption has been firmly established.^1,2 In cohort studies, fish consumption is associated with decreased risk of coronary heart disease (CHD) mortality^3,4 and sudden death.⁵ Recently, blood levels of long-chain n-3 fatty acids were found to be strongly associated with a reduced risk of sudden death among men without prior cardiovascular disease.⁶ Similar associations were reported in secondary prevention intervention trials. In the Diet And Reinfarction Trial (DART), increasing consumption of fatty fish to 2 or 3 portions per week reduced mortality in men with previous myocardial infarction.⁷ In the GISSI-II trial (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico), daily supplementation with 1 g of n-3 fatty acids lowered the risk of sudden death.^8,9

Increased heart rate is a risk factor for sudden death.^10–13 Therefore, one possible mechanism by which n-3 fatty acid may prevent sudden death and fatal cardiovascular events is by regulating cardiac rhythm¹⁴ and preventing arrhythmia.¹⁵ In support of this hypothesis, clinical evidence has accumulated showing a significant impact of n-3 fatty acids on ECG parameters. For example, the n-3 fatty acid content of blood cells and serum cholesterol esters is associated with increased heart rate variability.^16–18 In short-term pharmacological trials, highly purified n-3 fatty acids reduced heart rate, diminished ventricular extrasystoles, and normalized cardiac rhythm in healthy and high-CHD-risk subjects.^19–23

Most of the evidence linking n-3 consumption to ECG parameters has been obtained in clinical studies using high doses of purified fatty acids, and to date, it is not known whether regular fish consumption has any effect on cardiac rhythm. This is particularly important because fish is the most important source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the staple diet. Therefore, we investigated the association between fish consumption and heart rate in a cross-sectional study of European men at contrasting levels of CHD risk.

Methods

This study was conducted in a sample of 9758 men, age 50 to 59 years, without CHD who were recruited in 4 collaborating World Health Organization-MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) centers in the United Kingdom (Belfast; n=2399) and France (Lille, Strasbourg, and Toulouse; n=7359). Recruitment and examination methods have been described previously.²⁴

Self-administered questionnaires related to demographic factors, socioeconomic factors, and diet were completed at home by the participants and checked with the subject by survey staff at the clinic. Data on educational level, occupational activity, personal and family history, tobacco and alcohol consumption, drug intake, and physical activity were also collected. Educational level was classified into 3 categories: primary school, secondary school, and technical and university. Physical activity was assessed during work and leisure, on working days and weekends. Subjects were classified into the following 4 categories: intense exercise, if they took intense physical activity of more than 20 minutes 3 times or more per week; regular exercise, corresponding to intense physical activity 1 to 2 times per week; light physical activity, every week; and no leisure-time physical activity. Intense physical activity was defined by a physical activity that provoked sudation, increased heartbeats, and shortness of breath. Smoking habits were determined from questions on present and past habits and number and type of cigarettes, cigars, or pipes smoked per day. Smokers were defined in 3 categories: currently smoking at least 1 cigarette per day, ex-smokers, and never-smokers. Alcohol consumption was assessed by a questionnaire in which the subject reported his mean consumption (in units) of wine, beer, cider, and spirits for each day of the week. Intake of alcohol was expressed in drinks per day (1 drink equals 10 mL of pure ethanol). CHD was assessed with the London School of Hygiene Cardiovascular (Rose) Questionnaire for Chest Pain on Effort and Possible Infarction,²⁵ and a standard 12-lead ECG was recorded.

Fish consumption was assessed by means of 1 question from a semiquantitative food-frequency questionnaire that asked for the frequency of a standard portion of fish consumption. No data were available to differentiate the type of fish or, particularly, fatty from nonfatty fishes. Individuals were divided into 4 categories: (1) consumption of a standard portion of fish less than once per week (n=2662), (2) once per week (n=4576), (3) twice per week (n=1964), and (4) more than twice per week (n=556).

Anthropometric measurements included height (to the nearest centimeter) and body weight (to the nearest 200 g) of subjects in light clothing without shoes. Body mass index (BMI) was computed as weight (in kilograms) divided by height squared (m²). Blood pressure was measured once at the end of the examination, after a 5-minute rest in the sitting position. Hypertension was defined by systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or current blood pressure–lowering treatment. Heart rate was measured after 5 minutes of rest in the sitting position with an automatic device (the Spengler SP9) for blood pressure measurement that also recorded heart rate.

Blood Sampling and Assay Procedures

Plasma total cholesterol and triglyceride levels were measured by enzymatic methods with reagents from Boehringer Mannheim. HDL cholesterol was measured after precipitation of apolipoprotein B–containing lipoproteins with phosphotungstate magnesium chloride (Boehringer). The erythrocyte phospholipid fatty acid composition was determined in a random subsample from each center (for a total of 407 men) by gas chromatography (Palo Alto, Calif) equipped with a flame ionization detector and capillary column as described previously.²⁶

Statistical Analysis

Statistical analysis was conducted with SAS software (release 6.12; SAS Institute). The general linear model procedure was used to compare mean values of fatty acids, coronary risk factors, and heart rate across categories of fish consumption. Adjustment variables were age, recruitment center, education level, physical activity, smoking habit, alcohol consumption, BMI, and use of antiarrhythmic drugs (β-blockers, amiodarone, digitalis, and calcium channel blockers).

Results

Table 1 presents characteristics of the subjects according to fish consumption. The proportions of subjects consuming fish less than once per week, once per week, twice per week, and more than twice per week were 27.3%, 46.9%, 20.1%, and 5.7%, respectively. There was no difference between countries in the distribution of fish consumption. In contrast, fish consumers were more educated (P<0.0001), drank less alcohol (P<0.02), were less often smokers (P<0.0001), and were more physically active than nonconsumers.

Table 2 shows the fatty acid content of erythrocyte phospholipid according to fish consumption. There was no statistically significant difference among categories of fish consumption for palmitic, stearic, oleic, total saturated, total monounsaturated, total polyunsaturated, and n-6 fatty acids. In contrast, EPA (P<0.0005), DHA (P<0.0001), and total n-3 fatty acid (P<0.0008) content of erythrocyte phospholipid increased across fish consumption categories.

Triglycerides (P<0.0001) and systolic (P<0.006) and diastolic (P<0.0001) blood pressure were lower and HDL cholesterol levels (P<0.004) were higher among fish consumers than among nonconsumers (Table 3). In contrast, there was no evidence for any association between fish consumption and total cholesterol or LDL cholesterol levels.

Heart rate decreased across categories of fish consumption (P<0.0001; Table 4). After adjustment for age, center, education level, physical activity, smoking habit, alcohol consumption, BMI, and antiarrhythmic drugs, heart rate remained statistically lower in fish consumers (P for trend <0.0001). Adjusted heart rate ranged from 67.5 bpm in men consuming fish less than once per week to 65.6 bpm in those consuming fish more than twice per week. There was no evidence for heterogeneity among recruitment centers, which suggests a consistent association between fish consumption and heart rate in populations at contrasting levels of CHD risk.

Finally, in the subsample of 407 men, there was a statistically significant association between age- and center-adjusted erythrocyte DHA content (but not with EPA or other fatty acids) and heart rate (β=−0.73; P<0.03; Table 5). After further adjustment for education, physical activity, smoking habits, alcohol consumption, BMI, and antiarrhythmic drugs, this association was attenuated (β=−0.55; P<0.11). In addition, the DHA and total n-3 fatty acid content of erythrocyte was associated with diastolic blood pressure (β=−1.85, P<0.01 and β=−0.48, P<0.03, respectively), and EPA levels of erythrocyte were associated with plasma triglycerides (β=−0.16; P<0.05). There were no other statistically significant associations between erythrocyte free fatty acid content and cardiovascular risk factors.

Discussion

There is a strong indication that fish consumption reduces the risk of sudden cardiac death in patients with preexisting cardiovascular disease and in healthy individuals. The mechanism of this protection is under active investigation. Long-chain n-3 fatty acids from fish oil affect cardiovascular physiology at many different levels, including hemodynamics, hemostasis, lipids, cytokines, endothelial function, and antiarrhythmic properties (for review, see Kris-Etherton et al² and Jones and Lau²⁷). Of particular interest, n-3 fatty acids rapidly induce biochemical and morphological changes of atherosclerosis plaque that can enhance its stability.²⁸ In addition, long-chain n-3 fatty acids also prevent ischemia-induced ventricular fibrillation in dog models of sudden cardiac death.^29–32 The effects of n-3 fatty acids on the electrophysiology of the heart are reflected in surface ECGs.^{16–18,20–23}

In the present cross-sectional population study, we investigated whether fish consumption affects heart rate in healthy men without a personal history of CHD. This is particularly important because sudden death most often occurs in men without a known history of CHD and also because dietary fish intake is the principal source of EPA and DHA in the staple diet. The results showed that regular consumption of fish is associated with decreased heart rate in healthy men. These findings suggest that fish consumption affects regulation of heart rate in middle-aged men. The present study adds to evidence from pharmacological trials that consumption of fish, rather than supplements, may have a beneficial effect on heart rate. This observation has important implications for primary prevention of sudden death.

The most likely active component of the effect of fish on heart rate is n-3 fatty acids and possibly DHA. This interpretation is supported by the finding of an inverse relationship between heart rate and DHA content of erythrocyte phospholipid. It is also consistent with short-term dietary trials with n-3 fatty acids.^19,20 In those studies, pharmacological supplementation with highly purified DHA but not with EPA reduced heart rate in healthy and overweight subjects. In contrast, studies in dog models of sudden death showed that purified EPA, DHA, and α-linolenic acid can prevent ischemia-induced ventricular fibrillation.³¹ Therefore, additional studies are necessary to assess the contribution of individual n-3 fatty acids to cardiac electrophysiological regulation.

In the present study, the relationship between fish intake and heart rate was linear between men who consumed fish less than once per week and those declaring their consumption to be more than twice per week. For each increase in fish consumption of 1 portion per week, there was an average reduction of 0.5 bpm. Although this effect appears somewhat limited in absolute terms, it might still be important at the population level for the prevention of fatal cardiac events. In the Paris Prospective Study, which included more than 7700 men followed up for 23 years, the mean difference in heart rate between controls and patients who died of sudden death was 4.1 bpm,³³ in the range of the average 2-bpm difference between frequent consumers and nonconsumers of fish. Furthermore, the relationship between heart rate and risk of sudden death was linear,¹³ which suggests that even a small reduction in heart rate might have a significant public health impact because of the high incidence of fatal events in the population.

Heart rate may be affected by n-3 fatty acids in different ways. There is now strong in vitro evidence that n-3 fatty acids stabilize the electrical activity of isolated cardiac myocytes by elevating the action potential threshold and prolonging the relative refractory time. These striking electrophysiological effects result from the modulation by free n-3 fatty acids of sodium and calcium channels through the cell membrane (for review, see Kang and Leaf^15,32). These potent actions might also affect electrical stimuli, resulting in a lowering of heart rate. Alternatively, n-3 fatty acids could affect the sympathetic and parasympathetic control of heart rate by virtue of their interaction with the adrenergic system. Finally, the changes in heart rate may be due to some underlying benefit of fish components on cardiac physiology, such as improved ventricular or endothelial function and lower blood pressure, which may result in reduced heart rate.²⁰

The present study has several limitations. First, the cross-sectional design does not enable us to examine the temporality of the observed associations. Second, because fish consumers have different nutritional habits than nonconsumers, it is also possible that our findings are due to some unknown confounding nutritional variables that we were unable to control for in our analyses. Fish consumers may also consume special foods or nutrients that have heart rate–modifying properties, such as alcohol. To minimize the possibility of a residual effect, adjustments were performed with alcohol as a continuous variable or different categories of consumption. Third, fish consumers also differ from nonconsumers in a number of life habits and CHD risk factors that may play the role of a confounding factor associated both with an increased heart rate and cardiac fatal events (ie, physical activity and smoking). Although statistical adjustments for known confounders were made, a residual effect or an influence of unmeasured factors is still possible. However, the finding of consistent associations between fish intake and heart rate in Belfast and France, despite different life styles and contrasting cardiovascular risk factors between countries, suggests that this association is partly independent of lifestyle factors. Among possible confounders, physical activity is particularly important because of its strong association with reduced heart rates and fish intake. Therefore, to account for its possible residual effect, several analyses were performed that included activity at work and during leisure time, which did not affect the conclusions. Finally, fish consumption was assessed by means of a food-frequency questionnaire, the accuracy of which is somewhat limited. However, the finding of a significant agreement between reported fish intake and n-3 fatty acid content of erythrocyte fatty acids suggests that reported fish consumption was reasonably accurate. In any case, a misclassification of fish consumers would tend to underestimate the strength of the association.

In conclusion, the results of the present study provide evidence that fish consumption is associated with a decreased heart rate in men age 50 to 59 years without a known history of CHD. Given the existing evidence implicating increased heart rate as a risk factor of sudden death, this finding provides a possible explanation for the lower risk of sudden death among fish consumers. It is now well established that EPA and DHA have pleiotropic effects on the cardiovascular system. Therefore, the combined effect of these fatty acids on cardiac electrophysiology, vascular function, and atheroma plaque structure very likely contributes to prevention of fatal cardiac events.

Appendix

The PRIME Study Group comprised the Strasbourg MONICA Project, Department of Epidemiology and Public Health, Faculty of Medicine, Strasbourg, France (D. Arveiler, B. Haas); the Toulouse MONICA Project, INSERM U558, Toulouse, France (J. Ferrières, J.B. Ruidavets); the Lille MONICA Project, INSERM U508, Lille, France (P. Amouyel, M. Montaye); the Department of Epidemiology, Queen’s University, Belfast, Northern Ireland (A. Evans, J. Yarnell); the Department of Atherosclerosis, SERLIA-INSERM U545, Lille, France (G. Luc, J.M. Bard); the Laboratory of Hematology, La Timone Hospital, Marseille, France (I. Juhan-Vague); the Laboratory of Endocrinology, INSERM U326, Toulouse, France (B. Perret); the Vitamin Research Unit, University of Bern, Bern, Switzerland (F. Gey); the Trace Element Laboratory, Department of Medicine, Queen’s University, Belfast, Northern Ireland (D. McMaster); the DNA Bank, INSERM U525 INSERM, Paris, France (F. Cambien); and the Coordinating Center, INSERM U258, Villejuif, France (P. Ducimetière, P.Y. Scarabin, A. Bingham).

Footnotes