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2
*
Wageningen Centre for Food Sciences (WCFS), Wageningen, the Netherlands;
Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, the Netherlands;
**
Department of Medical Informatics, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Rotterdam, the Netherlands; and
Cardiology Department, Leiden University Medical Center, Leiden, the Netherlands
2To whom correspondence should be addressed. E-mail: anouk.geelen{at}staff.nutepi.wau.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • (n-3) fatty acids • ventricular arrhythmias • electrocardiogram • QTc interval • electrophysiology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–4
). Intervention studies show an effect of (n-3) fatty acids on mortality and sudden cardiac death, which is already visible after only a few months, and no effect on nonfatal events (5
,6
). This suggests an effect of (n-3) fatty acids on arrhythmia rather than on atherosclerosis or thrombosis. In animal studies, (n-3) fatty acids prevented and reduced the severity of arrhythmias, increased the threshold for ventricular fibrillation and improved the electrical stability of animal hearts (7
–11
). The (n-3) fatty acids also prevented and terminated tachyarrhythmias in cultured neonatal cardiomyocytes (12
,13
). Thus, we consider an effect of (n-3) fatty acids on arrhythmia the most plausible hypothesis for explaining the protective effect of (n-3) fatty acids on heart disease.
In vitro, (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 electrophysiologic effects may result from an action of free (n-3) fatty acids on sodium (14
–16
) and calcium (17
,18
) currents through heart cell membranes, which are essential for heart rhythm. The (n-3) fatty acids prolong the duration of the inactivated state of the sodium and calcium channels in addition to inhibiting the conductance of these channels (4
).
The striking effects on the electrophysiology of the whole heart in living organisms are expected to be detectable in a surface electrocardiogram (ECG),3
regardless of the precise processes that underlie the effects of (n-3) fatty acids at the cellular level. In dogs surgically prepared to be susceptible to ventricular fibrillation, infusion with (n-3) free fatty acids not only prevented cardiac arrhythmia, but also decreased the duration of the heart-rate corrected QT interval (QTc) (19
). The QT interval on the ECG reflects the duration of activation and recovery of the ventricular muscle and may be a relevant measure for arrhythmia risk. In the general population, several studies, although not all (20
), showed that subjects with a longer duration of QTc have an increased risk of all-cause and cardiac mortality (21
–23
). Thus, a decrease in the duration of QTc by (n-3) fatty acids in humans would support a protective effect of (n-3) fatty acids on heart disease.
The (n-3) fatty acids may also affect ECG characteristics other than QTc. For instance, QRS duration is a measure of ventricular depolarization. Apex-to-end-T duration (aeT) (24
,25
), T-loop morphology (26
), and the spatial QRS-T angle (27
,28
) have been proposed as markers of the heterogeneity of ventricular repolarization, which provides the condition for the genesis of ventricular arrhythmias.
Effects of (n-3) fatty acids on the standard ECG of humans have not been reported. Demonstration of such effects at the organ level could provide clues concerning how (n-3) fatty acids may prevent arrhythmia and sudden cardiac death. They would also suggest a new class of biomarkers, which could be used to study potentially antiarrhythmic food ingredients in humans. Therefore, we investigated the effect of (n-3) fatty acids on QTc, QRS duration, aeT, T-loop morphology and spatial QRS-T angle in healthy subjects.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Medical Ethical Committee of Wageningen University approved the study protocol. Subjects gave their written informed consent after we had explained the study protocol to them. Subjects were eligible if they were 50–70 y old and did not use drugs known to affect heart rhythm or autonomic regulation. In addition, subjects with past or present cardiovascular disease were excluded, as were those with diabetes, asthmatic complaints, mean systolic blood pressure >170 mm Hg, or mean diastolic blood pressure >100 mm Hg. Women had to be postmenopausal. At the start of the run-in period, we recorded a standard 12-lead ECG and performed blood pressure measurements for screening purposes in 97 subjects. Eight subjects were excluded and referred to their general practitioner, because their ECG warranted further medical examination. Two subjects were excluded because they had mean systolic blood pressure >170 mm Hg during repeated measurements. One subject was excluded because of allergy to gelatin (component of capsules) and two subjects dropped out during the study. Thus, 84 subjects successfully completed the study.
Design and treatment.
A power calculation showed that 35 subjects per group would be sufficient to detect a significant difference (P < 0.05) in response of QTc duration between the fish oil group and the placebo group with a power of 80%, if the real population effect exceeded 10 ms. The study was placebo controlled and double blind. We performed the baseline ECG measurements after a run-in period of 4 wk in which all subjects received placebo and we repeated the ECG measurements at the end of the 12-wk intervention period. Subjects were stratified by habitual fish consumption, diastolic blood pressure and sex and then randomized to receive either a daily dose of 3.5 g fish oil or placebo oil (high oleic sunflower oil) (Loders Croklaan, Wormerveer, the Netherlands) during the 12-wk intervention period. The oils were administered in seven soft gelatin capsules daily each containing 500 mg oil and 
0.15 mg 
-tocopherol, 0.75 mg 
-tocopherol and 0.60 mg 
-tocopherol as antioxidants. The peroxide value of the fish oil was 0.9 mEq/kg and of the placebo oil, 0.3 mEq/kg (Banner Pharmacaps Europe B.V., Tilburg, the Netherlands). Fish oil and placebo capsules were indistinguishable. The daily dose of fish oil provided 700 mg eicosapentaenoic acid [EPA, 20:5(n-3)], 560 mg docosahexaenoic acid [DHA, 22:6(n-3)] and 260 mg of other (n-3) fatty acids. The placebo capsules contained mainly oleic acid [18:1(n-9)].
Subjects were asked to maintain their usual diet and lifestyle, but not to eat any fish or seafood during the study. Compliance of the subjects with the protocol was objectively checked by analysis of (n-3) fatty acids in serum cholesteryl esters. We also counted the number of leftover capsules returned by the subjects. Intakes of energy, fatty acids, cholesterol and alcohol were estimated twice by a telephone-administered 24-h dietary recall. Body height and weight were measured at the start of the run-in period and body weight was monitored during the study.
ECG measurement and signal analysis.
After the subjects had lain down for a 30-min rest, we recorded the 12-lead ECG for 10 min on a modified Mortara ST-Surveyor electrocardiograph (Mortara Instrument, Mortara Rangoni Europe, Bologna, Italy). The subjects were asked to breathe at a fixed rate of 15 breaths/min because these recordings were also used in a related study that investigated the effect of (n-3) fatty acids on risk indicators of arrhythmia that reflect autonomic cardiac control: heart rate variability and baroreflex sensitivity (Geelen et al., unpublished data). The ECG recordings were processed without knowledge of treatment type or other subject variables. We used min 3 of the 10-min recordings for the analysis of the ECG measures. For data processing, the Modular ECG Analysis System (MEANS) was used. MEANS determines the overall QT interval for all 12 leads together on a representative beat, which results from selective averaging of dominant beats (29
). Bazett’s formula (QTc = QT/
RR) was used to correct for heart rate (30
). The aeT was calculated for leads V2–V5 as the difference between the end of the T wave and the peak of the T wave. T-loop morphology was characterized by two parameters, i.e., the spatial amplitude of the T loop and its width. These parameters were determined as described previously (26
). The QRS-T angle was taken as the spatial angle between the mean QRS axis and T axis.
Fatty acid analysis.
We took blood samples from subjects that were not fasting at the start of the run-in period and at the beginning, middle and end of the intervention period. Serum cholesteryl fatty acids were analyzed as previously described (31
).
Statistical analysis.
The primary outcome of the study was the response of the QTc. Secondary, more explorative outcomes were the responses of QRS duration, aeT, T-loop morphology and QRS-T angle. Individual responses were calculated as the value obtained for a subject at the end of the intervention period minus the value obtained for that same subject at the start of the intervention period. Differences in response between the fish oil group and the placebo group were analyzed by a two-sided Student’s t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Compliance was confirmed by a change in the proportion of EPA in serum cholesteryl esters from 0.76 ± 0.29 to 2.91 ± 0.67 g/100 g fatty acids in the fish oil group and by no change (0.69 ± 0.27 to 0.65 ± 0.24 g/100 g fatty acids) in the placebo group. The capsule count indicated that 98% of the capsules were ingested. Diaries kept by the subjects did not reveal any deviations from the protocol that could have affected the outcome. Body mass index remained constant in both groups. Background dietary intake was similar in the two treatment groups. The fish oil group consumed 35% of energy as fat, 0.5% of energy as (n-3) fatty acids, 6% of energy as alcohol and 23 mg/MJ cholesterol. In the placebo group, the corresponding figures were 33, 0.4 and 5%, and 23 mg/MJ.
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); it decreased by 0.8 ms (95% confidence interval, -6.1 to 4.4 ms) or 0.2% in the fish oil group compared with the placebo group (Table 2
). Intake of (n-3) fatty acids did not affect QRS duration, aeT, T-loop morphology or and QRS-T angle (Table 2)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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On the basis of the results of in vitro studies and one study in dogs, we hypothesized that (n-3) fatty acids would decrease the QTc duration in humans. Kang et al. (13
) showed that (n-3) fatty acids shorten the duration of the action potential, which may result in a shorter duration of the QT interval on the ECG. Our findings suggest that the mechanism postulated from in vitro and animal studies can not be directly translated to healthy humans because (n-3) fatty acids did not affect the ECG. The results of our study are in agreement with the results of a cross-sectional study that did not find a relationship between (n-3) fatty acids in cholesteryl esters and the QTc duration from 24-h Holter recordings in healthy subjects (32
).
However, our results do not exclude the possibility that (n-3) fatty acids could produce detectable effects on the ECG only in more susceptible people. Changes in ECG characteristics in healthy subjects may be too subtle to be demonstrated in a study like this. It is possible that (n-3) fatty acids affect the abnormal ECG in more susceptible populations of, for example, postinfarction patients, who have a much higher risk of arrhythmia than healthy subjects. Another explanation for our lack of findings might be that effects of diet on the electrophysiology of the human heart are too small to cause appreciable ECG changes. Nevertheless, (n-3) fatty acids may be the most effective dietary means to improve cardiovascular health with risk reductions of 30–50% (3
,5
,33
,34
).
The dose of 1.5 g of (n-3) fatty acids in the present study is equivalent to 2 servings of fish daily. Several epidemiologic studies suggest that the cardioprotective effect of (n-3) fatty acids is already present at low doses of 200 mg (n-3) fatty acids daily and that increasing the intake of fatty fish beyond 1 or 2 meals per week does not confer additional benefit (33
,35
,36
). Also, in the GISSI-Prevenzione trial, 1 g of (n-3) fatty acids daily was enough to lower the rate of death, nonfatal myocardial infarction and stroke (3
). Thus, the dose of (n-3) fatty acids in our study was high enough to detect relevant effects on the ECG.
In general, our results do not support the hypothesis that (n-3) fatty acids prevent cardiac arrhythmia through electrophysiologic effects on heart cell membranes, although an effect on the ECG in more susceptible populations should be tested. Our findings also do not suggest that intake of (n-3) fatty acids in healthy persons could not prevent future arrhythmias. Long-term intake of (n-3) fatty acids may reduce the development of an arrhythmogenic substrate during future ischemic events; such effects, of course, could not be demonstrated in the current study. To further study the mechanism of the antiarrhythmic effect of (n-3) fatty acids, research must include more susceptible populations such as postinfarction patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: aeT, apex-to-end-T duration; DHA, docosahexaenoic acid; ECG, electrocardiogram; EPA, eicosapentaenoic acid; MEANS, Modular ECG Analysis System; QTc, heart-rate corrected QT interval.
Manuscript received 7 June 2002. Initial review completed 24 June 2002. Revision accepted 5 July 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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