Association between n23 fatty acid consumption and ventricular
ectopy after myocardial infarction1–3
Patrick J Smith, James A Blumenthal, Michael A Babyak, Anastasia Georgiades, Andrew Sherwood, Michael H Sketch Jr,
and Lana L Watkins
Background: n23 (omega-3) Fatty acids are associated with a re-
duced risk of cardiovascular disease; however, the relation between
dietary intake of n23 fatty acids and ventricular arrhythmias has not
been investigated among acute post-myocardial infarction (AMI) pa-
tients—a group at elevated risk of malignant arrhythmias.
Objective: The objective was to examine the association between
n23 fatty acid consumption and ventricular ectopy among AMI
Design: In 260 AMI patients, dietary intake of n23 fatty acids was
assessed by using the Harvard food-frequency questionnaire, and
ventricular ectopy was estimated from 24-h electrocardiograph
docosahexaenoic acid 1 docosapentaenoic acid 1 a-linolenic acid)
trolled for (b ¼ 20.47, P ¼ 0.003). Higher concentrations of both
marine-based (eicosapentaenoic acid 1 docosahexaenoic acid)
(b ¼ 20.21, P ¼ 0.060) and plant-based (a-linolenic acid) (b ¼
20.33, P ¼ 0.024) fatty acids remained associated with lower ventric-
ular ectopy after cardiovascular comorbidities were controlled for.
Conclusion: These findings extend existing evidence linking n23
fatty acid consumption to a reduced risk of ventricular arrhythmias
by showing that a greater intake of n23 fatty acids may be associ-
ated with low ventricular ectopy among AMI patients.
Clin Nutr 2009;89:1315–20.
Increasing evidence over the past 3 decades indicates that n23
fatty acids may protect against the developmentof coronary heart
disease (CHD) (1–4). In particular, the intake of the long-chain
n23 fatty acids found in fatty fish or fish-oil supplements, eico-
sapentaenoic acid (EPA; 20:5n23), and docosahexaenoic acid
(DHA; 22:6n23) may provide CHD protection (2, 3, 5). Obser-
vational studies have shown that greater consumption of foods
containing long-chain n23 fatty acids is prospectively associated
with improved CHD survival (2, 3) and a reduced risk of ven-
tricular fibrillation (4) and sudden cardiac death (SCD) after
myocardial infarction (MI) (6), although increased n23 fatty acid
consumption does not appear to consistently reduce the risk of
nonfatal CHD (7), which suggests that the protective effects of
long-chain n23 fatty acids may be more strongly related to anti-
arrhythmic effects rather than to antiischemic effects.
Although previous studies have generally reported antiar-
rhythmic effects of long-chain n23 fatty acids among cardiac
patients (6, 8–10), not all studies have found protective effects
(11, 12). Furthermore, few studies have provided direct evidence
that plant-derived n23 fatty acids, such as a-linolenic acid (ALA;
18:3n23), are associated with reduced arrhythmic activity (13).
is predictive of increased risk of cardiac mortality (15), particu-
larly among post-MI patients (16). However, to our knowledge,
no studies have examined the relation between n23 fatty acid
intake and ventricular ectopy in this population, despite the in-
creased vulnerability to arrhythmia during the acute post-MI
(AMI) period. We therefore examined the association of self-
reported n23 fatty acid consumption and ventricular ectopy
among 260 patients evaluated within 72 h after acute MI.
SUBJECTS AND METHODS
A consecutive series of AMI patients were recruited during
of heart rate variability recovery after MI (the HARMONY
Study). The study was approved by the Duke University Medical
Center Institutional Review Board, and all patients gave written
informed consent before participating in the research protocol.
MI was defined by serial changes in cardiac enzymes (eg,
elevations in tropinin I or CKMB isoenzyme) .3 times the upper
1From the Departments of Psychiatry and Behavioral Sciences (PJS, JAB,
MAB, AG, AS, and LLW) and Medicine (MHS), Duke University, Durham,
2Supported by National Institutes of Health grants HL060826, HL070954,
3Reprints not available. Address correspondence to LL Watkins, Depart-
ment of Psychiatry and Behavioral Sciences, Box 3119, Duke Medical Cen-
ter, Durham, NC 27710. E-mail address: firstname.lastname@example.org.
Received August 12, 2008. Accepted for publication February 20, 2009.
First published online March 25, 2009; doi: 10.3945/ajcn.2008.26829.
Am J Clin Nutr 2009;89:1315–20. Printed in USA. ? 2009 American Society for Nutrition
limit of normal and either electrocardiograph (ECG) changes or
and screened for enrollment from January 2004 to August 2007.
Patients were excluded if they were too ill with cardiac compli-
cations, showed chronic arrhythmia or left ventricular ejection
fraction (LVEF) ,20%, or had a diagnosis of dementia, alco-
holism, recent coronary artery bypass grafting, or significant
communication barriers (Figure 1).
Harvard food-frequency questionnaire
semiquantitative food-frequency questionnaire (FFQ) during
hospitalization after acute MI (18). This FFQ includes 131 food
items with specified serving sizes corresponding to natural por-
tions (eg, 1 apple or 2 slices of pizza) or standard weight and
volume measures of the servings commonly consumed in this
study population. For each food item, participants indicated their
average frequency of consumption over the past year in terms of
the specified serving size by choosing 1 of 9 frequency categories
ranging from ‘‘almost never’’ to ‘‘?6 times/d.’’ The selected
frequency category for each food item was converted to a daily
intakevalue. For example, a response of ‘‘2–4 servings /wk’’ was
converted to 0.43 servings/d. The FFQ provides estimated daily
Ambulatory ECG monitoring
Patientsunderwent 24-hHolter monitoringwithaLifecardCF,
3-channel digitalrecorder (DelMar Reynolds,Irvine,CA)during
recordings wereanalyzedforisolated ventricularpremature beats
(VPBs), couplets, triplets, bigeminy, trigeminy, salvo, and ven-
tricular tachycardia. The total number of VPBs over this 24-h
of the above categories of ventricular arrhythmias. All Holter
Data reduction and analysis
General linear modeling equations (version 9.1.3; SAS Inc,
Cary, NC) were used to examine the association between self-
reported n23 fatty acid intakes and total VPBs over the 24-h as-
sessment period and to determine whether this association was
moderated by any clinically relevant cardiac variables. Separate
models were examined for total n23 fatty acid consumption,
fatty acids (ALA). Age, LVEF, sex, coronary artery disease se-
verity, ethnicity (white or nonwhite), history of prior MI (yes or
and cardiac medications (b-blockers and antiarrhythmics; 1 ¼
currently taking, 0 ¼ not currently taking) were selected a priori
as covariates in the model with n23 fatty acid intake as the in-
dependent predictor of 24-h VPBs. To account for the potentially
confounding effects of caloric intake, we examined the associa-
tion between n23 fatty acid consumption and ventricular ectopy
using the multivariate nutrient density method, as outlined by
Willett et al (20, 21). With this method, the intake of n23 fatty
acids was expressed per unit increase in caloric intake (in this
case, 1000 kcal). This method has intuitive understanding to
nutritionists, has been used in national dietary guidelines, and
adjusts for total energy intake. In addition to this energy-adjusted
nutrient density term, we included total caloric intake as a sepa-
rate covariate because it was directly associated with 24-h ven-
tricular ectopy (r ¼ 20.17, P ¼ 0.005), which can lead to
confounding in multivariate analyses (21). Coronary artery dis-
ease severity was indexed by the number of coronary vessels
with ?75% stenosis. LVEF was truncated such that patients with
an LVEF ? 60% were analyzed as having an LVEF of 60%. On
the basis of an analysis of model residuals, we used the natural
logarithm of the count of VPBs over the 24-h period as the re-
sponse variable in the regression model.
Continuous predictors were divided by their interquartile
range, which rescales their corresponding regression coefficients
FIGURE 1. Patient flow chart. FFQ, food-frequency questionnaire; ECG,
electrocardiogram; LVEF, left ventricular ejection fraction; CABG, coronary
artery bypass grafting.
SMITH ET AL
such that it can be interpreted as comparing a ‘‘typical’’ person in
the middle of the upper half of the predictor distribution (ie, 75th
of the predictor distribution (25th percentile). This rescaling
preserves the continuous nature of the predictor but places the
regression coefficient on a clinically meaningful scale. Before
analysis, model assumptions of additivity, linearity, and distri-
bution of residuals were evaluated and found to be adequate.
11.3 y), were primarily male (62.9%) and white (72.6%), and had
relatively preserved LV function (mean 6 SD LVEF: 52.1 6
10.8%) (Table 1). Most of the patients were taking b-blockers at
the time of their assessment (88.5%), although few were taking
antiarrhythmic medications (3.8%). Patients had expected car-
diovascular comorbidities typical of AMI patients; 59% of pa-
tients reported a history of hypertension, 41% diabetes, 12%
chronic obstructive pulmonary disorder, and 7% congestive heart
failure. Seventy-three percent of patients reported a history of
smoking, and 57% were current smokers. Sixteen percent had
a history of MI, 17% had a previous coronary artery bypass
grafting, and 15% had a history of percutaneous coronary
Omega fatty acids and VPBs
Analysis of FFQ data showed that the patients’ diets generally
contained modest amounts of n23 fatty acids (mean 6 SD daily
n23 consumption: 0.76 6 0.27 g/1000 kcal) relative to prior
studies (22). The mean (6SD) daily consumption of individual
fatty acids was also modest: EPA 1 DHA (0.14 6 0.14 g/1000
kcal) and ALA (0.60 6 0.22 g/1000 kcal) (Table 1). Ventricular
ectopy was relatively low, with substantial individual variation
across the sample (median VPB: 22; interquartile range: 122).
A greater intake of n23 fatty acids was associated with lower
ventricular ectopy (b ¼ 20.35, P ¼ 0.011), and this effect re-
mained after cardiovascular comorbidities were controlled for
(b ¼ 20.47, P ¼ 0.003) (Table 2, Figure 2). Higher intakes of
marine-based fatty acids (EPA 1 DHA) tended to be associated
with reduced ventricular ectopy after adjustment for cardiovas-
cular comorbidities (b ¼ 20.21, P ¼ 0.060). The association
between plant-based fatty acids (ALA) remained significant
after adjustment for cardiovascular comorbidities (b ¼ 20.33,
P ¼ 0.024).
We found that greater self-reported intakes of omega-3 (n23)
fatty acids was associated with reduced ventricular ectopy after
MI. Greater intake of n23 fatty acids was associated with fewer
VPBs during 24-h Holter-monitoring after acute MI, with every
1.0-g/d increase in total n23 fatty acid intake associated with
a reduction in VPBs of ’2850/d. Similarly, a 1.0-g/d increase in
EPA 1 DHAwas associated with a reduction in VPBs of 800/d.
Although a 1.0-g/d increase may represent a substantial increase
in the present sample, supplementation with 1.0 g EPA 1 DHA/d
has been shown to improve survival in previous trials (6). These
findings extend previous research showing a protective effect of
have a protective, antiarrhythmic effect in the high-risk period
after acute MI.
many studies to have a protective effect against CHD (1, 3, 7). In
a meta-analytic study of prospective cohort studies incorporating
intakes were associated with areduced riskof CHD mortality and
that every 20-g/d increase was associated with a 7% lower risk of
CHD mortality. Burr et al (23) showed a similar effect among
AMI patients, ie, that diets higher in fatty fish were associated
with a 29% reduction in 2-y all-cause mortality in the Diet and
Reinfarction Trial (DART). Several meta-analytic studies have
reported similar findings (3, 24, 25). In a meta-analysis of ran-
domized controlled trials among cardiac patients, Bucher et al
(24) found that both dietary and nondietary intakes of n23 fatty
acids were associated with reduced cardiac and all-cause mor-
tality as well as sudden death. Leon et al (25), in a meta-analysis
of randomized controlled trials using EPA and DHA as dietary
supplements, found that n23 fatty acids were associated with
Demographic and clinical characteristics of the patient sample1
Tertile of total n23 fatty acid consumption (EPA 1
DHA 1 DPA 1 ALA)
No. of vessels with significant stenosis
Peak CKMB (ng/mL)
LDL cholesterol (mg/dL)
HDL cholesterol (mg/dL)
No. of daily VPBs
Daily n23 fatty acid consumption (g/1000 kcal)
56.6 6 11.3
52.1 6 10.8
1.59 6 0.87
29.9 6 5.9
120.2 6 133.1
105.6 6 39.8
42.8 6 11.9
349.8 6 930
0.76 6 0.27
57.4 6 10.8
51.1 6 10.8
1.62 6 0.88
29.3 6 5.3
122.4 6 139.7
106.4 6 39.3
43.2 6 13.3
446.1 6 1090
0.59 6 0.19
56.6 6 9.9
50.7 6 11.0
1.59 6 0.91
29.6 6 5.6
134.4 6 147.3
106.5 6 41.0
43.3 6 12.6
385.0 6 970
0.72 6 0.18
56.1 6 13.4
53.0 6 10.6
1.56 6 0.84
30.4 6 6.4
114.1 6 118.5
104.6 6 39.6
42.0 6 10.0
235.0 6 716
0.94 6 0.31
1All values are means 6 SDs. CKMB, creatine kinase MB isoenzyme; LVEF, left ventricular ejection fraction; VPBs,
ventricular premature beats; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; ALA,
n–3 FATTY ACIDS AND VENTRICULAR ECTOPY
reductions in cardiac mortality, but did not have an effect on ar-
of controlled trials showed that n23 consumption was not asso-
ciated with reduced fatal or nonfatal CHD events (26).
Our findings are consistent with multiple prospective studies
and randomized controlled trials that have investigated the anti-
arrhythmic effects of n23 fatty acids among cardiac patients (13,
27). Albert et al (28), in a prospective case-control study, found
that higher blood concentrations of n23 fatty acids were associ-
ated with a reduced risk of SCD during a 17-y follow-up among
men in the Physicians’ Health Study. Aarsetoy et al (4) examined
this association among 460 acute coronary syndrome patients,
finding that those patients with lower serum n23 concentrations
were more likely to exhibit ventricular fibrillation than were
patients who did not experience arrhythmic complications.
Marchioli et al (6), in a randomized controlled trial of 11,323
patients, found that 3 mo of n23 supplementation was associated
as early as 4 mo after initiation of treatment. Leaf et al (29) also
found modest support for a protective effect of n23 fatty acids
among 402 high-risk patients with implanted cardioverter/de-
the time to the first arrhythmic event. Similarly, Sellmayer et al
(10) found that n23 supplementation reduced VPBs among 79
patients with suspected ischemic heart disease and moderate
ventricular ectopy at baseline.
Not all studies have reported a protective effect of n23 fatty
acids, however. Several controlled trials with smaller samples
have shown that n23 supplementation may not reduce VPBs in
cardiac patients (30, 31). More recently, Brouwer et al (32)
found no protective effect of n23 fatty acids in a double-blind
multicenter trial of 546 ICD patients. Although it is unclear why
findings have varied to such a degree between studies, drug-
nutrient interactions and/or variations in the comorbidities of the
participants may partially explain the observed pattern of results
(33). The discrepancy between our positive findings and the
negative results reported among ICD patients may be partially
explained by the superior relative health of our sample because
of specific exclusion criteria requiring greater patient mobility,
small sample sizes, and the low statistical power of these pre-
ALA has been prospectively associated with a reduced risk of
CHD development in many studies (34–38) and has been shown
to have antiarrhythmic properties in animal studies (39). In
a systematic review of clinical trials, Harper and Jacobson (7)
found that interventions using ALA supplements or ALA-
enriched diets showed possible benefits on SCD and nonfatal
infarction, although many of the existing studies at this time
were limited by design flaws and reduced statistical power.
Brouwer et al (34) reported similar findings, ie, that ALA con-
sumption may be associated with a reduced risk of fatal heart
disease but an increased risk of prostate cancer. More recent
systematic reviews have failed to support these findings, how-
ever, showing that ALA supplementation does not reduce
cardiac and sudden death (40). At present, the potentially anti-
arrhythmic effects of ALA are largely supported by epide-
miologic observational studies and have yet to be supported in a
large-scale randomized controlled trial (13).
n23 Fatty acids may be associated with reduced ventricular
ectopy by modulation of calcium ion fluxes (41, 42), stabilization
of cardiac myocytes (43), reduced platelet adhesion and re-
activity (44, 45), improved endothelial function (46), and altered
metabolism of adhesion molecules (47). Intravenous adminis-
tration of fish-oil extract, DHA, EPA, and ALA have all been
shown to effectively reduce the ventricular fibrillation threshold
in canine models of exercise-induced adrenergic stress and
myocardial ischemia (48, 49). However, the short-term benefits
of n23 administration remain unclear in humans.
The present study had several limitations. First, because our
study was cross-sectional, the causal relation between n23 fatty
acid consumption and ventricular ectopy could not be de-
termined. It is possible that individuals who experienced more
symptomatic ectopic beats were advised to alter their diets to
Association between total n23 fatty acid intake (eicosapentaenoic acid 1
docosahexaenoic acid 1 docosapentaenoic acid 1 a-linolenic acid) and
24-h log-transformed ventricular premature beats1
range of the
Cardiac medication use
Intake of n23 fatty
acids, g ? d21?
1The regression coefficients are from a multivariate model. LVEF, left
ventricular ejection fraction; MI, myocardial infarction.
FIGURE 2. n–3 Fatty acid consumption and log-transformed 24-h
ventricular premature beats (VPBs), adjusted for age, left ventricular
ejection fraction, sex, coronary artery disease severity, ethnicity, history of
prior myocardial infarction, BMI, diabetes, HDL cholesterol, LDL
cholesterol, cardiac medication use, and total caloric intake (n ¼ 260).
SMITH ET AL
include greater amounts of n23 fatty acid–rich foods or decided
to do so of their own accord. However, ancillary analyses in
which we controlled for any variables associated with previous
cardiac medical attention (eg, previous coronary artery bypass
grafting) did not alter the n23 and ventricular ectopy association,
which indicated that decreased ectopy was more likely a result of
improved diet and not the cause thereof. Second, our measure of
n23 fatty acid consumption was based on self-reported dietary
intake. Although the Harvard FFQ has been widely validated
using other more objective measures of dietary intake (18, 50), it
is unclear whether self-report was influenced by the hospital
setting or other sources of reporting bias. Furthermore, self-
reported dietary intake is an inherent source of error, and it is
unclear how this error may have influenced the observed asso-
ciation between n23 fatty acid intake and VPBs. Third, because
of our study criteria, which excluded individuals with compro-
mised LVEF, our results may only be generalized to AMI pa-
tients with relatively preserved LV function. Although frequent
VPBs are independently associated with SCD among patients
with a history of MI (51–53), VPBs in persons with preserved
LV function may be less predictive of clinical events. Fourth, the
present analysis was conducted during the initial days after acute
MI and did not incorporate data from other time points. It is
unclear from the present analysis whether n23 fatty acid levels
would be associated with reduced ventricular ectopy at later
time points after MI. Similarly, given the modest levels of both
n23 fatty acids and ventricular ectopy in our sample, it is un-
clear how the magnitude of this relation may differ among other
cardiac samples. A final limitation inherent to our observational
methodology is the potential for unmeasured variables to have
influenced the observed pattern of results.
Results of the present analysis indicate that a greater intake of
n23fatty acidsisassociatedwithreducedventricular ectopyafter
MI. The association between n23 intake and VPBs was ap-
proximately half the strength of that observed with coronary
occlusions, which indicated a clinically meaningful magnitude.
These results could have important implications for the man-
agement of AMI patients, who are at increased risk of malignant
Future randomized controlled trials should investigate whether
the administration of fish-oil supplements during hospitalization
for AMI is associated with reduced SCD during this time period.
Furthermore, future studies would benefit from more extensive
ECG follow-up assessments that examine patients prospectively
after AMI and incorporate longer follow-up time-points.
revised version of this manuscript.
The authors’ responsibilities were as follows—LLW, JAB, MAB, AS, and
MHS: initiated, designed, and attracted grant support for the study; PJS and
AG: recruited subjects and conducted study assessments; PJS: conducted the
statistical analyses and prepared the manuscript; and all authors reviewed and
approved the final version of the manuscript. None of the authors had a po-
tential conflict of interest.
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