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STROKEAHA.117.017935

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Original Contribution
Substitution of Linoleic Acid for Other Macronutrients
and the Risk of Ischemic Stroke
Stine K. Venø, MD; Erik B. Schmidt, MD, DMSc; Marianne U. Jakobsen, MSc, PhD;
Søren Lundbye-Christensen, MSc, PhD; Flemming W. Bach, MD, DMSc; Kim Overvad, MD, PhD
Downloaded from http://stroke.ahajournals.org/ by guest on October 26, 2017
Background and Purpose—Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on
stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its subtypes with a higher
intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or
glycemic carbohydrates.
Methods—In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline,
information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on
ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified
according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid
for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of
ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic
stroke adjusting for appropriate confounders.
Results—During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic
stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard
ratio, 0.98; 95% confidence interval, 0.83–1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval,
0.63–1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78–1.09), although not statistically
significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions.
Conclusions—This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty
acid with linoleic acid may be associated with a lower risk of ischemic stroke. (Stroke. 2017;48:00-00. DOI: 10.1161/
STROKEAHA.117.017935.)
Key Words: cohort studies ◼ epidemiology ◼ fatty acids, omega-6 ◼ linoleic acid ◼ stroke
N
-6 polyunsaturated fatty acids (PUFAs) are the most
widely consumed PUFAs in the human diet and primarily derived from intake of vegetable oils (eg, corn, sunflower,
safflower, and soy oil). The primary n-6 PUFA in the diet is
linoleic acid (LA), which accounts for ≈90% of the dietary
intake of n-6 PUFAs.1
The influence of dietary factors on ischemic stroke risk is
not well explored; however, intake of LA is known to reduce
plasma levels of low-density lipoprotein cholesterol2,3 and to
reduce the risk of hypertension.4,5 Therefore, a high intake
of LA is proposed to prevent ischemic stroke. If energy balance has to be maintained, a higher intake of LA must be followed by a concomitant lower intake of other macronutrients.
Previous studies showed that replacing saturated fatty acids
(SFAs) or carbohydrates with unsaturated fatty acids was
inversely associated with the risk of cardiovascular disease.6,7
However, to our knowledge, no studies have specifically
investigated substitution of LA for SFA, monounsaturated
fatty acids (MUFAs), or glycemic carbohydrates in relation to
the risk of ischemic stroke.
According to the TOAST (Trial of ORG 10172 in Acute
Stroke Treatment) classification,8 ischemic stroke can be categorized into 5 subtypes. The pathogenesis varies between
these subtypes, and a potential effect of LA may differ
between subtypes. With this study, we aimed at clarifying the
relationship between intake of LA and the risk of ischemic
stroke, as well as subtypes of stroke with emphasis on a higher
intake of LA and a concomitant lower intake of SFA, MUFA,
or glycemic carbohydrates in a cohort where a large number
of cases with verified ischemic stroke were identified.
Methods
Diet, Cancer, and Health
The Danish Diet, Cancer, and Health cohort has previously been
described in details.9 In brief, 160 725 men and women living in the
urban areas of Copenhagen or Aarhus were invited to participate in
Received May 4, 2017; final revision received September 12, 2017; accepted September 21, 2017.
From the Department of Cardiology (S.K.V., E.B.S., K.O.), and Unit of Clinical Biostatistics (S.L.-C.), Aalborg University Hospital, Denmark;
Department of Clinical Medicine (S.K.V., E.B.S.), Aalborg University, Denmark; and Department of Public Health, Section for Epidemiology (M.U.J.,
K.O.), Aarhus University, Denmark; and Department of Neurology (F.W.B.), Aarhus University Hospital, Denmark.
Presented in part at the International Society for the Study of Fatty Acids and Lipids (ISSFAL), EuroPrevent, and European Atherosclerosis Society (EAS).
Correspondence to Stine K. Venø, MD, Department of Cardiology, Aalborg University Hospital, Søndre Skovvej 15, 9000 Aalborg, Denmark. E-mail
[email protected]
© 2017 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.117.017935
1
2 Stroke December 2017
the study between 1993 and 1997. A total of 57 053 subjects corresponding to 35% accepted the invitation. With the invitation, a validated 192-item semiquantitative food frequency questionnaire (FFQ)
and a lifestyle questionnaire were enclosed. The inclusion criteria
were as follows: age between 50 and 64 years, born in Denmark,
and no previous cancer diagnosis registered in the Danish Cancer
Registry. The FFQs were scanned optically and checked for missing
values and reading errors at the study center. All participants gave
written informed consent, and the study was approved by the relevant Scientific Ethical Committees and the Danish Data Protection
Agency.
Dietary Assessment
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The participants filled in a 192-item semiquantitative FFQ, which
was designed for this study and validated against two 7-day weighed
diet records.10,11 Participants were asked to report their habitual intake
of food items within the past 12 months in 12 categories ranging from
never to >8× a day. The intake of specific foods and nutrients was calculated using the software program FoodCalc (http://www.ibt.ku.dk/
jesper/foodcalc), which is based on Danish food composition tables.
The exposures were intake of LA, SFA, MUFA, glycemic carbohydrates, and total energy intake.
Identification of Stroke Cases
The Danish National Health Service provides free universal taxsupported healthcare, including hospital care, for all inhabitants. The
Danish National Patient Register was established in 1977, and 99.4%
of all discharges from somatic hospitals (including public and private hospitals) have been recorded in this database.12 The outcome
measure was incident nonfatal and fatal ischemic stroke, as well as
subtypes of ischemic stroke. Potential stroke cases were identified by
linkage to the Danish National Patient Register. Possible stroke cases
included subjects with an International Classification of Diseases,
Tenth Revision discharge code I60, I61, I63, or I64 or International
Classification of Diseases, Eighth Revision discharge code 430, 431,
433, 434, 436.01, or 436.90 as either primary or secondary diagnosis. Their case records were reviewed and the diagnoses validated
and characterized on the basis of clinical appearance, brain imaging,
imaging of extra cranial arteries laboratory tests, electrocardiography
(ECG), and echocardiography.13 Stroke was defined as symptoms
that persisted beyond 24 hours with rapid onset of focal or global
neurological deficit of vascular origin. Ischemic strokes were divided
into 5 subtypes based on pathogenesis, according to the TOAST
classification8: Large-artery atherosclerosis, cardioembolism, smallvessel occlusion, stroke of other etiology, and stroke of undetermined
etiology.
Covariates
At baseline, a lifestyle questionnaire was used to obtain information
on social factors, health status, and lifestyle habits during the previous year. Education was self-reported as <7 years, 8 to 10 years,
or >10 years. Physical activity during the past year was reported as
number of hours per week spent on walking, biking, housework,
home maintenance, gardening, and sports during summer and winter. Information on alcohol intake was also reported in the FFQ.
Smoking habits during the past year were self-reported as frequency
(never, former, or current), number, and type (cigarettes, cigars, cheroots, and tobacco pipes smoked per day). Hypercholesterolemia
was also self-reported or defined by treatment with lipid-lowering
agents. Similarly, data on hypertension was self-reported or defined
by use of antihypertensive drugs. Information on diabetes mellitus was self-reported. Information on atrial fibrillation/atrial flutter was found in the National Patient Register using International
Classification of Diseases, Tenth Revision discharge code I489 or
International Classification of Diseases, Eighth Revision discharge
codes 42793 or 42794. At recruitment, anthropometric measurements (height, weight, and waist circumference) were obtained by
a laboratory technician. Body mass index was calculated as weight
(kg)/height (m).2
Statistical Analyses
Data were explored as delayed entry time-to-event data with age
as the underlying time-axis. Cox proportional hazard models were
used to estimate hazard ratios (HRs) with 95% confidence intervals
(CIs). The observation time for each participant was the period from
the date of enrollment into the Diet, Cancer, and Health cohort until
occurrence of ischemic stroke, death from another cause, emigration,
or end of follow-up (December 30, 2009).
Data were analyzed assuming equal association of the exposure
for the 2 sexes but allowing for different baseline hazards. We investigated the association of a 5% higher energy intake from LA and
a concomitant lower energy intake from SFA, MUFA, or glycemic
carbohydrate. To investigate the substitutions, we included all energy
components of the diet in the analyses except for the macronutrient to
be substituted.14 Three statistical models were used to investigate the
associations between substitutions of LA for SFA, MUFA, or glycemic carbohydrates and the risk of ischemic stroke:
The first model (model 1A) was an age-, sex-, and energy-adjusted
model with the following covariates included: total energy intake (the
sum of energy from intake of fat, glycemic carbohydrates [minus
fiber intake], and protein; kJ/d, continuous) and age at inclusion
(years, continuous). Sex was included by allowing for different baseline hazards. Model 1B included the same covariates as model 1A
plus socioeconomic and the lifestyle factors: education status (<7,
8–10, and >10 years), physical activity (hours/week, continuous),
waist circumference adjusted for body mass index (continuous), alcohol intake (continuous), alcohol abstain (yes, no), and smoking status
(noncurrent, current <15, ≥15 g tobacco per day).
Hypertension (yes, no, unknown), hypercholesterolemia (yes, no,
unknown), diabetes mellitus (yes, no, unknown), and atrial fibrillation/atrial flutter (yes, no) were considered possible intermediate
variables, as well as confounders and in model 2, these were added
to model 1A. All the substitution analyses were also performed
for noncardioembolic stroke (large-artery atherosclerosis+smallvessel occlusion+stroke of other etiology). In a sensitivity analysis,
all models were further adjusted for intake of fiber and n-3 PUFA.
The proportional hazards assumption in the Cox regression analyses was evaluated by a log-rank test based on Schoenfeld residuals.
Adjustment for continuous covariates was performed using restricted
cubic splines with 3 knots. Statistical analyses were done using Stata
14 (StataCorp, US).
Results
In total, 1151 participants from the cohort (n=57 053) were
excluded from the study because they had a diagnosis of
cancer or stroke before entry into the study. We were not
able to retrieve the medical records or had insufficient
information in 559 participants, who were subsequently
excluded. Thus, the final study population included 55 338
participants. During a median follow-up of 13.5 years, a
total of 1879 ischemic stroke cases were identified comprising 319 strokes because of large-artery atherosclerosis, 844
because of small-vessel occlusion, 102 because of cardioembolism, 98 strokes of other etiology, and 516 strokes of
undetermined etiology.
Baseline characteristics of cases and the full cohort are presented in Table 1. Compared with the full cohort, ischemic
stroke cases were older at baseline, a higher proportion was
men, had less education, were less physically active, had a
larger waist circumference, had a higher alcohol intake, were
more likely to be smokers, and were more likely to have
hypercholesterolemia, hypertension, diabetes mellitus, and
atrial fibrillation. Table 2 shows the median intakes of LA,
SFA, MUFA, glycemic carbohydrates, n-3 PUFA, and fiber
among cases and the full cohort.
Venø et al Linoleic Acid and Ischemic Stroke 3
Table 1. Baseline Characteristics
Cohort
(n=55 338)
Ischemic Stroke
Cases (n=1879)
56.1 (50.7–64.2)
58.8 (51.0–64.7)
Men
47.6 (26 351)
61.7 (1160)
Women
52.4 (28 987)
38.3 (719)
Total energy intake, kJ/d
8211.2
(5041.1–12 815.5)
8289.7
(4972.8–13 122.7)
<7 y
32.8 (18 177)
40.7 (764)
8–10 y
46.1 (25 515)
42.5 (799)
>10 y
21.1 (11 646)
16.8 (316)
Age at enrolment, y
Table 2. Intake (g/d) of LA, SFA, MUFA, Glycemic
Carbohydrates, Marine n-3 PUFA, and Fibers Among Ischemic
Stroke Cases and the Whole Cohort
Cohort
(n=55 338)
Ischemic Stroke Cases
(n=1879)
Median
(5–95 Percentiles)
Median
(5–95 Percentiles)
LA
10.7 (5.2–20.6)
10.9 (5.3–20.9)
SFA
31.1 (15.8–55.3)
32.0 (15.7–57.5)
MUFA
27.2 (14.4–48.6)
28.4 (14.7–51.3)
226.0 (132.9–358.8)
224.0 (129.6–363.3)
Sex % (n)
Education % (n)
Physical activity, h/wk
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2.5 (0.0–11.0)
2.0 (0.0–11.0)
BMI, kg/m2
25.5 (20.5–33.3)
26.2 (20.7–34.8)
Waist circumference, cm
88.8 (69.0–110.0)
93.0 (71.0–115.0)
Alcohol intake, g/d
12.9 (0.7–64.6)
14.6 (0.4–79.4)
Alcohol abstainer % (n)
Yes
2.3 (1271)
3.2 (60)
No
97.7 (54 067)
96.8 (1819)
Noncurrent smoker
64.1 (35 462)
49.6 (933)
Current <15 g/d
13.0 (7214)
15.5 (291)
Current ≥15 g/d
22.9 (12 662)
34.9 (655)
Yes
7.3 (4065)
10.5 (198)
No
50.3 (27 834)
48.9 (918)
Unknown
42.4 (23 444)
40.6 (763)
Yes
16.0 (8865)
28.4 (533)
No
70.9 (39 226)
58.3 (1096)
Unknown
13.1 (7247)
13.3 (250)
Yes
2.0 (1116)
4.6 (87)
No
93.4 (51 660)
89.4 (1679)
4.6 (2562)
6.0 (113)
Smoking status % (n)
Hypercholesterolemia % (n)
Hypertension (%)
Diabetes mellitus (%)
Unknown
Atrial fibrillation/atrial flutter (%)
Yes
No
0.8 (423)
99.2 (54 915)
1.5 (28)
98.5 (1851)
BMI indicates body mass index.
HRs and 95% CIs for the incidence of ischemic stroke and
subtypes with a 5% higher intake of LA and a concomitant
lower intake of SFA are given in Table 3. Replacing SFA with
LA was associated with a slightly lower risk of total ischemic
stroke, although when adjusting for socioeconomic and lifestyle factors, not statistically significant (HR, 0.98; 95% confidence interval [CI], 0.83–1.16). Substitution of SFA for LA
Glycemic carbohydrates
Marine n-3 PUFA
Fibers
0.6 (0.2–1.5)
0.7 (0.2–1.6)
20.3 (10.9–33.7)
19.3 (10.4–32.9)
LA indicates linoleic acid; MUFA, monounsaturated fatty acid; PUFA,
polyunsaturated fatty acid; and SFA, saturated fatty acid.
was associated with a nonsignificant lower risk of large-artery
atherosclerosis (HR, 0.84; 95% CI, 0.57–1.25) and smallvessel occlusion (HR, 0.96; 95% CI, 0.75–1.23). A positive
association was found for cardioembolism (HR, 1.46; 95% CI,
0.75–2.85), although not statistically significant.
HRs and 95% CIs for total ischemic stroke and subtypes associated with a higher intake of LA replacing MUFA are shown in
Table 4. When adjusting for socioeconomic and lifestyle factors,
replacement of MUFA with LA was associated with a nonsignificant lower risk of ischemic stroke (HR, 0.80; 95% CI, 0.63–
1.02). A slightly higher, although statistically nonsignificant risk
was found for large-artery atherosclerosis (HR, 1.05; 95% CI,
0.58–1.90). A statistically significant lower risk was found for
small-vessel occlusion (HR, 0.67; 95% CI, 0.46–0.96). A positive but statistically nonsignificant association was found for cardioembolism (HR, 1.35; 95% CI, 0.51–3.55).
Table 5 shows HRs and 95% CIs for total ischemic stroke
and subtypes with replacement of glycemic carbohydrates
with LA. A 5% higher intake of LA replacing carbohydrates
was associated with a lower risk of total ischemic stroke,
although not statistically significant when adjusting for socioeconomic and lifestyle factors (HR, 0.92; 95% CI, 0.78–1.09).
For stroke subtypes, we found a lower risk of large-artery atherosclerosis (HR, 0.96; 95% CI, 0.64–1.44) and small-vessel
occlusion (HR, 0.82; 95% CI, 0.64–1.05) and a higher risk for
cardioembolism (HR, 1.55; 95% CI, 0.81–3.00), although not
statistically significant.
Regarding noncardioembolic stroke, a lower risk was found
when LA replaced SFA (HR, 0.93; 95% CI, 0.76–1.13),
MUFA (HR, 0.76; 95% CI, 0.56–1.02), or glycemic carbohydrates (HR, 0.86; 95% CI, 0.70–1.06), although not statistically significant (Tables 3 to 5). When possible, intermediate
variables were included in the age-, sex-, and energy-adjusted
model estimates did not change fundamentally (model 2).
When further adjusting for intake of fiber and n-3 PUFA, the
estimates were slightly attenuated (data not shown).
Discussion
Overall, we found a lower risk of ischemic stroke when
dietary LA replaced intake of SFA, MUFA, or glycemic
4 Stroke December 2017
Table 3. Association Between a 5 Energy % Higher Intake of Linoleic Acid and a Concomitant
Lower Intake of Saturated Fatty Acid and Risk of Ischemic Stroke and Subtypes
Model 1A*
Model 1B†
Model 2‡
HR (95% CI)
HR (95% CI)
HR (95% CI)
Total ischemic stroke
0.86 (0.73–1.02)
0.98 (0.83–1.16)
0.80 (0.68–0.95)
Large-artery atherosclerosis
0.74 (0.50–1.10)
0.84 (0.57–1.25)
0.72 (0.48–1.07)
Cardioembolism
1.39 (0.71–2.73)
1.46 (0.75–2.85)
1.28 (0.65–2.54)
Small-vessel occlusion
0.84 (0.65–1.08)
0.96 (0.75–1.23)
0.79 (0.60–1.00)
Stroke of other etiology
0.76 (0.37–1.57)
0.93 (0.45–1.91)
0.73 (0.35–1.51)
Stroke of undetermined etiology
0.91 (0.67–1.25)
1.04 (0.76–1.42)
0.84 (0.61–1.15)
Noncardioembolic stroke
0.80 (0.66–0.99)
0.93 (0.76–1.13)
0.76 (0.62–0.93)
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BMI indicates body mass index; CI, confidence interval; and HR, hazard ratio.
*Model 1A included total energy intake and age at inclusion. Baseline HR was allowed to differ between the 2 sexes.
†Model 1B as model 1A plus education status, physical activity, waist circumference adjusted for BMI, alcohol intake,
alcohol abstain, and smoking.
‡Model 2 as model 1A plus hypertension, hypercholesterolemia, diabetes mellitus, and atrial fibrillation/atrial flutter.
carbohydrates. When LA intake replaced MUFA, we found
a statistically significant lower risk of small-vessel occlusion,
a statistically higher risk of cardioembolism, and a statistically nonsignificant higher risk of large-artery atherosclerosis. When substituting dietary LA for SFA or glycemic
carbohydrates, a lower risk of large-artery atherosclerosis and
small-vessel occlusion were found, although not statistically
significant. The same substitutions were associated with a statistically nonsignificant higher risk of cardioembolism.
The strengths of this study include the large number of
cases. Each single case of stroke has been validated and
subclassified according to the TOAST classification.8 The
proportion lost to follow-up was low, which limits the risk
of selection bias. The detailed information about risk factors for ischemic stroke limits but does not eliminate the
risk of residual confounding. The associations between a
higher intake of LA and a lower intake of SFA, MUFA, or
glycemic carbohydrates were weakened when the analyses
were adjusted for these risk factors. Adjustment for potential confounders was applied in different steps. Model 1A
represented an age-, sex-, and energy-adjusted model. In
model 1B, socioeconomic and lifestyle factors were added.
In model 2, hypertension, hypercholesterolemia, diabetes
mellitus, and atrial fibrillation/flutter that are known risk factors for ischemic stroke were added to model 1A. However,
the variables included in model 2 also represent potential
intermediate factors in the causal pathway between LA and
ischemic stroke. Hence, adjustment may introduce collider
stratification bias. The results from model 1B have a clear,
unbiased interpretation. Therefore, we consider the results
from model 1B our main results.
The potential limitations of the study include the assessment of diets from a single FFQ administered at baseline.
Any change in diet during follow-up was not captured.
Secondly, the study only included middle-aged persons who
had survived without diagnoses of cancer and stroke until
inclusion in the study, and the results may, therefore, not
be applicable to other age groups. Moreover, only 35% of
those invited to participate in the study agreed to participate.
This selection may be related to baseline exposure, but it
Table 4. Association Between a 5 Energy % Higher Intake of Linoleic Acid and a Concomitant
Lower Intake of Monounsaturated Fatty Acid and Risk of Ischemic Stroke and Subtypes
Model 1A*
Model 1B†
Model 2‡
HR (95% CI)
HR (95% CI)
HR (95% CI)
Total ischemic stroke
0.65 (0.51–0.82)
0.80 (0.63–1.02)
0.65 (0.51–1.83)
Large-artery atherosclerosis
0.85 (0.47–1.54)
1.05 (0.58–1.90)
0.87 (0.48–1.56)
Cardioembolism
1.13 (0.43–2.96)
1.35 (0.51–3.55)
1.12 (0.42–2.96)
Small-vessel occlusion
0.52 (0.37–0.75)
0.67 (0.46–0.96)
0.52 (0.36–0.75)
Stroke of other etiology
0.69 (0.24–1.99)
0.85 (0.29–2.45)
0.69 (0.24–2.01)
Stroke of undetermined etiology
0.68 (0.43–1.08)
0.81 (0.51–1.29)
0.69 (0.44–1.09)
Noncardioembolic stroke
0.60 (0.45–0.81)
0.76 (0.56–1.02)
0.60 (0.45–0.81)
CI indicates confidence interval; and HR, hazard ratio.
*Model 1A included total energy intake and age at inclusion. Baseline HR was allowed to differ between the 2 sexes.
†Model 1B as model 1A plus education status, physical activity, waist circumference adjusted for BMI, alcohol intake,
alcohol abstain, and smoking.
‡Model 2 as model 1A plus hypertension, hypercholesterolemia, diabetes mellitus, and atrial fibrillation/atrial flutter.
Venø et al Linoleic Acid and Ischemic Stroke 5
Table 5. Association Between a 5 Energy % Higher Intake of Linoleic Acid and a Concomitant
Lower Intake of Glycemic Carbohydrates and Risk of Ischemic Stroke and Subtypes
Model 1A*
Model 1B†
Model 2‡
HR (95% CI)
HR (95% CI)
HR (95% CI)
Total ischemic stroke
0.84 (0.71–0.99)
0.92 (0.78–1.09)
0.83 (0.71–0.99)
Large-artery atherosclerosis
0.89 (0.60–1.34)
0.96 (0.64–1.44)
0.90 (0.60–1.35)
Cardioembolism
1.46 (0.75–2.82)
1.55 (0.81–3.00)
1.47 (0.75–2.86)
Small-vessel occlusion
0.73 (0.57–0.94)
0.82 (0.64–1.05)
0.72 (0.56–0.93)
Stroke of other etiology
0.86 (0.41–1.79)
0.98 (0.47–2.05)
0.86 (0.41–1.80)
Stroke of undetermined etiology
0.90 (0.65–1.23)
0.97 (0.71–1.33)
0.90 (0.65–1.23)
Noncardioembolic stroke
0.78 (0.63–0.95)
0.86 (0.70–1.06)
0.77 (0.63–0.95)
Downloaded from http://stroke.ahajournals.org/ by guest on October 26, 2017
CI indicates confidence interval; and HR, hazard ratio.
*Model 1A included total energy intake and age at inclusion. Baseline HR was allowed to differ between the 2 sexes.
†Model 1B as model 1A plus education status, physical activity, waist circumference adjusted for BMI, alcohol intake,
alcohol abstain, and smoking.
‡Model 2 as model 1A plus hypertension, hypercholesterolemia, diabetes mellitus, and atrial fibrillation/atrial flutter.
is unlikely that the association between substitutions of LA
for other macronutrients in relation to ischemic stroke was
systematically different between participants and nonparticipants. After subtyping ischemic stroke according to the
TOAST-classification system, there was a low number of
cases of cardioembolism and stroke of other etiology, and,
therefore, the HRs had wide CIs. Because LA can be endogenously converted, serum LA represents a biomarker of LA
intake and metabolism.15 Serum levels of fatty acids could,
therefore, have served as objective markers of dietary intake
and metabolism. For this study, we did unfortunately not
have access to blood samples.
For the substitution analyses, we compared participants
with an identical total energy intake and an identical intake of
macronutrients except for the macronutrients to be substituted.
This allowed us to estimate a difference in risk of ischemic
stroke associated with a higher intake of LA and a concomitant lower intake of SFA, MUFA, or glycemic carbohydrates.
For dietary recommendations, a higher intake of 1 macronutrient will imply a lower intake of another. Because different
macronutrients may have different impact on the development
of ischemic stroke, it is important to specify the substitutions.
We found a nonsignificant lower risk of ischemic stroke
with a lower intake of SFA and a concomitant higher energy
intake from LA. The substitution of PUFA for SFA has been
studied by others, although only with myocardial infarction
as an outcome. In a 14 years follow-up study, Hu et al6 documented 939 cases of myocardial infarction and reported findings suggesting that replacing SFA with PUFA could lower
the risk of myocardial infarction. Furthermore, Jakobsen et
al7 identified 5249 coronary events and 2155 coronary deaths
and found a lower risk of coronary heart disease (CHD) associated with substitution of PUFA for SFA. Although CHD
and ischemic stroke share several risk factors, the influence
of diet on ischemic stroke risk is debated, at least partly
because data are limited. Our study suggested that a higher
intake of LA replacing glycemic carbohydrates, as well
as replacing SFA was associated with a lower risk of total
ischemic stroke. A meta-analysis16 of 13 prospective cohort
studies investigated the LA substitution aspect with CHD as
the outcome. When LA intake replaced either carbohydrate
or SFA, a lower risk of CHD was identified. Another study17
with 168 ischemic stroke cases found a positive association
between plasma total SFA or MUFA and risk of ischemic
stroke, whereas plasma LA was associated with a lower risk
of ischemic stroke. LA is a precursor of proinflammatory
eicosanoids, and, therefore, higher intakes have been suggested to be potentially harmful.15,18,19 In our study, a higher
intake of LA was associated with a lower risk of ischemic
stroke and ischemic stroke subtypes except for cardioembolism. This aspect needs further clarification. The association
between LA and ischemic stroke could be mediated through
different pathways, which include lowering plasma low-density lipoprotein cholesterol levels,2 suggesting a reduced risk
of atherosclerosis.
According to the TOAST classifications,8 ischemic stroke
can be divided into subtypes. With a 5% higher intake of LA
replacing other macronutrients, we found a nonsignificant
lower risk of small-vessel occlusions and large-artery atherosclerosis but a nonsignificant higher risk of cardioembolism.
Because pathogenesis varies within these subtypes, it is plausible that substitutions of macronutrients may have different
impact on subtypes of stroke. Several studies20–22 thus have
suggested that hypercholesterolemia and hypertension have
different impact on the large precerebral arteries and in the
small cerebral arteries and accordingly lead to different risks
of subtypes of ischemic stroke.
The subtype stroke of other etiology includes various cases
with rare causes of stroke, which have different origin. The
subtype stroke of undetermined etiology includes cases where
the cause of stroke could not be determined. By definition,
this subtype will include those cases with ≥2 potential causes
identified, as well as those with a negative or incomplete
evaluation. Because pathogenesis varies in these 2 subgroups,
usability from results of substitution analyses will be limited.
Because the 2 subgroups belong to the TOAST classifications,
we chose to report the results but not to discuss these subtypes
further.
6 Stroke December 2017
Conclusions
In conclusion, this study suggests that replacing SFA, MUFA,
or glycemic carbohydrates with LA was consistently associated with a lower risk of total ischemic stroke, large-artery
atherosclerosis, and small-vessel occlusions. The same substitution may be associated with a higher risk of cardioembolism.
Acknowledgments
We thank the Danish Cancer Society and the collaborators behind the
Diet, Cancer, and Health Study.
Sources of Funding
This study was supported by the Danish Cancer Society and the
Danish Heart Foundation.
Disclosures
None.
Downloaded from http://stroke.ahajournals.org/ by guest on October 26, 2017
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Substitution of Linoleic Acid for Other Macronutrients and the Risk of Ischemic Stroke
Stine K. Venø, Erik B. Schmidt, Marianne U. Jakobsen, Søren Lundbye-Christensen, Flemming
W. Bach and Kim Overvad
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Stroke. published online October 25, 2017;
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