- Click here for explanation of classification scheme.

To examine the association of alpha-linolenic acid (ALA) intake, specifically with the risk of sudden cardiac death as well as with other causes of cardiac death and non-fatal MI, during 18 years of follow-up.

• Enrolled in the Nurses' Health Study
• Returned the 1984 dietary questionnaire
• Could have a reported prior history of cardiovascular disease (CVD), including angina, MI, coronary revascularization or stroke, at baseline.

• 10 or more blank items on the 1984 dietary questionnaire
• Improbable reported food intakes (under 660kcal or over 3,500kcal per day) from the questionnaire
• History of cancer (except non-melanoma skin cancer) before 1984.

• Recruitment: Current participant in the Nurses' Health Study
• Design: Cohort study
• Blinding used: Physicians examining medical records to confirm outcomes were blinded to exposure status.

Intervention

• Semi-quantitative food frequency questionnaire (FFQ) was mailed to participants in 1984, 1986, 1990, 1994 and 1998
• Follow-up every two years, with mailed questionnaires that update exposure information and inquire about newly-diagnosed medical illnesses
• Deaths were reported by next of kin or postal authorities or identified through a search of the National Death Index
  • Acquisition of death certificates to confirm deaths
  • Medical record review
  • Interview next of kin if medical records were inadequate.

Statistical Analysis

•  Age-adjusted means or proportions of cardiovascular risk factors were calculated across quintiles of ALA intake
  • Person-months of follow-up were calculated from the date of return of the 1984 questionnaire to the date of the first end point, death or June 1, 2002, whichever came first
  • Because the authors thought short-term intake might be more likely to affect risk, an updated dietary analysis was performed that used the most recent dietary intake and carried forward the last observation for those with missing values (24% of updated observations).
• Proportional hazards models were used to compute age- and multivariate-adjusted hazard ratios as estimates of relative risk across quintiles of ALA
  • Two multivariate models used:
    • The first controlled for coronary risk factors, updated prior report of CVD, alcohol intake, aspirin, vitamin supplements and post-menopausal hormone use
    • The second included the covariates in Model One and additionally controlled for intake of other fatty acids that resulted in a change of more than 10% in the parameter estimate for ALA intake.
  • All variables, including dietary variables, were treated as time-varying covariates, with the most recent exposure used to predict outcome
  • Tests for linear trend were performed by assigning the median value to each quintile and modeling this as a continuous variable in separate proportional hazards models
  • Examined the possibility of a non-linear relationship between ALA intake and sudden cardiac death risk non-parametrically, by using restricted cubic spline transformations and tested for non-linearity with the likeihood ratio test.
• To determine whether the effect of ALA might differ in secondary or primary prevention, similar analyses were performed after stratifying the population by the presence or absence of a confirmed cardiovascular event
  • Performed stratified analyses that tested for an effect modification by long-chain n-3 fatty acids
  • Examined interactions with aspirin intake, age (under 60 vs. 60 or more years) and n-6 fatty acids, by adding cross-product terms between ALA and exposure of interest into the full multivariate model.

Timing of Measurements

• FFQ was completed and mailed at five time points
• Questionnaires updating exposure information and health information were mailed every two years.

Dependent Variables

• Sudden cardiac death: Death or cardiac arrest that precipitated death occurred within one hour of symptom onset
• Fatal CHD: Defined by ICD-9 codes 410 to 412, if confirmed by hospital records or autopsy or if CHD was the most probable cause and was listed as the cause of death on the death certificate
• Nonfatal MI.

Independent Variables

ALA intake: Total linolenic acid values were used as a surrogate for ALA intake, as the USDA database contains values only for total linolenic acid and ALA constitutes the vast majority of total dietary linolenic intake.

Control Variables

• Age
• Calories
• Smoking status
  • Never
  • In the past
  • Currently one to 14 cigarettes per day
  • 15 to 24 cigarettes per day
  • 25 or more cigarettes per day.
• BMI
  • Under 22
  • 22 to 22.9
  • 23 to 24.9
  • 25 to 28.9
  • 29 or higher.
• Menopausal status and post-menopausal hormone use
• Vigorous to moderate activity
  • Less than two hours per week
  • Two to 3.9 hours per week
  • Four or more hours per week.
• Usual aspirin use
  • Less than once per week
  • Once to six times per week
  • Seven times or more per week.
• Multi-vitamin use (yes or no)
• Vitamin E supplement use (yes or no)
• History of hypertension (yes or no)
• Hypercholesterolemia (yes or no)
• Diabetes (yes or no)
• Family history of MI
  • None
  • Before 60 years of age
  • After 60 years of age
• History of prior CVD (yes or no)
• Trans-unsaturated fat
• Ratio of polyunsaturated to saturated fat
• Omega-3 fatty acids.

Initial N

• 97,423 women returned the baseline questionnaire in 1984
  • 15,666 excluded for reasons related to completion of questionnaire
  • 4,994 excluded for history of cancer before 1984

Attrition (Final N)

76,763.

Age

See table below.

Ethnicity

Not described.

Other Relevant Demographics

See table below.

Anthropometrics

See table below.

Relationship of Quintiles of Linolenic Acid Intake to CHD Risk Factors at Baseline*

Variable		Quintile One	Quintile Two	Quintile Three	Quintile Four	Quintile Five
Median (Energy Percentage)		0.37	0.45	0.52	0.60	0.74
No. Women, Mean (SD), y		50.7 (7.3)	50.4 (7.2)	50.6 (7.1)	51.0 (7.1)	51.3 (7.0)
Smoking, N (Percentage)	Past	4,610 (30.0)	4,660 (30.4)	4,752 (31.0)	5,090 (33.2)	5,362 (34.9)
	Current; 1-14 Cigarettes Per Day	1,138 (7.4)	103 (7.2)	1,096 (7.1)	1,166 (7.6)	1,240 (8.1)
	Current ;15-24 Cigarettes Per Day	1,450 (9.4)	1,497 (9.7)	1,492 (9.7)	1,421 (9.3)	1,609 (10.5)
	Current; ≥25 Cigarettes Per Day	121 (7.3)	1,022 (6.6)	1,039 (6.7)	1,011 (6.6)	1,163 (7.6)
Reported Diagnosis	Diabetes, N (Percentage)	473 (3.1)	447 (3.0)	482 (3.2)	502 (3.2)	569 (3.6)
	Hypercholesterolemia, N (Percentage)	1,465 (9.6)	1,322 (8.8)	1,232 (8.1)	1,321 (8.5)	1,379 (8.8)
	Hypertension, N (Percentage)	3,475 (22.7)	3,270 (21.7)	3,289 (21.6)	3,457 (22.3)	3,532 (22.6)
	CVD, N (Percentage)	608 (3.9)	511 (3.4)	499 (3.3)	484 (3.1)	509 (3.2)
	BMI ≥29	2,301 (15.0)	2,432 (15.9)	2,463 (16.1)	2,615 (17.0)	2,666 (17.3)
	Parental h/o MI Before 60 Years	2,240 (14.6)	2,310 (15.0)	2,291 (14.9)	2,278 (14.9)	2,313 (15.1)
Alcohol Intake	0.1g to 4.9g Per Day	4,681 (30.4)	5,244 (34.0)	5,206 (33.9)	5,247 (34.3)	5,279 (34.5)
	5.0g to 14.9g Per Day	2,816 (18.3)	3,108 (20.2)	3,351 (21.8)	3,587 (23.4)	3,608 (23.5)
	≥15.0g Per Day	2,523 (16.5)	2,061 (13.5)	2,029 (13.3)	1,976 (12.9)	1,861 (12.1)
	Aspirin Use (≥7 Times Per Week, Percentage)	2,970 (19.3)	2,792 (18.3)	2,817 (18.4)	2,872 (18.7)	2,756 (17.9)
	Post-Menopausal Hormone Use (Current)	2,106 (3.8)	1,956 (13.0)	2,031 (13.4)	2,091 (13.5)	2,113 (13.4)
Physical Activity (Moderate and Vigorous)	2 to 3.9 Hours per week	2,641 (17.2)	2,808 (18.3)	2,726 (17.7)	2,696 (17.6)	2,651 (17.3)
	4 to 6.9 Hours per week	4,389 (28.6)	4,403 (28.6)	4,448 (28.9)	4,547 (29.7)	4,372 (28.6)
	≥7 Hours per week	538 (3.5)	450 (2.9)	450 (2.9)	527 (3.5)	513 (3.4)
Vitamin Supplement Use	Vitamin E, N (Percentage)	2,870 (18.7)	2,498 (16.4)	2,500 (16.3)	2,562 (16.7)	2,668 (17.3)
	Multivitamin, N (Percentage)	6,217 (40.5)	5,679 (37.0)	5,659 (36.9)	5,447 (35.5)	5,365 (34.9)

 *All percentages standardized for age to the total cohort.

Location

Brigham & Women's Hospital, Massachusetts General Hospital, Harvard School of Public Health; Boston, MA.

 Relative Risks (95% CI) of CHD According to Quintiles of Updated Linolenic Fatty Acid Intake

		Quintile One	Quintile Two	Quintile Three	Quintile Four	Quintile Five	P for Trend
Median, Energy Percentage		0.37	0.45	0.52	0.60	0.75
Sudden Cardiac Death	No. of Cases	54	44	40	32	36
	Person-Years	265,219	264,770	264,962	264,647	264,520
	Incidence Rate*	20	17	15	12	14
	Age-Adjusted	1.0	0.89 (0.60-1.33)	0.82 (0.54-1.25)	0.67 (0.43-1.04)	0.70 (0.45-1.07)	0.06
	Multivariate One	1.0	0.85 (0.57-1.27)	0.76 (0.50-1.16)	0.63 (0.40-0.98)	0.63 (0.41-0.98)	0.02
	Multivariate Two	1.0	0.86 (0.57-1.29)	0.76 (0.50-1.16)	0.62 (0.39-0.98)	0.60 (0.37-0.96)	0.02
Other Fatal CHD	No. of Cases	146	144	116	112	123
	Person-Years	262,158	261,640	261,741	261,735	261,359
	Incidence Rate*	56	55	44	43	47
	Age-Adjusted	1.0	1.18 (0.94-1.49)	1.03 (0.80-1.32)	1.03 (0.80-1.32)	1.04 (0.81-1.33)	0.89
	Multivariate One	1.0	1.13 (0.89-1.43)	0.91 (0.71-1.17)	0.93 (0.72-1.19)	0.93 (0.73-1.19)	0.27
	Multivariate Two	1.0	1.13 (0.89-1.43)	0.92 (0.71-1.18)	0.96 (0.74-1.25)	1.01 (0.77-1.33)	0.74
Non-Fatal MI	No. of Cases	340	321	307	302	334
	Incidence Rate*	130	123	117	115	128
	Age-Adjusted	1.0	1.06 (0.91-1.23)	1.07 (0.91-1.25)	1.07 (0.91-1.25)	1.14 (0.98-1.34)	0.11
	Multivariate One	1.0	1.03 (0.88-1.20)	1.01 (0.86-1.18)	1.00 (0.86-1.18)	1.05 (0.90-1.23)	0.62
	Multivariate Two	1.0	1.03 (0.88-1.20)	1.01 (0.86-1.18)	1.02 (0.86-1.20)	1.09 (0.92-1.29)	0.38

 *Incidence per 100,000 person-years

• ALA was the predominant N-3 fatty acid consumed, with intake ranging from 0.37% of total energy intake in the lowest quintile to 0.74% in the highest. Corresonding percentages for combined EPA and DHA were 0.03% to 0.23%, respectively. The median absolute intake of ALA was 0.66g per day in the lowest and 1.39g per day in the highest.
• In age-adjusted analyses, greater ALA intake was associated with a trend toward a lower risk of sudden cardiac death
• After controlling for multiple coronary risk factors, the inverse relationship became significant and remained significant when other fatty acids were included in the model
• ALA intake was not significantly related to other non-sudden fatal CHD events or to non-fatal MI in any of the age-adjusted or multivariate models
• The inverse association with sudden cardiac death became significant in the fourth quintile of intake, corresponding to a median absolute intake of 1.16g per day. Multivariate spline regression confirmed a linear relation (P for linear trend, 0.02).
• For every 0.1% increase in energy intake from ALA, the associated hazard ratio was 0.88 (95% CI: 0.80-0.98)
• Women in the two highest quintiles of ALA intake had a 38% to 40% lower sudden cardiac death risk.

Primary vs. Secondary Prevention: Relative Risks (95% CI) of Sudden Cardiac Death, According to Quintiles of Linolenic Acid Intake, Stratified by History of Non-Fatal CVD Before the Sudden Cardiac Death

		Quintile One	Quintile Two	Quintile Three	Quintile Four	Quintile Five	P for Trend
Median Energy Percentage		0.37	0.45	0.52	0.60	0.74
No Prior History of CVD	No. of Cases	40	34	34	24	27
	Person-Years	252,241	251,981	251,869	251,644	251,727
	Incidence Rate*	16	13	14	10	11
	Age-Adjusted	1.0	0.92 (0.58-1.45)	0.92 (0.58-1.47)	0.65 (0.39-1.09)	0.68 (0.41-1.12)	0.06
	Multivariate	1.0	0.89 (0.56-1.41)	0.86 (0.54-1.39)	0.60 (0.35-1.03)	0.59 (0.34-1.02)	0.03
Prior History of CVD	Median Energy Percentage	0.35	0.43	0.49	0.58	0.72
	No. of Cases	13	9	6	10	9
	Person-Years	13,007	12,965	12,936	12,907	12,841
	Incidence Rate*	100	69	46	77	70
	Age-Adjusted	1.0	0.67 (0.28-1.58)	0.44 (0.16-1.16)	0.75 (0.32-1.75)	0.65 (0.27-1.57)	0.50
	Multivariate	1.0	0.68 (0.28-1.64)	0.38 (0.14-1.06)	0.76 (0.30-1.88)	0.53 (0.19-1.45)	0.33

*Incidence per 100,000 person-years

1. The dose-response relationship between ALA and sudden cardiac death was only apparent among women without a history of prior CVD. The test for interaction was not significant (P=0.55).

Other Findings

• The lowest risks for sudden cardiac death were among those women with the highest intakes of both EPA and DHA. Compared with those with the lowest intakes, the relative hazard for sudden cardiac death was 0.41 (95% CI: 0.21-0.79, P=0.008) among those in the highest quintile of ALA intake who were also above the median for EPA plus DHA intake.
• There was no evidence of interaction between ALA intake and aspirin use, N-6 fatty acid intake or age.

This data provides evidence for an inverse association between alpha-linolenic acid intake and sudden cardiac death rise among women.

Government:

NIH