Heart disease: n-6/n-3 ratio does not matter

[Guest guest]

Hi All,

I thought that the take-home message of the below

pdf-available paper may be that n-6 polyunsaturated

fats (PUFAs) in our diets do no affect the beneficial effects of

the n-3 PUFAs.

Below the Medline abstract below is only the Discussion of

the full-text. However, from the pdf, I noted a remarkable to

me result. Although not significant, Fig. 2 showed that, among

the male humans that consumed more than 100 micrograms/day

of the long-chain PUFAs versus less than 100 micrograms/day,

the relative risk of sudden death from heart disease was 35%

higher with each microgram of alpha-linolenic acid (ALA) versus

45% lower. The great variation in the relative risks prevented

significant differences, but, still, the relative risks were 2.5-fold

higher for the higher versus lower level of long-chain PUFAs.

Of course, we might examine this in the reverse pattern.

Possibly, our consumption of greater levels of long-chain PUFAs

is a risk at increasing levels of ALA.

Circulation. 2005 Jan 3; [Epub ahead of print]

Interplay Between Different Polyunsaturated Fatty Acids and Risk

of Coronary

Heart Disease in Men.

Mozaffarian D, Ascherio A, Hu FB, Stampfer MJ, Willett WC,

Siscovick DS, Rimm

EB.

BACKGROUND: Consumption of polyunsaturated fatty acids (PUFAs) may

reduce

coronary heart disease (CHD) risk, but n-6 PUFAs may compete with n-3

PUFA

metabolism and attenuate benefits. Additionally, seafood-based, long-

chain n-3

PUFAs may modify the effects of plant-based, intermediate-chain n-3

PUFAs.

.... METHODS AND RESULTS: Among 45 722 men free of known cardiovascular

disease in 1986, usual dietary intake was assessed at baseline and

every 4 years

by using validated food-frequency questionnaires. CHD incidence was

prospectively ascertained. Over 14 years of follow-up, participants

experienced

218 sudden deaths, 1521 nonfatal myocardial infarctions (MIs), and

2306 total

CHD events (combined sudden death, other CHD deaths, and nonfatal

MI). In

multivariate-adjusted analyses, both long-chain and intermediate-

chain n-3 PUFA

intakes were associated with lower CHD risk, without modification by

n-6 PUFA

intake. For example, men with >/= median long-chain n-3 PUFA intake

(>/=250

mg/d) had a reduced risk of sudden death whether n-6 PUFA intake was

below

(<11.2 g/d; hazard ratio

---

=0.52; 95% confidence interval [CI]=0.34

to 0.79)

or above (>/=11.2 g/d; HR=0.60; 95% CI=0.39 to 0.93) the median

compared with

men with a < median intake of both. In similar analyses, >/= median

intake of

intermediate-chain n-3 PUFAs (>/=1080 mg/d) was associated with a

reduced total

CHD risk whether n-6 PUFA intake was lower (HR=0.88; 95% CI=0.78 to

0.99) or

higher (HR=0.89; 95% CI=0.79 to 0.99) compared with a < median intake

of both.

Intermediate-chain n-3 PUFAs were particularly associated with CHD

risk when

long-chain n-3 PUFA intake was very low (<100 mg/d); among these men,

each 1 g/d

of intermediate-chain n-3 PUFA intake was associated with an

approximately 50%

lower risk of nonfatal MI (HR=0.42; 95% CI=0.23 to 0.75) and total

CHD (HR=0.53;

95% CI=0.34 to 0.83). CONCLUSIONS: n-3 PUFAs from both seafood and

plant sources

may reduce CHD risk, with little apparent influence from background n-

6 PUFA

intake. Plant-based n-3 PUFAs may particularly reduce CHD risk when

seafood-based n-3 PUFA intake is low, which has implications for

populations

with low consumption or availability of fatty fish.

PMID: 15630029 [PubMed - as supplied by publisher]

... Discussion

In this large prospective cohort study, modest dietary intake of

long-chain n-3 PUFAs (>=250 mg/d) was associated with a 40% to 50%

lower risk of sudden death, regardless of background intake of n-6

PUFAs. This lower risk was observed after adjustment for a variety of

cardiac risk factors, lifestyle characteristics, and other dietary

habits. These results suggest that n-6 PUFAs neither greatly

counteract nor greatly augment the cardiovascular benefits of a

modest intake of long-chain n-3 PUFAs from seafood. EPA+DHA intake

was associated with a lower risk of sudden death but not of nonfatal

MI or total CHD. This is consistent with results from other

observational and experimental studies, which suggest an effect of

long-chain n-3 PUFAs on fatal ventricular arrhythmias.11–16,25,34,37

In vitro, long-chain n-3 PUFAs decrease myocyte excitability and

reduce cytosolic calcium fluctuations via inhibition of Na+ and L-

type Ca2+ channels,37 supporting a potential antiarrhythmic effect of

these fatty acids.

Relations between intermediate-chain n-3 PUFAs and CHD risk also

appeared independent of n-6 PUFA intake. Although theoretical

considerations and short-term studies of secondary outcomes have

suggested that n-6 fatty acids may counteract the effects of ALA on

CHD incidence,17–23 few prior studies have evaluated this hypothesis.

In the Nurses Health Study, intake of linoleic acid (18:2n-6) did not

appreciably modify the inverse association between ALA and CHD risk,

nor was the ratio of ALA to linoleic acid associated with risk 8;

however, these analyses were not the main focus, and detailed results

were not reported. Results were similar in the cross-sectional Family

Heart Study,38 although findings may be limited by the evaluation of

prevalent, rather than incident, CHD. Our findings provide the

strongest evidence to date that n-6 PUFA intake does not appreciably

counteract the effects of either intermediate- or long-chain n-3

PUFAs on the risk of CHD events.

Three randomized trials,39–42 but not 2 others,43,44 demonstrated

reductions in some CHD end points with higher n-6 PUFA intake (one

trial also increased ALA intake 41,42). In some prior cohorts, an

inverse association was observed between n-6 PUFA intake or the ratio

of polyunsaturated to saturated fat and CHD risk.2 We did not observe

an association between n-6 PUFA intake and CHD risk, even by

comparing extreme deciles of intake (comparing <7.6 g/d to >=15.9

g/d). The discrepancy of the findings between prior studies and our

study could be due to differences in age or body mass index

distribution or to the low trans fatty acid intake in these men,

although our secondary analyses do not support these hypotheses.

Although our findings do not exclude the possibility of a modest

effect, our results suggest that higher n-6 PUFA intake is unlikely

to substantially reduce CHD risk in men over the range that was

studied. Our results also indicate that higher n-6 PUFA intake is

unlikely to appreciably attenuate the beneficial effects of n-3 PUFA

intake on CHD risk.

The strongest relation between ALA intake and CHD risk was seen

when EPA+DHA intake was very low (<100 mg/d). Long-chain n-3 PUFAs

inhibit metabolism of ALA via feedback inhibition (Figure 1),

suggesting a potential biological mechanism for this observation. In

experimental studies, both intermediate-chain and long-chain n-3

PUFAs influence platelet aggregation, thrombosis, blood pressure,

lipids, inflammatory responses, and arrhythmia.1,17 Many of the

effects of long-chain n-3 PUFAs are seen only at pharmacological

doses, and our findings as well as those of prior studies 13,15,16

suggest that antiarrhythmic effects of EPA+DHA may predominate at

usual dietary doses. Conversely, ALA intake was associated with a

lower risk of nonfatal MI and total CHD, suggesting that in the

absence of significant long-chain n-3 PUFA intake, ALA may influence

CHD risk via multiple pathways, including non–arrhythmia-related

mechanisms. Further research is needed to determine whether ALA is

also related to the risk of sudden death in the setting of low long-

chain n-3 PUFA intake.

To our knowledge, this is the first prospective study to evaluate

whether EPA+DHA intake influences relations between ALA and CHD

incidence. Results of prior studies of ALA intake and CHD risk have

been mixed, with some 5–9 but not others 45–47 observing an inverse

association between ALA and CHD risk. If effects of ALA are

influenced by background EPA+DHA intake, as suggested by our results,

this may in part explain the prior null associations 45–47 between

ALA intake and CHD risk. Our findings suggest that plant sources of n-

3 PUFAs may particularly reduce CHD risk in men when intake of long-

chain n-3 PUFAs is low, which may have important implications for CHD

prevention in populations with low consumption or availability of

fatty fish. Further observational, clinical, and animal-experimental

studies are needed to investigate this relation and potential

underlying mechanisms.

Our study has several strengths. Nutrient intakes were estimated

with a validated dietary instrument in a large, well-described

cohort. Cumulative averaging of multiple diet assessments over time

reduced misclassification. Prospective assessment and cessation of

dietary updating after intermediate events reduced potential bias

from changes in diet due to known disease. Standardized assessment of

participant characteristics increased the ability to adjust for

potential confounding factors. Little loss to follow-up and

centralized adjudication of outcomes reduced the likelihood of missed

or misclassified outcomes.

There are also potential limitations to our findings. We may have

had inadequate power to detect more subtle interactions between n-6

PUFAs, EPA+DHA, and ALA intakes. Nutrient intakes were likely

estimated with some error owing to imperfect estimates of specific

food intakes and nutrient contents of foods. Such misclassification

would bias results toward the null, which might, for example, in part

account for the lack of significant overall associations between n-6

PUFA intake and CHD risk. There may also have been misclassification

of outcomes, particularly sudden death. Although such

misclassification would limit our ability to detect relations, the

robust association between EPA+DHA intake and sudden death, rather

than nonfatal MI or total CHD, is consistent with other observational

and clinical studies of EPA+DHA 11–16 and suggests that many events

are likely correctly classified. Participants were male health

professionals with generally healthier behaviors, and our findings

may not be generalizable to all populations. Although we adjusted for

a variety of clinical and dietary factors, residual confounding by

unmeasured or imprecisely measured factors cannot be excluded.

Our findings suggest that dietary intake of long-chain n-3 PUFAs

from seafood may lower the risk of sudden death regardless of the

background intake of n-6 fatty acids. This lower risk was seen with

modest dietary intake (>=250 mg/d), the equivalent of [almost equal

to]1 to 2 fatty fish meals per week. Our results also suggest that

when long-chain n-3 PUFA intake is low, dietary intake of

intermediate-chain n-3 PUFAs from plant sources may lower CHD risk,

regardless of background n-6 PUFA intake. Together these results

suggest that attention to relative intakes of n-3 and n-6 fatty acids

may be less important than simply increasing the intake of n-3 PUFAs.

Our findings also suggest that dietary consumption of plant sources

of n-3 fatty acids may be important for CHD prevention among persons

who do not regularly consume fatty fish or in populations in which

fatty fish is not readily available.

Cheers, Alan Pater,