Serum non-esterified fatty acid pattern and risk of coronary heart disease

Paula Berstad (née Yli-Jama)

Summary

The fraction of non-esterified fatty acids (NEFA) in serum is known as a risk marker for coronary heart disease (CHD). However, composition of this serum lipid fraction in this context is less studied.

  The purpose of this thesis was to clarify the role of individual fatty acids in serum NEFA fraction in the risk of myocardial infarction and development of atherosclerosis. It was also of interest to receive more detailed information on the relationship of individual fatty acid contents between serum NEFA and adipose tissue.

The part-studies were conducted as subprojects within two larger studies: a case-control study on first acute myocardial infarction (MI), and an intervention trial on dietary change and n-3 fatty supplementation, both at Ullevål University Hospital, Oslo.

Results of the four papers are summarized in the following:

Individual fatty acid contents in serum NEFA, adipose tissue and habitual diet were correlated to each other among men and postmenopausal women aged 45-75 years (1) . Significant correlations (n=186) were found between serum NEFA and adipose tissue, particularly for the percentage content of linoleic acid, eicosapentaenoic acid (EPA), a-linolenic acid and palmitoleic acid. The correlations did not seem to differ between patients with MI (n=92) and the controls (n=94). It was also shown that percentage contents of palmitic, stearic, linoleic and a-linolenic acid, EPA and docosahexaenoic acid (DHA) were higher in serum NEFA than in adipose tissue, whereas oleic and palmitoleic acid were relatively more abundant in adipose tissue. High correlations for PUFA were observed also between percentage contents of dietary and adipose tissue fatty acids. Correlation between fatty acids in diet and serum NEFA was weak, but a tendency towards higher correlations for PUFA was observed.

Relation between individual fatty acids in serum NEFA and first MI was studied among 103 cases and 104 age- and sex-matched controls, both men and post-menopausal women, aged 45 – 75 y (2) . The cases had significantly lower molar percentage content of EPA, DHA, stearic and myristic acid in serum NEFA fraction than the controls, whereas that of oleic and linoleic acid was higher in cases. It was found in multivariate analysis that increased percentage content of total very long-chain n-3 fatty acids (VLC n-3) in serum NEFA was highly significantly associated with decreased risk for MI. High percentage content of serum non-esterified stearic acid was also inversely associated with MI risk.

Possible relationships between the fatty acid composition in serum NEFA, and indicators of atherosclerosis, measured as blood levels of endothelial cell markers were studied among 152 elderly men with high risk for CHD (3) . Serum non-esterified EPA, DHA and arachidonic acid (AA) were particularly of interest. Levels of the endothelial cell markers, both adhesion molecules and hemostatic factors were related to molar percentage contents of serum non-esterified DHA, EPA and AA. A significant inverse linear association was found between serum non-esterified EPA and DHA, and soluble vascular cell adhesion molecule-1 (sVCAM-1), but also between EPA and DHA, and soluble intercellular adhesion molecule-1. An inverse linear association was found also between serum non-esterified AA and sVCAM-1 and von Willebrand factor. These associations with DHA and AA were independent from the serum content of other NEFA.

Effect of VLC n-3 supplementation on the relationship between serum non-esterified EPA, DHA and AA, and endothelial cell markers was studied among 171 elderly men with high risk for coronary heart disease (4) . In a randomised, 2 x 2 factorial trial, subjects were divided into four groups: diet, VLC n-3 supplementation (2.4 g EPA and DHA per day), a combination of diet and VLC n-3 supplementation, and control. Serum NEFA composition and endothelial cell markers were analysed before and after an 18-month intervention period. In the group that received VLC n-3 supplementation (n=91) in contrast to the group without VLC n-3 supplementation (n=80), there was a significant positive correlation between the change in serum non-esterified DHA and soluble sVCAM-1. Furthermore, there was a significant negative correlation between the change in serum non-esterified EPA and the relative change in sVCAM-1 in the group that did not receive fish oil supplementation, but not in the group with fish oil supplementation.  

Conclusions

The results indicate that percentage contents of individual fatty acids, especially PUFA are correlated between fasting serum NEFA, adipose tissue and diet, and that fatty acids are selectively mobilised from adipose tissue into serum NEFA.

Percentage content of VLC n-3 in fasting serum NEFA was inversely associated with risk of getting first acute MI, and this was associated with VLC n-3 in diet. 

These results might indicate that VLC n-3 in serum NEFA, especially serum non-esterified DHA have an anti-inflammatory effect on the vascular endothelium. However, these results also indicate that high increase in serum non-esterified EPA and DHA, which only can be attained by supplementation of these fatty acids, might increase inflammatory response in vascular endothelium.  

References 

1. Yli-Jama P, Haugen TS, Rebnord HM, Ringstad J, Pedersen JI. Selective mobilisation of fatty acids from human adipose tissue. Eur J Int Med 2001;12:107-15.
2. Yli-Jama P, Meyer HE, Ringstad J., Pedersen J.I. Serum free fatty acid pattern and risk of myocardial infarction - a case-control study. J Int Med 2002;251:19-28.
3. Yli-Jama P, Seljeflot I, Meyer H, Hjerkinn E, Arnesen H, Pedersen J. Serum non-esterified very long-chain PUFA are associated with markers of endothelial dysfunction. Atherosclerosis 2002;164:275-81.
4. Berstad P, Seljeflot I, Veierod MB, Hjerkinn EM, Arnesen H, Pedersen JI. Supplementation with fish oil affects the association between very long-chain n-3 PUFA in serum non-esterified fatty acids and sVCAM-1. Clin Sci 2003 (in press).