Circulation, Vol 87, 1017-1029, Copyright © 1993 by American Heart Association
LA Harker, AB Kelly, SR Hanson, W Krupski, A Bass, B Osterud, GA FitzGerald, SH Goodnight and WE Connor
BACKGROUND. Because of discrepant claims regarding the relative biological
effects of n-3 fatty acids (n-3FAs), we have concurrently measured the
effects of dietary n-3FAs on blood and vascular lipid composition,
hemostatic function, blood thrombotic responses, vascular thrombus
formation, and vascular lesion formation in baboons. METHODS AND RESULTS.
Dietary n-3FAs displaced n-6FAs in plasma, platelets, blood vessels, and
corresponding urinary eicosanoid metabolites (p < 0.01 in all cases)
within weeks after initiation of a semipurified diet containing 1 g/kg per
day n-3FA-ethyl ester concentrate (composed of two thirds eicosapentanoic
acid and one third docosahexanoic acid). Coincidentally, platelet
hemostatic function became minimally impaired (template bleeding times
prolonged from 4.3 +/- 0.5 minutes to 7.6 +/- 1.3 minutes, p = 0.039);
concentrations of collagen producing half- maximal platelet aggregation
increased (from 6.4 +/- 2.1 to 8.5 +/- 2.5 micrograms/mL, p = 0.045); and
tissue factor expression by endotoxin- stimulated blood monocytes fell
(from 6.5 +/- 1.2 to 1.7 +/- 0.14 mU/10(6) cells, p < 0.005). Dietary
n-3FAs decreased deposition of platelets onto thrombogenic segments of
Dacron vascular graft incorporated into chronic exteriorized femoral
arteriovenous (AV) shunts, a thrombotic process resistant to the effects of
both aspirin and heparin (111In-labeled platelet deposition decreased from
14.1 +/- 1.4 x 10(9) platelets/5-cm segment at 40-60 minutes with occlusion
to 7.5 +/- 0.8 x 10(9) platelets/5-cm segment without occlusion; p <
0.001). Platelet deposition onto segments of endarterectomized homologous
normal aorta in the AV shunts of n-3FA-treated animals was similarly
reduced (from 4.4 +/- 0.9 to 1.8 +/- 0.4 x 10(9) platelets; p < 0.01).
Dietary n-3FAs interrupted vascular thrombus formation at sites of surgical
carotid endarterectomy (platelet deposition, 1.5 +/- 0.4 versus 4.4 +/- 1.0
x 10(9) platelets in untreated controls; p < 0.001). Moreover,
endarterectomized aortic segments (EASs) from n-3FA- treated donors
exhibited little capacity to induce thrombus formation when tested in the
AV shunts of control recipient animals (0.24 +/- 0.10 versus 4.4 +/- 0.90 x
10(9) platelets). However, in the converse crossover experiments, EASs from
control animals actively accumulated platelets when studied in the AV
shunts of n-3FA-treated animals (1.8 +/- 0.4 x 10(9) platelets; p < 0.01
versus n-3FA-treated EASs in shunts of normal animals). Dietary n-3FAs also
abolished vascular lesion formation at sites of carotid endarterectomy 6
weeks after surgery (cross-sectional area of neointima 0.048 +/- 0.031 mm2
compared with 0.428 +/- 0.104 mm2 in control arteries; p = 0.010).
CONCLUSIONS. In nonhuman primates, dietary n-3FAs in high doses eliminate
both vascular thrombus formation and vascular lesion formation after
mechanical vascular injury while largely sparing hemostatic function and
modestly reducing blood thrombotic responses. These effects are attributed
to selective n-3FA-dependent alterations in cellular membrane functions.
ARTICLES
Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates
Department of Medicine, Emory University School of Medicine, Atlanta, Ga. 30322.
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