биохимия атеросклероза

544 Gene R. Herzberg

bleeding times, so it seems likely that EPA or a product derived from it is responsible for the prolongation of bleeding time after fish oil ingestion [17].

Accumulation of long-chain n3 fatty acids in platelets after fish oil supplementation is partially in place of arachidonic acid in membrane phospholipids. Consequently, the increased phospholipase activity after stimulation of platelets results in less arachidonic acid being released. A consequence of this is reduced conversion of arachidonic acid to the proaggregatory and vasoconstrictive thromboxane (TX) A2 due to the competitive inhibitory effect of the long-chain n3 fatty acids on cyclooxygenase (COX-2) activity [18].

An increase in the intake of long-chain n3 fatty acids, EPA in particular, is associated with a decrease in blood clotting and an increase in bleeding time in humans [19]. This was first reported by Bang and Dyerberg in 1980, who found that Greenland Eskimos had prolonged bleeding times related to their high intake of fat from marine mammals high in long-chain fatty acids [20]. The mechanism for the antithrombotic effect is not certain, but the most commonly proposed mechanism involves changes in TX levels. EPA competes with arachidonic acid for COX-2, which results in an increase in the TXA3/TXA2 ratio. Changes in this ratio are associated with reduced platelet aggregation and vasoconstriction and result in prolonged bleeding time [21]. Products of COX-2 action on arachidonic acid such as prostaglandin I2 and isoprostanes have been associated with reduced blood flow after traumatic cerebral insult [22]. As with clotting, competition for COX-2 by long-chain n3 fatty acids could decrease some of these products and lead to increased blood flow after cerebral trauma leading to increased blood flow. Increased n3 fatty acid intake has also been associated with several factors in the intrinsic clotting pathway and with reduced blood viscosity [21, 23].

Perhaps of greatest practical relevance to the relationship between longchain n3 fatty acids and bleeding time is the lack of significant bleeding in patients taking high doses of n3 fatty acids. These studies have included examination of bleeding after major surgical procedures or childbirth [24–26]. Thus it appears that while long-chain n3 fatty acids may prolong bleeding times, they do not contribute to increased incidence of bleeding except when consumed at very high levels.

Studies of the effects of dietary linoleic acid have generally found that measured platelet aggregation is reduced but with no change in bleeding time (summarized by Knapp [6]). Sanders and Hochland [27] compared a fish oil supplement with a supplement high in oleic and linoleic acids and reported similar reductions in collagen-induced platelet aggregation with both supplements. Overall, studies suggest that n6 PUFA may reduce thrombotic processes in vivo but have generally not found altered bleeding times.

The available data suggest that PUFA, particularly EPA may increase measured bleeding time or decrease platelet aggregation but there is little evidence, except at high levels of intake, that these fatty acids increase the risk of bleeding.

Fatty Acids and Blood Pressure

Grimsgard et al. studying Norwegian men 40–42 years old, found that blood pressure was linearly related to plasma phospholipid saturated fatty acids and inversely associated with linoleic acid [28]. These relationships were independent of body mass index. Studies in several other countries have also found a positive association between the blood level of palmitic acid and blood pressure [29–31]. Dietary intake of linoleic acid [32] and plasma levels of linoleate have been shown to be inversely associated with blood pressure [30, 31, 33].

Dietary supplementation with high doses of fish oil compared to safflower oil or a mixture of oils that approximated the types of fat present in the American diet can reduce blood pressure in men with essential hypertension [34]. Some [35, 36] but not all [37] clinical trials have supported a blood pressure lowering effect of dietary linoleic acid. A fish oil supplement of 15 g/day reduced blood pressure in a six-month study [38]. Meta-analyses of controlled clinical trials of the effects of fish oil on blood pressure concluded that daily intake of EPA + DHA (docosahexaenoic acid 22:6 n3) ≥ 3 g/day significantly lowered blood pressure [39, 40].

Studies in both spontaneously hypertensive rats [41] and humans [42–44] have shown that alpha-linolenic acid (ALA, 18:3 n3) lowers blood pressure. The effects in humans were seen when blood pressure was related to either dietary intake measured directly or indirectly as the adipose tissue content of alpha linolenate.

While the relationship between blood pressure and diet fatty acid content remains somewhat controversial, the majority of the evidence supports a positive correlation of blood pressure with saturated fat and an inverse relationship with polyunsaturated fat and the polyunsaturated/saturated (P/S) ratio.

Dietary Fatty Acids and Stroke

Saturated Fatty Acids

Results of studies of the relationship between saturated fat and stroke have been inconsistent. In an ecological study, Sasaki et al. [45] reported a positive correlation between saturated fat intake and total stroke mortality. Iso et al. [46] found an inverse relationship between the risk of hemorrhagic stroke in women and intake of saturated or trans-unsaturated fat intake but no association with PUFA or monounsaturated fat. Similarly, in men, the Framingham study found the risk of ischemic stroke declined with increasing intake of saturated fat and monounsaturated fat but not polyunsaturated fat. Too few cases of hemorrhagic stroke occurred to reach any conclusions [47]. In a study of Japanese men and women, a high consumption of animal fat was associated with a reduced risk of death from cerebral infarction [48].

546 Gene R. Herzberg

Results of the Seven Countries Study, after 20 years of follow-up, found a nonsignificant inverse relationship between consumption of saturated fats and stroke [49]. In a study of men of Japanese descent living in Japan, McGee et al. found the percentage of calories as saturated fat was inversely related to stroke mortality [50].

In both the Lyon Diet Heart Trial as well as in the large Finnish intervention study, decreasing the intake of saturated fat was associated with a large reduction in mortality from stroke [51, 52].

Polyunsaturated Fat

N3 Fatty Acids

The first suggestions that dietary n3 fatty acids might modify the risk of hemorrhagic stroke came from ecologic studies of Greenland Eskimos who have a very high intake of n3 fatty acids and were shown to have an increased risk of hemorrhagic stroke compared with Danish whites [53, 54]. It should be noted that the intake of n3 fatty acids by Greenland Eskimos (10.5 g/day) is much higher than that of Danish whites (0.8 g/day) [55] or of US residents (0.1–0.2 g/day) [56]. Increased mortality due to hemorrhagic stroke has also been reported in some traditional Japanese fishing communities with high intakes of long-chain n3 fatty acids [57]. However, Yamori et al. [58] found that n3 PUFA levels were significantly higher in the inhabitants of Japanese fishing villages with relatively low stroke morbidity compared to those of farming villages with extremely high stroke morbidity, although the type of stroke was not specified.

Iso et al. [46] examined the association between n3 PUFA intake and the risk of stroke in women and found that those in the highest quintile of intake had reduced risk of both total and thrombotic strokes with no increased risk of hemorrhagic stroke. The intake of long-chain n3 fatty acids by women in the highest quintile was 0.48 g/day.

In the GISISI-prevenzionne trial, subjects were given a supplement of n3 PUFA of 1 g/day, which reduced the risk of an acute heart attack but had no significant effect on the risk of stroke [59].

He et al. [60] examined the relationship between long-chain n3 PUFA intake and stroke in men and found an inverse relationship between intake and risk of ischemic stroke while there was no association found with hemorrhagic stroke. However, in a subsequent report, He et al. found no evidence that the type of dietary fat affects the risk of either hemorrhagic or ischemic stroke [61].

Mortality rates from stroke among Alaska Natives, who had previously been shown to have elevated concentrations of plasma n3 PUFA [62], are higher than rates for US whites [63]. High levels of long-chain n3 fatty acids in perirenal adipose tissue, which reflects high dietary intake, was found to be associated with increased incidence of hemorrhagic stroke [64].

A recent meta-analysis concluded that fish consumption is inversely related to risk of ischemic but not hemorrhagic stroke [65]. Fish is the main dietary source of long-chain n3 PUFAs, which have been shown to have many favorable effects on factors related to stroke risk such as hypertension and blood clotting as discussed previously and reviewed by Dyerberg et al. [66] and Nestel [67].

Simon et al. [68] found that higher serum levels of ALA were associated with a lower risk of stroke in middle-aged men at high risk for cardiovascular disease while stearic acid was associated with an increased risk of stroke. Similarly, Leng et al. [69] found that ALA was significantly lower in the red blood cell phospholipids of patients with stroke even after controlling for blood pressure.

Vegetable Fat

A multivariate analysis of the relationship between foodstuffs and stroke in 19 countries found both ischemic and hemorrhagic stroke to be positively correlated with vegetable fat intake [70]. A number of case control studies have found that a lower proportion of linoleic acid in tissues that reflect dietary intake is associated with increased risk of total or ischemic stroke [71–74]. Japanese, who have a higher mortality rate from both ischemic and hemorrhagic stroke [75], have lower serum levels of linoleic acid and higher levels of saturated and n3 fatty acids [76]. In a more recent case control study of Japanese men and women, Iso et al. [77] found that linoleic acid was inversely associated with the risk of total stroke and ischemic stroke.

Functional Outcome of Stroke and Effect of Dietary Fatty

Acids

Studies of the effects of dietary long-chain n3 fatty acids on functional outcome after a stroke have been limited to those with experimental animals. Black et al. [78] using an acute model of cerebral ischemia induced by ligation of the middle cerebral artery in cats found that the neurological deficit and volume of brain infarction was less in a group treated with fish oil than the control group. In contrast, Clarke et al. [79] found, in a model of intracerebral hemorrhage in rats, that a diet high in fish oil compared to safflower oil led to significantly greater impairment of forelimb dexterity and fine motor control. There was no difference in infarct volume but animals maintained on a diet enriched with fish oil exhibited increased cerebral blood flow after the stroke. The differences in these two studies suggest that the effects of fish oil may be related to effects on coagulation or blood flow, and that whether or not fish oil is beneficial depends on the type of stroke.

548 Gene R. Herzberg

Conclusion

Overall, given the conflicting results, it is difficult to reach a conclusion about saturated fat and stroke. Intake of n6 fatty acids, particularly linoleic acid, appears to be inversely related to stroke risk. Despite expressed concerns about a possible increase in risk of hemorrhagic stroke related to long-chain n3 intake, the results suggest that these fatty acids, when consumed at levels found in typical Western diets, reduce the risk of ischemic stroke with no increase in risk of hemorrhagic stroke.

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