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Albert,C.M., Hennekens, C.H., Odonnell,C.J., Ajani,U.A., Carey,V.J., Willett,W.C., et al.

Fish Consumption and Risk of Sudden Cardiac Death

Context. Dietary fish intake has been associated with a reduced risk of fatal cardiac end points, but not with nonfatal end points. Dietary fish intake may have a selective benefit on fatal arrhythmias and therefore sudden cardiac death.

Objective. To investigate prospectively the association between fish consumption and the risk of sudden cardiac death.

Design. Prospective cohort study.

Setting. The US Physicians' Health Study.

Patients. A total of 20,551 US male physicians 40 to 84 years of age and free of myocardial infarction, cerebrovascular disease and cancer at baseline who completed an abbreviated, semiquantitative food frequency questionnaire on fish consumption and were then followed up to 11 years.

Main Outcome Measure. Incidence of sudden cardiac death(death within 1 hour of symptom onset) as ascertained by hospital records and reports of next of kin.

Results. There were 133 sudden deaths over the course of the study.After controlling for age, randomized aspirin and beta carotene assignment, and coronary risk factors, dietary fish intake was associated with a reduced risk of sudden death, with an apparent threshold effect at a consumption level of 1 fish meal per week (P for trend--.03). For men who consumed fish at least once per week, the multivariate relative risk of sudden death was 0.48 (95% confidence interval, 0.24-0.96;P=.04) compared with men who consumed fish less than monthly. Estimated dietary n-3 fatty acid intake from seafood also was associated with a reduced risk of sudden death but without a significant trend across increasing categories of intake. Neither dietary fish consumption nor n-3 fatty acid intake was associated with a reduced risk of total myocardial infarction, nonsudden cardiac death, or total cardiovascular mortality. However, fish consumption was associated with a significantly reduced risk of total mortality.

Conclusion. These prospective data suggest that consumption of fish at least once per week may reduce the risk of sudden cardiac death in men.

JAMA 1998;279:23-28.

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Billman,G.E., Hallaq,H., & Leaf, A.

Prevention of Ischemia-induced Ventricular Fibrillation by w-3 Fatty Acids.

A specially prepared dog model of myocardial infarction was used to test the efficacy of the long chain polyunsaturated fish oil w-3 fatty acids eicosapentaenoic (20:53) and docosahexaenoic (22:6 n-3) acids to prevent ischemia-induced malignant cardiac arrhythmias. The dogs had sustained a prior experimental myocardial infarction from ligation of the left anterior descending coronary artery, and a hydraulic cuff was implanted around the the left circumflex artery at that operation.After recovery from that procedure the animals are tested during a treadmill exercise test. With compression to the left circumflex artery sensitive animals will predictably develop ventricular fibrillation (VF).In such prepared dogs an emulsion of fish oil fatty acids was infused i.v. over a 50-60 min period just before the exercise-plus-ichemia test, and the effect on the development of VF was recorded. The infusion was 60 ml of a 10% (vol/vol) of a fish oil concentrate containing 70% w-3 fatty acids with free eicosapentaenoic acid and docosahexaenoic acid composing 33.9% and 25.0% of that total, respectively. Alternatively, some animals similarly received an emulsion containing 5ml of the free fatty acid concentrate plus 5ml of a triacylglycerol concentrate containing 65% w-3 fatty acids with eicosapentaenoic acid and docosahexaenoic acid comprising 34.0% and 23.6% of that total, respectively. In seven of eight animals the infusion of the fish emulsion completely prevented the the acute occurrence of VF in the susceptible animals (P<0.005). In five of five of these animals the subsequent exercise-plus-ischemia test after a similar infusion of an emulsion in which soy bean oil replaced the fish oil fatty acid concentrates resulted in prompt development of VF. Possible mechanisms for this protective effect of w-3 fatty acids against exercise and ischemia-induced malignant arrhythmias are considered.

Proc. Natl. Acad. Sci. USA, 1994 91;pp4427-4430.

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Burr(a),M.L., Fehily,A.M., Gilbert,J.F., Elwood,P.C., et al .

Effects of Changes in Fat,Fish, and Fibre Intakes on Death: Diet and Re-infarction Trial (DART).

A randomised controlled trial with a factorial design was done to examine the effects of dietary intervention in the secondary prevention of myocardial infarction (MI). 2033 men who had recovered from MI were allocated to receive or not receive advice on each of three dietary factors: a reduction in fat intake and an increase in the ratio of polyunsaturated to saturated fat, an increase in fatty fish intake, and an increase in cereal fibre intake. The advice on fat was not associated with any difference in mortality, perhaps because it produced only a small reduction (3-4%) in serum cholesterol. The subjects advised to eat fatty fish had a 29% reduction in 2 year all-cause mortality compared to those not so advised. This effect, which was significant, was not altered by adjusting for ten potential confounding factors. Subjects given fibre advice had a slightly higher mortality than other subjects (not significant). The 2 year incidence of re-infarction plus death from ischaemic heart disease was not significantly altered by any of the dietary regimens. A modest intake of fatty fish (two or three portions per week) may reduce mortality in men who have recovered from MI.

Lancet. Sept 30th;1989: p 756-761.

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Burr(b),M.L., Sweetnam, P.M., & Fehily,A.,

Diet and Reinfarction.

The authors examined the DART trial data, and looked separately at the results for those subjects consuming fish oil rather than fish. The fish oil group (227 in total) experienced 8 heart deaths (10 deaths in total) during the study period, compared to 70 heart deaths (84 in total) among the 788 fish eaters. Among the 1018 subjects not advised to eat more fish, or to take fish oil, there were 116 heart deaths, and 130 deaths in total. The authors concluded that taking into account the smaller numbers in the fish oil group, there was no evidence that fish oil was any less effective at reducing heart deaths than fish itself. This indicated strongly that the beneficial effect on survival was due to the oil, and not to any other factors in fish.

Europ.Heart J.,1994,15;1152-54.

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Cartwright,I.J.,Pockley,A.G., Galloway,J.H., Greaves,M., & Preston,F.E.

The Effects of Dietary w-3 Polyunsaturated Fatty Acids on Erythrocyte Membrane Phospholipids, Erythrocyte Deformability & Blood Viscosity in Healthy Volunteers.

We have examined, in normal subjects, the effects of a daily dietary supplement of fish oil on erythrocyte membrane phospholipids, erythrocyte deformability & blood viscosity. After 3 weeks, incorporation of C20:5w3 into erythrocyte phosphatidyl choline (PC) was greater compared to phosphatidyl ethanolamine (PE) & serine (PS). Incorporation of C20:5w3 also occurred into PC, PE & PS. w-3 Fatty acids were incorporated almost entirely at the expense of C18:2w6, but total unsaturation of phospholipids was increased. This is consistent with increased lipid fluidity, which may be an important determinant of erythrocyte deformability. The same dosage of MaxEPA also resulted in a significant increase in erythrocyte deformability and a concomitant reduction in whole blood viscosity. Since plasma viscosity and haemocrit were unchanged, it seems likely that the effects on blood rheology were mediated by changes in erythrocyte lipid fluidity.

Atherosclerosis,1985;55:267-81.

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Charnock, J.S.

Dietary Fats and Cardiac Arrhythmia in Primates.

Several epidemiological surveys have suggested that an alteration in the habitual intake of the type rather than the amount of dietary fat may offer a nutritional means for a reduction in mortality from severe cardiac arrhythmia which cannot be achieved at present by the post hoc administration of anti-arrhythmic agents. We have examined this possibility in a series of long term feeding studies with the small non-human primate marmoset monkey Callithrix jacchus. In both in vitro and in vivo studies of the mechanical performance of cardiac muscle we have found that diets rich in saturated fatty acids promote arrhythmia when the heart is subjected to pharmacological or ischemic stress. Conversely, diets enriched in either omega-6 or omega-3 PUFA are beneficial, reducing the vulnerability o pharmacologically induced dysrhythmia in vitro or ischemic arrhythmia in vivo. In addition, PUFA enriched diets enhance myocardial performance (left ventricular ejection fraction and end diastolic volume) and raise the electrical threshold at which ventricular fibrillation can be induced. These diet-induced changes in cardiac performance are accompanied by significant alterations in the PUFA composition of cardiac muscle membranes, and the subsequent production of myocardial eicosanoids. Both omega-6 and omega-3 PUFA increase the ratio of myocardial prostacyclin:thromboxane, but omega-3 PUFA is more effective as less is required to achieve a significant decrease in pro-arrhythmic thromboxane. These results offer a nutritional basis for the epidemiological findings of reduced mortality from sudden cardiac death in populations who consume less saturated fatty acids of either animal or plant origin, but maintain their total fat intake by substitution with polyunsaturated fatty acids. Nevertheless, the greatest benefit might be expected amongst those populations having a regular intake of the long-chain omega-3 PUFA found in many marine species, even if considerable saturated fatty acids remain in the diet.

Nutrition, 1994,10,2,161-169.

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Christensen(a), J.H., Gustenhoff, P., Ejlersen, E., Jessen, T., Korup, E. ,Dyerberg, J. et al.

n-3 fatty acids and ventricular extrasystoles in patients with ventricular tachyarrhythmias.

The purpose of the study was to examine the effect of a dietary supplement with n-3 polyunsaturated fatty acids (n-3 PUFAs) on ventricular arrhythmias (extrasystoles) and on plasma lipids and lipoproteins in a double blind placebo-controlled design. Thirty-five patients discharged from the Department of Cardiology with a diagnosis of ventricular tachyarrhythmia between January 1988 and September 1991 were asked to participate in tile study and 24 patients gave their informed consent. These patients were randomized to receive either 5.2 g of n-3 PUFAs daily (4.3 g of eicosapentaenoic acid and docosahexaenoic acid) as 8 capsules of Pikasol(R) or corn oil rich in n-6 PUFAs (controls. The supplements were given for 16 weeks. A 48 hour Holter-recording was obtained and fasting blood samples were taken at baseline and repeated 16 weeks later at the end of the study in order to monitor the number of ventricular extrasystoles/48 h (VE/48 h), fasting plasma lipids and lipoproteins. The median logarithmic number of VE/48 h (1rd-3st quartiles within parentheses) decreased from 5.9 (1.6-6.7) to 2.9 (2.8-7.0) in the n-3 group and from 5.2 (4.0-7.7) to 4.6 (2.4-6.5) among controls. No statistically significant differences was found within or between the two groups. Plasma triglycerides significantly decreased in the n-3 group, and LDL-cholesterol significantly decreased in the control group. No significant changes were observed regarding total cholesterol and HDL-cholesterol.

Nutrition Research, 1995,15;1:1-8.

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Christensen(b), J.H., Aaroe, J., Knudsen, N., Dideriksen, K., Kornerup, H.J., Dyerberg, J., & Schmidt, E.B..

Heart rate variability and n-3 fatty acids in patients with chronic renal failure - a pilot study.

Patients with chronic renal failure (CRF) often have autonomic cardiac dysfunction, which can be assessed by measuring heart rate variability (HRV). This dysfunction predisposes the patients to sudden cardiac death. This study describes 24-hour HRV in patients with CRF compared to HRV in patients with a previous myocardial infarction (MI). Furthermore, associations between HRV in patients with CRF and the content of n-3 polyunsaturated fatty acids (PUFA) in cell membranes were examined, because n-3 PUFA may improve HRV. Twenty-nine patients with CRF treated with dialysis were enrolled. A 24-hour Holter recording was obtained at baseline and the HRV variables, RR (= mean of all normal RR interval during the 24-hour recording and SDNN (= standard deviation of all normal RR intervals in the entire 24-hour recording) were analyzed. Also, granulocyte fatty acid composition was determined. The patients were allocated to dietary supplementation with either 5.2 g of n-3 PUFA or a placebo oil (olive oil) daily for 12 weeks in a double-blind design. At the end of the supplementation period the Holter recording and blood sampling were repeated. At baseline the CRF patients' mean SDNN was 86 ms compared to 118 ms (p <0.01) in patients with a previous MI. After supplementation with either n-3 PUFA or placebo a highly significant correlation was observed between the content of n-3 PUFA in cell membranes and HRV (r = 0.71, p <0.01). Furthermore, when the patients were dichotomized according to their mean SDNN, it was found, that those with the highest SDNN had a higher content of n-3 PUFA in cell membranes compared to those with the lowest SDNN (7.8% vs 4.2%, p <0.05). In conclusion, HRV was decreased in CRF patients indicating a cardiovascular autonomic dysfunction. The positive correlation between the n-3 PUFA content in cell membranes and HRV suggests that the effects of an increased intake of n-3 PUFA in CRF patients should be further studied.

Clinical Nephrology,1998,49;2:102-106.

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Daviglus, M.L.,Stamler, J.,Shekelle, R.B.,et al .

Fish consumption and the 30-year risk of fatal myocardial infarction.

Background: Epidemiologic data on the possible benefit of eating fish to reduce the risk of coronary heart disease have been inconsistent. We used data from the Chicago Western Electric Study to examine the relation between base-line fish consumption and the 30-year risk of death from coronary heart disease.

Methods: The study participants were 1822 men who were 40 to 55 years old and free of cardiovascular disease at base line. Fish consumption, as determined from a detailed dietary history, was stratified (0, 1 to 17, 18 to 34, and greater than or equal to 35 g per day). Mortality from coronary heart disease, ascertained from death certificates, was classified as death from myocardial infarction (sudden or nonsudden) or death from other coronary causes.

Results: During 47,153 person-years of follow-up, there were 430 deaths from coronary heart disease; 293 were due to myocardial infarctions (196 were sudden, 94 were nonsudden, and 3 were not classifiable). Cox proportional-hazards regression showed that for men who consumed 35 g or more of fish dally as compared with those who consumed none, the relative risks of death from coronary heart disease and from sudden or nonsudden myocardial infarction were 0.62 (95 percent confidence interval, 0.40 to 0.94) and 0.56 (95 percent confidence interval, 0.33 to 0.93), respectively, with a graded relation between the relative risks and the strata of fish consumption (P for trend = 0.04 and 0.02, respectively). These findings were accounted for by the relation of fish consumption to nonsudden death from myocardial infarction (relative risk, 0.33; 95 percent confidence interval, 0.12 to 0.91; P for trend = 0.007).

Conclusions: These data show an inverse association between fish consumption and death from coronary heart disease, especially nonsudden death from myocardial infarction.

New Engl. J. Med 1997,336;15:1046-1053 .

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Dolecek,T.A.& Grandits,G.

Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial( MRFIT).

Data from the MRFIT study was used to examine the relationship between intake of specific dietary fatty acids, and subsequent health experience. The MRFIT study examined the lives and diets of 12,500 American men aged 35-57 at the start of the trial. Half the men received no special treatment, and thus formed the usual care, or control group. Data from this group was used for this study.The intake of fatty acids was estimated, and compared with subsequent health fate. The top 20% of consumers of the three major long chain polyunsaturates- 20:5w-3, 22:5w-3 and 22:6w-3 (consuming an average of 660mg/day) had only 24 deaths out of 1,251 men over a period of 12 years. Among the 1307 men who formed the lowest intake group (consuming an average of less than 90 mg/day) 42 died during the 12 years of the study. Relative risk of death was therefore reduced by 40% for the top omega-3 consumers. A dose response effect was seen.

In "Health Effects of w-3 Polyunsaturated Fatty Acids in Seafoods" .World Rev.Nutr.Diet., eds Simpoulos,A.P., Kifer,R.R., Martin,R, & Barlow,S. Karger, Basel 1991;66:205-216.

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Dyerberg, J., Bang,H.O., & Stoffersen,E.

Eicosapentaenoic acid and Prevention of Thrombosis and Atherosclerosis ?

Unlike arachidonic acid (eicosatetraenoic acid, C20:4,w-6,AA) eicosapentaenoic acid ( C20:5,w-3,EPA) does not induce platelet aggregation in human platelet-rich plasma(P.R.P.), probably because of the formation of thromboxane A3 (T.X.A.3) which does not have platelet aggregating properties. Moreover, EPA, like AA can be utilised by the vessel wall to make an anti-aggregating substance, probably a delta-17 prostacyclin (P.C.I.3). This finding suggests that in vivo, high levels of EPA and low levels of AA could lead to an antithrombotic state in which an active PCI3 and a non-active TXA3 are formed. Eskimos have high levels of EPA and low levels of AA, and they also have a low incidence of myocardial infarction and a tendency to bleed. It is possible that dietary enrichment with EPA will protect against thrombosis.

Lancet, 1978;July 15th;ii:117-9.

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Harris, W.S.

n-3 Fatty acids and serum lipoproteins: Human studies.

The effects of n-3 fatty acids from fish oils (eicosapentaenoic acid and docosahexaenoic acid) and plant oils (alpha-linolenic acid) on human serum lipids and lipoproteins are reviewed. Studies were included in this review if they were placebo-controlled, crossover, or parallel design studies providing < 7 g n-3 fatty acids/d and with treatment periods of greater than or equal to 2 wk duration. Only three studies were available for evaluation of the effects of alpha-linolenic acid on serum lipid concentrations. From these studies it appeared that alpha-linolenic acid (18:3n-3) was equivalent to n-6-rich oils vis-a-vis lipid and lipoprotein effects. Only when very large amounts of flaxseed oil were fed did the hallmark effect of marine n-3 fatty acids-reduced triacylglycerol concentrations-appear. Thus, in terms of effects on lipoprotein metabolism, the plant-derived n-3 fatty acid is not equivalent to the marine-based acids. More studies using the marine-based acids were examined and summarized. Both crossover (n = 36) and parallel (n = 29) design studies reached the same conclusions: total cholesterol is not materially affected by n-3 fatty acid consumption, low-density-lipoprotein cholesterol concentrations tend to rise by 5-10% and high-density-lipoprotein cholesterol by 1-3%, and serum triacylglycerol concentrations decrease by 25-30%. These effects of marine n-3 fatty acids are now well-established; what remains is to determine the mechanisms behind these effects and, more importantly, their health consequences.

Amer. J. Clinical Nutrition, 1997,65;5:Suppl.,S1645-S1654.

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Hokanson, J.E., & Austin,M.A.

Plasma Triglyceride is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol; a meta-analysis of population based studies.

Objectives:Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the magnitude of the association between triglyceride and cardiovascular disease in the general population, and to determine whether this relationship is independent of high-density lipoprotein (HDL) cholesterol, using the semi-quanititative techniques of meta-analysis.

Methods and design: Seventeen studies were selected for the analysis based on published reports of population-based, prospective studies, including 46,413 men and 10,864 women. To insure comparability, only studies reporting an association between fasting triglyceride levels and incident cardiovascular endpoints were included. Using standard meta-analysis calculations, relative risks(RR) and 95% confidence intervals(CI) were calculated and standardized with respect to a 1 mmol/l increase in triglyceride. Multivariable-adjusted RRs were determined for the six studies in men and two studies in women that reported adjustments for the HDL cholesterol.

Results: For men and women, the univariate RRs for triglyceride were 1.32(95%CI 1.26-1.39) and 1.76 (95%CI 1.50 - 2.07),respectively, indicating an approximately 30% increase in risk in men and a 75% increase in women. Adjustment of HDL cholesterol and other risk factors attenuated there RRs to 1.14 (95%CI 1.05 - 1.28) and 1.37 ( 95%CI 1.13 - 1/66) respectively, which were still statistically significant values.

Conclusions: Based on combined data from prospective studies, triglyceride is a risk factor for cardiovascular disease for both men and women in the general population, independent of HDL cholesterol. These findings demonstrate the necessity for clinical trials to evaluate whether lowering plasma triglyceride decreases the risk of cardiovascular disease.

J.Cardiovascular Risk,1996, 3;2:213-219.

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Horwood, L. J & Fergusson,D.

Breastfeeding and Later Cognitive and Academic Outcomes.

()objective. This study examines the associations between duration of breastfeeding and childhood cognitive ability and academic achievement over t he period from 8 to 18 years using data collected during the course of an 18 year longitudinal study of a birth cohort of >1000 New Zealand children.

Method. During the period from birth to age I year, information was collected on maternal breastfeeding practices. Over the period from 8 to 18 years. Sample members were assessed on a range of measures of cognitive and academic outcomes including measures of child intelligence quotient; teacher ratings of school performance; standardized tests of reading comprehension, mathematics, and scholastic ability; pass rates in school leaving examinations; and leaving school without qualifications.

Results . Increasing duration of breastfeeding was associated with consistent and statistically significant increases in 1) intelligence quotient assessed at ages 8 and 9 year; 2) reading comprehension, mathematical ability, and scholastic ability assessed during the period from 10 to 13 years; 3) teacher ratings of` reading and mathematics assessed at 8 and 12 years; and 4) higher levels of attainment in school leaving examinations. Children who were breastfed for > 8 months had mean test scores that were between 0.35 and 0.59 SD units higher than children who were bottle-fed. Mothers who elected to breasted tended to be older, better educated; from upper socioeconomic status families; were in a two-parent family; did not smoke during pregnancy; and experienced above average income and living standards . Additionally, rates of breastfeeding increased with increasing birth weight, and first-born children were more likely to be breastfed. Regression adjustment for maternal and other factors associated with breastfeeding reduced the associations between breastfeeding and cognitive or educational outcomes. Nonetheless, in 10 of the 12 models, fitted duration of breastfeeding remained a significant predictor of later cognitive or educational outcomes. After adjustment for confounding factors, children who were breastfed for >8 months had mean test scores that were between 0.11 and 0.30 SD units higher than those not breastfed.

It is concluded that breastfeeding is associated with small but detectable increases in child cognitive ability and educational achievement. These effects are 1) pervasive, being reflected in a range of measures including standardized tests, teacher ratings and academic outcomes in high school and 2) relatively long-lived, extending throughout childhood into young adulthood.

PEDIATRICS 1998;101:e9

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Keli, S.O., Feskens, E.J.M., & Kromhout, D.
Fish Consumption and Risk of Stroke - The Zutphen Study.

Background and Purpose :A low-to-moderate average daily fish consumption has been reported to convey protection against coronary heart disease incidence and mortality. Currently there is no information about its effect on stroke risk.

Methods: In 1960, 1965, and 1970 cross-check dietary histories were obtained in 552 men aged 50 to 69 years in 1970 in the town of Zutphen, The Netherlands, The association between fish consumption and stroke incidence in the period 1970 to 1985 was assessed by Cox proportional hazards models. Adjustments were made for confounding by age, systolic blood pressure, cigarette smoking, serum total cholesterol, energy intake, alcohol consumption, and prescribed diet.

Results: The mean fish consumption in 1970 was 17.9 g/d. Men who consumed more than 20 g of fish per day in 1970 had a reduced risk of stroke compared with those who consumed less fish. The hazard ratio (HR) amounted to 0.49 (95% confidence interval [CI], 0.24 to 0.99), and did not change after adjustment for potential confounders. Fewer strokes occurred among the 301 men who always reported fish consumption between 1960 and 1970 than among the men who changed fish consumption habits between 1960 and 1970 or did not consume fish at all (HR, 0.63; 95% CI, 0.34 to 1.16).

Conclusions: These results suggest that consumption of at least one portion of fish per week may be associated with a reduced stroke incidence.

Stroke 1994,25;2:328-332.

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Knapp, H.R.
Dietary fatty acids in human thrombosis and hemostasis.

The effects of fatty acids on hemostasis are controversial. It has been difficult to show convincing effects of saturated or monounsaturated fatty acids that are clearly related to hemostatic variables in humans. Unsaturated fatty acids alter platelet aggregation and processes related to coagulation and fibrinolysis. Indirect evidence exists that n-6 polyunsaturated fatty acids may exert favorable effects on thrombotic processes in vivo, but large clinical trials have failed to show benefits of 5-6 g linoleic acid (18:2n-6) or linolenic acid (18:3n-3)/d. Only long-chain n-3 fatty acids prolong the template bleeding time, and they may exert some beneficial effect on erythrocyte flexibility. It appears unlikely that n-3 fatty acids lower fibrinogen or interact with the fibrinolytic system directly. One prospective secondary prevention trial showed benefits that may have resulted from either an improved hemostatic profile or an antiarrhythmic effect. A similar time course of clinical improvement was noted with reduced rates of cardiac mortality and postoperative thrombosis in Norway during World War II, and this was associated with a drastic dietary alteration involving increased consumption of n-3 fatty acids and reduced consumption of saturated fatty acids. Further work is needed to develop better tools to examine in vivo hemostasis so that the mechanisms and eventual clinical utility of n-3 fatty acids can be elucidated in well-designed clinical trials.

American Journal of Clinical Nutrition, 1997,65,5 Suppl.,S1687-S1698.

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