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Will the dietary intake of fish prevent atherosclerosis in diabetic women?
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American Journal of Clinical Nutrition, Vol. 80, No. 3, September 2004
EDITORIAL
William E Connor
From the Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR
--Women who ate >=2 servings of fish per week had a higher educational level and were engaged more frequently with strenuous physical activity. Women who consumed >=2 servings of fish per week reported higher intakes of energy, protein, cholesterol, alcohol, and carotene and lower intakes of carbohydrates
--The findings support the view that regular fish consumption is a part of a healthy diet.
--Women who consumed >=2 servings of fish per week had significantly fewer new lesions. Seventeen (21%) of the women consuming >=2 servings of fish per week and 51 (34%) of the women consuming <2 servings of fish per week developed at least one new lesion (P = 0.03).
See corresponding article below.
The pioneering observations in Greenland Eskimos suggest that high intakes of n--3 fatty acids from fish and sea mammals prevent cardiovascular disease. This is in contrast with the high frequency of cardiovascular disease in Western populations, who have low fish intakes and high intakes of cholesterol and saturated fat. This presumed benefit of n--3 fatty acid intake from fish stimulated a large volume of scientific research. The evidence has suggested that dietary n--3 fatty acids might ameliorate the atherosclerotic process itself, which is the cause of coronary artery disease. Populations that consume more n--3 fatty acids from fish have a lower incidence of coronary artery disease. Patients with coronary artery disease who eat fish appear to have a lower subsequent rate of coronary artery disease and lower total mortality, especially from sudden death. The decrease in deaths from coronary artery disease as a result of fish-oil n--3 fatty acid intakes results from their antiarrhythmic effects (less sudden death from ventricular fibrillation and ventricular tachycardia), but myocardial infarction still occurred from thrombotic atherosclerosis. These studies included clinical trials in male survivors of myocardial infarction as well as epidemiologic associations in both men and women. Fish-oil feeding experiments in humans have shown many potential antiatherogenic effects: a lowering of plasma lipid and lipoprotein concentrations and decreased platelet aggregation, an antithrombotic action. Other factors believed to be involved in the pathogenesis of atherosclerosis are also affected by n--3 fatty acids, including the inhibition of intimal hyperplasia in canine autologous vein grafts, a decreased endothelial cell production of a platelet-derived growth factor- like protein, an increased activity of endothelium-derived nitric oxide (vasodilating), and a reduction in the cytokines involved in the inflammatory response associated with atherosclerosis.
Furthermore, fish oil has prevented the development of experimental atherosclerosis in pigs and rhesus monkeys. In the pig study, the intima of the coronary arteries was damaged by a balloon catheter at the same time that the animals were fed cholesterol and fat, and severe coronary atherosclerosis resulted (6). When the pigs were fed cod liver oil, which is rich in n--3 fatty acids, cholesterol, and saturated fat, a lower incidence of atherosclerosis developed despite little effect on the lowering of plasma cholesterol. This result suggests that fish oil had an effect on atherosclerosis that was unrelated to plasma lipid concentrations. In another study, the ingestion of fish oil led to less carotid atherosclerosis in monkeys fed a diet high in cholesterol and fat; the monkeys experienced some reduction in total cholesterol and LDL cholesterol. The data to date in humans have been inconclusive in showing that fish oil prevents restenosis after coronary artery balloon angioplasty.
In this issue of the Journal, the association between high fish and n--3 fatty acid intakes and a reduction in the incidence of atherosclerosis was given further credence (8). Fish intake was associated with a reduced progression of coronary atherosclerosis in postmenopausal women with coronary artery disease. In particular, the consumption of >=2 servings of fish or >=1 serving of tuna or dark fish each week was associated with smaller increases in the percentage of stenosis of the coronary arteries as documented by angiography. This association was particularly evident in diabetic women after adjustments for age, cardiovascular disease risk factors, and the dietary intakes of fatty acids, cholesterol, fiber, and alcohol. This association was not significant in nondiabetic women. Fish consumption was also associated with a smaller decrease in minimum coronary artery diameter and with fewer new lesions. These data are buttressed by the observation that the fish-oil fatty acids eicosapentaenoic and docosahexaenoic acids are actually incorporated into the phospholipids and cholesterol esters of severe atherosclerotic lesions in humans (3). Thus, it makes sense that a high consumption of fish oil will prevent the progression of atherosclerosis.
A particularly important finding of this study was that the benefit of a high fish-oil intake was especially apparent in diabetic women. Diabetes has now been ranked as a major risk factor for subsequent heart disease, in the same category as a previous episode of coronary artery disease. The incidence of diabetes has greatly increased as a result of the epidemic of obesity. The results of this study agree well with the epidemiologic observation that the risk of coronary heart disease is much lower in diabetic women who consume fish.
Despite the favorable effect of fish intake on coronary atherosclerosis in postmenopausal women with overt coronary artery disease, one must be cautious in interpreting these data. Fish intake did not prevent atherosclerosis but rather reduced its progression. In other words, atherosclerotic progression occurred more slowly with fish consumption. Clearly, this multifactorial disease—atherosclerosis—is not going to be cured or even prevented by fish intake alone. The predominant risk factors for coronary artery disease—smoking, hypertension, hyperlipidemia (particularly elevated LDL-cholesterol concentrations), obesity, diabetes, and low physical activity—must still be dealt with to obtain the best possible outcome. As far as diet is concerned, intakes of the predominant progenitors of atherosclerotic plaque—dietary cholesterol and saturated fat—must be reduced. What needs to be added to the usual low-fat diet prescription of fruit, vegetables, grains, beans, and small amount of animal products is fish.
Dietary factors that contribute to the development and progression of atherosclerosis, namely dietary cholesterol and fat (particularly saturated fat), have been known for almost 100 y. Monkeys fed egg yolk developed high cholesterol concentrations and severe coronary atherosclerosis (10). The removal of cholesterol from the monkeys' diets led to normal cholesterol concentrations and a considerable reduction in the amount of atherosclerotic plaque, from 60% blockage to 20% occlusion.
The influence of dietary factors on chronic disease is always of great interest, especially because these factors apply to atherosclerotic coronary artery disease. Dietary changes made to prevent disease have special value in that the cost of these changes is minimal compared with that associated with clinical interventions, and these changes can be applied to the whole population as a public health measure. The encouragement of fish consumption as a measure to prevent the ravages of coronary artery disease is an important public health message.
"Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease"
Arja T Erkkilä, Alice H Lichtenstein, Dariush Mozaffarian and David M Herrington
1 From the Cardiovascular Nutrition Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston (ATE and AHL); the Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland (ATE); the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston (DM); and the Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC (DMH)
2 Based on work supported by the US Department of Agriculture under agreement no. 58-1950-4-401
INTRODUCTION
The consumption of fish and the long-chain n--3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is associated with a reduced risk of cardiovascular events and mortality. Some of the favorable associations between n--3 fatty acid intake and low rates of cardiovascular disease mortality may be related to a decreased risk of sudden death. However, several lines of evidence suggest that n--3 fatty acid intake may also have favorable effects on the pathogenesis or progression of atherosclerosis. Direct evidence linking fish intake to the rate of progression of coronary disease is limited and, to date, is not available in women. On the basis of observational data, Hu et al recently reported that a high fish intake is associated with a reduced risk of coronary artery disease (CAD) and total mortality in diabetic women. It is unclear whether there is a direct relation between fish intake and the progression of coronary atherosclerosis. The aim of this study was to examine the relation between fish consumption and the progression of angiographically defined coronary atherosclerosis in a group of postmenopausal women undergoing baseline and 3-y follow-up coronary angiography as part of a randomized clinical trial of hormone replacement therapy (HRT).
Background: Higher intakes of fish and n--3 fatty acids are associated with a reduced risk of cardiovascular events and mortality. However, limited data exist on the effect of fish intake on actual measures of progression of coronary artery atherosclerosis.
Objective: The aim was to examine the association between fish intake and the progression of coronary artery atherosclerosis in women with coronary artery disease.
Design: This was a prospective cohort study of postmenopausal women (n = 229) participating in the Estrogen Replacement and Atherosclerosis trial. Usual fish intake was estimated at baseline with a food-frequency questionnaire. Quantitative coronary angiography was performed at baseline and after 3.2 ± 0.6 ( ± SD) y to evaluate changes in the mean minimum coronary artery diameter, the mean percentage of stenosis, and the development of new coronary lesions.
Results: Compared with lower fish intakes, consumption of >=2 servings of fish or >=1 serving of tuna or dark fish per week was associated with smaller increases in the percentage of stenosis (4.54 ± 1.37% compared with --0.06 ± 1.59% and 5.12 ± 1.48% compared with 0.35 ± 1.47%, respectively; P < 0.05 for both) in diabetic women after adjustments for age, cardiovascular disease risk factors, and dietary intakes of fatty acids, cholesterol, fiber, and alcohol. These associations were not significant in nondiabetic women. Higher fish consumption was also associated with smaller decreases in minimum coronary artery diameter and fewer new lesions.
Conclusions: Consumption of fish is associated with a significantly reduced progression of coronary artery atherosclerosis in women with coronary artery disease.
Most of the baseline characteristics, including concentrations of serum lipids and inflammatory markers and blood pressure did not differ significantly between women who reported <2 or >=2 servings of fish per week. Women who ate >=2 servings of fish per week had a higher educational level and were engaged more frequently with strenuous physical activity. Women who consumed >=2 servings of fish per week reported higher intakes of energy, protein, cholesterol, alcohol, and carotene and lower intakes of carbohydrates.
As previously reported, neither estrogen alone nor estrogen plus medroxyprogesterone acetate compared with placebo affected the progression of atherosclerosis in this population; however, the HRT was controlled in the multivariate models that assessed progression. Because of a prior report suggesting a selectively beneficial effect of fish intake in diabetic women on CAD events (16), we analyzed our data on the basis of diabetes. Forty-two percent of the women participating in this study were classified as having diabetes (Table 1). Change in minimum coronary artery diameter was significantly smaller in women who consumed >=2 servings of fish per week than in those who consumed <2 fish servings per week (P for fish intake = 0.02). Adjustment for age, location of coronary artery segment, time of follow-up, study clinic, CABG, PTCA, race, BMI, smoking, use of cholesterol-lowering medication, HRT, diabetes, and energy intake (model 1) diminished the relation (P = 0.06). Further adjustment for dietary variables known to affect CAD risk, saturated fat, monounsaturated fat, polyunsaturated fat, cholesterol, fiber, and alcohol (model 2) strengthened the association between fish intake and change in minimum coronary artery diameter (P = 0.006).
Women who consumed >=2 servings of fish per week had significantly fewer new lesions (P = 0.02, ANCOVA after adjustment for the specified factors) (Table 3). Seventeen (21%) of the women consuming >=2 servings of fish per week and 51 (34%) of the women consuming <2 servings of fish per week developed at least one new lesion (chi-square test, P = 0.03).
Tuna and dark fish are the major contributors of long-chain n--3 fatty acids in the American diet. The average content of EPA and DHA in tuna (0.3-1.3 g/serving) and dark fish (0.7-1.8 g/serving) is at least twice that of fish in the "other fish" category (0.1-0.4 g/serving).
DISCUSSION
Fish and n--3 fatty acid intakes have received considerable attention in the recent past as potential dietary factors to reduce the risk of developing CAD (4--6, 25). This growing body of data culminated with a 2002 recommendation by the American Heart Association for persons without documented CAD to eat fish twice or more per week and for patients with documented CAD to consume 1 g EPA + DHA/d (26). The importance of these and other recommendations for diabetic persons was highlighted when the National Cholesterol Education Program designated diabetes as a CAD risk equivalent. This may be particularly important in women, in whom the adverse effects of diabetes may be greater than those in men (28).
There are no previous data on fish intake and atherosclerosis progression in women. The present results extend prior observational data on CAD risk by showing that fish intake is associated with reduced progression of atherosclerosis in postmenopausal women with established CAD within the 3-y observational period of the study. Subsequent analysis indicated that this association was strongest in the subgroup of women with diabetes. The interaction terms between fish intake and diabetes were not significant in all of the analyses. The possibility that this observation was due to limited statistical power cannot be ruled out. Nevertheless, within the 3-y period, new lesions were observed in all women regardless of fish intake. Data from the current study are consistent with recent observational data, suggesting an association with fish and n--3 fatty acid intakes and a decreased incidence of CAD and total mortality in diabetic women. These data can be interpreted in 2 ways. The observation of a significant association of fish intake in diabetic, but not in nondiabetic women, may be due to a higher degree of sensitivity of diabetic women to n--3 fatty acids. However, the possibility cannot be excluded that the observation may reflect a more rapid rate of atherosclerosis progression in the diabetic women, hence, a greater likelihood that a positive association would be observed within the observational period.
The lower rate of angiographically documented atherosclerosis progression was significantly associated with tuna and dark fish intake, whereas these associations appeared to be weaker for the intake of "other fish." This finding is likely a reflection of the higher n--3 fatty acid content of tuna and dark fish than of "other fish." Alternatively, it may be related to the method used for preparation of tuna and dark fish relative to that for white fish. The later type of fish is more likely to be fried in fat that is high in either trans or saturated fatty acids. The findings of the current study are consistent with those of previous studies, which documented an inverse association between dark fish intake and total mortality and CAD morbidity in diabetic women participating in the Nurses' Health Study. Furthermore, intake of tuna or other broiled or baked fish has been shown to be associated with a reduced risk of cardiac death in female and male subjects participating in the Cardiovascular Health Study. Similarly, intake of fatty fish was associated with a lower risk of cardiac death in men participating in the Seven Countries Study.
Although fish intake and fish-oil supplements have been associated with a reduced risk of clinical events, the effect of fish or n--3 fatty acid intake on the progression of atherosclerosis has been controversial. Bairati et al reported that dietary n--3 fatty acid intake was associated with a lower frequency of restenosis at 6 mo after PTCA in men, whereas Watts et al reported no association between atherosclerosis progression and dietary intakes of EPA and DHA in men after 3 y of follow-up. Less progression of atherosclerosis has been reported after 1 y of treatment with fish-oil supplements in CABG patients and CAD patients after 2 y of treatment. In contrast, Sacks et al reported that fish-oil supplementation did not alter the progression of atherosclerosis in CAD patients over a 28-mo period. Self-reported intake of fish at least twice a week has been shown to be associated with a lower prevalence of myocardial lesions in men at autopsy. Fish-oil supplementation has been reported to have little effect on restenosis after PTCA. However, restenosis is a pathophysiologically distinct process compared with progression of native atherosclerosis. There are no data focusing on fish intake and atherosclerosis progression in women or in diabetic subjects. In most cases, the data sets include {approx} 80% male subjects, and data are not reported separately for female subjects.
Fish and n--3 fatty acids are suggested to have antiinflammatory properties that may contribute to the reduced risk of CAD, especially in diabetic subjects. Concentrations of most inflammatory markers, with the exception of VCAM-1, were not associated with fish intake in this study. VCAM-1, which is mainly expressed on atherosclerotic plaques, is suggested to predict CAD risk, especially in subjects with advanced atherosclerosis. These data may have been confounded by the relatively high BMI or proportion of diabetic women in the study population. These data are consistent with previous work suggesting that fish-oil supplementation does not affect concentrations of CRP and IL-6 or ICAM-1 and VCAM-1.
Our study had certain limitations. Higher fish intakes were associated with a healthier lifestyle. Although these factors were controlled for during the analysis, residual confounding cannot be ruled out. The results suggest that intake of tuna and dark fish is more strongly associated with a reduction in progression than is the intake of other types of fish. Because the latter category of fish is more likely to not only be fried but also to be consumed with other fried foods (eg, fried potatoes), such a dietary pattern could have contributed to the observed outcome. There have been some concerns that fish contaminated with mercury could diminish the benefits of fish. We were not able to evaluate the effect of mercury because there was no data collected on mercury exposure.
In conclusion, fish consumption was associated with a significantly reduced progression of coronary atherosclerosis in postmenopausal women with CAD. This relation was strongest in diabetic women. The findings support the view that regular fish consumption is a part of a healthy diet.
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