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Fats_Angina

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									Title
Dietary fats and risk of Angina in Women: 24 Years of Follow-up of the Nurses‟ Health Study

Abstract

Introduction
Angina is a common manifestation of coronary heart disease.{{2067 Centers for Disease Control and Prevention (CDC) 2007; }}. Few epidemiological studies investigating „diet-heart‟ hypothesis have focused on angina{{2008 Leren,P. 1970;1978 Ascherio,A. 1996; 1995 Ascherio,A. 1999; }}. Various animal studies suggest a role of dietary fat intake in atherosclerosis {{1776 Wolfe,M.S. 1994;1775 Rudel,L.L. 1995; }}. International correlations between diet and the prevalence of raised atherosclerotic lesions suggest that percentage of calories from total fat and animal protein but not cholesterol are positively related to risk of atherosclerosis, and that total carbohydrate intake is inversely associated with risk {{2229 Scrimshaw,N.S. 1968; }}. Higher intake of saturated fats and trans fats consistently increases LDL cholesterol while polyunsaturated fats decrease LDL cholesterol and raise HDL cholesterol {{2092 Mensink,R.P. 2003; }} while intake of PUFAs is associated with lower concentrations of inflammatory markers and higher levels of HDL cholesterol {{2184 Jump,D.B. 2002; 2092 Mensink,R.P. 2003}}. Results from Framingham Heart Study, indicate that LDL cholesterol was positively related to angina{{2305 U.S. Dept. of Health, Education, and Welfare, National Institutes of Health 1987; }}. We tested the hypothesis that different fats are related to risk of angina.

Methods
Study population
The Nurse's Health Study was initiated in 1976 when 121,700 female registered nurses 30-55 years completed a mailed questionnaire about their lifestyle factors and medical history, including previous cardiovascular disease, cancer, diabetes, hypertension, and high cholesterol levels. Follow-up questionnaires have been sent to these women every 2 years to update information and identify newly diagnosed major illnesses. Vital status of non-respondents was assessed using National Death Index. In this analysis, we included participants who returned the 1980 questionnaire and excluded individuals who had left 10 or more food items blank or whose energy intakes were implausible and those who had history of diabetes, hypercholesterolemia, cancer before June 1980. After these exclusions, 77,458 women remained in our analysis.

Ascertainment of diet

A detailed description of our food frequency questionnaire and documentation of its reproducibility and validity were published earlier{{1472 Hu,F.B. 2001; }}. For the current analysis, dietary information was obtained from 1980 through 2002 using a semi-quantitative food-frequency questionnaire (FFQ) using 61 food items (in 1980) and 116 items (1984 onwards). Participants were asked to report how often, on average, they consumed each of the foods and beverages included in the FFQ during the previous year. The questionnaire had nine options for frequency of intake, ranging from “never” or “less than once per month” to “six or more times per day”. Nutrient intakes were estimated by summing the nutrient contribution of all food items in the questionnaire, taking into consideration the brand and type of margarine and the types of fat used in cooking and baking. The nutrient content of each food and specified portion size was obtained from a nutrient database derived from the US Department of Agriculture {{2142 US Department of Agriculture 1993;}} and additional information obtained from food manufacturers.

Ascertainment of cases of angina
We considered a participant a case when she reported „angina pectoris‟ in a biennial questionnaire and confirmed a subsequent CABG, PTCA or Coronary Stenting, >70% stenosis on angiography or a positive stress test. In 1990, medical records were sought for all “questionnaire confirmed” cases and it was found that self-reported percent stenosis in this cohort was highly concordant with angiographic results and thereafter, self report of >70% stensosis was also accepted(Prof. M.J. Stampfer, personal communication, May 18, 2007).

Statistical analysis
We computed person time of follow up for each participant from the date the Food Frequency questionnaire was returned in 1980 to the date of angina confirmation, death from any cause, or, Jan 2004, whichever came first. The incidence rate for each category of different fat was calculated as the number of cases with angina divided by the person time of follows up. To reduce within person variation and better represent long term intake, we used cumulative average method that uses all available measurements of dietary up to the beginning of each two year period. For example, for women, dietary data from 1980 questionnaire was used to predict angina from June1980 to June 1984. Dietary data from 1980 and 1984 was used to predict Angina between June 1984 and 1986. To assess the effect of isocaloric substitution of dietary fat for carbohydrate, we used multivariate nutrient-density models that simultaneously included energy intake, percentage of energy derived from protein, and other potentially confounding variables{{2143 Willett,W C. 1999;}}. Tests for trends were conducted by assigning the median value to each quintile and modeling this value as a continuous variable. Results In 1,756,182 years of follow up, there were 1433 confirmed cases of angina. As previously published, intake of various fat was correlated with each other{{1479 Salmeron,J. 2001;}} and the intake of fat has changed over the period of the study{{2125 Oh,K. 2005}}. Table 1

describes the baseline description of our cohort. The women with higher intake of PUFA were younger, were less likely to be physically active and less likely to be current smokers. Women with higher intake of saturated fats were younger, more likely to be current smokers, lower alcohol intake and higher cholesterol intake and aspirin use. Women with higher intake of trans fats were less likely to smoke, use Vitamin E supplements, had lower cholesterol and alcohol intake. Women with a higher intake of polyunsaturated fat were less likely to engage in regular exercise, and more likely to be post-menopausal As expected {{2784 Markus,R.A. 1997;2791 Witteman,J.C. 1993;2792 Willeit,J. 1993;}}, compared to never smokers, the relative risk (RR) of angina was 1.38 (95% CI: 1.22,1.56 ) in past smokers, 1.65 (95% CI: 1.31,2.08) in smokers smoking 1-14 cigs/day, 2.60 (95% CI: 2.14,3.16 ) in smokers smoking 15-24 cigs/day and 3.08 (95%CI: 2.42,3.90) in smokers smoking >24 cigs/day. BMI was also associated with the risk of angina. The RR of angina was 1.24(95%CI, 0.981.58) for BMI 22-23 kg/m2, 1.34 (95%CI 1.11,1.61) for BMI 23-24 kg/m2, 1.72 (95% CI 1.45, 2.02) for BMI 25-28 kg/m2, 1.96(95%CI 1.65, 2.33) for BMI =>29 kg/m2. In age-adjusted analyses, total fat, vegetable fat and animal fat intake was associated with increased risk of CHD (table 2). In the multivariate analyses, the association of total fat with angina was attenuated (p value: 0.2152) while vegetable fat and animal fat remained significant in all analysis. The RR for quintiles for animal fat were 1(referent), 1.06, 0.97, 1.17, 1.28(p trend = 0.0031). Intake of specific types of fat, saturated fat, monounsaturated fat, polyunsaturated fat, and transfat was each significantly associated with risk of angina in age-adjusted analyses. In the multivariate model, which included fish intake, greater polyunsaturated fat intake was significantly associated with lower risk of CHD (RR = 0.70, 95 percent confidence interval (CI): 0.57,0.86; p trend = 0.0016). Individual polyunsaturated fats were weakly related to risk of angina. The risk of angina in the extreme quintiles was 0.87(95% CI: 0.71, 1.08) for Alpha Linolenic Acid, 0.82 (95%CI: 0.67,1.02) for Linoleic acid and 0.83(95%CI: 0.67, 1.03) for long chain omega-3 fats. trans-fat intake was positively associated with risk of angina (RR = 1.29, 95 percent CI: 1.04,1.59; p trend = 0.005). Intakes of saturated fat and monounsaturated fat were not related to the risk of angina after adjusting for dietary and nondietary risk factors. However, the ratio of polyunsaturated fat to saturated fat was inversely associated with risk of angina; the relative risks for the ratio of polyunsaturated fat to saturated fat were 1 (referent), 0.99, 0.93, 0.93 and 0.77 (95% CI: 0.64, 0.94; p trend= 0.007). Keys score (in quintiles) was also weakly related to risk of angina; the relative risks were 1(referent), 0.98, 1.06, 1.07, 1.32 (p trend=0.0004). We also estimated the effect of various isoenergetic dietary substitutions on the risk of diabetes (table 3). Replacing 5% of energy from carbohydrates with the same amount of energy from polyunsaturated fats was associated with a 37% lower risk of Angina (RR=0.63, 95% CI: 0.48,0.81; p value 0.0004). Replacing 2% of energy from polyunsaturated fatty acids with trans fatty acids was associated with a 23% higher risk (95% CI: -0.02%, 55%, p value 0.0682) and replacing 2% energy from saturated fats with trans fat was associated with 47% higher risk (95% CI: 14%, 89%, p value 0.0026). Substituting 5% of carbohydrates with total fat was associated with RR 1.03 (95% CI 0.98,1.08) (Model 3).

We assessed the possibility that the relation between different types of dietary fat and risk of angina might be modified by nondietary risk factors. The relation between specific types of fat and risk of CHD did not differ statistically by age and BMI categories. Because diabetes can mask the symptoms or alter diagnostic work-up for chest pain, we performed sensitivity analysis by restricting the analysis on non-diabetics and found that the results did not change. Discussion In this study, we found that higher intake of polyunsaturated fatty acids decrease the risk of angina and higher intake of trans fats increase the risk of angina independent of established lifestyle risk factors and other fats. This is consistent with various animal studies {{1776 Wolfe,M.S. 1994; }}{{1744 Clarkson ,T.B. 1962;1735 Lichtenstein,A.H. 1990; }} and previous observational studies on fat intake and myocardial infarction{{2089 Hu,F.B. 1999,2122 Oomen,C.M. 2001}}.

Few epidemiological studies have assessed the role of diet in coronary atherosclerosis {{2043 Ornish,D. 1990;2103 Niebauer,J. 1995; }}. In comparison to ecological studies on atherosclersosis{{2742 Lopez,A. 1966;2740 Masironi,R. 1970;2229 Scrimshaw,N.S. 1968; } and human studies{{1685 Mozaffarian,D. 2004;}}, total fat intake was not related to risk of angina in our study. This is consistent with Women's Health Initiative Dietary modification trial in which the RR of CABG/PCI was 0.96 (0.88-1.06) in lower fat group {{2309 Howard,B.V. 2006;}}. Various animal studies suggest that type of dietary fat rather than the total fat is stronger predictor of atherosclersosis{{2672 Dubey,M. 1979;2752 Kritchevsky,D. 1976;}}. We did not find a positive relationship between saturated fat intake and angina in contrast to crosssectional studies on atherosclerosis{{2590 Watts,G.F. 1996;2591 Watts,G.F. 1994;2592 Boniface,D.R. 2002;}} and prospective studies on atherosclerosis progression {{1685 Mozaffarian,D. 2004; 2784 Markus,R.A. 1997;}}. Observational studies on PUFA‟s and carotid atherosclerosis have shown divergent results {{2321 Bottcher, C.J.F. 1961;2320 KINGSBURY,K.J. 1962; }}. Various cross-sectional studies suggest a protective role of linoleic acid in carotid atherosclerosis {{2800 Bemelmans,W.J. 2002; 2802 Ma,J. 1997; 2798 Merchant,A.T. 2008; }}. However, Djousse et. al. found that linolenic acid but not linoleic acid and long-chain fatty acids were related to thickness of carotid intima thickness{{1699 Djousse,L. 2005;}}. Various randomized trials and observational studies on the role of marine omega-3 oils and atherosclerosis have reported divergent results {{1686 Erkkila,A.T. 2004; 1943 von Schacky,C. 2001;1689 Sacks,F.M. 1995;}}. In animal models, trans-unsaturated fat adversely affected lipid profile but not the extent of atherosclersosis{{2755 WEIGENSBERG,B.I. 1964;2748 Ruttenberg,H. 1983;2747 Kritchevsky,D. 1984;}}. In some human studies {{2590 Watts,G.F. 1996;2034 Hodgson,J.M. 1996; 2798 Merchant,A.T. 2008; }} but not others {{1685 Mozaffarian,D. 2004;}}, higher levels of trans fat were related to higher atherosclerosis. Overall, these results are similar to the previous published results for fat intake and composite CHD endpoint, which excluded diagnosis of angina and CABG {{2125 Oh,K. 2005;2743 Willett,W.C. 2006;}}.

Various mechanisms could mediate the relationship between fat consumption and angina. The role of consumption of different fats and blood lipids is well studied. In summarizing more than 60 studies, Mensink et al. showed that substitution of 1% of trans 18:1 with SFAs decreased total:HDL cholesterol by 0.019 mmol/L, while replacement with cis PUFAs decreased total:HDL cholesterol by 0.054. Replacement of carbohydrates by polyunsatured fats could decrease lipoprotein(a), low density lipoprotein particle size.{{2092 Mensink,R.P. 2003;}} Fat intake, particularly trans fat intake, is also associated with endothelial function and systemic inflammation, which are related to formation of atheromas and atherosclerosis{{2063 Calder,P.C. 2006;2598 Lopez-Garcia,E. 2005;2756 Mozaffarian,D. 2004;2757 Mozaffarian,D. 2004;}}. This study has various strengths. The repeated measurement of diet and regular updating of food composition tables allows us to account for changing fat intake and changing food composition over nearly a 24-year period. High rates of continuing participation preclude the potential of selection bias. The relatively homogenous study population of health care professionals minimizes the disparities in diagnosis, treatment and misreporting of clinical conditions influencing our results. Blinded assessment of outcome also decreases possibility of bias. There are few potential limitations to our findings. There is no standard case definition for angina but we used both clinically verified cases and self reported cases of angina to assess the sensitivity of our results to the case definition. However, our results are broadly consistent with prior studies on lifestyle risk factors such as smoking, BMI {{ 2797 Bonithon-Kopp,C. 1996;2786 Rubba,P. 2001;Markus,R.A. 1997;2791 Witteman,J.C. 1993;2792 Willeit,J. 1993;}}. Prior incidence of MI or pre-existing clinical condition like diabetes could increase the probability of coronary artery bypass procedure or angiography, which we used to confirm reported angina. Detailed information on various disease collected and confirmed, allows us to account and rule out these potential explanations. We also assessed both self-reported and clinically verified cases of angina. We calculated nutrients using food intake and nutrient contents, which could introduce error in our measurement of long term nutrient intakes. We minimized such error by using detailed food frequency questionnaire and cumulative dietary intake. Our results add to previous studies and suggest that high intake of trans-fat increases the risk of angina and higher intake of polyunsaturated fats, particularly when replacing carbohydrates, could prevent angina, besides fatal and nonfatal myocardial infarction. Prudent diets for prevention of coronary heart disease should encourage healthy fats.

Table 1: Baseline distribution of covariates by levels of fatty acid consumption Saturated Fat Polyunsaturated fat intake Q1(low) Median intake (% energy) Age 2 BMI (kg/m ) Physical Activity(hrs/wk) Post-menopausal Never smoker Past smokers Smokers(1-14 cigs/day) Smokers(1524cigs/day) Smokers(>25 cigs/day) Alcohol intake (gm/day) Aspirin (%) Vitamin E supplement(%) Calories (Kcal/day) Cholesterol intake(mg/day) Energy % Saturated fat Polyunsaturated fat Trans fat 10.8 45.55 23.61 3.52 40 44 31 8 10 6 8.42 13 16 1439 189.3 11.0 4.8 1.8 Q3 14.2 45.06 24.08 3.19 41 46 28 8 11 7 6.13 14 11 1584 212 15.7 5.4 2.3 Q5(high) 18.4 46.32 24.76 2.95 35 43 25 8 14 10 4.8 15 11 1672 237.5 20.0 5.3 2.4 Q1(low) 3.9 46.86 24.23 3.33 34 42 29 8 12 9 8.99 15 14 1543 208.6 26.1 3.5 1.6 Q3 5.4 45.11 24.02 3.24 40 47 27 8 11 7 5.91 13 12 1577 215.6 27.9 5.0 2.2 Q5(high) 7.3 45.01 24.19 3.04 41 45 28 8 12 8 4.77 14 12 1555 209.1 27.6 7.3 2.8

Trans fat intake Q1(low) 1.3 45.89 23.64 3.64 39 41 33 9 10 7 9.13 14 19 1462 220.5 13.5 4.1 1.3 Q3 2 45.13 24.15 3.18 41 45 27 8 11 8 5.95 14 11 1595 212.9 16.1 5.1 2.2 Q5(high) 2.9 45.88 24.59 2.85 36 48 25 7 12 8 4.08 14 9 1610 204.2 16.5 6.6 3.2

Table 2: Fat intake and Risk of Angina in women (NHS1, 1980-2004) Total fat intake Q1 Cases Person Time Model 1 Model 2 Cases Person Time Model 1 Model 2 294 350983 1 1 264 350937 1 1 Q2 255 350891 0.90(0.76,1.07) 0.88(0.74,1.05) 281 350845 1.11(0.94,1.32) 1.06(0.89,1.26) Q3 Q4 Q5 315 351757 1.34(1.14,1.57) 1.1(0.93,1.31) 325 352025 1.57(1.33,1.85) 1.28(1.06,1.55) 264 351104 0.75(0.63,0.88) 0.82(0.69,0.99) 0.73(0.6,0.88) p for trend

266 303 351539 351013 0.97(0.82,1.15) 1.16(0.99,1.36) 0.92(0.77,1.09) 1.05(0.88,1.24) Animal Fat 254 309 350992 351384 1.04(0.87,1.23) 1.33(1.13,1.57) 0.97(0.81,1.16) 1.17(0.98,1.4) Vegetable fat 281 351141 0.79(0.67,0.93) 0.88(0.74,1.04) 0.84(0.7,0.99) 269 350854 0.75(0.64,0.89) 0.84(0.71,1) 0.77(0.64,0.93)

0.0000 0.0837

0.0000 0.0031

Cases 320 299 Person Time 351798 351285 Model 1 1 0.85(0.73,1) Model 2 1 0.93(0.79,1.09) Model 3 1 0.91(0.78,1.08) Model1=Age and calorie adjusted

0.0002 0.0220 0.0005

Model2=Additionally adjusted for smoking(5 categories), BMI(5 categories), menopausal status and post menopausal hormone use, Mutivitamin and Vitamin E supplement intake, Aspirin intake, physical activity(hrs/week, 5 categories), parental history of MI, history of high blood pressure, protein intake, cholesterol intake (quintiles) and other fats(animal/vegetable fat). Model 3: Additionally adjusted for trans fats

Table 3: Fat intake and Risk of Angina in women (NHS1, 1980-2004) Saturated Fat Q1 Q2 Q3 Q4 Cases Person Time Model 1 Model 2 Model 3 Cases Person Time Model 1 Model 2 Model 3 Cases Person Time Model 1 Model 2 Model 3 278 351033 1 1 1 324 351740 1 1 1 279 351072 1 1 1 266 350889 1.01(0.85,1.19) 0.97(0.81,1.14) 0.96(0.79,1.17) 295 350961 0.88(0.76,1.04) 0.92(0.78,1.07) 0.88(0.75,1.04) 274 350647 1.03(0.87,1.21) 0.98(0.83,1.16) 1.01(0.85,1.21) 279 304 351017 351373 1.07(0.91,1.27) 1.26(1.07,1.49) 0.98(0.82,1.16) 1.10(0.93,1.30) 0.95(0.76,1.17) 1.00(0.79,1.26) Polyunsaturated fats 252 302 351187 350918 0.76(0.65,0.9) 0.93(0.79,1.09) 0.80(0.68,0.94) 0.97(0.83,1.14) 0.74(0.62,0.89) 0.87(0.72,1.04) Trans fats 257 305 351176 351249 1.05(0.88,1.24) 1.21(1.03,1.43) 0.98(0.82,1.16) 1.12(0.94,1.32) 1.03(0.86,1.24) 1.21(1.00,1.47) Monounsaturated fats 257 305 351176 351249 1.00(0.84,1.18) 1.24(1.05,1.46) 0.93(0.79,1.11) 1.11(0.94,1.32) 0.98(0.78,1.24) 1.15(0.89,1.49)

Q5 315 351870 1.46(1.24,1.72) 1.15(0.96,1.37) 0.97(0.75,1.27) 260 351376 0.84(0.71,0.99) 0.84(0.71,0.99) 0.70(0.57,0.86) 318 352039 1.31(1.11,1.54) 1.14(0.96,1.35) 1.29(1.04,1.59) 318 352039 1.45(1.23,1.70) 1.18(0.99,1.40) 1.18(0.87,1.59)

p for trend

0.0000 0.0462 0.9374

0.1000 0.1049 0.0016

0.0002 0.0475 0.0050

Cases 279 274 Person Time 351072 350647 Model 1 1 1.04(0.88,1.22) Model 2 1 1.00(0.85,1.19) Model 3 1 1.06(0.87,1.29) Model1=Age and calorie adjusted

0.0000 0.0251 0.2257

Model2=Additionally adjusted for smoking(5 categories), BMI(5 categories), menopausal status and post menopausal hormone use, Mutivitamin and Vitamin E supplement intake, Aspirin intake, physical activity(hrs/week, 5 categories), parental history of MI, history of high blood pressure, protein intake, cholesterol intake (quintiles) Model3=Additionally adjusted for all other fats. Model3 for polyunsaturated fats additionally included fish intake (in quintiles)

Table 4: Fat intake and risk of Angina (replacement of carbohydrates) RR 95% CI Model 1 Saturated fat (5% increase) Monounsaturated fats (5% increase) Polyunsaturated fats (5% increase) trans Unsaturated fats (2% increase) Model 2 Vegetable fat(5% increase) Animal fat(5% increase) Model 3 Total Fat (5% increase) 1.02 1.03 0.63 1.51 0.86,1.20 0.85,1.25 0.48,0.81 1.16,1.96

p value 0.8049 0.7193 0.0004 0.0017

0.92 1.02

0.84,0.99 0.97,1.08

0.0412 0.3109

1.03

0.98,1.08

0.1335

Model 1:Adjusted for smoking(5 categories), BMI (5 categories), menopausal status and post menopausal hormone use, Mutivitamin and Vitamin E supplement intake, Aspirin intake, physical activity(hrs/week, 5 categories), parental history of MI, history of high blood pressure, protein intake, cholesterol intake and all fats included simultaneously Model 2:Adjusted for smoking(5 categories), BMI(5 categories), menopausal status and post menopausal hormone use, Mutivitamin and Vitamin E supplement intake, Aspirin intake, physical activity(hrs/week, 5 categories), parental history of MI, history of high blood pressure, protein intake, cholesterol intake and vegetable fat and animal fat included simultaneously Model 3: Mutually adjusted for calories, protein intake, cholesterol, physical activity (quintiles), smoking (5 categories), BMI(5 categories), menopausal status and post-menopausal status, alcohol intake, multivitamin, vitamin E, aspirin intake, history of high blood pressure

Change in angina risk (%)

100 80 60 40 20 0 -20 -40 PUFA -->carbo trans->carbo trans->PUFA PUFA->SFA trans->SFA

Figure 1: Estimated changes in risk of angina associated with isoenergetic substitutions of 2% of energy. Associations were adjusted for the same covariates as in Table 2. trans, transfatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; Carbo, carbohydrates; The arrows indicate substitution of the second nutrient by the first nutrient. Bars represent 95% CIs.


								
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