Among postmenopausal women with established CHD, greater saturated fat intake was associated with less progression of coronary atherosclerosis over an average follow-up of 3 y, whereas polyunsaturated fat and carbohydrate intakes were associated with greater progression. To our knowledge, this is the first study that evaluated the associations between dietary macronutrients and atherosclerotic progression in women. Although the findings do not establish causality, the associations were independent of a variety of other risk factors, including age, diabetes, smoking, body mass index, physical activity, prior MI or PTCA, and other dietary habits. Thus, known clinical risk factors do not appear to account for the observed relations.
The inverse association between saturated fat intake and atherosclerotic progression was unexpected. However, this finding should perhaps be less surprising. Ecologic and animal experimental studies showed positive relations between saturated fat intake and CHD risk (8
). However, cohort studies and clinical trials in humans have been far less consistent (9
). Furthermore, most studies of dietary fat and CHD risk have been performed in men (15
). The relations in women—particularly postmenopausal women—are much less well-established, and evidence from dietary intervention trials suggests that diets low in saturated fat may have different effects on CHD risk factors in women (15
Women were excluded from prior studies evaluating nutrient intake and atherosclerotic progression (2
). In the only large cohort study to focus on relations between dietary fat and CHD events in women, saturated fat intake was positively associated with CHD risk, but this association was attenuated and no longer significant after adjustment for intakes of polyunsaturated fat and other nutrients (16
). The absence of an inverse association in that study may have been due to different study populations (generally healthy pre- and postmenopausal women compared with postmenopausal women with established CHD), outcomes (incident CHD events compared with atherosclerotic progression), or background diets (eg, mean total fat intake of 38% compared with 25%). In a prospective study of 661 diabetic persons, saturated fat intake was inversely (P
= 0.007) and carbohydrate intake was positively (P
= 0.002) associated with incident MI in women but not in men (22
); however, the analyses were not adjusted for other risk factors. Of 15 trials that included dietary intervention for primary or secondary prevention of CHD (32
), 10 excluded women and 3 included only ≈10% women and did not report results by sex (). Even among trials comprised exclusively or largely of men, diets low in saturated fat have not consistently reduced CHD risk (32
), especially when compared with diets focusing on fish, α-linolenic acid, fruit, vegetables, nuts, and monounsaturated fat (40
). Thus, there is a relative paucity of literature on dietary fat and CHD risk in women, particularly postmenopausal women.
Clinical trials including dietary intervention for primary or secondary prevention of coronary heart disease (CHD)1
The magnitude, independence, and consistency of the inverse association between saturated fat intake and atherosclerotic progression are notable. Are there plausible biologic mechanisms for such an effect? In contrast with the findings of experimental studies (20
), saturated fat intake was not associated with LDL concentrations in our study. Women with lower saturated fat intake at enrollment may have previously had higher LDL-cholesterol concentrations and thus lowered their saturated fat intake. If so, they were successful in lowering their LDL cholesterol to concentrations similar to those of other women in this cohort; however, even at similar LDL-cholesterol concentrations, their rate of atherosclerotic progression was much higher, which indicates that factors besides LDL are important in determining atherosclerotic progression in postmenopausal women. A greater saturated fat intake was associated with other lipid differences, including higher HDL, higher HDL2
, higher apoprotein A-I, lower triacylglycerol concentrations, and a lower TC:HDL cholesterol ratio. These findings are consistent with those of experimental studies that showed unfavorable effects of low-fat, low-saturated-fat diets on HDL cholesterol, HDL2
cholesterol, the TC:HDL cholesterol ratio, and postprandial triacyl-glycerol concentrations in women (18
), particularly when compared with men (18
). For example, among hypercholesterolemic subjects treated with a National Cholesterol Education Program Step II diet (< 30% fat, < 7% saturated fat), HDL decreased 1.3% in men and 7.6% in women (P
< 0.001 for sex difference), HDL2
increased 0.5% in men and decreased 16.7% in women (P
< 0.001), apoprotein A-I was unchanged in men but decreased 5.3% in women (P
< 0.001), and the TC:HDL cholesterol ratio decreased 3% in men and increased 3% in women (P
< 0.01) (20
Although LDL cholesterol strongly predicts CHD risk in men, these non-LDL lipid variables are stronger predictors in women (19
). Effects of saturated fat intake on HDL and triacylglycerols may be especially important after menopause, when HDL-cholesterol concentrations are lower and CHD risk is correspondingly greater (23
). In our study, the inverse association between saturated fat intake and atherosclerotic progression was greater among women not taking lipid-lowering medication; if saturated fat intake reduces CHD risk via lipoprotein effects, such an influence may be less pronounced when lipids are more potently affected by lipid-lowering medication. This relation was also less pronounced among women with higher monounsaturated fat intake, which has similar favorable effects on HDL and triacylglycerols (4
). Thus, these results are consistent with potential biologic effects of saturated and monounsaturated fat intakes in postmenopausal women. However, lipid concentrations at baseline and follow-up did not appear to mediate the observed relations, which suggests either mediation by non-lipid effects of these nutrients or that single baseline and follow-up fasting lipid panels do not adequately capture effects on serum lipids.
Carbohydrate intake was positively associated with atherosclerotic progression when replacing saturated fat and monounsaturated fat but not when replacing total fat, polyunsaturated fat, or protein. The association was perhaps stronger among women with lower physical activity, who would be more susceptible to adverse effects of carbohydrates—particularly refined carbohydrate—on HDL cholesterol, triacylglycerols, glucose metabolism, insulin sensitivity, and weight gain (4
). Consistent with such biologic mechanisms, the relation between carbohydrate intake and atherosclerotic progression appeared to be stronger in women with a higher glycemic index.
Polyunsaturated fat intake was not associated with atherosclerotic progression when replacing carbohydrate or protein but was positively associated when replacing other fats, especially saturated fat. Few prior studies have evaluated relations between polyunsaturated fat intake and CHD risk in women; those that have been conducted have had conflicting results. In one observational study in women, polyunsaturated fat intake was inversely associated with incident CHD (16
). However, in a cohort of diabetic persons, a higher ratio of polyunsaturated to saturated fat (P:S) predicted lower CHD risk in men but not in women (22
). Among 591 institutionalized women, a higher P:S diet nonsignificantly lowered CHD risk by 60% (P
= 0.10), but the intervention diet also included much higher (by 500%) amounts of n−3 α-linolenic acid (41
). A higher P:S causes a greater decline in HDL in women than in men (18
). In a clinical trial of 4393 men and 4664 women, a higher-P:S diet did not affect risk in men and women combined, but there were nonsignificant trends toward 32% more CHD events (P
= 0.16) and 16% higher total mortality (P
= 0.29) in women (42
). The positive association seen in our study was more pronounced in diabetic women and in those with a lower HDL cholesterol, a lower protein intake, and a higher glycemic index; confirmation of these results in other studies is indicated.
Our study has several strengths. Outcomes were prospectively ascertained, which reduced the potential for recall bias. A variety of participant characteristics were assessed by using standardized methods, which increased the capacity to adjust for confounding. Angiographic outcomes were centrally evaluated by operators using validated methods who were unaware of the participants’ dietary habits or the temporal sequence of films, which minimized the potential for misclassified or biased outcome measures. The precision in the outcome due to repeated measures provided ample power to detect differences in change in mean minimal luminal diameter from baseline to follow-up.
There were also potential limitations to our findings. Usual dietary intake was assessed at baseline, and there may have been changes in diet over time. Nutrient intakes were estimated from a variety of food items, which limited precise estimation (though relative intakes were probably ranked correctly at the extremes). Without apparent bias, dietary changes over time and measurement errors would attenuate findings toward the null; however, such errors would not cause a harmful association to appear beneficial. Relations of saturated fat intake with atherosclerotic progression may be different among women in whom follow-up coronary angiography is not available; however, the baseline characteristics of these women were generally similar to those included in the analysis, and only 12 women (4%) died before follow-up angiography. We could not assess the relations of nutrient intake with other factors related to CHD risk, such as platelet aggregation or thrombosis; on the other hand, progression of atherosclerosis predicts clinical events (54
). Residual confounding by incompletely measured or unknown factors cannot be excluded. This was a post hoc analysis among participants in a randomized trial, and our findings may not be generalizable to all postmenopausal women.
Although CHD is the leading cause of death among both men and women, prior studies have historically focused on relations between risk factors and CHD in men. Our findings are not consistent with the hypothesis—based largely on observations in men—that saturated fat intake increases atherosclerotic progression in postmenopausal women but instead suggest that saturated fat intake may reduce such progression, especially when mono-unsaturated fat intake is low or carbohydrate intake is high. Our findings also suggest that carbohydrate intake may increase atherosclerotic progression, especially when refined carbohydrates replace saturated or monounsaturated fats. Confirmation of these findings in other studies and examination of potential mechanisms and alternative explanations are warranted.