Heart failure (HF) remains a major public health issue in

Egg Consumption and Risk of Heart Failure in the Physicians Health Study Luc Djoussé, MD, MPH, DSc; J. Michael Gaziano, MD, MPH Background Reduction in dietary cholesterol is widely recommended for the prevention of cardiovascular disease. Although eggs are important sources of dietary cholesterol and other nutrients, little is known about the association between egg consumption and heart failure (HF) risk. Methods and Results In a prospective cohort study of 21 275 participants from the Physicians Health Study I, we examined the association between egg consumption and the risk of HF. Egg consumption was assessed with the use of a simple abbreviated food questionnaire, and we used Cox regression to estimate relative risks of HF. After an average follow-up of 20.4 years, a total of 1084 new HF cases occurred in this cohort. Although egg consumption up to 6 times per week was not associated with incident HF, egg consumption of 7 per week was associated with an increased risk of HF. Compared with subjects who reported egg consumption of 1 per week, hazard ratios (95% confidence intervals) for HF were 1.28 (1.02 to 1.61) and 1.64 (1.08 to 2.49) for egg consumption of 1 per day and 2 per day, respectively, after adjustment for age, body mass index, smoking, alcohol consumption, exercise, and history of atrial fibrillation, hypertension, valvular heart disease, and hypercholesterolemia. Similar results were obtained for HF without antecedent myocardial infarction. Conclusions Our data suggest that infrequent egg consumption is not associated with the risk of HF. However, egg consumption of 1 per day is related to an increased risk of HF among US male physicians. (Circulation. 2008;117: 512-516.) Key Words: diet epidemiology heart failure Heart failure (HF) remains a major public health issue in the United States. The development of hypertension and myocardial infarction, 2 major risk factors for HF, is influenced by elevated plasma low-density lipoprotein (LDL) cholesterol. Hence, dietary guidelines to prevent the underlying atherosclerosis emphasize the reduction of dietary cholesterol. 1,2 Although each egg contains on average 200 mg of cholesterol that can negatively influence the development of atherosclerosis, it is also known that eggs are rich in other important nutrients such as minerals, folate, B vitamins, proteins, and monounsaturated fatty acids that could reduce the risk of coronary heart disease (CHD). 3,4 Current data on the effects of dietary cholesterol on serum cholesterol have been inconsistent, ranging from positive associations 5 9 to no effects. 7,10,11 The relation between dietary and serum cholesterol is complicated by the large variability in individual response to dietary cholesterol. 11 13 Despite the fact that some studies have shown an association between egg consumption and CHD, 14 no previous study has examined whether egg consumption is associated with the risk of HF in a community setting. Clinical Perspective p 516 Because eggs could serve as a good source for vitamins, proteins, and other nutrients in the United States, it is important to understand whether egg consumption as a whole food (as opposed to an individual component of eggs such as cholesterol) confers a lower or higher risk of HF. In the present project, we sought to prospectively assess whether egg consumption was associated with an increased risk of HF among US male physicians. In a secondary aim, we examined whether the relation between egg consumption and HF differs between HF with and without antecedent myocardial infarction. Methods Study Population We used data from the Physicians Health Study (PHS) I, a randomized, double-blind, placebo-controlled trial designed to study the effects of low-dose aspirin and beta carotene on cardiovascular disease and cancer among US male physicians. A detailed description of the PHS I has been published previously. 15 For the present analyses, we excluded 796 subjects with missing data on egg consumption Received August 13, 2007; accepted November 8, 2007. From the Divisions of Aging (L.D., J.M.G.) and Preventive Medicine (J.M.G.), Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Mass. Guest Editor for this article was Martin M. LeWinter, MD. Correspondence to Luc Djoussé, MD, MPH, DSc, Division of Aging, Brigham and Women s Hospital and Harvard Medical School, 1620 Tremont St, Third Floor, Boston MA 02120. E-mail ldjousse@rics.bwh.harvard.edu 2008 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.734210 512

Djoussé and Gaziano Egg Consumption and Heart Failure 513 Table 1. Characteristics of the 21 275 Study Participants According to Egg Consumption Egg Consumption 1/wk (n 4527) 1/wk (n 6621) 2 4/wk (n 6971) 5 6/wk (n 1419) 1/d (n 1473) 2/d (n 264) Age, y 53.0 9.3 53.4 9.3 53.6 9.5 54.0 9.4 57.1 10.2 55.7 9.9 Body mass index, kg/m 2 24.5 2.7 24.7 2.7 24.9 2.7 25.2 2.9 24.9 3.1 25.2 3.4 High cholesterol, % 13.7 12.2 11.3 10.8 10.8 9.1 Current smoking, % 8.1 9.8 11.9 14.8 17.0 15.9 Current drinking, % 70.1 75.0 75.3 74.7 74.2 72.3 Exercise 1/wk, % 72.0 72.8 73.0 72.9 70.1 70.8 Hypertension, % 21.9 23.6 23.7 25.2 29.0 25.8 Arial fibrillation, % 1.3 1.5 1.4 1.8 1.2 1.9 Aspirin assignment, % 47.0 50.6 51.4 50.5 49.4 49.4 Valvular disease, % 0.2 0.2 0.1 0.1 0.2 1.1 Diabetes mellitus, % 1.9 2.5 2.7 3.1 7.3 6.8 Total cholesterol, mg/dl* 214 42 215 42 213 41 213 41 215 36 211 29 HDL cholesterol, mg/dl* 42 15 42 15 42 14 41 15 43 15 40 12 Total-to-HDL cholesterol ratio* 5.7 2.7 5.7 2.4 5.8 2.5 5.8 2.4 5.7 2.6 5.8 2.2 *Serum cholesterol measures available on 4672 subjects with 1046, 1500, 1542, 298, 231, and 55 subjects in the egg consumption categories of 1/wk, 1/wk, 2 4/wk, 5 6/wk, 1/d, and 2/d, respectively. High cholesterol was defined as total cholesterol of 240 mg/dl or reported current/past treatment for elevated cholesterol. (n 396) or covariates (n 400), leaving a final sample of 21 275 participants for current analyses. Each participant gave written informed consent, and the institutional review board at Brigham and Women s Hospital approved the study protocol. Egg Consumption Information on egg consumption was self-reported with the use of a simple abbreviated semiquantitative food frequency questionnaire. Participants were asked to report how often, on average, they had eaten eggs during the past year. Possible response categories included rarely/never, 1 to 3/month, 1/week, 2 to 4/week, 5 to 6/week, daily, and 2 /day. This information was obtained at baseline and 24, 48, 72, 96, and 120 months after randomization. We combined the first 2 categories to create a large and stable reference group. Ascertainment of HF in the PHS End points in the PHS have been ascertained with the use of annual follow-up questionnaires. Specifically, a questionnaire was mailed to each participant every 6 months during the first year and has been mailed annually thereafter to obtain information on compliance with the intervention and the occurrence of new medical diagnoses, including HF. The validation of HF in the PHS has been reported previously. 16 Other Variables Demographic data were collected at baseline. Information on comorbidity (ie, atrial fibrillation, hypertension, and diabetes mellitus) has been collected through annual follow-up questionnaires as described above. Data on selected foods such as fruits and vegetables; breakfast cereals; physical activity; smoking; alcohol consumption; and history of hypercholesterolemia (defined as total cholesterol 240 mg/dl or past/current treatment for elevated cholesterol) were obtained at baseline. Of the total subjects with reported egg consumption, total and high-density lipoprotein (HDL) cholesterol were measured at baseline on 4672 individuals by standard methods. We computed the ratio of total to HDL cholesterol. Statistical Analyses At baseline and subsequent time points at which information on egg consumption was collected (24, 48, 72, 96, and 120 months after randomization), we classified each subject into 1 of the following categories of egg consumption: 1 per week, 1 per week, 2 to 4 per week, 5 to 6 per week, 1 per day, and 2 eggs per day. For primary analyses, we used baseline egg consumption as exposure. We computed person-time of follow-up from baseline until the first occurrence of (1) HF, (2) death, (3) date of receipt of last follow-up questionnaire, or (4) censoring date (January 30, 2007). Within each egg consumption group, we calculated the incidence rate of HF by dividing the number of cases by the corresponding person-time. We used Cox proportional hazards models to compute multivariableadjusted hazard ratios with corresponding 95% confidence intervals with subjects in the lowest category of egg consumption used as the reference group. We assessed confounding by using 10% change in hazard ratio. Assumptions for the proportional hazards models were tested (by including main effects and product terms of covariates and time factor) and were met (all probability values 0.05). The parsimonious model controlled for age (5-year categories), body mass index ( 25, 25 to 29.9, and 30 kg/m 2 ), smoking (never, past, and current smokers), alcohol consumption ( 1,1to4,5to6, 7 drinks per week), and history of diabetes mellitus (yes/no), hypertension (yes/no), and atrial fibrillation (yes/no). Finally, the fully adjusted model also controlled for hypercholesterolemia (yes/no), physical activity ( 1, 1 per week), and history of valvular heart disease. We computed probability value for linear trend by creating a new variable that assigned ordinal values (0 to 5) from the lowest to the highest category of egg consumption and then modeled the new variable in the multivariable Cox regression. In secondary analyses, we examined the association between egg consumption and HF with and without antecedent myocardial infarction. For HF with antecedent myocardial infarction, we did not have enough cases in the categories of 1 per day and 2 eggs per day for stable estimates (data not shown). We tested for 2-way interactions between egg consumption and history of hypertension, diabetes mellitus, smoking, and hypercholesterolemia. In addition, we excluded individuals with a follow-up time of 2 years. Finally, we repeated the main analysis using updated egg consumption at 24, 48, 72, 96, and 120 months in a time-dependent Cox model. To examine whether the relation between egg consumption and HF was mediated through cholesterol, we compared multivariable-adjusted mean total cholesterol, HDL cholesterol, and the ratio of the 2 variables using ANCOVA. All analyses were completed with the use of SAS,

514 Circulation January 29, 2008 Table 2. Relative Risk (95% Confidence Interval) of HF According to Egg Consumption Hazard Ratios for HF (95% Confidence Interval) Egg Intake Cases Crude Age-Adjusted Model 1* Model 2 1/wk 206 1.0 1.0 1.0 1.0 1/wk 307 1.02 (0.85 1.22) 0.99 (0.83 1.18) 0.93 (0.80 1.16) 0.93 (0.78 1.12) 2 4/wk 359 1.15 (0.97 1.37) 1.10 (0.92 1.30) 1.02 (0.83 1.19) 1.03 (0.86 1.22) 5 6/wk 75 1.19 (0.91 1.55) 1.12 (0.86 1.45) 1.01 (0.78 1.32) 1.01 (0.78 1.32) 1/d 112 1.96 (1.56 2.46) 1.47 (1.17 1.85) 1.27 (1.01 1.60) 1.28 (1.02 1.61) 2/d 25 2.45 (1.62 3.71) 1.94 (1.28 2.95) 1.61 (1.06 2.44) 1.64 (1.08 2.49) P for trend 0.0001 0.0001 0.007 0.006 *Adjusted for age ( 45, 45-49, 50-54, 55-59, 60-64, and 65), body mass index ( 25, 25-29.9, 30 kg/m 2 ), smoking (never, former, current smokers), alcohol consumption ( 1, 1-4, 5-7, 8 drinks per week), and history of diabetes mellitus, atrial fibrillation, and hypertension. Additional adjustment for physical activity ( 1/wk, 1/wk) and history of valvular heart disease and treatment for cholesterol. version 9.1 (SAS Institute, Cary, NC). Significance level was set at 0.05. The authors have full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Results Among 21 275 participants in the PHS I, the mean age at randomization was 53.7 9.5 years (range, 39.7 to 85.9 years). Approximately 64% reported egg consumption of 1 to 4 per week in this population, and only 8% reported consumption of 1 per day. Table 1 presents baseline characteristics of the study participants. Frequent consumption of eggs was associated with older age; higher body mass index; higher proportion of current drinkers and smokers and of physical inactivity; higher prevalence of diabetes mellitus and hypertension; and lower prevalence of hypercholesterolemia. During an average follow-up of 20.4 years, 1084 cases of HF (4.7%) occurred in this cohort. Egg consumption declined over time, with 23.5% of subjects reporting no egg consumption at 10-year follow-up versus 6.9% at baseline. In addition, egg consumption of 1 per day decreased from 8.1% at baseline to 2.1% after 10 years of follow-up. In multivariable Cox regression models, egg consumption up to 6 per week was not related to HF, whereas consumption of 1 per day and 2 per day was associated with a 28% and 64% increased risk of HF, respectively (Table 2). Restricting the analysis to subjects with follow-up times beyond 2 years yielded similar results (P for trend 0.004). Similar findings were obtained when egg consumption and interim myocardial infarction were updated with the use of a time-dependent Cox model (data not shown). There was no evidence for 2-way interaction between egg consumption and diabetes mellitus (P 0.27), history of hypertension (P 0.97), smoking (P 0.70), or hypercholesterolemia (P 0.85). Finally, we observed a similar association between egg consumption and HF without antecedent myocardial infarction (Table 3). We did not have enough cases of HF with antecedent myocardial infarction to obtain stable estimates. Using the subsample of individuals with data on cholesterol, we did not find an association between egg consumption and total cholesterol (P 0.86), HDL cholesterol (P 0.74), or ratio of total to HDL cholesterol (P 0.97) in a model controlling for age, body mass index, smoking, alcohol consumption, exercise, and diabetes mellitus. Controlling for measured cholesterol Table 3. Relative Risk (95% Confidence Interval) of HF Without Antecedent Myocardial Infarction According to Egg Consumption Hazard Ratios for HF (95% Confidence Interval) Egg Intake Cases Crude Age-Adjusted Model 1* Model 2 1/wk 178 1.0 1.0 1.0 1.0 1/wk 252 0.97 (0.80 1.17) 0.94 (0.77 1.14) 0.89 (0.73 1.08) 0.89 (0.73 1.07) 2 4/wk 294 1.09 (0.91 1.32) 1.04 (0.86 1.25) 0.97 (0.80 1.17) 0.97 (0.80 1.16) 5 6/wk 64 1.18 (0.88 1.57) 1.10 (0.83 1.46) 0.99 (0.75 1.32) 0.99 (0.74 1.31) 1/d 102 2.06 (1.62 2.63) 1.54 (1.21 1.97) 1.33 (1.04 1.69) 1.33 (1.04 1.70) 2/d 21 2.38 (1.51 3.74) 1.88 (1.20 2.95) 1.55 (0.99 2.44) 1.56 (0.99 2.46) P for trend 0.0001 0.0001 0.007 0.006 *Adjusted for age ( 45, 45 49, 50 54, 55 59, 60-64, and 65 y), body mass index ( 25, 25 29.9, 30 kg/m 2 ), smoking (never, former, current smokers), alcohol consumption ( 1, 1 4, 5 7, 8 drinks per week), and history of diabetes mellitus, atrial fibrillation, and hypertension. Additional adjustment for physical activity ( 1/wk, 1/wk) and history of valvular heart disease and treatment for cholesterol.

Djoussé and Gaziano Egg Consumption and Heart Failure 515 instead of prevalent hypercholesterolemia had no effect on the findings among subjects with blood lipids. Discussion In this prospective cohort, we demonstrated that infrequent consumption of eggs (up to 6 per week) was not associated with HF, whereas consumption of 7 eggs per week was associated with an increased risk of HF among male physicians. Furthermore, a similar association was observed for HF without antecedent myocardial infarction, and we did not find evidence for effect measure modification by hypercholesterolemia, diabetes mellitus, smoking, or hypertension on the observed associations. Because eggs are rich in dietary cholesterol, researchers have been interested in the effects of egg consumption on serum cholesterol or other intermediate phenotypes. However, limited and inconsistent data have been reported on egg consumption and incident cardiovascular disease and mortality. Data from 514 Western Australian Aborigines showed a 2.6-fold increased risk of CHD comparing egg consumption of 2 versus 2 per week after 14 years of follow-up. 14 Compared with egg consumption of 1 per week, the incidence rate ratio for total mortality was 1.23 and 2.68 among subjects consuming 1 to 5 and 6 eggs per week, respectively, after adjustment for age, sex, smoking, and social class. 17 Qureshi et al 18 reported a 2-fold increased risk of CHD among people reporting an intake of 6 eggs per week compared with intakes of 1 per week. In addition, compared with egg intake of 1 per week, Hu et al 19 reported a 2-fold increased risk of CHD for egg consumption of 1 per day among 37 851 diabetic men from the Health Professionals Follow-up Study after adjustment for potential confounders; these data suggest that the observed increased risk of HF with egg consumption could be mediated through CHD. Unfortunately, we did not have enough cases of HF with antecedent myocardial infarction to examine this hypothesis further. The fact that we observed elevated risk of HF without antecedent myocardial infarction suggests that alternative physiological mechanisms could be responsible for the observed association. Alternatively, additional lifestyle/dietary factors associated with frequent egg consumption could be responsible for the observed relationship. Given the observational nature of our design, we cannot exclude chance or residual confounding by measured and unmeasured factors as a possible explanation of our findings. In particular, the lack of details on the dietary questionnaire prevented us from controlling for energy intake and other major nutrients. The hypothesis of chance finding or residual confounding is supported by the lack of association between egg consumption and CHD in other studies. 20,21 Changes in dietary patterns may lead to a spurious association between baseline exposure and incident outcome. In our data, we used timedependent Cox regression models to update reported egg consumption at 24, 48, 72, 96, and 120 months after randomization. Such exposure update over time led to similar conclusions, suggesting that our findings are robust and not sensitive to possible changes in egg consumption over time. In addition, adjustment for interim cases of myocardial infarction had little effect on the results. A wide variability in individual response to dietary cholesterol (hyperresponders versus hyporesponders) has been reported. It has been suggest that among hyperresponders, dietary cholesterol from eggs leads to a modest increase in serum LDL and HDL cholesterol and no effect on LDL/HDL ratio. 8,22 25 Thus, it is possible that the observed increased risk of HF with egg consumption might be limited to hyperresponders. However, the fact that we did not observe an association between egg consumption and baseline cholesterol in our study does not lend support to this theory. The lack of a relationship between egg consumption and serum cholesterol is consistent with other reported findings showing no effect of egg consumption on the LDL subfraction. 22 Our study has additional limitations. Our participants are male physicians who may have different behaviors than the general population, thereby limiting the generalizability of our findings. Furthermore, we did not have data on protein intake, serum albumin, and creatinine to explore the influence of protein load on the observed association, especially in the presence of kidney dysfunction and/or type 2 diabetes mellitus. Egg consumption was assessed with the use of an abbreviated food questionnaire. This might have led to underreporting of usual egg consumption and a bias toward the null. However, if such a bias were present, we would anticipate the true effect measure to be even larger between frequent egg consumption and HF. In this study, we did not directly validate the abbreviated food questionnaire used to assess egg consumption. However, validation of full food frequency questionnaires (including the egg consumption questionnaire used in this study) has been published elsewhere. 26,27 Finally, measured plasma total and HDL cholesterol were available at baseline only in a limited number of subjects. On the other hand, the large sample size, the longer duration of follow-up, and the robustness of our findings in sensitivity analyses are strengths of the present study. In conclusion, our data suggest that egg consumption up to 6 per week is not associated with HF, whereas consumption of 7 eggs per week is related to an increased risk of HF. Confirmation of these findings is warranted along with exploration of underlying biological mechanisms. Acknowledgments We are indebted to the participants in the PHS for their outstanding commitment and cooperation and to the entire PHS staff for their expert and unfailing assistance. Sources of Funding The PHS is supported by grants CA-34944 and CA-40360 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, Md. Dr Djoussé is Principal Investigator on grant K01 HL-70444 from the National Heart, Lung, and Blood Institute, Bethesda, Md. None. Disclosures References 1. Krauss RM, Deckelbaum RJ, Ernst N, Fisher E, Howard BV, Knopp RH, Kotchen T, Lichtenstein AH, McGill HC, Pearson TA, Prewitt TE, Stone NJ, Horn LV, Weinberg R. Dietary guidelines for healthy American

516 Circulation January 29, 2008 adults: a statement for health professionals from the Nutrition Committee, American Heart Association. Circulation. 1996;94:1795 1800. 2. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486 2497. 3. Hu FB, Manson JE, Willett WC. Types of dietary fat and risk of coronary heart disease: a critical review. J Am Coll Nutr. 2001;20:5 19. 4. Song WO, Kerver JM. Nutritional contribution of eggs to American diets. J Am Coll Nutr. 2000;19:556S 562S. 5. Mattson FH, Erickson BA, Kligman AM. Effect of dietary cholesterol on serum cholesterol in man. Am J Clin Nutr. 1972;25:589 594. 6. Keys A. Serum cholesterol response to dietary cholesterol. Am J Clin Nutr. 1984;40:351 359. 7. Chakrabarty G, Manjunatha S, Bijlani RL, Ray RB, Mahapatra SC, Mehta N, Lakshmy R, Vashisht S, Manchanda SC. 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A double-blind, randomized, controlled trial of the effects of two eggs per day in moderately hypercholesterolemic and combined hyperlipidemic subjects taught the NCEP step I diet. J Am Coll Nutr. 1997;16:551 561. 23. Katz DL, Evans MA, Nawaz H, Njike VY, Chan W, Comerford BP, Hoxley ML. Egg consumption and endothelial function: a randomized controlled crossover trial. Int J Cardiol. 2005;99:65 70. 24. Herron KL, Vega-Lopez S, Conde K, Ramjiganesh T, Roy S, Shachter NS, Fernandez ML. Pre-menopausal women, classified as hypo- or hyperresponders, do not alter their LDL/HDL ratio following a high dietary cholesterol challenge. J Am Coll Nutr. 2002;21:250 258. 25. McNamara DJ. The impact of egg limitations on coronary heart disease risk: do the numbers add up? J Am Coll Nutr. 2000;19:540S 548S. 26. Stein AD, Shea S, Basch CE, Contento IR, Zybert P. Consistency of the Willett semiquantitative food frequency questionnaire and 24-hour dietary recalls in estimating nutrient intakes of preschool children. Am J Epidemiol. 1992;135:667 677. 27. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol. 1992;135:1114 1126. CLINICAL PERSPECTIVE Heart failure (HF) is a major cause of hospitalization and emergency department visits among older adults. Although previous studies have examined the influence of lifestyle and dietary factors on the risk of HF, it is not known whether egg consumption is associated with an increased risk of HF. An egg can contain as much as 200 mg of dietary cholesterol. In the present study, we followed 21 275 participants from the Physicians Health Study I for an average of 20 years to examine the association between egg consumption and the risk of HF. Egg consumption was assessed with the use of a simple abbreviated food questionnaire. During the follow-up, a total of 1084 new HF cases occurred in this cohort. Although egg consumption up to 6 times per week was not associated with incident HF, consumption of 1 egg per day was associated with a 28% increased risk of HF, whereas consumption of 2 eggs per day was associated with a 64% increased risk of HF after accounting for confounding factors. Similar results were obtained for HF without antecedent myocardial infarction. Overall, our data suggest that although infrequent egg consumption has no influence on the risk of HF, frequent consumption may increase the risk of HF among US male physicians.