Abstract
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 examine the association between egg consumption and the risk of HF. Egg consumption was assessed using 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 1,084 new HF cases occurred in this cohort. While egg consumption up to 6 times per week was not associated with incident HF, egg consumption of 7 or more per week was associated with an increased risk of HF. Compared to subjects who reported egg consumption of < 1 per week, hazard ratios (95% CI) for HF were 1.28 (1.02-1.61) and 1.64 (1.08-2.49) for egg consumption of 1/day and 2+/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, consumption of 1 or more eggs per day is related to an increased risk of HF among US male physicians.
Keywords: Diet, heart failure, epidemiology, and nutrition
Introduction
Heart failure (HF) remains a major public health issue in the United States. The development of hypertension and myocardial infarction – two major risk factors for HF – is influenced by elevated plasma LDL-cholesterol. Hence, dietary guidelines to prevent the underlying atherosclerosis emphasize the reduction of dietary cholesterol1,2. While each egg contain 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 effects7,10,11. The relation between dietary and serum cholesterol is complicated by the large variability in individual response to dietary cholesterol11-13. Despite the fact that some studies have shown an association between egg consumption and CHD14, no previous study has examined whether egg consumption is associated with the risk of HF in a community setting.
Because eggs could serve as a good source for vitamins, proteins, and other nutrients in the US, it is important to understand whether egg consumption as a whole food (as opposed to individual component of eggs such as cholesterol) confers a lower or higher risk of HF. In the current 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.
Materials and 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 previously15. For the present analyses, we excluded 796 subjects with missing data on egg consumption (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 using a simple abbreviated semi-quantitative food frequency questionnaire. Participants were asked to report how often, on average, they had eaten eggs (one) during the past year. Possible response categories included “rarely/never”, “1-3/month”, “1/week”, “2-4/week”, “5-6/week”, “daily”, and “2+/day”. This information was obtained at baseline, 24, 48, 72, 96, and 120 months after randomization. We combined the first two categories to create a large and stable reference group.
Ascertainment of HF in the PHS
Endpoints in the PHS have been ascertained using 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 previously16.
Other variables
Demographic data were collected at baseline. Information on comorbidity (i.e., 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 HDL-cholesterol were measured at baseline on 4,672 individuals using standard methods. We computed the ratio of total-to-HDL-cholesterol.
Statistical analyses
At baseline and subsequent time points, where information on egg consumption was collected (24, 48, 72, 96, and 120 months post randomization), we classified each subject into one the following categories of egg consumption: < 1 per week, 1 per week, 2-4 per week, 5-6 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 a) HF, b) death, c) date of receipt of last follow-up questionnaire, or d) censoring date (1/30/2007). 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 hazard models to compute multivariable adjusted hazard ratios with corresponding 95% confidence intervals using subjects in the lowest category of egg consumption as the reference group. We assessed confounding by using 10% change in hazard ratio. Assumptions for the proportional hazard models were tested (by including main effects and product terms of covariates and time factor) and were met (all p values >0.05). The parsimonious model controlled for age (5-year categories), body mass index (<25, 25-29.9, and ≥ 30 kg/m2), smoking (never, past, and current smokers), alcohol consumption (<1, 1-4, 5-6, 7+ drinks/week), and history of diabetes mellitus (yes/no), hypertension (yes/no), and atrial fibrillation (yes/no). Lastly, the fully adjusted model also controlled for hypercholesterolemia (yes/no), physical activity (<1, 1+/ week), and history of valvular heart disease. We computed p 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. Lastly, 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-, HDL-cholesterol, and the ratio of the two variables using analysis of covariance. All analyses were completed using SAS, version 9.1 (SAS Institute, 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). About 64% reported egg consumption of 1-4 per week in this population and only 8% reported consumption of 1+/day. Table 1 presents baseline characteristics of the study participants. Frequent consumption of eggs was associated with older age; higher body mass index; lower frequency of breakfast cereal consumption; higher proportion of current drinkers and smokers, and physical activity; higher prevalence of diabetes mellitus and hypertension; and lower prevalence of hypercholesterolemia. During an average follow up of 20.4 years, 1,084 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 vs. 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 were associated with a 28% and 64% increased risk of HF, respectively (Table 2). Restricting the analysis to subjects with follow-up times beyond two years yielded similar results (p for trend 0.004). Similar findings were obtained when egg consumption and interim myocardial infarction were updated using 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). Lastly, 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 instead of prevalent hypercholesterolemia had no effect on the findings among subjects with blood lipids.
Table 1.
Characteristics of the 21,275 study participants according to egg consumption
| Egg consumption | ||||||
|---|---|---|---|---|---|---|
| < 1 / week (n=4527) |
1 /week (n=6621) |
2-4/ week (n=6971) |
5-6 /week (n=1419) |
1 /day (n=1473) |
2+ /day (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/m2) | 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+/ week (%) | 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 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/week, 1/week, 2-4/week, 5-6/week, 1/day, and 2+/day, respectively. High cholesterol defined as total cholesterol of 240 + mg/dl or reported current/past treatment for elevated cholesterol.
Table 2.
Relative risk (95% CI) of heart failure according to egg consumption
| Hazard ratios for heart failure (95% CI) | |||||
|---|---|---|---|---|---|
| Egg intake | Cases | Crude | Age-adjusted | Model 1* | Model 2† |
| < 1 per week | 206 | 1.0 | 1.0 | 1.0 | 1.0 |
| 1 per week | 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 per week | 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 per week | 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 per day | 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+ per day | 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/m2), smoking (never, former, current smokers), alcohol consumption (<1, 1-4, 5-7, 8+ drinks/week), and history of diabetes mellitus, atrial fibrillation, and hypertension.
Additional adjustment for physical activity (<1, 1+ per week), and history of valvular heart disease and treatment for cholesterol.
Table 3.
Relative risk (95% CI) of heart failure without antecedent myocardial infarction according to egg consumption
| Hazard ratios for heart failure (95% CI) | |||||
|---|---|---|---|---|---|
| Egg intake | Cases | Crude | Age-adjusted | Model 1* | Model 2† |
| < 1 per week | 178 | 1.0 | 1.0 | 1.0 | 1.0 |
| 1 per week | 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 per week | 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 per week | 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 per day | 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+ per day | 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+), body mass index (<25, 25-29.9, 30+ kg/m2), smoking (never, former, current smokers), alcohol consumption (<1, 1-4, 5-7, 8+ drinks/week), and history of diabetes mellitus, atrial fibrillation, and hypertension.
Additional adjustment for physical activity (<1, 1+ per week), and history of valvular heart disease and treatment for cholesterol.
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 or more eggs per week was associated with an increased risk of HF among male physicians. Furthermore, 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 (CVD) and mortality. Data from 514 Western Australian Aborigines showed a 2.6-fold increased risk of CHD comparing egg consumption of 2+ vs. < 2/week after ∼14 years of follow up14. Compared with egg consumption of less than 1/week, the incidence rate ratio for total mortality was 1.23 and 2.68 among subjects consuming 1-5 and 6+ eggs/week, respectively, after adjustment for age, sex, smoking, and social class17. Qureshi et al.18 reported a 2-fold increased risk of CHD among people reporting an intake of 6+ eggs/week compared with intakes of < 1 per week. In addition, compared to 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 further examine this hypothesis. The fact that we observed elevated risk of HF without antecedent myocardial infarction suggests that alternative physiologic 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 studies20,21. Changes in dietary patterns may lead to a spurious association between baseline exposure and incident outcome. In our data, we used time-dependent 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 if myocardial infarction had a little effect on the results.
A wide variability in individual response to dietary cholesterol (hyper-responders vs. hypo-responders) has been reported. It has been suggest that among hyper-responders, 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 hyper-responders. 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 subfraction22.
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. Egg consumption was assessed using an abbreviated food questionnaire. This might have led to under-reporting 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 no directly validate the abbreviated food questionnaire used to assess egg consumption. However, validation of full food frequency questionnaires (including egg consumption questionnaire used in this study) has been published elsewhere26,27. Lastly, 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/week is not associated with HF whereas consumption of 7+/week is related to an increased risk of HF. Confirmation of these findings is warranted along with exploration of underlying biologic 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.
Funding/Support: The Physicians' Health Study 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 a K01 HL-70444 from the National Heart, Lung, and Blood Institute, Bethesda, MD.
Footnotes
Authors' contribution: Djoussé L: Designed study, conducted data analyses, obtained funding, and drafted manuscript. Gaziano JM: Collected data, provided significant advice for data analysis, critically reviewed the manuscript, and obtained funding.
Conflict of Interest: None of the authors has relevant conflict of interest to disclose. A full disclosure regardless of relevance to this paper is provided in the cover letter for the editors' appraisal.
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