A reader (thanks, Syd!) pointed out an article in The Huffington Post that was critical of the Cleveland Clinic study suggesting carnitine causes cardiovascular disease (see Carnitine, Red Meat, TMAO & CVD).

While the Huffington Post article was one of many criticizing the Cleveland Clinic study, it was the only one I saw that made any good points. The article is Does Carnitine Really Cause Heart Disease? by Alan Gaby, MD, who is the past president of the American Holistic Medical Association. Towards the very end of the article, Dr. Gaby says, “It is noteworthy that the observed association between heart disease and carnitine levels disappeared completely when the researchers corrected for differences in kidney function.”

This is true – when the researchers corrected for a number of conditions, including kidney function and TMAO levels, the association of carnitine with major adverse cardiac events (MACE) disappeared. The researchers used that model to say that it proved that TMAO was the problem, not carnitine, and it didn’t occur to me in my first analysis that perhaps TMAO levels were high simply because the kidneys couldn’t clear the TMAO. After reading Dr. Gaby’s article I downloaded the online supplementary material and found that kidney function did progressively get worse as carnitine levels increased among the subjects, and this trend was statistically significant. So it seems plausible that perhaps the higher TMAO levels were simply a result of poor kidney function. But this is such an obvious possibility that I couldn’t believe the researchers didn’t consider it and perhaps run an unreported model to test for it. I then wrote the corresponding author of the study, Dr. Stanley Hazen, who is out of the office until the end of the month.

But there’s more. On Thursday, I awoke to news that the Cleveland Clinic group of researchers had published yet another study on TMAO! This time, it was on eggs and lecithin (1). In 2011, they had reported that choline can increase TMAO levels and TMAO was associated with the existence of cardiovascular disease in a cross-sectional study (more info). This time, they were testing phosphatidylcholine (lecithin) from eggs to see if it increased TMAO levels. It did.

Then they performed a prospective study much like the one in the carnitine study (maybe even an arm of the same one?) to see if TMAO was associated with more MACE. Once again, people with higher TMAO levels also had poorer kidney function. But even after adjusting for kidney function, TMAO was still significantly associated with MACE (1.43, 1.05–1.94).

That fully adjusted model included age, sex, smoking status, systolic blood pressure, LDL, HDL, diabetes, C-reactive protein, myeloperoxidase, glomerular filtration rate (kidney function), total white-cell count, body-mass index, medications (aspirin, statins, ACE inhibitor, ARB, or beta-blocker), and the extent of disease as seen on angiography. That’s a lot of adjustments some of which might even be too much, dampening the true effect of TMAO.

As things stand, it appears that kidney function is not the cause of high TMAO and that TMAO might, after all, be a significant cause of MACE. Stay tuned – this story is not over.

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Reference

1. Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. N Engl J Med 2013(April 25, 2013);368:1575-1584. | link

As foods go, eggs are very high in cholesterol. Back when it was thought that eating cholesterol caused an increase in blood cholesterol, people with high cholesterol or heart disease were warned away from eggs. But then it was found that while some people’s cholesterol levels rise significantly from eating cholesterol, most people’s do not. So where does that leave eggs?

The findings have been somewhat mixed over the years. The most recent paper I found was a 2008 report from the Physicians’ Health Study (a trial to study low dose aspirin and beta-carotene’s effects on the primary prevention of cardiovascular disease and cancer among US male physicians) (1). They found the following when comparing consumption of 7+ eggs per week to less than 1 per week:

• No correlation with stroke or heart attacks
• A 23% increased risk of mortality (1.23, 1.11-1.36)
• A doubled risk of mortality among men with type 2 diabetes (2.01, 1.26-3.20)

These results were adjusted for age, body mass index, smoking, hypertension, vitamin intake, alcohol consumption, vegetable consumption, breakfast cereal consumption, physical activity, treatment group, atrial fibrillation, diabetes mellitus, hypercholesterolemia, and parental history of premature myocardial infarction.

The authors of this paper reviewed the previous literature on eggs and mortality:

“Limited and inconsistent data have been reported on the association between egg consumption and coronary heart disease. Among 514 Australian Aborigines, consumption of 2+ eggs per week was associated with a 2.6-fold increased risk of coronary heart disease in a prospective analysis (2). Mann et al. (3) reported a 2.7-fold increased risk of death with a higher egg consumption (6+ per week) among British subjects. In contrast, other large prospective cohorts with longer follow-ups did not observe any association between egg consumption and CHD or mortality (4-7).”

They discussed other research showing 7+ eggs increased the risk of heart disease in men and women with diabetes (5).

In conclusion, it appears that in comparison to less than one egg per week, eating 7+ egg per week could increase your risk of early death, especially if you have type 2 diabetes.

References

1. Djousse L, Gaziano JM. Egg consumption in relation to cardiovascular disease and mortality: the Physicians’ Health Study. Am J Clin Nutr. 2008 Apr;87(4):964-9.

2. Burke V, Zhao Y, Lee AH, et al. Health-related behaviours as predictors of mortality and morbidity in Australian Aborigines. Prev Med 2007;44:135–42. [PubMed: 17069878]

3. Mann JI, Appleby PN, Key TJ, Thorogood M. Dietary determinants of ischaemic heart disease in health conscious individuals. Heart 1997;78:450–5. [PubMed: 9415002]

4. Dawber TR, Nickerson RJ, Brand FN, Pool J. Eggs, serum cholesterol, and coronary heart disease. Am J Clin Nutr 1982;36:617–25. [PubMed: 7124663]

5. Hu FB, Stampfer MJ, Rimm EB, et al. A prospective study of egg consumption and risk of cardiovascular disease in men and women. JAMA 1999;281:1387–94. [PubMed: 10217054]

6. Nakamura Y, Okamura T, Tamaki S, et al. Egg consumption, serum cholesterol, and cause-specific and all-cause mortality: the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980 (NIPPON DATA80). Am J Clin Nutr 2004;80:58–63. [PubMed: 15213028]

7. Nakamura Y, Iso H, Kita Y, et al. Egg consumption, serum total cholesterol concentrations and coronary heart disease incidence: Japan Public Health Center-based prospective study. Br J Nutr 2006;96:921–8. [PubMed: 17092383]