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.
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