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

Just before going on my break, I wrote about a recent study showing that meat-eaters have bacteria in their digestive tracts that turn carnitine (found in high amounts in red meat) into TMAO which causes atherosclerosis (see Carnitine, Red Meat, TMAO & CVD). That very day, a meta-analysis was released indicating that carnitine supplements can reduce mortality in people who have had heart attacks (1).

Does that meant that red meat actually prevents heart disease via it’s carnitine content?

When someone has a heart attack, their carnitine levels become depleted. The meta-analysis showed that supplementing with large doses of carnitine (an optimal dosage of 6-9 g/day, many times more than one could get from eating red meat) can reduce mortality, particularly in the first 5 days after the heart attack.

Ventricular arrhythmias and angina were also reduced, but heart failure and second heart attacks were not. The paper did not show how long these studies lasted – this information might have been included in their on-line charts, but I could not access them. Many of the studies were not double-blinded and there were some other methodological problems, so it’s not even clear whether carnitine does provide a benefit for all of these parameters, though I would not be surprised if the reduction in 5-day post-heart attack mortality holds true.

In any case, this meta-analysis has basically nothing to do with the study on carnitine and TMAO.

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Reference

1. Dinicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O’Keefe JH. L-Carnitine in the Secondary Prevention of Cardiovascular Disease: Systematic Review and Meta-analysis. Mayo Clin Proc. 2013 Apr 15. doi:pii: S0025-6196(13)00127-4. 10.1016/j.mayocp.2013.02.007. [Epub ahead of print] | link

A few months ago a study was published on carnitine absorption in the muscles of vegetarians. Here is what I added to VeganHealth.org’s Vegan Weightlifting: What Does the Science Say?, which is where most of my info on carnitine resides (italics added to the new sentences):

“Carnitine levels tend to be lower in people eating lower fat, higher carbohydrate diets. When intake of carnitine is low, less carnitine is excreted. Vegans and lacto-ovo vegetarians have lower blood levels of carnitine. Researchers in one study did not think the lower carnitine levels of vegetarians were unhealthy. It is not known if the lower levels have any bearing on athletic performance. A 2011 study showed vegetarians’ muscles to have a lower ability to absorb carnitine than omnivores. Vegetarians also excreted less carnitine than omnivores, indicating that other tissues or muscles that were not tested were possibly absorbing the carnitine.”

Some added thoughts:

This paper included two studies. In the first study, subjects were given both insulin and carnitine intravenously. The researchers thought the insulin would help enhance carnitine absorption. I would not rule out the possibility that the insulin might have confounded the study in terms of what normally would occur.

In the second study, subjects ate 3 g of carnitine in one dose and had their measurements taken about 24 hours later, only one time. This would give the body very little time to adapt to a larger carnitine intake.

Finally, it is still not clear that vegetarians’ lower levels of muscle carnitine have any physiological significance. I once supplemented with carnitine for a few days and experienced no noticeable health improvement (such as increased energy). But I do know of one person who did very poorly on a vegan diet until he started supplementing with carnitine.

Reference

Stephens FB, Marimuthu K, Cheng Y, Patel N, Constantin D, Simpson EJ, Greenhaff PL. Vegetarians have a reduced skeletal muscle carnitine transport capacity. Am J Clin Nutr. 2011 Sep;94(3):938-44. | Link