Follow-Up to Carnitine and Atherosclerosis

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

17 Responses to “Follow-Up to Carnitine and Atherosclerosis”

  1. Syd Baumel Says:

    Hi Jack,

    When I looked into this a bit (as you know, I seem to have a need for carnitine to prevent lassitude on my vegan diet), I was kind of stunned to see that the same Cleveland Clinic team have also reported much the same results from feeding choline to CVD-prone mice and documenting a very strong association between choline levels and CVD in a human clinical population: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086762/. In their abstract they wrote: “Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort….Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.” Obviously, this would implicate soy too and any other food, from eggs to chocolate bars, that’s rich in choline or phosphatidylcholine (PC), aka lecithin. Yet remarkably, in the full study (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086762/), the authors only cite animal sources of PC:

    “Foods rich in the lipid phosphatidylcholine (PC, also called lecithin), which predominantly includes eggs, milk, liver, red meat, poultry, shell fish and fish, are believed to be the major dietary sources for choline, and hence TMAO production.”

    This made me wonder if the lead scientist, Stanley Hazen, could be letting a vegan agenda distort his science, but Dr. Google informed me he’s an omnivore, although he says he’s moderated his red meat intake since doing the carnitine research.

    On the science itself, if the carnitine/PC>gut flora>TMAO>CHD connection proves legit, it opens up the possibility that probiotics – some of which are vegan – could be preventive or, in someone like me who may already have cultivated a massive colony of well-nourished, TMAO-synthesizing bacteria – therapeutic.

    I also found this critique – http://www.huffingtonpost.com/alan-r-gaby-md/carnitine-heart-health_b_3100191.html – of the carnitine study interesting, although I don’t have the time or the chops to try and fact-check his claim that the authors “manipulated the data.” Considering how many compliments the study has received for high-quality design, I’m skeptical of that.

  2. Andrei Says:

    Thank you for making that clear. The ‘senior investigator’ seemed to believe that it does relate to that study and that, in fact, their results are more conclusive because they come from humans. But he failed to specify that the levels of carnitine are depleted after a heart attack and that the supplementation doses are much larger than you can get from red meat. He does say, however, that the are many types of carnitine (both papers appear to focus on the same type, though) and that their results concern only human who already experienced heart attacks.

  3. AmyLu Says:

    1. “When someone has a heart attack, their carnivore levels become depleted.”

    Is this causation documented, or do the two coexist, with the possibility of the depletion being a causal factor in a heart attack?

    2. I read elsewhere that this study had only five human subjects, and that only one of them was a non-meat eater. Is that accurate? If so, do you consider that good enough methodology for us to even consider the study’s findings?

    Thanks!

  4. Matt Says:

    So this might be just a short-term study (e.g., 5 days?). Or, in other words, this isn’t really anything counter to the other study re: gut bugs and red meat?

  5. Jack Norris RD Says:

    Syd,

    In my article on choline ( http://veganhealth.org/articles/choline ), I note their research. If you look at the Average Choline Intakes section of that article you’ll see that intakes for meat-eaters are about 660 mg for men and 408 mg for women. In calculating what a vegan’s intake would be, it is much lower. So, I don’t think that it is necessary for vegans to worry about avoiding soy in order to decrease TMAO. And, this research is fairly preliminary and, in my opinion, it’s far too soon to change anything based on it (choline or carnitine).

  6. Jack Norris RD Says:

    Andrei,

    Yes, I don’t understand why Dr. Lavie thought the two papers were relevant to each other. Lavie also says, “but the main study reported there was in animals.” I guess the definition of “the main study” is open to debate, but I would consider the studies on the humans reported in the Cleveland Clinic paper to impressive on their own.

  7. Jack Norris RD Says:

    AmyLu,

    I’m going to start with your second question:

    2. Their preliminary test contained 5 omnivores and 1 vegan, but they followed up with 23 vegans and vegetarians and 51 omnivores. So the articles that fail to mention this are either simply spinning the results or didn’t read the paper very carefully.

    1. I don’t think depletion is a causal factor in a heart attack, but I don’t know what research there is to back that up. If you want to check into it more, this is what the paper says:

    “As myocardial carnitine levels are quickly diminished during an ischemic event, exogenous supplementation with L-carnitine has been shown to replenish depleted myocardial carnitine levels and improve cardiac metabolic and left ventricular (LV) function. (4-7)

    4. Rizzon P, Biasco G, Di Biase M, et al. High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects. Eur Heart J. 1989;10(6):502-508.

    5. Liedtke AJ, DeMaison L, Nellis SH. Effects of L-propionylcarnitine on mechanical recovery during reflow in intact hearts. Am J Physiol. 1988;255(1, pt 2):H169-H176.

    6. Micheletti R, Giacalone G, Canepari M, Salardi S, Bianchi G, Reggiani C. Propionyl-L-carnitine prevents myocardial mechanical alterations due to pressure overload in rats. Am J Physiol. 1994;266(6, pt 2):H2190-H2197.

    7. Colonna P, Iliceto S. Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Am Heart J. 2000; 139(2, pt 3):S124-S130.

  8. Jack Norris RD Says:

    Matt,

    It was a meta-analysis of 13 different studies, the average duration of I do not know (although I could look each one up to see). Conveniently, the largest study which contributed 62% of the deaths, was 6 months long, assessing both 5-day and 6-month mortality. http://www.ncbi.nlm.nih.gov/pubmed/16685128 Based on the abstract, they found a reduction in 5-day mortality, but not 6-month.

  9. Jack Norris RD Says:

    Syd,

    As for the article in Huffington Post by Alan Gaby, MD ( http://www.huffingtonpost.com/alan-r-gaby-md/carnitine-heart-health_b_3100191.html ), I think he may be making a good point when he talks about the finding for carnitine disappearing after adjustments for kidney function.

    In Figure 4, part e they plot carnitine levels and major adverse cardiac events (MACE). They have 3 models:

    1. unadjusted:

    Carnitine was highly associated with MACE.

    2. traditional cardiovascular risk factors:

    Carnitine was associated with MACE in the highest quartile.

    3. traditional cardiac risk factors plus creatinine clearance, history of myocardial infarction, history of CAD, burden of CAD (one-, two- or three-vessel disease), left ventricular ejection fraction, baseline medications (angiotensin-converting enzyme (ACE) inhibitors, statins, beta blockers and aspirin) and TMAO levels (open squares):

    Carnitine was no longer associated with MACE.

    They say, “After further adjustment for both plasma TMAO concentration and a larger number of comorbidities that might be known at time of presentation (for example, extent of CAD, ejection fraction, medications and estimated renal function), the significant relationship between carnitine and MACE risk was completely abolished (Fig. 4e). Notably, we observed a significant association between carnitine concentration and incident cardiovascular event risks in Cox regression models after multivariate adjustment, but only among those subjects with concurrent high plasma TMAO concentrations (P < 0.001) (Fig. 4f). Thus, although plasma concentrations of carnitine seem to be associated with both prevalent and incident cardiovascular risks, these results suggest that TMAO, rather than carnitine, is the primary driver of the association of carnitine with cardiovascular risks.”

    But if kidney function is driving up carnitine or TMAO levels in these patients, then it seems reasonable that they should have adjusted for kidney function in the traditional-risk-factors-only model.

    Online, they have a PDF of supplemental material and in Table 2 they show the glomerular filtration rate of the different quartiles of carnitine and it steadily goes from 86 to 79 as carnitine increases (p < .05). So, it seems quite possible to me that the higher carnitine levels are simply an artifact of poorer kidney function.

    I’d be happy to send you the material to take a look for yourself…

  10. Jack Norris RD Says:

    Syd,

    I have written Dr. Hazen about the issue regarding kidney function. He is out of the office until Apr 29.

  11. Jack Norris RD Says:

    Syd,

    More info in case you didn’t see my post:

    http://jacknorrisrd.com/eggs-tmao-and-heart-disease/

  12. Syd Baumel Says:

    Thanks for this detective work, Jack. I keep having a brain fart whenever I try and grok the complex correlations and multivariate adjustments, so I’d like to borrow your brain (again). Is the evidence consistent with the possibility that a) TMAO is indeed a cardiovascular disease-promoting compound which the body normally clears (more or less) via healthy kidney function, and b) the clinical evidence of TMAO’s harm in these studies has been correlated with impaired kidney function?

    P.S. Thanks for setting me straight about the comparatively (to eggs and other animal foods) low choline level of soy. I hadn’t checked any nutritional tables because I just assumed it was high, given all the soy lecithin and soy-based phosphatidylcholine out there.

  13. Jack Norris RD Says:

    Syd,

    a) It appears that way, but it’s really hard to say with all the different variables. What I would say for now is that they were able to tease out an association that may or may not hold.

    b) If I’m understanding your question, I would say “no”. The harm from TMAO in the lecithin paper was independent of kidney function, while it is not known (by me) regarding the carnitine paper.

    Soy is probably the highest of plant foods but from a quick look, a glass of soymilk has about 1/3 the amount of choline as a large hard-boiled egg. Not sure how soy does it! Soy seems to be highest among plant foods for an amazing number of things – isoflavones, phytates, choline, lysine.

  14. Syd Baumel Says:

    Thanks again, Jack. I found this earlier today via a wide-net google search: http://tmaufoundation.org/page14.html . It turns out there’s a rare genetic metabolic disorder – trimethylaminuria (TMAU, of all things) – for which a very low choline diet is therapeutic, so the disease foundation has compiled extensive choline food tables for sufferers. Interestingly, carnitine is another dietary no-no for them. Wikipedia says that “Taking low doses of antibiotics such as neomycin and metronidazole[6] in order to reduce the amount of bacteria in the gut” is another piece of the treatment puzzle. Perhaps Hazen et al. should know about this if they don’t already. Wait … it gets better:

    “Additionally, at least one study[7] has suggested that daily intake of the supplements activated charcoal and copper chlorophyllin may improve the quality of life of individuals afflicted with TMAU by helping their bodies to oxidize and convert TMA [the smelly, problem metabolite] to the odorless N-oxide (TMAO) metabolite. Study participants experienced subjective reduction in odor as well as objective reduction in TMA and increase in TMAO concentration measured in their urine.”

    (TBC)

  15. Syd Baumel Says:

    (Cont’d)

    Without looking any further (insufficient time today), something tells me TMAU may have a lot to teach us about the possible significance of this apparent TMAO>MACE connection and vice-versa.

    The Foundation’s food table (which may be out of date) says there’s more free choline in a cup of chickpeas than in a whole egg, and nearly as much in a cup of brown rice (cooked in all cases). In fact, healthful and commonly eaten high-choline foods appear to be ubiquitous. All the more reason to suspect that, perhaps as is the case with TMAU, people need to have some pre-existing condition like impaired kidney function, an abnormal gut flora or a metabolic quirk to suffer health consequences from consuming a lot of choline. One wonders if it’s the same for carnitine.

    Another piece of the puzzle (just found):

    “TMAO is a homeostatic ‘rescue’ compound that allows blood proteins to handle increased concentrations of urea and guanidine (both strong protein denaturants) that arise during renal failure or renal stress [20,25]. Additionally TMAO is known to be a marker of renal medullar injury.” (http://www.metabolomics.ca/News/publications/MetabolomicsInMonitoringKidneyTransplants.pdf)

  16. Jack Norris RD Says:

    Syd,

    Thanks for all the info.

    Very interesting about the kidney failure. I suppose that could nullify the results of the Cleveland Clinic group’s studies, though they did adjust for kidney function in their egg study.

    As for the choline content of the foods you mentioned, the site you found does not mesh with the USDA database (brought to you by PeaCounter.com):

    Chickpeas (garbanzo beans, bengal gram), mature seeds, cooked, boiled, without salt
    http://peacounter.com/foods_pub.php?ndb=16057
    70 mg

    Egg, whole, cooked, hard-boiled – large
    http://peacounter.com/foods_pub.php?ndb=1129
    147 mg

    Rice, brown, long-grain, cooked
    http://peacounter.com/foods_pub.php?ndb=20037
    18 mg

    Also, I had mentioned trimethylaminuria in my article on choline and pointed out that the researchers said that some people eat a vegan diet to help treat it, so apparently, a typical vegan diet does have less choline (or, at least, less choline + carnitine, which is no surprise).

    http://veganhealth.org/articles/choline#gut

  17. Syd Baumel Says:

    Have you seen this? http://www.theheart.org/article/1532541.do Deeper analysis than one usually finds in the popular media. Among other things, there’s acknowledgement of the possibility that a “probiotic” approach could solve the problem:

    “In his editorial, Loscalzo writes that the current findings “raise the distinct possibility that atherothrombogenesis can be modulated or attenuated by a variety of novel strategies. These include, but are not limited to, modifying the diet to limit the intake of choline-rich food; altering gut microbiota with the use of probiotic approaches to limit synthesis of trimethylamine . . . or suppressing the synthesis of TMAO pharmacologically.””

    I just read a Mojo story that makes one pessimistic about the viability of typical probiotic supps, but fermented vegan whole foods might be another story. Intuitively, it just seems unlikely that such a ubuiquitous nutrient as choline should be such a potent risk factor for CVD/MACE/whatever, absent some enabling pathology.

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