Sunday, November 16, 2014

Carnitine and Cardiovascular Disease

Since we ‘know’ red meat increases cardiovascular disease (CVD)* researchers have been investigating possible mechanisms.  Attention has recently turned to carnitine (and choline but this post will focus on carnitine) as the components in red meat responsible for red meat supposedly increasing CVD [1]
 
Essentially the argument is that carnitine and choline increase TMAO in the blood, which is associated with CVD and in high amounts of TMAO can induce CVD in genetically susceptible mice [1].  (Which sounds an awful lot like the arguments against SFA, such as SFA >> LDL-C >> CVD)
 
* Even though a recent (2010) systematic review and meta-analysis found that no RCTs were identified that evaluated effects of red, processed, or total meat consumption on CVD or diabetes events” and in prospective cohort studies “red meat intake was not associated with CHD” [2], which is consistent with data from the NHANES III survey [3]
 
What is Carnitine?
 
Carnitine is a compound that is found almost exclusively in meat (hence ‘carn-’) and can be synthesised by humans from methionine and lysine using vitamin C dependent enzymes.  However, vegetarians tend to have slightly lower blood carnitine levels [4]
 
The main function of carnitine is to transport fatty acids into the mitochondrial matrix to be metabolised*.  Carnitine also functions as an antioxidant and supports mitochondrial function.
 
Examine has a page on the evidence regarding the effects of carnitine supplementation and it seems carnitine is beneficial compound in a variety of contexts [5].  For example, carnitine reduces blood pressure [5], improves insulin sensitivity [5] and reduces cognitive decline in the elderly [5]
 
* Due to this function, carnitine has been promoted as a ‘fat burner’.  However, it doesn’t appear to increase fat oxidation unless one has inadequate carnitine [5]
 
Does Carnitine cause CVD?
 
The proposed mechanism of carnitine >> TMAO >> CVD (therefore red meat >> TMAO >> CVD) has been thoroughly critiqued by Chris Masterjohn [6].  Other people have also critiqued the study (though not as well as Chris Masterjohn), but almost all these critiques have focussed on the study design and/or the mechanisms, with very little attention paid to the real question: ‘does carnitine increase the risk of CVD?’  Fortunately we have some fairly good evidence to help us answer that question
 
A systematic review and meta-analysis of clinical trials (13 trials, N = 3629) was conducted in 2012 looking at the effects of carnitine supplementation on CVD events and total mortality in secondary prevention (people who have had a heart attack) [7].  It found that carnitine associated with:
 
·         “A significant 27% reduction in all-cause mortality
(odds ratio, 0.73; 95% CI, 0.54-0.99; P=.05; risk ratio [RR], 0.78; 95% CI, 0.60-1.00; P=.05)”
·         “A highly significant 65% reduction in ventricular arrhythmias
(RR, 0.35; 95% CI, 0.21-0.58; P<.0001)”
·         “A significant 40% reduction in the development of angina
(RR, 0.60; 95% CI, 0.50-0.72; P<.00001)”
·         “No reduction in the development of heart failure
(RR, 0.85; 95% CI, 0.67-1.09; P=.21)
or myocardial reinfarction*
(RR, 0.78; 95% CI, 0.41-1.48; P=.45)”
 
These results are superior to statins (see table below), and unlike statins (which increase the risk of type 2 diabetes [8] and may impair cognitive function), carnitine seems to improve cognitive function and insulin resistance [5].  Carnitine supplements are fairly cheap, so I don’t see much reason why they aren’t prescribed to people who have had a heart attack
 
The Number Needed to Treat (NNT)
(lower is better)
Statins [8]
Carnitine [7]
Total Mortality
83
38
Non-Fatal Heart Attack
39
NS*
Ventricular Arrhythmias**
?
4
Angina**
?
3
 
This is secondary prevention so it’s unknown whether carnitine will have a similar beneficial effect in primary prevention (people who have not had a heart attack).  However, based on these results and overall effects of carnitine (see the Examine article) it’s likely that carnitine is beneficial for primary prevention as well.  At the very least, it would be surprising if something which is beneficial for secondary prevention is harmful for primary prevention
 
* There were only 38 myocardial reinfarctions which makes the study pretty underpowered (by comparison there were 250 deaths)
 
** Ventricular arrhythmias and angina would be expected to have a lower NNT (due to higher incidence) and therefore shouldn’t be compared to the statin NNT for non-fatal heart attack.  I included those two figures just to emphasise how therapeutic carnitine seems to be
 
The Limitation of Mechanisms
 
The take away from this is that biological mechanisms are just hypotheses for what happens in real world.  If we reduce most mechanisms to A >> B >> C*, then logic tells us that we can only be certain that A causes C if at least one of these conditions is true:
 
·         A only causes B
·         B only causes C
 
This is rarely the case in biology, as biological systems are highly interconnected and biologically active compounds have many effects**.  In this case, although carnitine may have some adverse effect by increasing TMAO, carnitine also has many beneficial effects, resulting in a net positive effect for CVD events and total mortality in secondary prevention.  The only way to test this is to do clinical trials
 
* Carnitine >> TMAO >> CVD
Saturated fat >> LDL-C >> CVD
 
** Also, when we get carnitine from meat we are also ingesting many other nutrients and various compounds in meat, all of which have their own biological effects.  With this in mind, reducing a given food (or food group) to one nutrient (or several) ignores the net biological effect of all the nutrients and compounds in a given food, not to mention any nutrient interactions.  A good example of this is demonising fruit by reducing it to sugar
 
Summary
 
·         There have been no clinical trials to examine the effect of red meat on CVD
·         Red meat is not associated with CVD in observational studies
·         Carnitine is a beneficial nutrient in a variety of contexts
·         Carnitine reduces CVD events and total mortality in secondary prevention
·        Just because A causes B and B causes C doesn't mean A causes C
 
If you haven’t already, I recommend you read the Examine article on carnitine and Chris Masterjohn’s critique

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