L-carnitine study and news misleading
Vitamin D, Parkinson’s disease and MS
Vitamin E slows Alzheimer’s progression
Mediterranean diet prevents vascular disease
Last year, I heard a news broadcast on National Public Radio interviewing a researcher about L-carnitine, a dietary component and supplement, and its possible link to an increased risk of heart disease. His research was widely reported, including by means of this interview, and it may have led many people to avoid carnitine supplements, but the conclusions were unwarranted from the data, and yet another example of negative press about supplements. The report was based on a study of genetically engineered mice that are particularly prone to atherosclerosis. They lack the gene for production of apolipoprotein E, which is helpful in clearing cholesterol from the blood. The mouse study was only part of the research. The same report also included a study of 2595 human subjects, showing an increased risk of cardiac events associated with a higher level of carnitine in the blood. (Koeth RA, et al., Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 May;19(5):576-85 doi: 10.1038/nm.3145. Epub 2013 Apr 7.)
Carnitine is a critical substance for energy production. It is the molecule that transports fatty acids into the mitochondria where they can be converted to energy. We manufacture carnitine in the liver and kidneys, but with age and disease, we may not produce enough. In that case, supplements become important to maintain cardiovascular and muscle health. Numerous studies have confirmed that carnitine supplements are helpful for heart function, reducing angina pectoris, increasing exercise capacity, and reducing mortality after a heart attack. Carnitine can also increase walking distance by reducing leg pain due to narrowing of the arteries to the legs (intermittent claudication). A study that claims to show that carnitine is harmful needs a lot of evidence to refute these known benefits.
A few problems are evident in the design of this study and the conclusions. They are a bit difficult to explain, but worth looking at. Some intestinal flora (microbes, such as bacteria) convert phosphatidyl choline (PC) by enzyme activity to trimethyl amine (TMA) and further to trimethylamine-N-oxide (TMAO). TMAO is harmful to the heart. These organisms also convert carnitine to TMAO, and they are particularly abundant in humans who consume red meat, partly because of the large amount of carnitine in the meat. Meat eaters develop a higher number of the bacteria that create TMAO, while the number is very low in vegetarians and vegans. Antibiotics block this increase in TMAO, indicating that the bacteria are the cause. TMAO is also found in large amounts in saltwater fish, but consuming these fish appears to be helpful to the heart, so TMAO itself is not the whole answer.
Another problem with the mouse part of the research is the dose of carnitine that the mice were given. They were supplemented for 15 weeks with carnitine in the drinking water at 1.3 percent. This translates to an approximate dose of 2 gms per Kg of body weight per day, so a 155 pound human would have to consume 140 GRAMS per day to get the same dose. This is about 800 times what one would get by eating an 8-ounce steak every day. Supplements are typically one to three grams per day. (Ussher JR, et al., Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis. 2013 Dec;231(2):456-61.) As Ussher and colleagues point out, mice are not humans (as if we didn’t know) because they metabolize cholesterol and lipids differently, have different cardiovascular physiology and plaque pathology, and do not develop thrombotic vascular occlusion.
In the human part of the study by Koeth, et al., they found that after taking a carnitine supplement of 250 mg, the TMAO level in the blood rose within hours. The problem with drawing conclusions from this is that they also fed the subjects an 8-ounce sirloin steak containing 180 mg of carnitine at the same time. Steak is also a rich source of choline as well as carnitine, so we don’t know what led to the rise in TMAO. However, the vegans in this part of the study were given only the carnitine supplement, without the steak, and their TMAO showed a negligible change over 24 hours. Prior consumption of meat appears to stimulate the growth of the bacteria that create TMAO from choline and carnitine.
The finding of increased cardiac events among subjects with higher blood carnitine levels does not mean that carnitine in the blood is harmful. As this is an observational study, we can’t draw conclusions as to a causal relationship to carnitine levels. It is possible that atherosclerosis and cardiac events actually led to the higher levels of carnitine in the blood, rather than the other way around. When they adjusted their data for kidney function, the relationship of blood carnitine to heart disease disappeared, further suggesting that the high carnitine might be the result of poor kidney function, which is commonly seen in cardiovascular disease.
Further data dispute the theoretical conclusions in the Koeth, et al., study. In a meta-analysis (review of studies) of 13 studies with a total of 3629 subjects, researchers evaluated the effects of carnitine supplements on mortality, ventricular arrhythmias (VAs), angina, heart failure, and reinfarction (repeat heart attack). Compared with placebo or control subjects, carnitine was associated with a 27 percent decline in all-cause mortality, a 65 percent reduction in VAs, and a 40 percent reduction in angina. They also found a decline of heart failure and reinfarction, but these did not reach statistical significance. This study was first published online one week after the negative study, but was not reported in the popular press. (DiNicolantonio JJ, et al., L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. Mayo Clin Proc. 2013 Jun;88(6):544-51. doi: 10.1016/j.mayocp .2013.02.007. Epub 2013 Apr 15.
Carnitine is a valuable supplement for anyone with heart disease, and improves symptoms and overall function, and it also reduces mortality from heart disease and all causes. In athletes, it reduces tissue damage during intense exercise, and may help recovery after exercise training, but the data are not consistent. Our production of carnitine declines with age, so supplements may have a general benefit as we get older. It is extremely safe, and 3000 mg per day or more may be beneficial, although occasional reports suggest that that dose can cause nausea and diarrhea. I take 3000 mg daily, and at times have taken as much as 6000 mg to help my heart, but even higher doses are very safe.
A new study shows that vitamin D might help patients with Parkinson’s disease (PD), but you would never know it from the headline, which said “Vitamin D levels linked to Parkinson’s symptoms” suggesting that vitamin D was leading to those symptoms. In fact, the opposite is true, but if you only read the headline you would never know this. Vitamin D receptors are found throughout the brain. Animal studies suggest that it is important for neural development, stabilizing mitochondrial function, and anti-oxidation, as well as increasing levels of neuro-trophic factors.
This new research included 286 participants with PD. They were evaluated for cognitive function, verbal memory, fluency, visual function, executive function PD severity rating scales, and depression. Higher vitamin D levels in the blood were associated with better performance on numerous neuropsychiatric tests, especially verbal fluency and verbal memory. Higher vitamin D also correlated with better depression scores. (Peterson AL, et al., Memory, mood, and vitamin d in persons with Parkinson's disease. J Parkinsons Dis. 2013;3(4):547-55. doi: 10.3233/JPD-130206.)
Another recent study shows that low vitamin D levels have an adverse effect on progression and outcomes in patients with Multiple Sclerosis (MS). In this study, 465 patients with MS were evaluated for vitamin D status and followed for five years. Higher vitamin D levels predicted reduced MS activity and a slower rate of progression. A 20 nanogram/millileter (ng/ml) increase in blood 25-hydroxy vitamin D within the first 12 months predicted a 57 percent lower rate of new active lesions and a 57 percent lower relapse rate, and there were further benefits for the entire length of the study. (Ascherio A, et al., Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014 Jan 20. doi: 10.1001/jamaneurol.2013.5993. [Epub ahead of print])
With all of the known benefits of higher levels of vitamin D in the blood, it is important to have your level of 25-hydroxy vitamin D checked and, if necessary, take supplements to assure adequate amounts. Conventional normal levels are over 20 to 40 ng/ml. However, many experts believe that your level is satisfactory if it is 40-50 ng/ml. The Vitamin D Council suggests that 40 to 50 ng/ml is fine, but notes that there might be further benefits at higher levels. For Parkinson’s and MS patients, this is particularly important. Supplements are often needed to maintain these high levels, and 3000 IU daily is what some people need to bring their levels up to a healthy range. Levels even as high as 100 ng/ml are well within the safety limits. On 5000 IU per day, my level only went up to 48 ng/ml, so I decided to take double that for a while and then retest. I’ll report the results when I can.
Vitamin E supplements have been associated with delayed progression of Alzheimer’s disease (AD) for many years, as has high-dose coenzyme Q10, another antioxidant nutrient. For example, a study in 1997 showed delayed progression of AD with supplements of 2000 IU of alpha-tocopherol (AT) per day (synthetic dl-alpha-tocopherol is the most common form used in large trials, rather than the natural d-alpha-tocopherol, and they rarely study the gamma-tocopherol that is more common in food). (Sano M, et al., A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22.)
In this most recent study, 613 patients with mild to moderate AD received either 2000IU of AT, 20 mg/d of the drug memantine, a combination of the two, or a placebo. They looked at symptom scores and cognitive, neuropsychiatric, functional, and caregiver measures. They followed these patients for five years. (Dysken MW, et al., Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44.)
Over the course of the study, those on vitamin E alone improved their AD score by a significant 3.15 points, while the drug and placebo groups did not decline significantly. The change in the AT group translated into a delay in clinical progression of 19 percent per year, or a delay of 6.2 months during the follow-up period. While this may not seem like much, it means a striking saving of caregiver time, the cost and burden of a nursing home, and patient comfort, with some patients experiencing significantly greater benefits than the average.
In the earlier two-year study in 1997, the primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia. In that study, the AT alone was better than placebo, drug treatment, or a combination of drug and AT, with the AT group, the primary outcome was delayed by about eight months compared to placebo.
Although the press has been fairly negative about vitamin E recently, numerous studies show its benefits, even when they use the synthetic pure dl-alpha-tocopherol, rather than the natural form or added gamma-tocopherol. I recommend 400 IU of d-alpha plus additional gamma tocopherol of approximately an equal amount for preventive medicine, and larger doses when there is a patient history or family history of dementias. Vitamin E is very safe even in the larger doses of 2000 IU per day. Supplements of mixed tocopherols that are high in gamma-tocopherol are available.
Last year I reported on a study showing the benefits of the Mediterranean diet (MD) in prevention of heart attacks and strokes. The study was from Spain, and referred to as “PREDIMED” for Prevencion con Dieta Mediterranea. In a recent follow-up analysis of their latest data, the researchers evaluated the relationship of the MD to the prevention of peripheral arterial disease (intermittent claudication, or pain in the legs on walking) in patients with particular risk factors for the disease. They followed 7435 subjects who were placed in three groups, one on the MD with extra nuts, one on the MD with extra olive oil, and a control group that was instructed in a “low-fat” diet.
They followed the subjects (men aged 55-80 years old, and women aged 60-80) from 2003 to 2010. Their risk factors for vascular disease included smoking, diabetes, or obesity, among others. For the control diet subjects, the rate of arterial disease was 4.7 per 1000 person-years. In the MD subjects plus nuts, the rate dropped to 2.5, and in the MD group plus olive oil, the rate was 1.5, or a drop in relative risk of 70 percent. The drop in absolute risk was only 3.5 percent, because the maximum rate was not very high, but when you calculate the change for large populations, the number of patients saved from this serious disease becomes meaningful (for 100,000 people followed for 10 years, that works out to delaying or preventing suffering for 35,000 people). (Ruiz-Canela M, et al., Association of Mediterranean diet with peripheral artery disease: the PREDIMED randomized trial. JAMA. 2014 Jan 22-29;311(4):415-7. doi: 10.1001/jama.2013.280618.)
This is pretty simple. Eat a diet high in vegetables, fruits, whole grains, legumes, nuts and seeds, and small amounts of olive oil and wild fish, while minimizing sugar, refined flour, meats, and dairy products. The data are pretty clear that this approach helps to reduce chronic diseases and mortality. If you read the book “Paleofantasy,” by evolutionary biologist Marlene Zuk, you will find out that efforts to emulate what people think of as the Paleolithic diet are misguided. The “paleo” lifestyle of today is rooted in evolutionary myths.
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