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Higher Carnitine Tied to Almost Quintupled MI Risk in People With HIV
Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
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"Additional studies need to be done to determined whether HIV-associated changes in the gut microbiome and mucosa have an effect on carnitine and betaine serum levels."
Mark Mascolini
Carnitine, a small molecule produced in the gut, almost quintupled the risk of type 1 myocardial infarction (MI) in a case-control analysis involving HIV-positive people in the US CNICS cohort [1]. The study suggested high betaine levels may lower MI risk.
Adults with HIV have a 50% higher risk of MI than the general population, but reasons for this increase remain poorly understood. University of California, San Francisco (UCSF) researchers who conducted this study note that HIV infects gut CD4 cells and thereby alters gut microbiota, including the small molecules betaine, carnitine, choline, and trimethylamine N-oxide (TMAO). Previous work linked carnitine and betaine to carotid artery intima-media thickness in people with HIV. To determine whether any of these gut molecules affects MI risk with HIV, the UCSF investigators conducted this study.
The analysis involved adults in the 8-site US CNICS network [2] who had an undetectable viral load on antiretroviral therapy. Cases had a confirmed type 1 MI in 2001-2012. Controls without an MI were matched to cases by incidence density sampling and by calendar time, age, gender, race, duration of HIV suppression, and CD4 count. From samples collected before MIs, technicians at a single center measured plasma levels of TMAO, betaine, carnitine, and choline. To explore associations between small molecules and MI, the researchers used conditional logistic regression with adjustment for traditional cardiovascular risk factors.
As planned, the 36 MI cases and 69 non-MI controls were similar in age (median 50 and 49), race (about half black and half white), proportion of men (78% and 77%), CD4 count (median 536 and 616), and months with a viral load below 400 copies (median 2.8 and 2.5). Cases and controls did not differ significantly in cardiovascular risk factors including active smoking, hypertension, diabetes, and cholesterol. But the MI cases had significantly higher triglyceride levels (median 184 versus 146 mg/dL, P = 0.05).
The researchers split small-molecule levels into quartiles (four evenly divided groups). In an unadjusted analysis having a carnitine level in the fourth (highest) quartile versus the lower three quartiles tended to raise odds of MI (odds ratio [OR] 2.4, 95% confidence interval [CI] 0.9 to 6.6, P = 0.09), while having betaine levels in the highest quartile tended to lower odds of MI (OR 0.4, 95% CI 0.1 to 1.1, P = 0.08).
After adjustment for triglycerides, carnitine levels in the highest quartile versus the lower three quartiles was associated with almost 5-fold higher odds of MI (adjusted OR 4.9, 95% CI 1.3 to 19.0, P = 0.02). After adjustment for high-density lipoprotein (HDL) cholesterol, carnitine levels in the highest quartile tripled odds of MI (adjusted OR 3.2, 95% CI 1.0 to 10.0, P = 0.04). After adjustment for hypertension, smoking, or diabetes, having betaine levels in the highest quartile versus the lower three quartiles tended to cut odds of MI about 60%, but these associations stopped short of statistical significance.
The researchers believe their findings "suggest that one potential mechanism of atherosclerosis in the setting of HIV involves carnitine synthesis from betaine." They call for additional research to determine whether HIV-associated changes in the gut affect carnitine or betaine levels. L-carnitine and acetyl-L-carnitine supplementation have been studied for their impact on HIV- and antiretroviral-associated complications [3], but these studies have been small and largely inconclusive. Whether carnitine in meat affects heart disease risk in the general population also remains controversial [4]. Carnitine supplementation is popular among some people with HIV [5]. Whether supplementation affects carnitine levels in the gut--and thus possibly MI risk--is unknown.
References
1. Sinha A, Hunt PW, Martin JN, et al. Higher carnitine levels are associated with subsequent myocardial infarctions in HIV. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 625. http://www.croiconference.org/sites/default/files/posters-2017/625_Hsue.pdf
2. CNICS. CFAR Network of Integrated Clinical Systems. https://www.uab.edu/cnics/
3. Ilias I, Manoli I, Blackman MR, Gold PW, Alesci S. L-Carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. Mitochondrion. 2004;4:163-168.
4. NATAP. L-Carnitine--good or bad for your heart? Culprit in heart disease goes beyond meat's fat. http://www.natap.org/2013/HIV/041513_08.htm
5. CATIE. Acetyl-L-carnitine and L-carnitine. http://www.catie.ca/en/fact-sheets/vitamins-and-supplements/acetylcarnitine-and-carnitine
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http://www.natap.org/2013/HIV/041513_08.htm......."Ultimately, researchers said the findings make it clear that red meat consumption should be limited, and that people taking carnitine supplements for a boost or drinking energy drinks containing it should stop."
"Carnitine is not an essential nutrient; our body naturally produces all we need," Hazen said in the statement. "We need to examine the safety of chronically consuming carnitine supplements as we've shown that, under some conditions, it can foster the growth of bacteria that produce TMAO and potentially clog arteries.”
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http://www.natap.org/2013/HIV/nm.3145.pdf .......The association between high plasma carnitine concentration and CVD risk disappeared after TMAO levels were added to the statistical model. These observations are consistent with a proposed mechanism whereby oral l-carnitine ingestion contributes to atherosclerotic CVD risk via the microbiota metabolite TMAO. There are only a few reports of specific intestinal anaerobic and aerobic bacterial species that can use l-carnitine as a carbon nitrogen source10,11,56.
l-carnitine is essential for the import of activated long-chain fatty acids from the cytoplasm into mitochondria for β-oxidation, and dietary supplementation with l-carnitine has been widely studied. Some case reports of l-carnitine supplementation have reported beneficial effects in individuals with inherited primary and acquired secondary carnitine deficiency syndromes13. l-Carnitine supplementation studies in chronic disease states have reported both positive and negative results57,58. Oral l-carnitine supplementation in subjects on hemodialysis raises plasma l-carnitine concentrations to normal levels but also substantially increases TMAO levels57. A broader potential therapeutic scope for l-carnitine and two related metabolites, acetyl-l-carnitine and propionyl-l-carnitine, has also been explored for the treatment of acute ischemic events and cardiometabolic disorders (reviewed in ref. 58). Here too, both positive and negative results have been reported. Potential explanations for the discrepant findings of various l-carnitine intervention studies are differences in the duration of dosing or in the route of administration. In many studies, l-carnitine or a related molecule is administered over a short interval or via the parenteral route, thereby bypassing gut microbiota (and hence TMAO formation).
Discovery of a link between l-carnitine ingestion, gut microbiota metabolism and CVD risk has broad health-related implications. Our studies reveal a new pathway potentially linking dietary red meat ingestion with atherosclerosis pathogenesis. The role of gut microbiota in this pathway suggests new potential therapeutic targets for preventing CVD. Furthermore, our studies have public health relevance, as l-carnitine is a common over-the-counter dietary supplement. Our results suggest that the safety of chronic l-carnitine supplementation should be examined, as high amounts of orally ingested l-carnitine may under some conditions foster growth of gut microbiota with an enhanced capacity to produce TMAO and potentially advance atherosclerosis.
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Higher Carnitine Levels are Associated with Subsequent Myocardial Infarctions in HIV
Arjun Sinha1, YifeiMa1, Rebecca Scherzer1, Sophia Hur1, Danny Li1, Heidi Crane2, Daniel Drozd2, Jeffrey Martin1, Peter Ganz1, Steven Deeks1, Peter Hunt1, Priscilla Hsue11University of California at San Francisco, CA, USA; 2University of Washington, Seattle, WA, USA
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