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Do gut flora play key role in cardiovascular disease with HIV?
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
Levels of trimethylamine (TMA), a pivotal player in choline metabolism via gut microbiota, were linked to presence of calcified plaque and total coronary plaque burden in a comparison of people with and without HIV infection [1]. The findings by Steven Grinspoon's Massachusetts General Hospital team and colleagues at other institutions suggested to them a potential association of gut-based choline metabolism to subclinical atherosclerosis in HIV-positive people.
Suman Srinivasa and coworkers spelled out the rationale for their 222-person study this way: (1) Ongoing inflammation in people with HIV may heighten the risk of atherosclerotic plaque, but no one has pinned down the precise mechanism. (2) Research links HIV to changes in the gut microbiome, and altered gut flora may elevate markers of inflammation and immune activation even in people with well-controlled HIV. (3) Trimethylamine-N-oxide (TMAO) may play a part in cardiovascular disease by altering cholesterol metabolism and other mechanisms. (4) Elevated TMAO is linked to increased risk of cardiovascular events in HIV-negative people. (5) Metabolism of choline to TMAO from TMA depends on gut microbiota. (TMA accounts for the bad smell of rotting fish, halitosis, and some infections [2].)
With that pathogenic scaffold in place, the investigators set out to compare serum phosphatidylcholine metabolites in HIV-positive and HIV-negative people in relation to subclinical atherosclerotic disease. They hypothesized that people with HIV "would demonstrate unfavorable coronary plaque characteristics in association with increased TMAO" compared with HIV-negative people.
The analysis included 18- to 60-year-olds with and without HIV. They excluded people with known cardiac disease or symptoms, or signals of kidney impairment. The 155 HIV-positive people had taken antiretroviral therapy for more than 3 months. Along with 67 HIV-negative controls, they underwent 64-slice coronary CT angiography (CCTA). They also had metabolic assessment of inflammatory markers, dietary assessment of choline and betaine [3], and measurement of serum choline, betaine, L-carnitine, TMA, and TMAO.
Age averaged 47 in the HIV group and 46 in the HIV-negative group; 53% and 49% were Caucasian, and 61% and 58% were men. The HIV group had a significantly higher proportion of people coinfected with HCV (27% versus 9%, P = 0.002), had significantly higher alanine aminotransferase (35 versus 24 U/dL, P = 0.0001), higher triglycerides (97 versus 83 mg/dL, P = 0.001), and higher lipopolysaccharide, an inflammation marker (0.09 versus 0.07 ng/mL, P = 0.003). Similar proportions of people with and without HIV smoked (44% and 42%). Dietary intake of choline and betaine and levels of metabolites measured were similar in the HIV group and the control group.
People with HIV had been infected for an average 14 years, 99% ever took antiretroviral therapy, and treatment duration averaged 8 years. Current CD4 count averaged 552, current viral load 1.8 log (about 65 copies), and 86% had a viral load below 50 copies.
CCTA detected coronary plaque in 53% of the HIV group and 35% of the HIV-negative group, a significant difference (P = 0.01). People with HIV also had a significantly higher number of arterial segments affected by plaque (about 1.8 versus 1.2, P = 0.03) and a higher number of segments affected by rupture-prone noncalcified plaque (about 1.0 versus 0.5, P = 0.003). The groups did not differ significantly in number of segments affected by less dangerous calcified plaque.
Serum TMA, but not TMAO or choline, was positively and significantly associated with coronary plaque features in people with HIV. Specifically, serum TMA correlated significantly with total plaque segments, calcified plaque segments, calcium score, calcium volume of plaque, and calcium mass of plaque. TMA, but not TMAO or choline, was also significantly and positively associated with lipopolysaccharide in people with HIV (r = 0.19, P = 0.03). These correlations were not seen in HIV-negative controls. Serum TMAO and choline did not correlate with coronary plaque features in the HIV-negative group.
Multivariate analysis determined that TMA was independently associated with several measures of calcified plaque burden in people with HIV: calcium score, total plaque segments, calcified plaque segments, calcium volume of plaque, and calcium mass of plaque.
The Massachusetts General team concluded that serum TMA, but not TMAO, "is associated with the presence of calcified and total coronary plaque burden in HIV-infected patients." They noted that the association of TMA with calcified plaque indices was largely independent of traditional cardiovascular risk factors in multivariate analysis.
The researchers suggested further study should address three questions: (1) "Is TMA itself pathogenic or simply a marker of altered microbiome in the HIV population?" (2) Why are TMA but not TMAO levels associated with plaque burden?" (3) "What is the significance of this association with calcified versus noncalcified plaque?"
Srinivasa and coworkers proposed that their findings suggest "a potential association of choline metabolism to subclinical atherosclerosis" in people with HIV, as assessed by CCTA. They suggested that this association may reflect altered gut flora or microbial translocation unique to HIV populations. If true, that could partly explain the higher cardiovascular disease risk with HIV infection.
References
1. Srinivasa S, Fitch KV, Lo J, et al. Calcified plaque burden is associated with serum gut microbiota-generated TMA in HIV. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 138.
2. ChEBI. CHEBI:18139--trimethylamine. http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI%3A18139
3. Craig SAS. Betaine in human nutrition. Am J Clin Nutr. 2014;80:539-549. http://ajcn.nutrition.org/content/80/3/539.full
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