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Calcified Plaque Burden Is Associated With Serum Gut Microbiota-Generated TMA in HIV
Suman Srinivasa1, Kathleen V. Fitch1, Janet Lo1, Hanane Kadar2, Kimberly Wong1, Suhny Abbara3, Dominique Gauguier2, Jacqueline Capeau2, Franck Boccara2, Steven K. Grinspoon1
1 Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. 2 University Pierre & Marie Curie, Paris, France. 3 University of Texas Southwestern Medical Center, Dallas, TX, United States.
Background: Some gut microbiota-generated metabolites of phosphatidylcholine are recognized to be pro-atherogenic. The HIV population is more vulnerable to cardiovascular disease (CVD) than the general population and can develop impaired intestinal wall integrity and dysbiosis associated with inflammation. We investigated the novel relationship between microbiota-derived choline-related metabolites and coronary atherosclerosis in HIV.
Methods: 155 HIV-infected and 67 non-HIV-infected subjects without known CVD were previously recruited in a prospective study to assess coronary plaque by cardiac CT angiography. In the current study, we evaluated serum choline, trimethylamine (TMA) and trimethylamine N-oxide (TMAO) in association with plaque features and systemic inflammatory markers. A mass spectrometry-based method was designed to assay choline-related metabolites from serum. Linear regression was performed by Pearson's correlation after non-normally distributed variables were log transformed.
Results: Young, asymptomatic HIV-infected subjects(mean age 47±7 yrs, duration HIV 14±6 yrs, duration ART 8±5 yrs, CD4+ count 552± 290 cells/μl, undetectable VL 86%) demonstrated significantly higher prevalence of plaque(53 vs. 35%, P=0.01) and total plaque segments(1.8±2.5 vs. 1.2±2.2, P=0.03) when compared to well-matched non-infected subjects with similar co-morbidities. TMA was significantly associated with number of total(r=0.20, P=0.02) and calcified(r=0.18, P=0.03) plaque segments; calcium score(r=0.22, P=0.006); calcium plaque volume (r=0.19, P=0.02) and mass(r=0.22, P=0.009); and lipopolysaccharides (LPS) (r=0.19, P=0.03) in the HIV cohort only. In multivariate modeling among HIV-infected subjects, TMA remained significantly associated with number of total(P=0.005) and calcified(P=0.02) plaque segments; calcium score(P=0.008); and calcium plaque volume(P=0.01) and mass(P=0.007), independent of Framingham Risk Score (FRS). Furthermore, TMA was still an independent predictor of total plaque segments(P=0.03), calcium score(P=0.04), and calcium plaque mass(P=0.03), after controlling for FRS and LPS. In contrast, there was no association of TMAO to plaque features in either cohort.
Conclusions: TMA, a microbiota-derived precursor of TMAO, may be a non-traditional cardiovascular risk factor which has independent effects on the number of coronary plaque segments and severity of calcified plaque burden in HIV. This relationship may derive from altered gut flora or microbial translocation unique to HIV.