Background: HIV-infected individuals are at increased risk for atherosclerosis. The underlying mechanisms may include alterations in gut microbial flora, leading to immune activation. Trimethylamine-N-oxide (TMAO) is metabolized by intestinal microbiota from dietary lipids. In uninfected persons, TMAO levels are associated with cardiovascular events. The objective of this study was to investigate factors associated with TMAO and determine if TMAO is associated with subclinical atherosclerosis in HIV-infected individuals.
Methods: TMAO levels in 83 HIV-infected individuals were compared to an external cohort of uninfected individuals referred for cardiac catheterization for suspected coronary artery disease (CAD) from Tang et al (NEJM 2013; 368:1575-1584). Carotid intima-media thickness (IMT) was assessed using high resolution ultrasound. Multivariable analysis was performed to identify the relationship between TMAO and mean IMT.
Results: Compared to controls, the HIV group was younger (50 ± 10 vs 63 ± 11 yrs), primarily male (94% vs 64%), and had lower rates of DM (11% vs 32%) and HTN (46% vs 72%). Nearly 75% of the HIV cohort were on anti-retroviral therapy (ARVs). Median TMAO level in the HIV cohort was 3.7 µM (IQR 2.5-6.3), which was identical to that in uninfected controls with CAD (3.7, IQR 2.4-6.2). In adjusted analysis, age, cigarette smoking, triglycerides, and current ARV use were independently associated with higher TMAO levels in the HIV group. Viral load and CD4 count were not associated with TMAO levels. The mean carotid IMT was 0.105 ± 0.035 mm in HIV-infected individuals. TMAO per doubling was associated with 9% greater mean carotid IMT in univariate analysis (p=0.002), but the association weakened in the adjusted model (+4%, p=0.14). Age, Latino/Asian race, HTN, cigarette smoking, total cholesterol, and lipodystrophy were also associated with greater IMT.
Conclusions: Despite being younger and having fewer traditional risk factors, HIV-infected patients had similar TMAO levels as uninfected individuals with CAD. While viral load and CD4 count were not predictive of higher TMAO levels, current ARV use was. In conclusion, these results suggest that TMAO levels are elevated and may be associated with mean carotid IMT in HIV-infected individuals. Future studies will need to establish whether these elevated circulating TMAO levels in HIV patients are associated with an increased risk of cardiovascular events.