HIV infection is associated with an increased risk of myocardial infarction (MI); however, the pathophysiology is incompletely understood. HIV alters the gut microbiome. Choline, carnitine, betaine, and trimethylamine N-oxide (TMAO), are small molecules that are metabolized or produced by the gut microbiome and TMAO is associated with MIs among adults without HIV. We have shown that carnitine and betaine are independently associated with carotid artery intima-media thickness in HIV-infected subjects, but TMAO and choline are not. We assessed the hypothesis that these gut microbiota-associated small molecules are independently predictive of MI in HIV-infected adults.
This was a nested case-control study of HIV-infected individuals with suppressed viral load (VL) on antiretroviral therapy (ART) within the US based 8-site CNICS network. The cases had adjudicated and confirmed Type 1 MI from 2001-2012. The controls were matched by incidence density sampling to each case by calendar time, age, gender, race, duration of VL suppression, and CD4 count. Plasma levels of TMAO, Betaine, Carnitine, and Choline were measured at Cleveland Clinic using stable isotope dilution liquid chromatography tandem mass spectrometry. Plasma samples for cases and controls were collected prior to the event date. Associations between the small molecules and MI were assessed using conditional logistic regression.
There were 36 cases and 69 controls. The median age was 49 years (46, 58) and 77% were male. The median time of VL suppression was 3 months (1, 5) and the median CD4 count was 562 cells/mm3 (381, 809). The two groups had similar proportion of hypertension, T2DM, and active smoking. Cholesterol levels were similar as well but the cases had higher median triglycerides (184 mg/dL vs 146 mg/dL, p=0.05). After adjusting for triglycerides, elevated carnitine levels were strongly associated with MI (OR=4.95 for the top quartile (>33 µM) versus quartiles 1-3; (95% CI [1.29, 18.95], p=0.02, see Table). The other small molecules did not have a significant association with MI. Cholesterol and triglyceride levels as well as smoking were not associated with carnitine levels.
Carnitine is independently predictive of MI in treated and suppressed HIV-infected individuals and appears to be independent of TMAO. This finding suggests that the mechanism of atherosclerosis in HIV is distinct from uninfected individuals and unique interventions may be indicated in HIV to reduce CV risk.