Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV

Nalini A Colaco, Teresa S Wang, Yifei Ma, Rebecca Scherzer, Olga R Ilkayeva, Patrice Desvigne-Nickens, Eugene Braunwald, Adrian F Hernandez, Javed Butler, Svati H Shah, Sanjiv J Shah, Priscilla Y Hsue, Nalini A Colaco, Teresa S Wang, Yifei Ma, Rebecca Scherzer, Olga R Ilkayeva, Patrice Desvigne-Nickens, Eugene Braunwald, Adrian F Hernandez, Javed Butler, Svati H Shah, Sanjiv J Shah, Priscilla Y Hsue

Abstract

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (R=0.35; P<0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://ichgcp.net/clinical-trials-registry/NCT02860156" title="See in ClinicalTrials.gov">NCT02860156.

Keywords: HIV; diastolic dysfunction; myocardial fibrosis; transmethylamine‐N‐oxide.

Conflict of interest statement

Dr Hsue has received honoraria from Gilead and Merck, outside of the submitted work. The remaining authors have no disclosures to report.

Figures

Figure 1. Spearman rank correlation values of…
Figure 1. Spearman rank correlation values of gut metabolites, cardiac magnetic resonance measures, and biomarkers.
Correlation values of gut metabolites with MRI measures are shown in the blue box, gut metabolites with biomarkers in the red box, and MRI measures with biomarkers in the orange box. Statistically significant correlation values (P<0.05) are shaded green. ECV indicates extracellular volume; MRI, magnetic resonance imaging; NT‐proBNP, N‐terminal pro–brain natriuretic peptide; and TMAO, transmethylamine‐N‐oxide.
Figure 2. Proposed mechanism of HIV leading…
Figure 2. Proposed mechanism of HIV leading to diastolic dysfunction via TMAO and the gut.
HIV and the intestinal microbiome interact substantially, leading to gut permeability, inflammation, and immune activation and microbial translocation. TMAO is upregulated in this pathway and is associated with diffuse myocardial fibrosis, which may be a precursor to structural heart disease and diastolic dysfunction. Figure created with Biorender.com. HFpEF indicates heart failure with preserved ejection fraction; and TMAO, transmethylamine‐N‐oxide.

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