Circulating biomarker correlates of left atrial size and myocardial extracellular volume fraction among persons living with and without HIV

Abstract

Background: Infection with human immunodeficiency virus (HIV) is associated with higher risk for myocardial disease despite modern combination antiretroviral therapy (cART). Factors contributing to this excess risk, however, remain poorly characterized. We aimed to assess cross-sectional relationships between elevations of left atrial volume index (LAVI) and myocardial extracellular volume (ECV) fraction that have been reported in persons living with HIV and levels of circulating biomarkers of inflammation, fibrosis, and myocyte stretch among persons living with and without HIV (PLWH, PLWOH).

Methods: Participants from three cohorts of PLWH and PLWOH underwent cardiovascular magnetic resonance imaging for measurement of LAVI and ECV. Levels of circulating proteins (IL-6, sCD14, galectin-3, NT-proBNP, GDF-15, TIMP-2, MMP-2, and hsTnI) were measured using immunoassays. Associations were assessed using logistic and linear regression, adjusting for demographics, substance use, and clinical characteristics.

Results: Among 381 participants with and without HIV, median age (IQR) was 55.1 (51.2, 58.4) years, 28% were female, 69% were Black, and 46% were current smokers. Sixty-two percent were PLWH (n = 235), of whom 88% were receiving cART and 72% were virally suppressed. PLWH had higher levels of sCD14 (p = < 0.001), GDF-15 (p = < 0.001), and NT-proBNP (p = 0.03) compared to PLWOH, while levels of other biomarkers did not differ by HIV serostatus, including IL-6 (p = 0.84). Among PLWH, higher sCD14, GDF-15, and NT-proBNP were also associated with lower CD4 + cell count, and higher NT-proBNP was associated with detectable HIV viral load. NT-proBNP was associated with elevated LAVI (OR: 1.79 [95% CI: 1.31, 2.44]; p < 0.001) with no evidence of effect measure modification by HIV serostatus. Other associations between HIV-associated biomarkers and LAVI or ECV were small or imprecise.

Conclusions: Our findings suggest that elevated levels of sCD14, GDF-15, and NT-proBNP among PLWH compared to PLWOH observed in the current cART era may only minimally reflect HIV-associated elevations in LAVI and ECV. Future studies of excess risk of myocardial disease among contemporary cohorts of PLWH should investigate mechanisms other than those connoted by the studied biomarkers.

Keywords: Extracellular volume fraction; Fibrosis; Human immunodeficiency virus; Inflammation; Left atrial volume; Myocardial disease.

Fig. 1

Adjusted associations between biomarkers of inflammation, fibrosis, and myocyte stretch that differed by HIV serostatus and cardiac structural characteristics (ECV and LAVI), overall and by HIV serostatus. Odds ratio and 95% confidence interval for high left atrial volume index (≥ 40 mL/m²) and high extracellular volume fraction (≥ 30% among women and ≥ 28% among men) are reported per standard deviation increment in biomarker, estimated using logistic regression adjusting for HIV serostatus, age, sex, race/ethnicity, education level, history of cardiovascular disease, systolic blood pressure, blood pressure-lowering therapy, dyslipidemia, diabetes, pack-years of smoking in 5 years preceding CMR, and hazardous alcohol use in 5 years preceding CMR. Null hypothesis is that odds ratio = 1. Interaction p-value is for a multiplicative interaction parameter, biomarker × HIV serostatus, used to assess effect measure modification. ECV = extracellular volume; LAVI = left atrial volume index; PLWH = persons living with HIV; PLWOH = persons living without HIV; sCD14 = soluble cluster of differentiation 14; GDF-15 = growth differentiation factor 15; NT-proBNP = N-terminal prohormone of brain natriuretic peptide