Excessive Adiposity and Metabolic Dysfunction Relate to Reduced Natriuretic Peptide During RAAS Activation in HIV

Abstract

Purpose: Natriuretic peptides (NPs) negatively feedback on the renin-angiotensin-aldosterone system (RAAS) and play a critical role in preserving cardiac structure and maintaining metabolic homeostasis. Well-treated HIV-infected individuals are at risk for fat redistribution and demonstrate evidence of RAAS dysregulation, which relates to metabolic dysfunction. We investigated circulating NPs in relation to RAAS physiology and metrics of body composition in HIV.

Methods: We assessed atrial natriuretic peptide, brain natriuretic peptide (BNP), and amino terminal pro B-type natriuretic peptide (NT-proBNP) during acute activation of the RAAS using a low-sodium controlled diet among 20 HIV-infected and 10 non-HIV-infected individuals well phenotyped for body composition.

Results: BNP was significantly lower [median, 60 (interquartile range, 44, 152) pg/mL vs 196 (91, 251) pg/mL, respectively; P = 0.04], and serum aldosterone was higher, among HIV-infected than among non-HIV-infected individuals. BNP was significantly and inversely associated with body composition [waist circumference: r = -0.46 (P = 0.04); BMI: r = -0.55 (P = 0.01); body adiposity index: r = -0.49 (P = 0.03)], metabolic indices [total cholesterol: r = -0.44 (P = 0.05), insulin resistance calculated by using homeostatic model assessment: r = -0.44 (P = 0.05); mean arterial pressure: r = -0.44 (P = 0.05)], and serum aldosterone (r = -0.49; P = 0.03) among the HIV-infected group. These relationships were not demonstrated in the non-HIV-infected group. In a four-group comparison stratifying by HIV serostatus and above or below a body mass index (BMI) of 25 kg/m2, BNP decreased significantly across groups; it was highest in non-HIV-infected patients with a BMI <25 kg/m2 and lowest in HIV-infected patients with a BMI ≥25 kg/m2 (overall P = 0.01).

Conclusion: Relatively reduced NP, particularly BNP, among HIV-infected individuals with excess adiposity may contribute to reduced suppression of aldosterone and potentially drive aldosterone-mediated metabolic complications. Strategies that target RAAS blockade and/or augment NPs may be useful to reduce cardiometabolic disease among HIV-infected individuals in whom these systems are perturbed.

Trial registration: ClinicalTrials.gov NCT01407237.

Figures

Figure 1.

Hypothesized mechanisms of metabolic dysfunction via inappropriate cardiac natriuretic peptide feedback among HIV-infected individuals. HIV-infected individuals with a clinical phenotype of excessive adiposity demonstrate increased aldosterone during an RAAS-activated state. BNP is a negative regulator of RAAS. Dysfunctional adipose tissue is highly inflamed and may be linked to upregulation of NPR-C. When bound to NPR-C, BNP is degraded and cleared. Relatively lower BNP may permit an exaggerated increase in aldosterone and could be detrimental to preventing metabolic dysfunction. Appropriate BNP response among individuals with healthy adipose tissue may contribute to maintenance of metabolic homeostasis through physiologic suppression of aldosterone. Triangular structures represent NPR-C and star-like structures represent the inflammatory milieu.

Figure 2.

Relationship between BNP (pg/mL) and measures of body composition [iliac waist circumference (cm), BMI (kg/m2), and BAI (%fat)] among HIV-infected individuals (a–c) and non–HIV-infected individuals (d–f) during the RAAS-activated state. Data were analyzed by using Pearson correlation coefficient and are represented here as linear regression.

Figure 3.

Comparison of BNP (pg/mL) during the RAAS-activated state among HIV-infected and non–HIV-infected individuals stratified by above and below overweight BMI. P value reported is based on the appropriate statistical test applied to the log-transformed values.