Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation

Abstract

Background: There is significant interest in NO pathway modulators, specifically type 5 phosphodiesterase inhibitors (PDE5is), to treat patients with a Fontan circulation. Trials, however, have had mixed results. The relationship between the NO pathway and clinical status in patients with Fontan circulation is a significant knowledge gap.

Methods and results: We performed targeted metabolomic analysis using liquid chromatography coupled to mass spectrometry to quantify plasma NO pathway metabolite concentrations from 2 well-characterized populations of patients with Fontan circulation: the Boston Adult Congenital Heart Disease Biobank and Fontan Udenafil Exercise Longitudinal studies. We investigated associations between NO metabolite concentrations and clinical outcomes, exercise capacity, and response to PDE5is. Increased plasma concentration of asymmetric dimethyl arginine (ADMA), an inhibitor of NO production, was associated with risk for hospitalization or death. Increased ADMA and symmetric dimethyl arginine (another inhibitor of NO production) concentrations were associated with decreased baseline exercise capacity among patients with Fontan circulation with <90% predicted peak oxygen uptake, and change in ADMA and symmetric dimethyl arginine concentrations were predictive of change in exercise capacity over time. Treatment with the PDE5i udenafil uncoupled this association. Finally, baseline ADMA and symmetric dimethyl arginine concentrations predicted response to PDE5is among patients with subnormal peak oxygen uptake.

Conclusions: Plasma concentrations of metabolites that inhibit NO flux are associated with negative clinical outcomes and worse exercise capacity. Moreover, metabolite shifts over time associated with increased NO flux are associated with improved exercise capacity. In patients with a Fontan circulation, the NO pathway modulators ADMA and symmetric dimethyl arginine may be useful as biomarkers of clinical status and predictive of response to PDE5is.

Keywords: Fontan; metabolomics; nitric oxide; type 5 phosophodiesterase inhibitor.

Figure 1. Schematic depiction of the NO metabolic pathway.

ADMA indicates asymmetric dimethyl arginine; PDE5i, type 5 phosphodiesterase; and SDMA, symmetric dimethyl arginine.

Figure 2. Survival curves for individuals in BACHB cohort by tertile plasma concentrations of ADMA and SDMA.

Red: highest plasma concentration tertile for ADMA or SDMA; orange: middle tertile; green: lowest tertile. ADMA indicates asymmetric dimethyl arginine; BACHB, Boston Adult Congenital Heart Disease Biobank; and SDMA, symmetric dimethyl arginine.

Figure 3. Scatter plots depicting the relationship between baseline ADMA and SDMA and baseline exercise parameters in the FUEL cohort.

ADMA indicates asymmetric dimethyl arginine; FUEL, Fontan Udenafil Exercise Longitudinal; SDMA, symmetric dimethyl arginine; and Vo ₂, oxygen consumption.

Figure 4. Scatter plots depicting the relationship between changes in plasma concentrations of ADMA and SDMA (normalized to arginine) and in exercise parameters at baseline and at study end for both placebo and udenafil groups in the FUEL cohort.

ADMA indicates asymmetric dimethyl arginine; FUEL, Fontan Udenafil Exercise Longitudinal; and SDMA, symmetric dimethyl arginine.

Figure 5. Three‐dimensional scatter plot representing the relationship between baseline plasma concentrations of ADMA and SDMA normalized to arginine concentration, baseline peak Vo ₂ and change in peak Vo ₂ in the udenafil group in the FUEL cohort.

The 2 figures in the top row depict the distribution of data points in this analysis with baseline maximum Vo ₂ on the y axis, change in maximum Vo ₂ on the z axis and normalized ADMA and SDMA concentrations on the x axis, respectively. The color bar demonstrates a gradient of colors corresponding to the range of change in maximum Vo ₂ values throughout the figure panel. The 2 figures in the second row of the figure present the results of hyperplane equations obtained through linear regression analysis extracting the coefficient and intercept variables using the 3 variables and present them in a 3‐dimensional scatter plot of data points for ADMA and SDMA, respectively. The 2 figures in the third row of the figure build upon the hyperplane equations and demonstrate a 3‐dimensional surface plot representation of the respective hyperplanes depicting the associations and behavior of the data points. ADMA indicates asymmetric dimethyl arginine; FUEL, Fontan Udenafil Exercise Longitudinal; SDMA, symmetric dimethyl arginine; Vo ₂, oxygen consumption.