Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease

Figures

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  Figure 1. Results from age‐ and sex‐ adjusted linear regression between metabolites and multibeat E es/E a in the discovery cohort. A, β‐coefficients with 95% CI for metabolites with P value <0.05. B, Manhattan plot illustrating –log (P value) for metabolites separated by metabolic pathway. E es/E a indicates end‐systolic elastance/arterial elastance; and TCA, tricarboxylic acid.

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  Figure 2. Results from age‐ and sex‐adjusted linear regression between metabolites and SV/ESV in the validation cohort. A, β‐coefficients with 95% CI for TCA cycle metabolites with q value <0.05. B, Manhattan plot illustrating –log (q value) separated by metabolic pathway, with TCA cycle metabolites in red. SV/ESV indicates stroke volume/end‐systolic volume; and TCA, tricarboxylic acid.

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  Figure 3. Results from age‐ and sex‐adjusted linear regression between metabolites and TAPSE/PASP in validation cohort. A, β‐coefficients with 95% CI for TCA cycle metabolites with q value <0.05. B, Manhattan plot illustrating –log (q value) separated by metabolic pathway, with TCA cycle metabolites in red. TAPSE/PASP indicates tricuspid annular plane systolic excursion/pulmonary artery systolic pressure; and TCA, tricarboxylic acid.

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  Figure 4. Venn diagram illustrating overlap in metabolites associated with E es/E a, SV/ESV, and TAPSE/PASP in linear regression. Fifteen metabolites significantly associated with all 3 coupling metrics are listed. E es/E a indicates end‐systolic elastance/arterial elastance; SV/ESV, stroke volume/end‐systolic volume; and TAPSE/PASP, tricuspid annular plane systolic excursion/pulmonary artery systolic pressure.

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  Figure 5. Results from PLS‐DA of inferred metabolic flux from RV transcriptomics (N=34). A, Model discrimination of clinically defined RV functional states. Colored point clouds represent different RV functional states. B, VIP plot illustrating relative importance of each metabolic reaction contributing to class separation by component 1, with higher values reflecting greater contribution. Colored boxes to the right represent the relative metabolic flux of each reaction across the 3 RV functional states. PLS‐DA indicates partial least squares discriminant analysis; RV, right ventricle; and VIP, variable importance in projection.

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  Figure 6. Results from PLS‐DA of inferred metabolite balance from RV transcriptomics (N=34). A, Model discrimination of clinically defined RV functional states. Colored point clouds represent different RV functional states. B, VIP plot illustrating relative importance of each metabolite contributing to class separation by component 1, with higher values reflecting greater contribution. Colored boxes to the right represent the relative balance of each metabolite across the 3 RV functional states. PLS‐DA indicates partial least squares discriminant analysis; RV, right ventricular; and VIP, variable importance in projection.