Development of a Quantitative Systems Pharmacology Model to Interrogate Mitochondrial Metabolism in Heart Failure

Abstract

The metabolic hallmarks of heart failure (HF) include diminished ATP hydrolysis potential and alterations in myocardial energy substrate metabolism, such as a switch in substrate utilization away from fatty acid (FA) to carbohydrate oxidation and reduced metabolic flexibility. However, the mechanisms underlying these phenomena and their potential contributions to impaired exercise tolerance are poorly understood. We developed a comprehensive quantitative systems pharmacology (QSP) model of mitochondrial metabolism to interrogate specific pathways hypothesized to contribute to reductions in reserve cardiac power output in heart failure. The aim of this work was to understand how changes in mitochondrial function and cardiac energetics associated with heart failure may affect exercise capacity. To accomplish this task, we coupled published in silico models of oxidative phosphorylation and the tricarboxylic acid cycle with a model of {beta}-oxidation and extended the model to incorporate an updated representation of the enzyme pyruvate dehydrogenase (PDH) to account for the role of PDH in substrate selection. We tested several hypotheses to determine how metabolic dysfunction, such as a decrease in PDH activity or altered mitochondrial volume, could lead to marked changes in energetic biomarkers, such as myocardial phosphocreatine-ATP ratio (PCr/ATP). The model predicts expected changes in fuel selection and also demonstrates PDH activity is responsible for substrate-dependent switch driven by feedback from NAD, NADH, ATP, ADP, CoASH, Acetyl-CoA and pyruvate in healthy and simulated HF conditions. Through simulations, we also found elevated malonyl-coA may contribute to lower PCr/ATP ratio during exercise conditions as observed in some HF patients. Key PointsO_LIExercise intolerance is a hallmark of heart failure in patients with preserved ejection fraction C_LIO_LIWe developed a quantitative systems pharmacology modeling approach with the potential to interrogate mitochondrial pathways hypothesized to contribute to exercise intolerance C_LIO_LIThe model was developed and evaluated based on simulating in vitro experimental data C_LIO_LISubstrate selection is an emergent property of the model with an increase in ATP demand resulting in a relative increase in the use of carbohydrates to fuel oxidative phosphorylation, an effect driven by feedback regulation of pyruvate dehydrogenase C_LIO_LIThe model was used to predict the potential effects of targeted perturbations to key mitochondrial pathways C_LI