CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases

Abstract

Background: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach.

Method: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MVATP[rest]), at maximal workload (MVATP[max]), and by the myocardial ATP production reserve, representing the span between MVATP(rest) and MVATP(max).

Results: Compared with controls, in both groups of patients, MVATP(rest) was increased and MVATP(max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MVATP(max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled.

Conclusions: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03172338 and NCT04068740.

Keywords: energy metabolism; heart valve diseases; mathematical model; metabolism; proteomics.

Figures

Figure 1.

Reaction scheme of the metabolic model. Arrows symbolize reactions and transport processes between compartments. A, Glycogen metabolism, (B) glycolysis, (C) oxidative pentose phosphate pathway in the endoplasmic reticulum and cytosol, (D) nonoxidative pentose phosphate pathway, (E) triglyceride synthesis, (F) synthesis and degradation of lipid droplets, (G) tricarbonic acid cycle, (H) respiratory chain and oxidative phosphorylation, (I) β-oxidation of fatty acids, (J) ketone body utilization, (K) glutamate metabolism, (L) mitochondrial electrophysiology (membrane transport of ions), and (M) utilization of branched-chain amino acids. Small cylinders and cubes symbolize ion channels and ion transporters. Double arrows indicate reversible reactions, which, according to the value of the thermodynamic equilibrium constant and cellular concentrations of their reactants, may proceed in both directions. Reactions are labeled by the short names of the catalyzing enzyme or membrane transporter given in the small boxes attached to the reactions arrow. Metabolites are denoted by their short names. Full names and kinetic rate laws of reaction rates are outlined in Supplement S1. Full names of metabolites and a comparison of experimentally determined and calculated cellular metabolite concentrations are given in Table S1.

Figure 2.

Simulated and measured myocardial substrate uptake rates in vivo. A, Substrate uptake rates at rest and at moderate pacing (50% maxVo2). (sim) Uptake rates were computed from reported extraction rates (1 – arterial concentration/concentration in coronary sinus) putting the coronary blood flow to 0.8 mL/min/g and heart weight to 300 grams. (exp) The data points represent the means of various experimental studies.,,–,B, Dependence of the glucose uptake rate from the plasma concentration of free fatty acids (FFAs). The solid line represents model values; squares symbolize in vivo data taken from Nuutila et al.

Figure 3.

MVATP(rest) and MVATP(max) for controls and patients with mitral valve disease and aortic stenosis. A, Bottom values of the bars refer to MVATP(rest); top values refer to MVATP(max). The bar length indicates the myocardial ATP production reserve (MAPR=MVATP[max] – MVATP[rest]). B through D, Box plots showing mean values, upper and lower quartiles, and total span of MVATP(rest), MVATP(max), and MAPR for controls and patients with mitral valve insufficiency (MVI) and aortic stenosis (AS). Significant differences between the patient groups are indicated by connecting brackets with asterisks giving the significance level (*P<0.05, **P<0.01, ***P<0.001). A Bonferroni correction was applied to account for multiple testing.

Figure 4.

Contribution of energy-delivering substrates. A and B, Relative contribution of the energy-delivering substrates to total energy expenditure at MVATP(rest) and MVATP(max) for the control group for 60 minutes pacing. Areas of the pie charts represent total energy expenditure. Changes of substrate uptake rates of patients with mitral valve insufficiency (MVI) or aortic stenosis (AS) relative to controls are shown at rest (C) and during maximal pacing (D). Plots show the relative change of substrate uptake rates of glucose (blue), lactate (orange), fatty acids (yellow), and ketone bodies (purple) for patients with MVI or AS during rest and at maximal ATP production rate after 60 minutes of pacing. Relative uptake rates are normalized to control values (ie, all control values are equal to 1). Significant changes from control are indicated by asterisks (*P<0.05, **P<0.01, ***P<0.001).

Figure 5.

Correlation between tMVATP(rest) and tMVATP(max) and internal myocardial power as well as cardiac output for patients with mitral valve insufficiency or aortic stenosis. A through D, Patients with mitral valve insufficiency (MVI). E through H, Patients with aortic stenosis (AS). iMP indicates internal myocardial power; and CO, cardiac output.

Figure 6.

Metabolic characterization of 3 patients with aortic stenosis. On the left, relative substrate utilization rates are shown compared with healthy controls at rest (A) and at maximal load (C). On the right, relative contribution of the different substrates (glucose [blue], lactate [orange], fatty acids [yellow], and ketone bodies [purple]) to overall ATP production rate at rest (B) and maximal load (D) are presented. Areas of pie diagrams represent total ATP production rate.