The heart is energetically one of the most expensive organs. One-third of the cellular volume of cardiac myocytes is occupied by mitochondria. Per gram tissue, the heart has the highest oxygen consumption rate and the ATP turnover during one day amounts to 20 times its weight. This requires a robust and high rate of ATP production to maintain cardiac functionality. ATP is spent on electrophysiological processes of ion pumping as well as on mechanical work in its contractile apparatus. Perturbations in ATP-generating processes may therefore directly affect contractile function. The heart can rely on any energy source available like carbohydrates, amino acids, lipids, and ketone bodies. Under normal conditions, oxidation of free fatty acids is the prevailing energy source contributing around 70% to ATP production rate, while the utilization of glucose becomes increasingly important during ischemia, hypoxia, or increased workload. The use of different substrates is tightly regulated under physiological conditions and there is ample crosstalk between the different metabolic pathways.

Kinetic modeling of cardiac metabolism has a long tradition starting in the late 70s, but all of the available models neglect crucial factors determining the energetic status of the heart, such as the influence of alternating substrate supply, hormonal metabolic control, or variable gene expression of key metabolic enzymes necessary for the understanding of metabolic alterations in heart disease. In this work, we developed a kinetic multi-pathway model for cardiomyocytes with hitherto unprecedented scope and level of detail [1]. The model includes the regulation of enzyme activities by allosteric effectors, hormone-dependent reversible phosphorylation, and variable protein abundances. For each enzyme, rate equations have been developed that take into account the enzyme’s kinetic and regulatory features determined by decades of biochemical research. We use the model to analyze proteomic data obtained from patients with valve disease. We show that ATP production capacity is significantly diminished in patients and correlates with mechanic energy demand. However, there are large differences in the energetic state of the myocardium even between patients with similar clinical and imaging-based hypertrophy and functional markers.

Publications:

1. Berndt N, Eckstein J, Wallach I, Nordmeyer S, Kelm M, Kirchner M, Goubergrits L, Schafstedde M, Hennemuth A, Kraus M, Grune T, Mertins P, Kuehne T, Holzhütter HG. CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases. Circulation. 2021 Dec 14;144(24):1926-1939.

Project funding: This project is funded by the German Research Foundation (DFG) (grant no. 422215721) and by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU initiative ERA PerMed „Personalised Medicine: Multidisciplinary Research towards Implementation" (grant no. 01KU2011A, „HeartMed“).

Cooperation partners:

• Hermann-Georg Holzhütter (Charité, Institute of Biochemistry, Computational Systems Biochemistry Group)
• Titus Kühne (Charité, Institute of Computer-assisted Cardiovascular Medicine)
• Philipp Mertins (Max Delbrück Center for Molecular Medicine, Proteomics)

For proper functionality, the heart relies on coordinated utilization of different energy-providing substrates like glucose, fatty acids, glycogen, and lactate. Depending on substrate availability and energy demand, the heart needs to adapt its internal energy delivering pathways to ensure demand-matching energy supply. In pathological situations like aortic stenosis (AS), the efficiency of cardiac muscle activity is disturbed and maladaptation might lead to metabolic alterations contributing to declined cardiac function. Experimental assessment of cardiac energy metabolism is not possible due to ethical and technical restrictions.

In this project, we present a detailed, comprehensive, biochemistry-based kinetic model of the central cardiac metabolism including the regulation of enzymes by kinetic allosteric and hormonal regulation [1]. We show the ability of the model to investigate substrate utilization under different conditions. We use the model to investigate the alterations in cardiac energy metabolism in a cohort of patients with AS and mitral valve insufficiency (MVI).

The figure depicts the specific energetic parameters myocardial ATP consumption at rest (MV_ATP(rest)), at maximal workload (MV_ATP(max)), and the myocardial ATP production reserve (MAPR) for individual patients. Compared with controls, the individual variations of these parameters were much larger for the two patient groups (see box plots B-D). For patients with MVI, the mean value of the parameter MV_ATP(rest) was significantly higher, whereas MV_ATP(max) was significantly lower when compared with control values. For patients with AS, the mean value of the parameter MV_ATP(rest) was also significantly higher and MV_ATP(max) was also significantly lower. For both groups of patients, the parameter MAPR was on average significantly lower compared with the controls. Hence, both groups of patients had on average a reduced ATP production reserve, which was caused by increased MV_ATP(rest) and decreased MV_ATP(max).

Publication:

1. Berndt N, Eckstein J, Wallach I, Nordmeyer S, Kelm M, Kirchner M, Goubergrits L, Schafstedde M, Hennemuth A, Kraus M, Grune T, Mertins P, Kuehne T, Holzhütter HG. CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases. Circulation. 2021 Dec 14;144(24):1926-1939.

Project funding: This project is funded by the German Research Foundation (DFG) (grant no. 422215721) and by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU initiative ERA PerMed „Personalised Medicine: Multidisciplinary Research towards Implementation" (grant no. 01KU2011A, „HeartMed“).

Cooperation partners:

• Hermann-Georg Holzhütter (Charité, Institute of Biochemistry, Computational Systems Biochemistry Group)
• Titus Kühne (Charité, Institute of Computer-assisted Cardiovascular Medicine)
• Philipp Mertins (Max Delbrück Center for Molecular Medicine, Proteomics)

Diabetes mellitus is an epidemically growing disease worldwide having an overall prevalence of 9.8% in Germany in 2015, with the vast majority of cases (9.5%) attributable to type2 diabetes mellitus. Heart failure, the most common cardiovascular disease associated with diabetes, is a clinical syndrome in which myocardial pump function is inadequate for maintaining and supporting an individual’s physiological requirements. Heart failure in a patient with diabetes may arise from myocardial damage resulting from an ischemic, thrombotic event. In many cases, however, heart failure cannot be attributed to any cardiovascular disease, such as hypertension or coronary artery disease.

Adaptive processes start often at the cellular level with changes in signaling and metabolic pathways, typically evolving to changes in the structural organization of the tissue as, for example, enhanced formation of extracellular matrix (fibrosis) and finally resulting in alterations of functional parameters such as the cardiac output. A major problem in the treatment of cardiovascular diseases consists in the poor predictability of the responses that are potentially elicited by medical intervention, whether it is dietary, pharmacologically, or surgically. In the worst case, treatment-induced adaptive changes can even exacerbate the pathological situation. A promising approach to overcome this dilemma consists of the use of mathematical models, which integrate existing knowledge on central molecular and physiological circuits operative at the cellular levels and provide reliable predictions of the heart's functional capacity and performance in response to intervention.

The goal of this project is to systematically investigate the metabolic and functional changes associated with the diabetic heart. To this end, we developed, tested, and verified a computational model of cardiac energy metabolism [1]. The main objective is to understand the short- and long-term metabolic adaptations of cardiomyocytes and the functional metabolic changes arising from changes in metabolic enzyme abundance and signaling pathways in dependence on external substrate supply, hormonal stimuli, and internal demand.

Publication:

1. Berndt N, Eckstein J, Wallach I, Nordmeyer S, Kelm M, Kirchner M, Goubergrits L, Schafstedde M, Hennemuth A, Kraus M, Grune T, Mertins P, Kuehne T, Holzhütter HG. CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases. Circulation. 2021 Dec 14;144(24):1926-1939.

Project funding: This project is funded by the German Research Foundation (DFG) (grant no. 422215721).

Cooperation partner:

• Hermann-Georg Holzhütter (Charité, Institute of Biochemistry, Computational Systems Biochemistry Group)
• Tilman Grune (German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE)/Dept. of Molecular Toxicology)

Obesity is a major contributing feature of heart failure with preserved ejection fraction (HFpEF) and is known to stimulate chronic low-grade inflammation. Cells respond to inflammatory stimuli with the reprogramming of their posttranslational modification pathways and activation of protein ISGylation [1]. This project pursues the hypothesis that chronic inflammation in cardiometabolic HFpEF provokes a metabolic adaptation of the heart possibly through the activation of the ISG15 machinery. By combining system biochemistry with computational metabolic modeling [2], this project will investigate the metabolic alterations occurring in the heart and define how the ISG15 system intersects with the regulation of cardiac metabolic capability in HFpEF.

Publications:

1. Kespohl M, Bredow C, Klingel K, Voß M, Paeschke A, Zickler M, Poller W, Kaya Z, Eckstein J, Fechner H, Spranger J, Fähling M, Wirth EK, Radoshevich L, Thery F, Impens F, Berndt N, Knobeloch K-P, Beling A. Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming. Science Advances. 2020 Mar 11;6(11):eaay1109.
2. Berndt N, Eckstein J, Wallach I, Nordmeyer S, Kelm M, Kirchner M, Goubergrits L, Schafstedde M, Hennemuth A, Kraus M, Grune T, Mertins P, Kuehne T, Holzhütter HG. CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases. Circulation. 2021 Dec 14;144(24):1926-1939.

Project funding: This project is funded by the DFG (German Research Foundation) – SFB-1470 – A08.

Cooperation partner: Antje Beling (Charité, Institute of Biochemistry, Lab Cardiac Infection Biology and Immunology