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Mathematical modeling of the metabolic implications of the diabetic heart

Subject Area Cardiology, Angiology
Public Health, Healthcare Research, Social and Occupational Medicine
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 422215721
 
Final Report Year 2023

Final Report Abstract

Cardiac metabolism needs to adapt to short-term and long-term variations in oxygen and nutrient supply and energy demand to ensure sufficient ATP supply for proper cardiac function. Metabolic adaptation results from substrate availability, allosteric regulation, and hormonal regulation as well as protein abundance changes in the metabolic pathways and regulatory signaling pathways. Especially type 2 diabetes mellitus (DMT2) is characterized by alterations in blood plasma nutrient and hormone compositions resulting in cardiac remodeling. The associated adaptive processes can result in mitochondrial dysfunction, ATP deficiency, and impaired cardiac functionality thereby contributing significantly to cardiac dysfunction and heart failure. This project aimed to develop a computational model of the central metabolism of cardiomyocytes including carbohydrate, fatty acid, and amino acid metabolism to evaluate metabolic alterations occurring during DMT2 progression. We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism and allows the individual/personalized assessment of metabolic cardiac functionality based on proteomic data. We used the model to study the effect of a high-fat diet on cardiac metabolism and function in a high-fat diet mouse model. After 13 weeks, animals displayed a significant reduction in heart mass and deteriorated cardiac function, without developing significant weight gain or insulin resistance. Associated metabolic reprogramming of the heart was characterized by worsened cardiac carbohydrate utilization in favor of increased fatty acid utilization. While the overall ATP production capacity seemed to be decreasing, it displayed a remarkably high variability, with a tendency to increase with decreasing heart mass. Thus, metabolic adaption appears to compensate in part for the overserved loss of cardiac mass. As our work showed a close connection between reduced cardiac function and metabolic reprogramming, we assessed the relation between myocardial ATP production and cardiac workload as an important parameter for a better understanding of cardiac function. The energetic status was tightly coupled with mechanic energy demand and a decreased ATP production capacity was associated with a decreased cardiac output.

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