Systems Physiology

To maintain energy homeostasis, blood flow in the heart is tightly intertwined with mechanics via multiple interactive pathways. As a result, the mechanisms governing these pathways is not well-understood. Therefore, we will develop a predictive, computational framework that encodes the primary system elements responsible for maintaining homeostasis within the myocardium to develop a deeper understanding of the heart’s energy demand-production-supply feedback system. This multiscale framework will include organelle physiology and scale up to whole organ physiology.

Much of the available evidence points towards metabolic signals that underly the system response to perturbations that press against homeostatic mechanisms. For example, oxidative stress caused by mitochondria disrupt the vasoactive components that impairs blood supply and forces the system into a vicious cycle. To elucidate how such phenomenon contribute to the heart’s mechanical function, we will evaluate this and other concepts using novel experimental data spanning biological spatial scales to challenge a predictive computer model. By doing so, we will have identified the major contributing mechanisms that influence the system behavior.

This work, including the developed code, will be publicly available and entails the following aims. First, we will develop a computational model that integrates mechanistic descriptors of mitochondrial energetics with coronary blood flow regulation and multiscale tissue mechanics. This will elucidate the coupling between cardiac mechanics, metabolism, and blood flow regulation. Second, we will perform experiments to calibrate and validate the model. We will then use this model to identify the causal relationships between microvasculature function and mitochondrial energetics. Third, we will apply the model to characterize the system response to a multitude of perturbations to investigate essential feedback loops that control energy supply and demand in the myocardium. As a result, we will gain a complete picture of the fundamental mechanisms that govern cardiac metabolic and functional homeostasis.