Elucidating the myocardial energy demand-supply-production feedback system

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The heart’s function is determined by the close interaction between the energy demanded by mechanical and electrical work with the energy supplied by metabolism. Metabolism in the heart requires the transport of oxygen in blood vessels embedded in the heart tissue. Since the heart consumes nearly all the oxygen in its blood supply, it signals to the blood vessels to dilate and increase blood flow and oxygen delivery. While the basics of these processes are known, the critical feedback loops required to keep the system working at an optimal level are unresolved. This project will use advanced engineering, modeling and experimental techniques to understand how the heart regulates its function and maintains adequate blood flow during physiology conditions and during stress in physiologically impaired conditions. This project will impact society by exposing high school, undergraduate, and graduate students to engineering, computational, cardiovascular principles; lead to the development of a new course that bridges engineering and physiology; and recruit from underrepresented populations to improve equity. In the end, this project will help motivate a new generation of STEM students for the betterment of society.The heart is a well-designed system capable of matching energy demand with energy production and energy supply. Specifically, cardiac pump function inherently depends on energy (in the form of adenosine triphosphate, ATP) produced by the mitochondria, which in turn depends on the transport of oxygen in the coronary vasculature that is embedded and envelopes the cardiac tissue. Perfusion in the coronary vasculature, however, is affected by mechanical contraction of the heart in addition to cardiac-coronary signaling mechanisms. As such, the heart is a closed-feedback loop system. The components of this system each possess unique, and in some cases, general feedback mechanisms that operate in a coordinated fashion. While great effort has gone into studying each of these system components in isolation, we lack the necessary insight to piece together how each component is wired and interacts with each other when integrated together. In response, this project will combine advanced computational modeling and experimental validation studies to elucidate the feedback mechanisms governing the heart’s ability to regulate its function under physiological and pathological conditions. The project will first elucidate the primary coupling factors associated with cardiac mechanics, metabolism, and blood flow regulation using a multiscale computational model. Next, the relationship between microvascular function and mitochondrial energetics will be resolved. Finally, the model will be validated using a variety of hemodynamic perturbations using data acquired from healthy and diseased animal models. Overall, this project will help further our collective understanding on the feedback mechanisms operating in the healthy and diseased heart.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.