Mechanism of Exercise Intolerance in Heart Diseases Predicted by a Computer Model of Myocardial Demand-Supply Feedback System

Abstract

The myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. To investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply system where myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility (𝐸 !" ) in a feedback system was developed. We demonstrated that the framework can recapitulate key features found during exercise in clinical and animal studies. Specifically, the framework predicts that the increase in pressure-volume loop area (PVA) and heart rate (HR) arising from an increase in 𝐸 !" during exercise dilates the coronary vessels and increases the blood flow (𝑄# #!$ ), which in turn, further increases myocardial work rate until a stable equilibrium is achieved. We showed that the reduction in coronary flow reserve (CFR) during exercise is the result of a simultaneous increase in 𝑄# #!$ and the decrease in fullyvasodilated coronary blood flow. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in HR is necessary to maintain the baseline cardiac output. Correspondingly, the resting CFR is exhausted and the range of HR before exhaustion of CFR is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of CFR.

Keywords: Exercise, left ventricular function, coronary perfusion, flow regulation, computational modeling