Hemodynamic load changes can affect the cardiac function by triggering adaptation mechanisms that lead to cardiac tissue remodeling. However, it has not been possible to completely dissociate preload and afterload pressures from each other or other concurrent inputs and directly connect changes caused solely by load to the remodeling observed in patients. Existing models lack the ability to simulate all four phases of the cardiac cycle, to control dynamically and independently both the preload and afterload, and to capture critical output variables of in vivo systems such as ventricular pressure-volume loops, compliance, contractility and ejection fraction. The goal of this study is to produce an in vitro system that incorporates the aforementioned properties to model simultaneously on a tissue, cellular and subcellular level the effect of hemodynamic load changes on cardiac function and the progression of ventricular cardiomyopathies as observed in vivo.I have engineered a fluid-containing micro-cardiac chamber made from human induced pluripotent stem cells that simulates a cardiac ventricle and allows direct pressure and volume measurements. I have also fabricated check valves functioning at unprecedently low pressures, that can impose unidirectional flow when actuated by the cardiac chamber and permit the independent control of the preload and afterload. Using our micro-hearts, I will evaluate the dynamic effect of independent and concurrent changes in ventricular preload and afterload on tissue morphology, contractile performance, cellular morphology, sarcomeric structure, gene expression and calcium handling. I will establish the validity of our model by demonstrating the Frank-Starling mechanism (FSM), then I will induce cardiac remodeling, aiming to recapitulate the in vivo image of cardiomyopathies. I hypothesize that hemodynamic load changes are sufficient to elicit healthy and maladaptive remodeling as observed in vivo, and that different combinations of preload and afterload lead to different cardiomyopathy types in vitro.Aim 1: Establish a 3D culture platform that models the pressure forces the myocardium experiences throughout the cardiac cycle and characterize the myocardial function under physiological hemodynamic load conditions.Aim 2: Study the myocardial response to pathologically increased loading conditions, and how it correlates to changes in cellular morphology, subcellular architecture, gene expression and calcium handling.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|