An Investigation of Reverse Remodeling Phenomena in Engineered Heart Tissues

Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Campbell, Stuart

Abstract

Reverse remodeling is a myocardial recovery process of the failing heart often seen in advanced heart failure patients after left ventricular assist device (LVAD) implantation. In most cases, LVADs serve either as a short-term bridge-to-transplantation therapy or as a long-term destination treatment. Interestingly, over time, many patients experience variable degree of recovery. In some rare cases, patients are able to achieve significant functional and structural recovery to qualify for LVAD explantation and go into heart failure remission. Despite these findings, there is currently limited knowledge on why only a small subset of patients respond to LVAD and undergoes reverse remodeling, and there is no consensus on the optimal medication regime that might enhance this beneficial recovery. We undertook a series of studies to first optimize an in vitro myocardial tissue model and then to use this model for systematic investigation of remodeling phenomena. Engineered heart tissues (EHTs) formed from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) formed the basis for our studies. Knowing the immaturity of hiPSC-CMs after differentiation, we undertook to develop a simple and generalizable protocol to accelerate tissues’ functional maturation. We find that physiological-level Ca2+ combined with continuous ramp pacing can provide accelerated functional improvements to EHTs’ peak force, twitch kinetics, calcium handling, and adrenergic response to isoproterenol in two different cell lines. Moreover, during optimization of the EHT production process, we discovered that decellularized pork tenderloin has more consistent passive mechanic properties, similar active mechanics, and comparable ECM protein compositions to the porcine left ventricle. These findings make tenderloin a good alternative tissue scaffold material. Using our EHTs made of decellularized porcine left ventricular scaffolds, we found that myofilament-based active contractions play an important role in reverse remodeling. Using cardiac specific modulators, we discover the lack of functional reverse remodeling when sarcomeric contractions are inhibited. Along with modulation of cardiac fibroblast activities, we demonstrate that instead of simply providing beat-to-beat cardiac output, cardiomyocytes are essentially in driving the passive extracellular matrix (ECM) remodeling of the tissues by cardiac fibroblasts in a long-term time scale. Moreover, knowing the role active contractions play in reverse remodeling, we carefully compared two novel sarcomeric activators danicamtiv (DAN) and omecamtiv mecarbil (OM) in late-stage clinical trials to find the more suitable one to enhance the recovery. Through acute drug administration and dose response studies, the results show that DAN offers more systolic benefits at less diastolic cost than OM while OM offers a longer force-time integral for each contraction and may help accelerate reverse remodeling. This discovery motivated us to further establish the in vitro reverse remodeling model with hiPSC-CMs and human adult cardiac fibroblasts. We demonstrate that, tissues treated with OM achieve significantly improved recovery in terms of both passive and active mechanics. In the final chapters, we identify a potentially more beneficial mode of administration of OM. With this new strategy, tissues with both healthy control cells and cells of a mutant dilated cardiomyopathy line exhibit improved systolic function at minimal diastolic cost. This presents a potential new option to improve clinical outcomes for OM and similar sarcomeric activators. Furthermore, discussions on the implications of this study and perspectives in the myocardial reverse remodeling context are presented.

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