Author ORCID Identifier

https://orcid.org/0009-0008-4955-254X

Date Available

5-11-2023

Year of Publication

2023

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Engineering

Department/School/Program

Mechanical Engineering

Advisor

Dr. Jonathan F. Wenk

Abstract

The heart functions within a complex system that adapts its function to any alteration in loading via several mechanisms. For example, the baroreflex is a short-term feedback loop that modulates the heart's function on a beat-to-beat basis to control arterial pressure. On the other hand, cardiac growth is a long-term adaptive response that occurs over weeks or months in response to changes in left ventricular loading. Understanding the mechanisms that drive ventricular growth and biological remodeling is critical to improving patient care. Multiscale models of the cardiovascular system have emerged as effective tools for investigating G&R, offering the ability to evaluate the effects of molecular-level mechanisms on organ-level function.

This dissertation presents MyoFE, a multiscale computer model that simulates the left ventricle (LV) pumping blood around a systemic circulation by bridging from molecular to organ-level mechanisms. The model integrates a baroreflex control of arterial pressure using feedback to regulate heart rate, intracellular Ca2+ dynamics, the molecular-level function of both the thick and thin myofilaments, and vascular tone. MyoFE is extended via a growth algorithm to simulate both concentric growth (wall thickening / thinning) and eccentric growth (chamber dilation / constriction). Specifically, concentric growth is controlled by the time-averaged total stress over the cardiac cycle, while eccentric growth responds to time-averaged intracellular myofiber passive stress.

Our integrated model replicated clinical measures of left ventricular growth in two types of valvular diseases - aortic stenosis and mitral regurgitation - at two different levels of severity for each case. Furthermore, our results showed that incorporating the effects of baroreflex control of arterial pressure in simulations of left ventricular growth not only led to more realistic hemodynamics, but also impacted the magnitude of growth. Specifically, our results highlighted the role of regulating venous compliance (vasoconstriction) by the baroreflex immediately after the onset of valvular diseases, which has a significant role on the extent of LV growth in the long term.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.216

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