Modeling and Measurement of Pressure Overload-Induced Changes in Left Ventricular Structural and Function

Abstract

Biomechanical modeling of pressure overload-induced changes in left ventricular (LV) structure and function has the potential to make significant contributions to both basic science and clinical treatment strategies for hypertension. Hypertension affects approximately one third of the population of the United States, and in spite of increased pharmacological treatment in recent decades, it continues to lead to heart failure for tens of thousands of people per year [1]. Cardiac biomechanical analysis is still a relatively new field, having had to wait for advances in computation, medical imaging, and theoretical frameworks appropriate for describing biological soft tissues. While finite element analysis of normal left ventricular mechanics is well described in the literature [2-4], the analysis and prediction of altered mechanics in diseased states is complicated by the adaptive nature of biological tissues. Growth and remodeling of the left ventricle in response to pressure overload (hypertension) is a decades-long process of thickening and stiffening that begins as a mild adaptive response but that ultimately can lead to heart failure. The degree of hypertrophy can actually predict medical outcomes [5]. The ability to predict hypertrophy, and understand the altered mechanics that occur in a hypertrophied LV is integral to the development of mechanics-based treatment strategies for an organ that is normally an incredibly effective pump. In this dissertation, the first chapter presents relevant background information, the second chapter describes an experimental study of longitudinal changes in LV strain in hypertensive hypertrophy, and the third and fourth chapters describe a new approach to modeling load-induced hypertrophic adaptation used to assess systolic work as a potenetial mechanical growth stimulus for modeling hypertensive hypertrophy in the SHR. In Chapter 2, an FEA-based image registration technique was used to determine strain distributions in the left ventricle (LV) over the cardiac cycle. This analysis technique was applied to microPET images from hypertensive rats and normal controls over their respective lifespans, and focused on gaining a better understanding of the longitudinal changes in LV deformation behavior that occur in relation to progressive hypertrophy in the hypertensive subjects. The results of this study indicated that diastolic dysfunction preceded systolic dysfunction, and that changes in diastolic and systolic strains are related to different physiological changes. Chapter 3 describes (1) the development of a novel approach for modeling load-induced hypertrophic growth that can incorporate mechanical stimuli from throughout the cardiac cycle, and (2) a model study that uses this framework to evaluate the hypothesis that systolic work is an appropriate mechanical growth stimulus for pressure-overload hypertrophy. Growth and Remodeling (G&R) is a relatively new branch in the field of cardiac solid mechanics that seeks to model the changes in cardiac geometry that occur in response to altered or diseased mechanics. Hypertensive hypertrophy is an example of load induced cardiac adaptation in which G&R models can be applied. Prior work in this field had yielded a constitutive modeling approach to G&R and numerous computational implemetations. However a need was observed for a way to incorporate information from the whole cardiac cycle into the growth stimulus. A method was developed for predictive modeling of pressure overload-induced left ventricular growth, which can incorporate multiple mechanical stimuli from throughout the cardiac cycle. This was implemented using FEBio, an open-source finite element analysis package designed for biomechanics (FEbio.org), and a custom program called CGR ("cardiac growth and remodeling"). The model has the ability to determine the degree of hypertrophy that might occur for a given level of pressure overload (hypertension), and has the ability to create a distribution of element growth through the LV wall that is based on any measure(s) of stress or strain from the full cardiac cycle mechanics. This approach was used to assess the hypothesis that systolic work can be used as an appropriate growth stimulus for the modeling of hypertensive hypertrophy. The systolic work normalization yielded predictions of wall thickness that were realistic compared with the experimental data, indicating that systolic work may indeed be a good choice of growth stimulus for pressure overload. The fourth chapter describes a model study which quantifies the effects of changes in systolic pressure and changes in material stiffness on the systolic workload, and the resulting growth predictions. Both systolic pressure and material stiffness caused linear increases in the LV workload. Increases in the LV workload caused increases in LV wall thickness with a nonlinear which increases slope as the workload increases. The range of systolic pressures and material stiffnesses evaluated were representative of what is observed experiementally. This study quantified the effects of incremental increases in systolic work, and revealed the importance of the way the growth law is defined. Potential future extensions of this work are discussed.