Sharifikia, Danial
(2021)
Right Ventricular Biomechanics in Pulmonary Hypertension.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Pulmonary hypertension (PH) is a disease resulting in increased right ventricular (RV) afterload, myocardial hypertrophy and ventricular remodeling. RV failure remains the main cause of mortality for nearly 70% of PH patients, with 33-38% mortality rates 3 years post-diagnosis. RV biomechanics has been closely linked to physiological function. From a biomechanical perspective, pressure overloaded RV myocardium experiences increased wall thickness, fiber remodeling and increased stiffness to restore the cardiac output.
Despite the development of multiple therapeutics for management of PH, lung transplantation remains the only curative treatment. Moreover, age-related differences exist in the survival rates of PH patients and although the current evidence suggests an association between PH and aging, limited data exist on age-associated differences in RV biomechanical properties.
A major biomechanical remodeling event experienced by the pressure overloaded RV is the reorientation of myofibers forming the RV tissue, which results in altered biomechanical properties and function. However, RV wall thickness in human patients and large animal models complicates the study of fiber reorientation throughout the RV thickness, mainly due to the limited imaging depth of current modalities such as confocal or multi-photon microscopy.
In this work, we aimed to evaluate the effects of a novel dual-acting heart failure therapeutic (Sacubitril/Valsartan) on RV remodeling in PH. Additionally, we analyzed the effects of aging on RV structure and biomechanics. Moreover, an ultrasound image processing framework, coupled with computational models, was utilized to study the effects of different loading scenarios on the reorientation patterns of RV myofibers.
Our results showed that Sacubitril/Valsartan has the potential to prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen and myofiber re-orientation as well as RV stiffening both at the tissue and myofiber-level. Additionally, our findings demonstrated the potential of healthy aging to modulate RV remodeling via increased peak pressures, cardiomyocyte loss, fiber reorientation, and altered collagen/myofiber stiffness. The developed ultrasound imaging framework effectively characterized the transmural orientation of RV myofibers. Computational models demonstrated that chronic pressure overload, but not solely an acute rise in pressures, results in kinematic shift of RV fibers towards the longitudinal direction.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 January 2021 |
| Date Type: |
Publication |
| Defense Date: |
30 October 2020 |
| Approval Date: |
26 January 2021 |
| Submission Date: |
21 October 2020 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
154 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Right Ventricle; Biomechanics; Pulmonary Hypertension; Sacubitril/Valsartan; Aging; Fiber Orientation; Finite Element Modeling |
| Date Deposited: |
26 Jan 2021 16:50 |
| Last Modified: |
26 Jan 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39807 |
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