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Right Ventricular Biomechanics in Pulmonary Hypertension

Sharifikia, Danial (2021) Right Ventricular Biomechanics in Pulmonary Hypertension. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Sharifikia, Danialdas313@pitt.edudas313
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairSimon, Marcsimoma@upmc.edu
Committee CoChairKim, Kangkangkim@upmc.edu
Committee MemberAbramowitch, Stevensdast9@pitt.edu
Committee MemberMaiti, Spandanspm54@pitt.edu
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 2021 16:50
URI: http://d-scholarship.pitt.edu/id/eprint/39807

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