Date of Award
Fall 12-5-2024
Embargo Period
12-4-2029
Document Type
Dissertation - MUSC Only
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular and Cellular Biochemistry and Pathobiology
First Advisor
Donald Menick
Second Advisor
Jeffrey Jones
Third Advisor
Kristine Deleon-Pennell
Fourth Advisor
Andrew Atz
Fifth Advisor
Eric Graham
Abstract
The most severe form of congenital heart disease includes patients with single right ventricle (SRV) physiology who exhibit 40% mortality by 5 years of age. These patients are all at very high risk for heart failure. Therapies proven to be efficacious in adults do not appear to improve heart failure in SRV patients. The reason behind this disparity is unclear due to inability of investigators to assess the effects of drugs on these patients’ non-invasively. The goals of our research were to develop and validate non-invasive surrogates for contractility, afterload, and ventricular stiffness in children, then, utilize those measures to better understand these patients’ physiology, predict their outcomes, and evaluate drug effects on their cardiovascular system.
We utilized three-dimensional echocardiography and non-invasive blood pressure measurements to develop novel non-invasive assessments contractility and afterload. We validated these measurements against reference-standard measures obtained using invasive microconductance derived pressure-volume loop analysis. We utilized these measurements to assess drug effects in previous SRV clinical trials. We found that heart failure drugs, including enalapril and digoxin, did not change SRV patients’ myocardial mechanics as hypothesized, leading to negative clinical trials.
To assess diastolic function, we utilized spectral Doppler, tissue Doppler, and three-dimensional echocardiography to develop a novel non-invasive assessment of ventricular stiffness and again validated it against the reference-standard. We used this measure to perform the first identification of Fontan patients with high ventricular stiffness with preserved ejection fraction and showed their exercise tolerance was decreased compared to controls and their systolic dysfunction counterparts. We next discovered a novel Fontan phenotype, those patients’ low ventricular stiffness. We showed that these patients had worse outcomes in the post-operative period after all three palliative operations and worse exercise tolerance compared to controls.
We concluded that the non-invasive measures of cardiac mechanics we developed and validated were useful for understanding physiology, predicting outcomes, and determining drug effects in children with congenital heart disease. We utilized these measures to perform novel identifications of both a high stiffness and a low stiffness phenotype in the SRV population. Future studies should validate these phenotypes utilizing invasive assessments and tissue-based studies.
Recommended Citation
Chowdhury, Shahryar, "Invasive and Non-invasive Pressure-Volume Loop Analysis in Children with Heart Disease: Validation, Clinical Utility in Predicting Outcomes, and Heart Failure Phenotyping" (2024). MUSC Theses and Dissertations. 981.
https://medica-musc.researchcommons.org/theses/981
Rights
Copyright is held by the author. All rights reserved.