Author ORCID Identifier
https://orcid.org/0000-0001-5547-2441
Date Available
10-28-2025
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Physiology
Faculty
Kenneth S. Campbell
Abstract
Heart failure has diverse underlying etiologies, complicating research. While some types, like ischemic disease or inherited mutations, are well-studied, research on rarer forms has lagged. Understanding the molecular drivers in these populations may enhance diagnostics and therapies. This work examines two rare groups: patients with ATTR cardiac amyloidosis and those receiving mechanical assist device support. We show that myocardium from patients with amyloidosis has increased fibrosis and reduced force production without changes in cross-bridge kinetics. Additionally, we show that the passive stiffness of amyloidosis myocardium is not different from non-failing myocardium, indicating increased ventricular wall thickness may cause restrictive filling. Lastly, we show decreased phosphorylation of troponin I (TnI) and myosin binding protein-C (MyBPC). We also examined samples from patients before and after mechanical assist device implantation to assess unloading's impact on the myocardium. We found increased phosphorylation of proteins like TnI and MyBPC, indicating that unloading promotes sarcomere-level reverse remodeling. However, patients with high BMI and HbA1C did not show increased protein phosphorylation, suggesting metabolic factors may influence unloading's effect. This dissertation expands understanding of cardiac amyloidosis pathology at the tissue and sarcomere levels, highlighting the impact of mechanical unloading on sarcomere regulation via increased phosphorylation and altered transcription.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.70
Funding Information
This study was supported by the American Heart Association's Predoctoral Fellowship Grant (24PRE1191551) from 2024 through 2025.
Recommended Citation
Milburn, Gregory Nathaniel, "BIOCHEMICAL AND BIOPHYSICAL PROPERTIES OF FAILING MYOCARDIUM IN RARE PATIENT POPULATIONS" (2025). Theses and Dissertations--Physiology. 71.
https://uknowledge.uky.edu/physiology_etds/71
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Cardiology Commons, Cardiovascular Diseases Commons, Circulatory and Respiratory Physiology Commons
