Author ORCID Identifier
https://orcid.org/0000-0002-4198-2456
Date Available
12-19-2025
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Physiology
Faculty
Kenneth S. Campbell
Faculty
Lance A. Johnson
Abstract
Heart failure (HF) exhibits considerable heterogeneity, posing significant challenges for research involving human cohorts. Diastolic dysfunction is a common pathophysiological feature; however, its molecular mechanisms remain incompletely elucidated. Sarcomeric proteins are integral to cardiac contraction and relaxation. Nonetheless, the phosphoproteome and the structural remodeling effects of these proteins on diastolic function within the context of HF have not been comprehensively characterized. This study examined sarcomeric modifications in diastolic dysfunction in human HF, focusing on Dilated and Ischemic HF, with non-failing donor hearts as controls. Analyzing myocardial samples from ~150 patients using electrophoretic and biochemical techniques, it found significant titin remodeling and a ~8-14% increase in N2BA content in HF. Similarly, collagen was 2-3 times higher in HF. Higher N2BA content correlated with worse diastolic function, indicating isoform shifts alone don’t reduce myocardial stiffness. Additionally, key sarcomeric regulatory proteins (RLC, TnI, MyBP-C) were hypophosphorylated. Proteomics revealed extracellular matrix remodeling and changes in kinase regulators. These molecular changes correlated with echocardiographic measures of diastolic function (i.e., e’ velocities, E/A, and E/e’ ratios). The study emphasizes coordinated sarcomeric remodeling, including compensatory titin shifts and maladaptive hypophosphorylation, which may contribute to diastolic dysfunction and elucidate potential avenues for enhancing cardiac relaxation in HF.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.601
Funding Information
This study was supported by the National Heart, Lung, and Blood Institute's Predoctoral Fellowship Grant (1F31HL170558) from 2024 through 2025.
Recommended Citation
Wellette-Hunsucker, Austin Grey, "BIOCHEMICAL PROPERTIES OF CARDIAC SARCOMERES IN HUMAN HEART FAILURE" (2025). Theses and Dissertations--Physiology. 73.
https://uknowledge.uky.edu/physiology_etds/73
