Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Pathology and Laboratory Medicine

Collaborative Specialization

Molecular Imaging

Supervisor

Dhanvantari, Savita

Abstract

Heart disease (HD) is the leading cause of mortality worldwide. Currently, diagnosis is based on clinical features, imaging, and circulating cardiac biomarkers. Cardiac imaging technologies, such as echocardiography and cardiac magnetic resonance imaging (cMRI), enable the non-invasive detection of changes in heart function. Although these modalities can detect changes in structure and anatomy, it is usually at later stages, where prevention may not be possible. In conjunction with imaging, circulating biomarkers of heart failure (HF), notably B-type natriuretic peptide (BNP) and cardiac troponin I and T, can be detected with increased levels in the blood. These biomarkers are associated with other comorbidities and may not be specific to cardiac tissue. Thus, there is a critical need to develop imaging agents to detect the biochemical and molecular changes that precede gross structural changes in HD. There is evidence that the growth hormone secretagogue receptor (GHSR) and its ligand ghrelin, could be a potential molecular imaging target where expression is increased in HF. The purpose of my work was to characterize GHSR as a biomarker for the underlying biological mechanisms involved in heart disease and heart.

To characterize GHSR in end stage HF and valvular HD in humans, I used quantitative fluorescence microscopy with a custom far-red ghrelin analog to evaluate changes in the ghrelin-GHSR system and its downstream signalling. In this way, the ghrelin-GHSR system was elevated in HF and showed specific regional changes in HD. The ghrelin-GHSR system was correlated to heart function through left ventricular ejection fraction in HF while this system correlates regionally in only the left atrium in HD and no correlations are present in healthy tissue. Therefore, the ghrelin-GHSR system shows scalability from healthy to HD to HF.

After characterization of ghrelin-GHSR in the human heart, I evaluated this system using ­in vivo imaging techniques to track the heart after a myocardial infarction in canines. A novel molecular imaging agent demonstrated a unique binding pattern in the heart before and after a myocardial infarction. This binding pattern did not simply reflect cardiac perfusion showing specificity and correlated strongly with histological analysis of this system in the heart showing sensitivity. Therefore, I identified a novel in vivo imaging agent to bind specifically and selectively in the canine heart.

In summary, my thesis describes the characterization of the changes in the myocardial ghrelin-GHSR system using novel imaging agents in situ and in vivo. These findings have important clinical application for the early detection of HD.

Summary for Lay Audience

Heart disease is the leading cause of death worldwide. It is defined by any condition that negatively affects the structure or function of the heart. Heart disease may eventually develop into heart failure, which is defined by a weakened or damaged heart muscle that cannot pump blood throughout the body sufficiently. It is a difficult problem as there is no way to predict who will proceed to heart failure, or who will respond to therapies. Currently, heart disease is diagnosed using imaging methods, mainly ultrasound, that detect changes in the heart’s anatomy and function. However, these changes are associated with late stages of the disease when prevention may not be possible. In addition to imaging, other signs, or markers, of heart failure can be measured in the blood, although they are not necessarily specific to cardiac tissue. Thus, there is a need to detect heart disease at earlier stages with markers specific to cardiac tissue using non-invasive imaging methods. I have used one such marker, called the growth hormone secretagogue receptor (GHSR), as a tool to develop new methods of imaging the heart. GHSR is known to be beneficial to heart health, as it helps to strengthen the heart muscle and prevents heart tissue from dying. Changes in GHSR levels may indicate early stages of heart disease. The purpose of my work was to identify how GHSR changes in heart disease and heart failure, and to design new imaging methods that target GHSR in the heart. I used advanced microscope techniques to show that GHSR increases in advanced heart failure, and changes to a much smaller extent in mild heart disease. I then developed a non-invasive radioactive imaging method to measure changes in GHSR in dogs before and up to 1 year after a heart attack. I found that GHSR levels decreased in the area of the heart injured in the heart attack, and increased specifically in the area surrounding the injured area immediately after the heart attack, and these changes were sustained for a period of one year. Therefore, I developed a new non-invasive imaging method that can evaluate specific changes in GHSR in the heart. In summary, my thesis describes the changes in GHSR in the heart in human heart disease, and the development of a specific imaging tool to detect these changes in GHSR non-invasively. This is important as alterations in GHSR can indicate early stages of heart disease and therefore will lead to improvements in early detection, which may lead to improved treatments and management of heart disease, thus decreasing the likelihood of progression to heart failure.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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