Novel Imaging Tools Reveal the Dynamics of the Myocardial Growth Hormone Secretagogue Receptor in Heart Disease and Heart Failure
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.