Doctor of Philosophy, Case Western Reserve University, 2011, Biomedical Engineering

Ca2+ cycling between the cellular and subcellular compartments plays an important role in regulating cardiac contraction. Disturbance in Ca2+ handling occurs in heart failure and is closely related to abnormal contractile performance. The influx of extracellular Ca2+ through L-type calcium channel is the trigger and a key player in the Ca2+ cycling process. However, there are limited ways to measure it in vivo. Recently, manganese (Mn2+)-enhanced MRI (MEMRI) has been proposed as a promising probe to assess Ca2+ uptake because Mn2+ also enters the cell through the Ca2+ channels. However, quantitative analysis and substantial validation are still lacking, which has limited the application of MEMRI as an in vivo method for quantitative delineation of the Ca2+ influx rate. In the current thesis project, a quantitative MEMRI method was developed and validated using small animal models. The sensitivity to subtle alterations in Ca2+ influx rate was demonstrated in a qualitative MEMRI study using a genetically manipulated mouse model that manifested slightly altered L-type Ca2+ channel activity. To provide quantitative estimation of Mn2+ dynamics, fast T1 mapping techniques were developed based on the direct linear relationship between Mn2+ concentration and proton R1. An ECG-triggered saturation recovery Look-Locker (SRLL) method and a model-based compressed sensing method was developed and validated, respectively. When these two methods were combined, rapid T1 mapping (< 80s) of both myocardium and blood were achieved at high spatial resolution (234x469 μm2). Subsequently, a kinetic model was developed to determine Ca2+ influx rate from the quantitative MEMRI measurements. The robustness and accuracy of estimated Ca2+ influx rate was validated using perfusion MEMRI datasets with L-type Ca2+ channel activity well controlled by buffer ingredients. In conclusion, the accomplishment of this project provides a robust MEMRI method for in vivo quantification of L-type Ca2+ (open full item for complete abstract)

Committee: Xin Yu (Committee Chair); Chris Flask (Committee Member); Mark Griswold (Committee Member); David Rosenbaum (Committee Member); David Wilson (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Medical Imaging; Radiation; Radiology