A Quantitative Manganese-Enhanced MRI Method For In Vivo Assessment Of L-Type Calcium Channel Activity In Heart

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⁺ channel activity in small animals. It can improve the diagnosis and treatment evaluation of diseases that involve abnormal Ca²⁺ influx rate, e.g., hypertension. The fast T1 mapping methods developed in the current study can also be readily applied to other dynamic contrast enhanced MRI studies to provide quantitative estimation of contrast agent accumulation.