Development and Application of Molecular MRI Techniques for Nonischemic Heart Disease

Heart disease remains the leading cause of death globally, including in the United States. Mortality rates and hospitalization from nonischemic heart disease are projected to increase. The pathophysiological cardiac remodeling processes in nonischemic cardiomyopathies (NICM) happen over years, if not decades, prior to overt cardiac dysfunction and heart failure development. Impaired myocardial energetics, altered intracellular protein content, and myocardial fibrosis are the three typical cardiac remodeling hallmarks, which have been repeatedly reported in multiple NICM. Importantly, changes in myocardial energetics and the development of cardiac fibrosis have been shown to start early during the disease progression preceding the clinical manifestation of cardiac dysfunction. The currently available imaging techniques for mapping cardiac energetics metabolites have predominantly been done by magnetic resonance spectroscopy (MRS). Still, it suffers many limitations that hindered the widespread application of MRS in clinical settings. Similarly, the increasing safety concerns of late gadolinium enhancement (LGE) MRI for cardiac fibrosis imaging have pushed the need to develop contrast-free techniques for that application. Chemical exchange saturation transfer (CEST) MRI is an emerging technique for imaging endogenous metabolites that offers much higher sensitivity compared to MRS. CEST enables the imaging of creatine in the cardiac creatine kinase system for mapping myocardial energetics, as well as changes in cardiomyocytes’ intracellular protein content via the amide protons transfer (APT) CEST imaging. Similarly, utilizing the semi-solid macromolecule protons’ magnetization transfer (MT) in the myocardial extracellular matrix for cardiac fibrosis imaging has shown to be a promising technique. We tested the developed cardiac CEST technique to map changes in myocardial creatine content in the setting of obese adults. Results have revealed that, despite preserved ventricular structural and functional measures in the obese cohort, CEST-MRI reveals a significant reduction of creatine CEST contrast in obese adults compared to healthy controls. The reduction of creatine measures was inversely correlated with increased fat masses and septal wall thickness. In CEST, the generated CEST contrast is a function of saturation B1 used during CEST preparation. We quantify the impact of spatial in vivo B1 inhomogeneity on measurements of underlying cardiac CEST contrasts of creatine, APT, and MT in healthy adults. Spatial B1 variability existed across the left ventricle and consistently higher in lateral wall segments than septal segments. This B1 variability generated a parallel increase in direct water saturation and MT that falsely diminished creatine CEST contrast at heightened saturation B1 segments compared to both septal segments. Whereas, APT CEST contrast remained consistent despite B1 variability. The development of reliable molecular imaging techniques may play an important role in understanding disease pathophysiology, early diagnosis, mapping disease progression, and therapeutic innovations and follow-up in the multiple settings of nonischemic cardiomyopathies.

Advisor: Vandsburger, Moriel MV