Novel MRI Techniques for Imaging Cardiac Fibrosis to Improve Clinical Practice in Patients with Renal Failure

Cardiovascular disease affects millions of Americans, most of whom progress to heart failure and suffer high mortality and morbidity. The development of cardiac fibrosis occurs early in cardiovascular disease, promotes heart failure, and provides arrhythmogenic substrate leading to increased frequency of adverse cardiac events and higher mortality. Cardiac magnetic resonance imaging (CMR) is routinely used to measure changes in ventricular structure and function in cardiovascular disease with balanced steady state free precession (bSSFP) imaging. With intravenously delivered gadolinium contrast agents, late gadolinium enhancement (LGE) CMR is the clinical standard for identifying focal fibrosis and quantifying fibrotic burden, and when combined with mapping of T1-relaxation times can quantify diffuse fibrosis through measurement of increased extracellular volume fraction (ECV). Identification of fibrosis can indicate a need to test for and treat coronary artery disease and is emerging as a novel criteria for implantable cardiac defibrillator treatment. Cardiovascular disease remains the leading cause of death in individuals with chronic kidney disease with a strong link to cardiac fibrosis, however LGE is contraindicated due to the danger of nephrogenic systemic fibrosis. Emerging studies suggest that specific circulating hormones (e.g. Fibroblast Growth Factor 23 (FGF23)) and peptides (e.g. cardiac Troponin T (cTnT)) can serve as biomarkers of cardiac fibrosis and potential therapeutic targets in chronic kidney disease. However, the inability to measure fibrosis in such patients represents a major gap to the discovery of potential biomarkers, and leaves most studies measuring cardiac hypertrophy as an insensitive surrogate of fibrosis. Further, the design of therapeutic interventions around successful biomarkers is stymied by the inability to measure changes in fibrotic burden over time. The development of a gadolinium free method to measure fibrotic burden would better risk stratify such patients, and would enable non-invasive repeated measurement of fibrotic burden for evaluation of emerging therapies. Recently we developed a novel gadolinium free CMR method, termed 2-point bSSFP, for rapid (~36 seconds per slice) imaging of myocardial fibrosis. This method utilizes reduced magnetization transfer (MT) in areas of increased ECV to identify fibrosis via an endogenous contrast mechanism. Fibrotic tissue is identified through large changes in signal between two differently MT-weighted bSSFP images. In our preliminary clinical study in 47 patients, 2-point bSSFP identified edema, fibrotic scar tissue, and reactive fibrosis in close agreement with LGE. Further, the change in signal in 2-point bSSFP correlated strongly with gadolinium derived measurements of fibrotic density. We propose to fully validate 2-point bSSFP for imaging of focal and diffuse fibrosis, and to utilize this novel and safe method to identify meaningful biomarkers of cardiac fibrosis in chronic kidney disease patients.