Year of Publication

2016

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Physiology

First Advisor

Dr. Moriel Vandsburger

Second Advisor

Dr. Brian Delisle

Abstract

Cardiac magnetic resonance (CMR) is a powerful tool to noninvasively image ventricular fibrosis. Late gadolinium enhancement (LGE) CMR identifies focal and, with T1 mapping, diffuse fibrosis. Despite prevalent cardiac fibrosis and heart failure, patients with end stage renal disease (ESRD) are excluded from LGE. Absence of a suitable diagnostic has limited the understanding of heart failure and obstructed development of therapies in the setting of ESRD. A quantitative, gadolinium free fibrosis detection method could overcome this critical barrier, propelling the advancement of diagnostic, monitoring, and therapy options. This project describes the development of a gadolinium free CMR technique and application for cardiac fibrosis measurement in patients with ESRD.

Magnetization transfer (MT) occurs during standard cine balanced steady state free precession (bSSFP) CMR, where extracellular matrix protons exchange magnetization with water molecules. Extracellular water volume expansion, concomitant with fibrosis, reduces MT and subtly elevates signal intensity. Our technique, 2-pt bSSFP, extracts endogenous contrast sensitive to tissue fibrosis by obtaining pairs of high and low MT-weighted images and calculating normalized signal differences, denoted by ΔS/So.

We tested 2-pt bSSFP in patients referred for CMR and found excellent agreement spatially with LGE and quantitatively with extracellular volume fraction. Diagnostic and clinical application of 2-pt bSSFP was comparable to LGE. We applied 2-pt bSSFP to patients with ESRD for multiscale comparison with correlates of fibrosis ranging from blood biomarkers to whole organ function. Patients with ESRD displayed hypertrophy with reduced contraction, but elevated ΔS/So and fibrosis. Some biomarkers correlated with both hypertrophy and fibrosis, highlighting the need to distinguish between hypertrophic and fibrotic remodeling. We monitored fibrosis over 1 year using 2-pt bSSFP in a cohort of patients with ESRD. ΔS/So and fibrotic burden increased substantially, despite minor changes in structure and function.

Collectively these studies validate and apply 2-pt bSSFP for gadolinium free fibrosis CMR in patients with ESRD. While ventricular structure and function are commensurate with progression toward heart failure, it is now possible to specifically describe global and focal patterns of cardiac fibrosis in ESRD, along with comparisons to blood biomarkers which may lead to improved diagnostics and molecular treatment targets.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2016.443