Cardiovascular disease affects millions of Americans, with heart failure as a common endpoint. 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 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). In individuals with chronic kidney disease a strong link exists between cardiac fibrosis and adverse cardiac events, however LGE is contraindicated due to the danger of nephrogenic systemic fibrosis. Emerging studies suggest that specific circulating hormones and peptides may be 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. This proposal seeks to develop a gadolinium free MRI method to measure fibrotic burden via reduced magnetization transfer (MT) in areas fibrotic tissue. This method, termed 2-point bSSFP, exploits an endogenous contrast mechanism in bSSFP imaging to identify fibrotic and edematous tissue. The proposed aims will validate 2-point bSSFP against standard of care LGE and measurement of diffuse fibrosis through ECV mapping. Finally, comparison of fibrotic burden (measured with 2-point bSSFP) to blood chemical workup in CKD patients will examine the correlation between fibrosis and potential biomarkes. The successful completion of these aims will enable rapid and gadolinium free imaging of cardiac fibrosis over the entire heart. Further, correlation of cardiac fibrosis with blood serum biomarkers in chronic kidney disease patients can help identify potential therapeutic targets to halt or reverse fibrosis, the efficacy f which can be serially monitored using 2-point bSSFP.

Public Health Relevance

Cardiovascular disease remains the leading cause of death amongst Americans, particularly for patients with chronic kidney disease. The emerging link between fibrosis and adverse cardiac events has motivated development of gadolinium contrast agent based diagnostics of cardiac fibrosis that are not suitable for patients with compromised renal function. The proposed work fully validates a completely non-invasive and gadolinium free fibrosis imaging technique and applies this method to the identification of novel blood biomarkers of cardiac fibrosis in chronic kidney disease patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128592-04
Application #
9268565
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2015-06-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704