Cardiac magnetic resonance imaging for non-invasive detection of myocardial fibrosis

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI--COLUMBIA AT REQUEST OF AUTHOR.] Cardiovascular diseases involve heart and blood vessels and affects both young and aged population. This research focuses on myocardial fibrosis, a precursor of cardiovascular diseases. At least initially, myocardial fibrosis is a healing response when the human heart is injured or inflamed. An increase in the deposition of collagen I and collagen III occur in the heart during this process. Under physiological conditions, the turnover of collagen-breakdown and deposition-in heart naturally occurs, maintain its structure and contractile function. However, when deposition exceeds breakdown, it inevitably leads to excess myocardial fibrosis, resulting in stiffness and thickening of the heart muscle, leading ultimately to impaired cardiac function, heart disease and heart failure. Therefore, it is paramount to develop non-invasive technology for the early detection of myocardial fibrosis in order to slow, treat or prevent heart disease and heart failure. Currently, detection of fibrosis in the clinic is limited. It is detected by analyzing biopsy or by enzyme-linked immunosorbent assays (ELISA) of cleaved collagens in serum. However, both methods have limitations-either invasive or not having accurate sampling or non-specific or insensitive. Alternatively, imaging modalities such as echocardiogram, single photon emission computed tomography (SPECT), positron emission tomography (PET) and computerized tomography (CT) have too low spatial resolutions and tissue contrasts to accurately detect the extent of myocardial fibrosis. Cardiac magnetic resonance imaging (MRI) is a powerful high-resolution technology. It is also non-invasive and has a high tissue contrast. Importantly, it involves no ionizing radiation. Therefore, the objective of my work is to develop a sensitive and quantitative MRI technology to detect and map myocardial interstitial fibrosis in the beating heart in pre-clinical mouse models. To characterize left ventricular (LV) remodeling, we analyzed cardiac structure, function and myocardial fibrosis in two mouse models: a transverse aortic constriction (TAC) pressure overload (PO) mouse model (moderate and severe phenotypes), and a naturally aging mouse model and their respective controls. In vivo cine MRI was performed to measure the progression of LV morphology and dysfunction using an IntraGate Fast Low Angle Shot (IgFLASH) pulse sequence. PO mice developed LV hypertrophy, systolic dysfunction and interstitial fibrosis at 2 weeks post-TAC. In vivo T1 relaxation time was obtained for LV longitudinally in the moderate PO mouse model. At 2 weeks post-TAC, there was an increase in T1, showing myocyte hypertrophy and myocardial fibrosis. As PO progresses to 12 weeks, T1 relaxation time decreases indicating myocyte necrosis and increased myocardial fibrosis. Aging mouse model mimics heart disease caused by natural aging. Fifteen month-old male CF1 (aged) mice developed LV hypertrophy, systolic and diastolic dysfunction, and increased interstitial fibrosis as compared to young mice (6-8-week-old). We developed a T2 map MRI method and applied it to detect myocardial fibrosis without the use of MRI contrast agent. T2 map shows a detailed color map of each tissue pixel. Aged mice at 15 months showed two phenotypes, fibrotic and mild-fibrotic; both developed a significant increase in interstitial fibrosis compared to the young mice. While no correlation was found between mild-fibrosis and the T2 map, the T2 of the aged fibrotic subgroup was significantly shortened compared to young mice. Decreased T2 values correlated with increased fibrosis in the heart histologically. The T2 map MRI was further evaluated in PO mouse model. The PO mice showed lower myocardial T2 relaxation time and correlated histologically with higher percentage of collagen volume fraction in the heart as compared to control sham-operated mice. When there is more collagen in extracellular matrix (ECM), it causes more interactions between water proton spins that in turn result in non-uniformity in the magnetic environment experienced by each proton, which ultimately causes dephasing, and results in decreased T2 relaxation time. In summary, we have successfully developed a method to detect and map myocardial fibrosis non-invasively that have shown reproducible results in different mouse models. The developed T2 map MRI is a sensitive technique to detect moderate, but not mild, cardiac fibrosis. Therefore, the T2 map MRI could serve as a novel and non-invasive technique to detect and monitor progression of fibrosis during cardiac diseases, and to determine the effectiveness of anti-fibrotic therapies. MRI can be cost effective and useful for early detection of myocardial fibrosis by replacing the previous multi-step detection methods that have low resolution and low accuracy. The newly developed method has the potential to improve patient care.