Development of Methods for Cardiac Tissue Characterization Using Magnetic Resonance Imaging in Animal Models
by Majid Ramedani
Date of Examination:2024-09-02
Date of issue:2024-09-26
Advisor:Prof. Dr. Susann Boretius
Referee:Prof. Dr. Susann Boretius
Referee:Dr. Stefan Glöggler
Referee:Prof. Dr. Elisabeth Zeisberg
Referee:Prof. Dr. Wolfram-Hubertus Zimmermann
Referee:Prof. Dr. Rüdiger Behr
Referee:Prof. Dr. Ralf Heinrich
Persistent Address:
http://dx.doi.org/10.53846/goediss-10748
Files in this item
Name:PhD_Thesis.pdf
Size:10.6Mb
Format:PDF
Description:PhD Thesis
This file will be freely accessible after 2025-09-01.
Abstract
English
Cardiovascular diseases (CVDs) are the primary cause of death and disability globally. The progression of CVDs is often associated with functional and structural alterations, including reduced myocardial contractility, collagen accumulation, and changes in cardiac energy metabolism. A robust and accurate assessment of these alterations is essential for early diagnosis and monitoring treatment effectiveness. Magnetic Resonance Imaging (MRI) is a widely used medical imaging modality valued for its accuracy and reliability in evaluating a range of morphological and functional changes in the heart and vessels. Due to its noninvasive nature and capability to generate high-resolution tissue images, MRI is highly favored in cardiovascular research. However, analyzing distinct components of myocardial alteration remains challenging, particularly the in vivo quantification of myocardial fibrosis, which often appears during aging or as a result of coronary artery diseases. In this thesis, I employed a multi-model approach, including structural, functional, and metabolic imaging, to investigate and enhance the capabilities of MRI in characterizing myocardial tissue and exploring in vivo biomarkers for cardiac-related changes in various species. I utilized different mouse and non-human primate models to achieve this goal and exploited various MR techniques. Accurate cardiac function measurement relies on precise heart structure segmentation. Manual delineation by clinical experts is time-consuming and labor-intensive. Therefore, an efficient automatic segmentation method for heart chambers and myocardium is needed. Existing commercial software is not fully automated, designed for human data, and may not provide sufficient accuracy for animals. In my first study (Chapter 1), I developed a segmentation model using a convolutional neural network that expanded on the standard U-Net architecture for automatic segmentation and evaluated the model separately for cardiac cine and real-time MR images. The trained model demonstrated robust performance with limited training data, not only on the animals whose images were employed for training but also on other species. Comparative analysis revealed that the model’s performance closely aligns with existing published human models and exhibits a high degree of correlation with manual segmentation performed by various observers. During MRI, patients must remain motionless to ensure image quality. Often, breathholding is necessary to prevent artefacts due to chest movement. In patients, clinicians avoid using general anesthesia for this purpose due to its potential risks. Therefore, patients typically breathe freely without ventilation assistance. Unlike humans, animals are anesthetized to prevent movement, usually requiring mechanical ventilation to facilitate gas exchange and enable forced breath-holding. However, the influence of different breathing maneuvers on cardiac function is often overlooked. In the second study (Chapter 2), I investigated the effect of respiration on left ventricle (LV) volumes during free breathing in humans and under mechanical ventilation in anesthetized rhesus macaques using real-time MRI. When comparing free breathing and forced ventilation, I found that volumetric values exhibit opposing trends during inspiration and expiration. Furthermore, I examined the relationship between cardiac and respiratory cycles in both groups, showing opposite correlation patterns. Our findings indicate that different respiratory maneuvers significantly affect LV measurements, making direct quantitative comparisons inaccurate. Myocardial infarction (MI) is caused by an acute coronary artery blockage. After MI, damaged tissue is replaced with fibrous scar tissue. Although the scar is essential to prevent ventricular wall rupture, it expands over time to non-infarct areas, resulting in myocardial fibrosis and altered cardiac structure. This structural change compromises cardiac function and increases the risk of heart failure. Numerous studies aim to develop therapies for acute MI, but post-MI heart remodeling often hampers therapeutic success. Non-invasive imaging methods are crucial to better understand the underlying mechanisms and monitor early therapeutic response. In my third study (Chapter 3), I retrospectively characterized the myocardial tissue of rhesus macaques. A longitudinal study with serial cardiovascular MRI was conducted, including MRI at baseline, post-infarction and multiple time points over a period of 1 year. Analyzing this data extensively, I showed that artificial infarction significantly changed several cardiac MR parameters. By comparing different MR parameters in the damaged tissue and the remote area, I observed that following MI, functional and structural parameters improved substantially in rhesus macaques without treatment but remained impaired compared to the baseline. Cardiac aging in humans is often associated with the development of LV hypertrophy and fibrosis, leading to heart dysfunction and failure. Among non-human primates (NHPs), the common marmoset has gained increasing popularity in preclinical research due to its genetic similarity to humans and relatively short generation time. However, their size and faster heart rate require higher spatiotemporal resolution in MRI. Moreover, the stronger magnetic field in preclinical MR systems can distort the electrocardiogram (ECG) necessary for gated cardiac MRI. Additionally, mechanical ventilation is often needed to ensure safe anaesthesia over several hours. All these factors limit cardiovascular studies in these monkeys. Therefore, I first aimed to establish feasible and robust MRI protocols (Chapter 4) for data acquisition and reconstruction. Using the proposed techniques, I quantitatively assessed cardiac MR parameters in marmosets and presented normal values of cardiac parameters across different ages. I showed that the proposed protocols are reliable, facilitate imaging and spectroscopy, and provide comparable, accurate values. I also identified significant age-related changes in cardiac MR biomarkers. In my fifth and final study (Chapter 5), I utilized the developed methods and pipelines to characterize a mouse model to study the development and regression of LV hypertrophy and myocardial fibrosis in response to injecting angiotensin II. Compared to controls, the angiotensin-treated mice showed higher indices of LV hypertrophy. Additionally, we noted that myocardial fibrosis and alterations in cardiac function were only partially reversible following the removal of the stimulus.
Keywords: MRI; Animal; Cardiovascular diseases; Method developement
