Title:
STRUCTURAL, MECHANICAL AND BIOLOGICAL ALTERATIONS TO THE LEFT VENTRICLE IN CHRONIC MITRAL REGURGITATION

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Corporan, Daniella
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Advisor(s)
Padala, Muralidhar
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Abstract
Heart failure (HF) is often the result of a direct stressor such as myocardial ischemia that injures the myocardium, or an indirect stressor such as valvular heart disease that alters the hemodynamic state in the heart and elevates wall stresses on the myocardium. In either state, the heart chambers undergo remodeling, which includes functional deterioration, structural rearrangement, and altered tissue mechanical properties. With direct stressors such as ischemia, these changes occur rapidly and over a shorter duration, whereas with indirect stressors, the remodeling is phasic with time periods of accelerated and decelerated remodeling. The timing of remodeling from the onset of the valvular lesion is vague, and whether there is a point-of-no-return beyond which removing the stressor by treating the valve lesion can be of benefit is unknown. In this thesis, I sought to investigate the chronic, left ventricular remodeling that occurs in response to mitral regurgitation, a common heart valve lesion. The challenging aspect of this lesion is that mitral regurgitation imposes a volume overload stressor on the left ventricle, which causes persistent left ventricular remodeling, without inducing symptoms of cardiac dysfunction in the patients for long periods of time. Thus, traditional markers to identify patients at risk and treat them appropriately are lacking. In this thesis, three aims were accomplished: (Aim 1) Developed an ultrasound guided, beating heart mitral valve puncture technique to induce mitral regurgitation in rats, and mapped left ventricular functional and geometric changes over 280 days of follow-up (equivalent to 20 human years). (Aim 2) Quantified the biomechanical changes in left ventricular tissue from these rats to test the hypothesis that changes in myocardial passive stiffness, parallel dysfunction, providing a potential marker to identify patients at risk. (Aim 3) Performed an unbiased transcriptomics analysis to investigate the signaling cascades involved in the left ventricular remodeling process, and identify potential biomarkers that reflect the myocardial changes. Altogether, the three aims accomplished in this thesis provide a rodent model that parallels the human patient with mitral regurgitation, and provides several new markers that can be useful in identifying patients for mitral valve intervention.
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Date Issued
2020-11-11
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Dissertation
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