BME Seminar: Jeffrey Holmes, M.D., Ph.D., University of Virginia
Friday,
January 31, 2020
11:00 AM - 12:00 PM
All are welcome, (attendance required for graduate students). Lunch is provided.
Jeffrey Holmes, M.D., Ph.D.
Professor of Biomedical Engineering and Medicine
Director, Center for Engineering in Medicine
Co-Lead, Translational Endeavors Core, iTHRIV CTSA
University of Virginia
Model-Based Design of Novel Therapies for Heart Disease
The mechanics of healing myocardial infarcts are a critical determinant of left ventricular function and the risk of an array of post-infarction complications including catastrophic rupture and progression to heart failure. Yet it has proven remarkably difficult to devise therapies to improve post-infarction prognosis by manipulating scar properties. This failure is largely due to the difficulty of predicting the outcome of interventions in such a complex system. Recently, computational models that harness rather than ignore this complexity have begun to provide novel insights into post-infarction mechanics and function, scar formation, and growth and remodeling of the heart, and to suggest new and unexpected therapeutic approaches. We used finite-element models to identify anisotropic reinforcement as a novel strategy to improve pump function of the heart following myocardial infarction, and validated this approach experimentally. We constructed an agent-based model of scar formation in the heart and showed that while chemokine gradients are a dominant regulator of collagen alignment in many healing wounds, mechanical stretch and pre-existing matrix orientation are more important in the heart. Using differential-equation-based models of collagen turnover and fibrosis signaling pathways, we explained the failure of prior attempts to modify infarct scar collagen content using matrix metalloproteinase (MMP) inhibitors, and proposed a novel strategy for achieving spatial control when modulating fibrosis in the heart. We are now beginning to predict growth and remodeling of the heart during the evolution of heart failure and in response to therapies such as cardiac resynchronization therapy (CRT). Similar approaches to atrial fibrillation in adults and congenital heart disease in children are also under development in the Cardiac Biomechanics Group at UVA. These models incorporate individual variability in hemodynamic responses, electrical and mechanical function, and anatomy, and predict outcomes and responses over the months and years relevant to clinical decision-making. Such models have the potential to provide customized design of therapies for individual patients with heart disease, but important regulatory and financial challenges must be addressed to achieve widespread impact.
Jeffrey Holmes, M.D., Ph.D.
Professor of Biomedical Engineering and Medicine
Director, Center for Engineering in Medicine
Co-Lead, Translational Endeavors Core, iTHRIV CTSA
University of Virginia
Model-Based Design of Novel Therapies for Heart Disease
The mechanics of healing myocardial infarcts are a critical determinant of left ventricular function and the risk of an array of post-infarction complications including catastrophic rupture and progression to heart failure. Yet it has proven remarkably difficult to devise therapies to improve post-infarction prognosis by manipulating scar properties. This failure is largely due to the difficulty of predicting the outcome of interventions in such a complex system. Recently, computational models that harness rather than ignore this complexity have begun to provide novel insights into post-infarction mechanics and function, scar formation, and growth and remodeling of the heart, and to suggest new and unexpected therapeutic approaches. We used finite-element models to identify anisotropic reinforcement as a novel strategy to improve pump function of the heart following myocardial infarction, and validated this approach experimentally. We constructed an agent-based model of scar formation in the heart and showed that while chemokine gradients are a dominant regulator of collagen alignment in many healing wounds, mechanical stretch and pre-existing matrix orientation are more important in the heart. Using differential-equation-based models of collagen turnover and fibrosis signaling pathways, we explained the failure of prior attempts to modify infarct scar collagen content using matrix metalloproteinase (MMP) inhibitors, and proposed a novel strategy for achieving spatial control when modulating fibrosis in the heart. We are now beginning to predict growth and remodeling of the heart during the evolution of heart failure and in response to therapies such as cardiac resynchronization therapy (CRT). Similar approaches to atrial fibrillation in adults and congenital heart disease in children are also under development in the Cardiac Biomechanics Group at UVA. These models incorporate individual variability in hemodynamic responses, electrical and mechanical function, and anatomy, and predict outcomes and responses over the months and years relevant to clinical decision-making. Such models have the potential to provide customized design of therapies for individual patients with heart disease, but important regulatory and financial challenges must be addressed to achieve widespread impact.
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