Abstract:
An undesirable side effect of drugs are cardiac arrhythmias, in particular a condition called torsades de pointes. Current paradigms for drug safety evaluation are costly, lengthy, and conservative, and impede efficient drug development. Here we combine multiscale experiment and simulation, high-performance computing, and machine learning to create an easy-to-use risk assessment diagram to quickly and reliable stratify the pro-arrhythmic potential of new and existing drugs. We capitalize on recent developments in machine learning and integrate information across ten orders of magnitude in space and time to provide a holistic picture of the effects of drugs, either individually or in combination with other drugs. We show, both experimentally and computationally, that drug-induced arrhythmias are dominated by the interplay of two currents with opposing effects: the rapid delayed rectifier potassium current and the L-type calcium current. Using Gaussian process classification, we create a classifier that stratifies safe and arrhythmic domains for any combinations of these two currents. We demonstrate that our classifier correctly identifies the risk categories of 23 common drugs, exclusively on the basis of their concentrations at 50% current block. Our study shapes the way towards establishing science-based criteria to accelerate drug development, design safer drugs, and reduce heart rhythm disorders.
Bio:
Ellen Kuhl is the Walter B. Reinhold Professor in the School of Engineering and Robert Bosch Chair of Mechanical Engineering at Stanford University. She received her PhD from the University of Stuttgart in 2000 and her Habilitation from the University of Kaiserslautern in 2004. Her area of expertise is Living Matter Physics, the design of theoretical and computational models to simulate and predict the behavior of living systems. Ellen has published more than 200 peer-reviewed journal articles, edited two books, and published a textbook on COVID-19. She is a founding member of the Living Heart Project, a translational research initiative to revolutionize cardiovascular science through realistic simulation with 400 participants from research, industry, and medicine from 24 countries. Ellen is the current Chair of the US National Committee on Biomechanics and a Member-Elect of the World Council of Biomechanics. She is a Fellow of the American Society of Mechanical Engineers and of the American Institute for Mechanical and Biological Engineering. She received the National Science Foundation Career Award in 2010, was selected as Midwest Mechanics Seminar Speaker in 2014, and received the Humboldt Research Award in 2016 and the ASME Ted Belytschko Applied Mechanics Award in 2021. Ellen is an All American triathlete, a multiple Boston, Chicago, and New York marathon runner, and a Kona Ironman World Championship finisher.

Zoom Link: https://umich.zoom.us/j/96508834308

Organized by:
Dr. Brendon Baker,
Assistant Professor, Biomedical Engineering

Dr. David Nordsletten,
Associate Professor, Department of Biomedical Engineering and Cardiac Surgery