Scientists at Washington University in St. Louis have developed the first mathematical model of a canine cardiac cell that incorporates a vital calcium regulatory pathway that has implications in life-threatening cardiac arrhythmias, or irregular heartbeats.
Thomas J. Hund, Ph.D., post-doctoral researcher in Pathology ( in Dr. Jeffrey Saffitz laboratory) at the Washington University School of Medicine, and Yoram Rudy, The Fred Saigh Distinguished Professor of Engineering at Washington University, have incorporated the Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) regulatory pathway into their model, improving the understanding of the relationship between calcium handling in cardiac cells and the cell’s electrical activity.
Normal contraction of the heart relies on normal generation of electrical signals, called action potentials, and their organized spread through cardiac tissue. The normal conduction of action potentials is reliant upon sodium channels. But slow conduction of action potentials that can lead to heart arrhythmias depends on calcium channels, which, in turn, are modulated by cell calcium.
“CaMKII mediates an important regulatory pathway that influences calcium cycling in the cell and modulates many processes involving calcium, including activities of calcium channels” said Rudy. “Having this pathway modeled is a valuable research tool because there is a strong link between abnormalities of calcium handling and cardiac arrhythmias. In addition, being a first mathematical model of a regulatory pathway involved in cell electrophysiology, it can serve as a paradigm for modeling effects of other regulatory pathways on cell function.”
Rudy and Hund published their findings in the Nov. 16, 2004 issue of Circulation, a journal of the American Heart Association. The work was funded by grants from the National Institutes of Health — National Heart, Lung, and Blood Institute, and a Whitaker Foundation Development Award.
Throughout all living cells there is a broad array of charged atoms called ions interacting in a dynamic environment. Ion channels along cell membranes open and close to allow these interactions. In heart cells, for instance, many different kinds of ion channels interact to generate the action potentials that go through the heart and cause a synchronized, normal contraction.
In a normal heart, action potentials form very organized waves of activity and contraction. In arrhythmia, though, normal spread of action potentials can be disrupted, either by a focal activity of a confined group of heart cells or by electrical waves that break the heart’s synchrony in a number of different scenarios.
The largest killer of Americans is heart disease, claiming one million Americans annually. Over 300,000 of these deaths are attributed to arrhythmia, seven million worldwide. Rudy has used a computational biology approach to study arrhythmias at various levels (ion channels, cell, multicellular tissue) of the cardiac system, and his laboratory also has developed detailed computer models of the workings of cardiac cells and their alteration by genetic mutations (Nature 1999;400:566).
Until recently, heart specialists have not had noninvasive tools like MRI and CT to better understand the heart’s electrical function. In work supported by a Merit Award from the NIH, Rudy has pioneered a novel, noninvasive imaging modality for cardiac electrophysiology and arrhythmias (Nature Medicine 2004;10:422). The new method, Electrocardiographic Imaging (ECGI), adds a much-needed clinical tool for the diagnosis and treatment of erratic heart rhythms; it also provides a noninvasive method for mechanistic studies of cardiac arrhythmias in humans.
“ECGI has much potential,” Rudy said. “One application could be as a screening tool to identify patients at risk of sudden death from arrhythmia. Another is diagnosis and guidance of therapeutic interventions. We have tested and validated the technology extensively in animal experiments and recently have started its application in humans.”
Rudy’s technology, instead of using 12 electrodes like EKG, uses 250 electrodes in a vest a patient wears. This vest takes the equivalent of 250 EKGs simultaneously, getting electrical data from the entire torso. At the same time, anatomical data that include the torso geometry and the shape and location of the heart are obtained via a CT scan.
“We obtain two pieces of information – the EKG field on the body surface and the CT information for the geometrical relationship of the heart and torso” said Rudy. “Over the years, we’ve developed the mathematics and computer algorithms to combine these two pieces of information and solve for the electrical activity of the heart.”
Rudy joined Washington University last September, bringing with him from Case Western Reserve University in Cleveland a group of 22 people that includes two faculty members (Jianmin Cui, Ph.D., and Igor Efimov, Ph.D.), Ph.D. students, and laboratory personnel. He is a professor of biomedical engineering, cell biology & physiology, medicine, radiology, and pediatrics. He will establish an interdisciplinary center for the study of cardiac electrophysiology and arrhythmias, the Cardiac Bioelectricity and Arrhythmia Center (CBAC), with faculty in various departments in the School of Medicine and the School of Engineering and Applied Science.