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AREA OF EXPERTISE and PRIMARY INTEREST
Detailed mechanisms of electrical activity of the heart represent extremely complex phenomena. Single ionic channels (protein molecules) change their state (conducting or non-conducting) depending on the electric potential across the cellular membrane. There are many different types of ionic channels each responsible for the movement of different ions across the plasma membrane, and there are thousands of channels of each type imbedded into membrane. Properly timed openings and closings of these channels result in a highly specific change of electric potential across cellular membrane in the form of the action potential. There are billions of cardiac cells in the heart and their delicately orchestrated activation and contraction ensures effective blood pumping by four heart chambers. Acquired disease or inherited mutation of one type of ionic channels may destroy this delicate balance and result in life-threatening heart malfunction. In order to restore proper balance, we need to understand the root cause of the problem. My primary interest over the past several years is focused on theoretical and computer modeling spanning several areas of cardiac electrophysiology. Most of the time new theoretical ideas come about unexpectedly when I am working on seemingly unrelated project. Different levels of any biological system, including heart - macromolecules (proteins, channels), sub-cellular organelles, myocytes, and cardiac tissues - are tightly integrated. Thus, thinking on one level helps to see better what can be happening on the other one. One of my earliest projects was focused on the nature of the U wave on the ECG. While the model developed to describe this phenomenon was moderately successful, it was readily expanded into the model of another diagnostic recording – the monophasic action potential – by modifying the original ECG model. This work led to the first major breakthrough – the model predicted that currently used clinical interpretation of the source of the signal is incorrect. Further experimental studies confirmed this theoretical prediction and proposed modification of the clinical method to obtain accurate diagnostic data. While working on the monophasic action potential model it became clear that currently available models that describe electrical activity of single cardiac myocytes do not always give correct results, especially under conditions that were important for our laboratory. For example, there was no model for the transient outward potassium current, which is essential in canine and human hearts, but does not exist in guinea pig hearts. Such a model was readily developed and incorporation into the guinea-pig action potential model. Even this simple addition was sufficient to explain the mechanism of arrhythmia development in patients with Brugada Syndrome. Further work was focused on modification of other ionic current models in order to accurately reproduce experimental data obtained in our laboratory using canine ventricular myocytes. All individual models for ionic currents were subsequently combined together in the form of the action potential model, capable of reproducing correct behavior of all four ventricular cell types (RV Epicardial, LV Epicardial, M cell, and Endocardial). This model was thoroughly tested under numerous conditions and perpetually yielded excellent agreement with experiment. We currently use this canine ventricular action potential model to investigate mechanisms of action of novel antiarrhythmic drugs (e.g. Ranolazine) as well as to link genetic mutations found in patients to clinical findings. Major Publications
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Changing the Face of Medicine Cardiac Arrhythmias - Cardiovascular Diseases - Sudden Cardiac Arrest  |
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