Interim Director of Research
Research Scientist – Experimental Cardiology Jon-2016-a

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Areas of Interest

  • Cardiac Cellular Electrophysiology and Pharmacology
  • Biophysics of ion channels
  • Intracellular calcium regulation
  • Confocal microscopy
  • Excitation-contraction coupling
  • Cardiac Safety Pharmacology

Professional Memberships

  • American Physiological Society, Cardiovascular Section and Cell Section
  • American Heart Association, Basic Cardiovascular Science Section
  • Biophysical Society
  • Cardiac Electrophysiology Society

Research Statement

I am currently a Research Scientist I at the Masonic Medical Research Laboratory (MMRL) where i have established a broad based research program aimed at identifying the functional roles of ion channels in various regions of the heart and pharmacological modification of these ion channels.

Efficient ejection of blood from the heart requires coordinated contraction of the ventricles. The Purkinje fiber conduction system allows the rapid spread of electrical activity (via action potentials) throughout the ventricles and, therefore, activates the ventricular muscle in a uniform manner. Action potentials (AP) are an important physiological parameter: a) the upstroke of the AP is important for activation, b) APs modulate the refractory period, c) associated with each AP is a contraction (a process called excitation-contraction coupling or EC coupling).

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The majority of my research can be subdivided into 3 main areas. A summary of these projects are as follows:

1) Purkinje fibers are specialized myocardial tissue that contact the ventricle at discreet points and provide rapid transmission of the action potential. However, cardiac Purkinje fibers are particularly susceptible to drug-induced prolongation of the action potential leading to potentially fatal cardiac arrhythmias. Repolarization of the cardiac action potential is due to activation of several time- and voltage dependent ion channels which are selective only to K+ ions. These ion channels are located in the membrane of cardiac cells. Alterations in repolarization of the cardiac action potential play a critical role in the development of arrhythmias. In mammalian heart, the Purkinje fiber action potential waveform is different than the ventricular action potential. These differences in repolarization suggest different K+ currents and molecular proteins between the cell types. Among the repolarizing currents, (i) the inward rectifier K+ channel (ii) the transient outward current K+ channel; (iii) and the delayed rectifier(s) K+ channel are likely to be different. In addition, these K+ channels are frequently targeted by anti-arrhythmic drugs. Surprisingly, despite their extensive use in cardiac electrophysiology as well as their use as bioassays for pharmaceutical companies, very little is known about ionic complement of repolarizing K+ currents as well as the molecular identity of the K+ currents in Purkinje fibers. These studies should provide a better understanding of why Purkinje fibers are susceptible to QT prolongation and the initiation of life-threatening ventricular arrhythmias, and will provide an understanding of how Purkinje and ventricular tissue respond to certain pharmacological agents.

2) Another project of mine involves examining regional differences in excitation-contraction (EC) coupling. It is well established that intracellular calcium cycling is essential for normal EC coupling in cardiac cells. Recently, I have discovered regional differences in the mechanical aspects of EC coupling which are in part due to differences in intracellular calcium regulation. Using simultaneous voltage clamp and confocal imaging of calcium transients, I have sought to determine the mechanisms involved. It is essential to have a clear understanding of the mechanisms responsible for regional variations of contractile function in the normal heart before we can understand the basis for contractile dysfunction under various conditions such as hypertrophy or heart failure. For example during heart failure, there are defects in the Ca2+ transient and a depression of cardiac contraction and alteration in several Ca2+ regulatory proteins have been implicated

3) A final project involves studying the electrophysiological characteristics of ion channel mutations involved in inherited diseases such as Short QT Syndrome, Brugada Syndrome, and the recently described combined Brugada/Short QT phenotype. Through a collaborative effort between clinicians, geneticists, and molecular biologists, I have characterized the biophysical basis by which mutations in cardiac ion channels render individuals susceptible to cardiac arrhythmias. A) For example, I have studied how a mutation in the gene HERG produces a functional increase in IKr (a type of K+ channel), renders the channel resistant to blockade by Class III antiarrhythmic agents and is responsible for the Short QT Syndrome. B) Also, I have determined the functional effects of how mutations in Cav1.2 (a type of Ca2+ channel) alter Ca2+ channel function and leads to a distinct clinical entity characterized by ECG abnormalities and sudden cardiac death. C) The Brugada syndrome is a disease that usually strikes young males. The development of Brugada Syndrome is often associated with mutations in the cardiac sodium channel. I have characterized the biophysical changes produced by a number of different Na+ channel mutations in patients with Brugada Syndrome.