In the healthy, normal heart electrical activity is highly organized and follows a regular activation pattern that permits maximum pumping efficiency. Disruptions of this regular pattern can result in atrial or ventricular tachycardia (fast heart rate), flutter (slight disorganization), or fibrillation (major disorganization). Antiarrhythmic drugs developed to counter these disorganized rhythms interact with cardiac ion channels to either decrease or increase the movement of specific ions across the cell membrane to restore normal sinus rhythm.

My long term focus is to identify electrical mechanisms that underlie a number of clinical arrhythmias. It is only after learning the basis of specific atrial and ventricular arrhythmias that we can successfully assess drug safety and develop interventions that reduce morbidity and death from these diseases in the human population. I am currently engaged with investigations in four related areas of electrophysiology

Among the current strategies for suppression of atrial fibrillation/flutter and prevention of their recurrence are the development of antiarrhythmic agents that preferentially affect atrial, rather than ventricular electrical parameters. An example of this atrial selective approach would be pursuit of an agonist of the ultrarapid delayed rectifier potassium current (IKur), which is only present in atria. Unfortunately, the majority of potential ion channel targets for antiarrhythmic drugs are not unique to the atria. Our current investigation tests the hypothesis that sodium channel characteristics differ between atrial and ventricular cells and that atrial-selective sodium channel block is another effective strategy for the management of AF. Preliminary results suggest sodium currents differ between atrial and ventricular cells with regards to steady state inactivation and kinetics, which then results in differences in tonic and use-dependent block, and recovery from steady state block. Our ultimate goal is to determine if these differences are sufficient to sanction atrial-selective sodium channel block as an effective strategy for the management of AF. Ongoing experiments will contribute to a computer model of the interactions of antiarrhythmics and sodium channel binding sites.

My interest in arrhythmias extends to a study of factors that potentially contribute to sudden infant death syndrome (SIDS). Researchers at the Masonic Medical Research Laboratory have led the way to an understanding that regional electrical differences serve as a substrate for some cardiac arrhythmias. I am currently characterizing developmental changes that occur in regional distributions of atrial ion channels. The bulk of this work is directed towards understanding how this distribution contributes to developmental changes in responses to cardiac agents, and the ease of triggering atrial arrhythmias at an early age.

As an outgrowth of our new understanding of cardiac arrhythmias we have developed numerous collaborations with pharmaceutical companies directed towards drug safety and identification of potential antiarrhythmics. Recent projects have included testing of potential therapies for atrial fibrillation, Brugada syndrome, Timothy syndrome, and several variants of Long-QT syndrome. These studies have characterized the interactions of cardiac agents with calcium channels, sodium channels, and numerous types of potassium channels. Related to these investigations, we have initiated a collaboration with an Gene Network Sciences to provide experimental results that will be used to build a model of drug interactions with ion channels that result in specific changes to cardiac action potentials. The goal of this project is to “reverse-engineer” interactions among cardiac agents, ion channels, and action potentials in a computer model that will speed development of antiarrhythmics and identify drug safety issues.

Selected Publications

Burashnikov A, Di Diego JM, Zygmunt A, Belardinelli L, Antzelevitch C. (2007) Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation. 116(13):1449-57.
PubMed ID: 17785620

Sicouri S, Timothy KW, Zygmunt A, Glass A, Goodrow R, Belardinelli L, Antzelevitch C. Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: Effects of ranolazine. Heart Rhythm, 4(5):638-647, 2007.
PubMed ID: 17467634

Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM. (2004) Electrophysiologic Properties of Ranolazine: A Novel Anti-Anginal Agent with Antiarrhythmic Properties. Circulation, 110:904-910
PubMed ID: 15302796

Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM, Goodrow RJ, Scornik F, Perez G. (2004) Electrophysiologic Properties of Ranolazine: A Novel Anti-Anginal Agent. J Cardiovas Pharmacol Ther, 9 Suppl 1:S65-S83.
PubMed ID: 15378132

Antzelevitch, C.; Zygmunt, A. C.; and Dumaine, R. (2003) Electrophysiology and pharmacology of ventricular repolarization. In: Cardiac Repolarization. Bridging Basic and Clinical Science. I. Gussak and C. Antzelevitch, eds. Humana Press, NY, pages 63-90.

Zygmunt, A. C. (2002) Physiological role of the Ca2+ - activated Cl- current in mammalian heart. In: Calcium-activated Chloride Channels. Catherine M. Fuller, ed. Academic Press, Inc. Current Topics in Membranes 53:81-98.