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Areas of Interest
Dr. Jonathan Cordeiro is currently a Research Scientist I at the Masonic Medical Research Laboratory (MMRL). He has 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). 
The majority of Dr. Cordeiro’s 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. The overall goal of this project is to identify the molecular identity of the ion channels proteins underlying the major K+ currents in rabbit Purkinje fibers and determine their functional contribution to repolarization. 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 contributed to studies designed to delineate 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) Recently, I have contributed to studies designed to determine 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.
Brugada R, Hong K, Dumaine R, Cordeiro JM, Gaita F, Borggrefe M, Brugada J, Pollevick G, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C (2004) Mutations in HERG associated with sudden death in the Short QT Syndrome
Cordeiro JM, Greene L, Heilmann C, Antzelevitch D, Antzelevitch C. (2004) Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle.
Antzelevitch C, Belardinelli L, Zygmunt A, Burashnikov A, Di Diego J, Fish J, Cordeiro JM. (2004) Electrophysiologic and antiarrhythmic effects of ranolazine. A novel anti-anginal agent with antiarrhythmic properties.
Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM, Goodrow RJ, Scornik F, Perez GJ. (2004) Electrophysiologic properties of ranolazine: A novel anti-anginal agent.
Haufe V, Cordeiro JM, Zimmer T, Wu YS, Benndorf K, Dumaine R. (2005) Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles.
Wolpert C, Schimpf R, Giustetto C, Antzelevitch C, Cordeiro JM, Dumaine R, Brugada R, Hong K, Bauersfeld U, Gaita F, Borggrefe M. (2005) Further insights into the effects of quinidine in Short QT Syndrome caused by a mutation in HERG.
Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. (2005) Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in Short QT Syndrome.
Brugada R, Hong K, Cordeiro JM, Dumaine R. (2005) Short QT Syndrome.
Spitzer KW, Pollard AE, Yang L, Zaniboni M, Cordeiro JM, Huelsing DJ. (2006) Cell-to-cell electrical interactions during early and late repolarization.
Cordeiro JM, Barajas-Martinez H, Hong K, Burashnikov E, Pfeiffer R, Orsino AM, Wu YS, Hu D, Brugada J, Brugada P, Antzelevitch C, Dumaine R, Brugada R. (2006) Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada Syndrome.
Dumaine R, Cordeiro JM. (2007) Comparison of K+ currents in cardiac Purkinje cells isolated from rabbit and dog.
Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP, Burashnikov E, Wu YS, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haissaguerre M, Schimpf R, Borggrefe M, Wolpert C, (2007) Loss of Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST Segment Elevation, Short QT Intervals and Sudden Cardiac Death. Hu D, Viskin S, Oliva A, Carrier T, Cordeiro JM, Barajas-Martinez H, Wu YS, Burashnikov E, Sicouri S, Brugada R, Rosso R, Guerchicoff A, Pollevick GD, Antzelevitch C. (2007) Novel mutation in the SCN5A gene associated with arrhythmic storm developing during acute myocardial infarction
Aizawa Y, Ueda K, Scornik FS, Cordeiro JM, Wu YS, Desai M, Guerchicoff A, Nagata Y, Iesaka Y, Kimura A, Hiraoka M, Antzelevitch C. (2007) A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome.
Hu D, Viskin S, Oliva A, Cordeiro JM, Guerchicoff A, Pollevick GD, Antzelevitch C. (2007) Genetic predisposition and cellular basis for ischemia-induced ST segment changes and arrhythmias.
Cordeiro JM, Malone JE, Di Diego JM, Aistrup GL, Antzelevitch C, Wasserstrom JA. (2007) Cellular and subcellular alternans in the canine left ventricle.
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Medical Research Saves Lives Cardiac Arrhythmias - Cardiovascular Diseases - Sudden Cardiac Arrest  |
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