Clinical Phenotyping of Outflow Tract Tachycardia.
Key Faculty: Bruce B. Lerman, MD (Professor), Sei Iwai, MD (Assistant Professor)

Our research in this area has characterized the clinical mechanisms of outflow tract tachycardia as well as the its unique phenotypic expression and its differentiation from other forms of right ventricular tachycardia. In addition, we have organized and developed one of the world's largest and most complete databases for this group of patients.

Selected References

Slotwiner DJ, Christini DJ, Stein KM, Markowitz SM, Iwai S Das M, Cohen J, Hao S, Lerman BB. Muscle sympathetic nerve traffic during spontaneous vs. adenosine-mediated termination of right ventricular outflow tract tachycardia. Am J Cardiol. 2003;91:86-88.

Yarlagadda RK, Iwai S, Stein KM, Markowitz SM, Shah BK, Lerman BB. Tachycardia-induced cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation. 2005; 112:1092-1097

Pathogenesis and Mechanisms of Atrial Tachycardia.
Key Faculty: Bruce B. Lerman, MD (Professor), Steven Markowitz, MD (Associate Professor), Sei Iwai, MD (Assistant Professor), Bindi Shah, MD (Assistant Professor)

Our laboratory investigates the mechanism and site predilection for focal right and left atrial tachycardias. We have made fundamental contributions in identifying delayed afterdepolarizations and triggered activity as the predominant mechanism for this form of tachycardia as well as its preferential sites of origin from the tricuspid and mitral valve annuli and the crista terminalis.

Selected References

Markowitz SM, Brodman RF, Stein KM, Slotwiner DJ, Iwai S, Das M, Lerman BB. Lesional Tachycardias related to mitral valve surgery. J Am Coll Cardiol. 2002;29:1973-1983.

Stein KS, Markowitz SM, Slotwiner DJ, Iwai S, Lerman BB. Anatomic determinants of atrial arrhythmias: New insights from 3D mapping. Chaos. 2002;12:740-746.

Iwai S, Markowitz SM, Stein KM, Slotwiner DT, Das MK, Cohen JD, Hao S, Lerman BB. Response to adenosine differentiates focal from macroreentrant tachycardia: Validation using three-dimensional electroanatomic mapping. Circulation. 2002;106:2793-2799.

Improvement of Computerized Electrocardiography.
Key Faculty: Paul Kligfield, MD (Professor)

The Cardiac Graphics Laboratory is a world leader in development of new and improved methods and algorithms for computerized electrocardiography. Trainees and medical students use the resources of the laboratory to improve understanding of the relationship of the electrical activity of the heart to its surface recording.

Selected References

Lee KW, Kligfield P, Dower GE, Okin PM. QT dispersion, T wave projection, and heterogeneity of repolarization in patients with coronary disease. American Journal of Cardiology. 2001;87:148-151.

Kligfield P, Badilini F, Brown B, Helfenbein E, Kohls M. The ISCE genome challenge: a 2004 progress report. Journal of Electrocardiology. 2004;37 Suppl: 144-148.

Poon K, Okin PM, Kligfield P. Diagnostic performance of a computer-based ECG rhythm algorithm. Journal of Electrocardiography. 2005;38:235-238.

Electrocardiographic Analysis of Ventricular Repolarization Abnormality and Complexity.
Key Faculty: Peter Okin, MD (Professor)

We are developing and applying novel computerized measures of the degree of repolarization abnormality (references 2 and 3) and complexity (references 1 and 2) for assessment of risk in a variety of populations. Ongoing work will examine risk in relation to changes in these parameters over time.

Selected References

Okin PM, Devereux RB, Fabsitz RR, Lee ET, Galloway JM, Howard BV. Principal component analysis of the T-wave and prediction of cardiovascular mortality in American Indians: The Strong Heart Study. Circulation. 2002;105:714-719.

Okin PM, Devereux RB, Lee ET, Galloway JM, Howard BV. Ventricular repolarization complexity and abnormality predict all-cause and cardiovascular mortality in diabetes: The Strong Heart Study. Diabetes. 2004;53:434-440.

Okin PM, Roman MJ, Best LG, Lee ET, Galloway JM, Howard BV, Devereux RB. C-reactive protein and electrocardiographic ST segment depression additively predict mortality: The Strong Heart Study. J Am Coll Cardiol. 2005;45:1787-1793.

Atrioventricular Nodal Physiology in Humans.
Key Faculty: Steven Markowitz, MD (Associate Professor)

Our laboratory investigates AV nodal physiology, with emphasis on understanding the basis for dual pathway physiology. We have presented evidence for the existence of separate anterior and posterior inputs to the AV node, with different electrophysiological properties.

Selected References

Markowitz SM, Stein KM, Lerman BB. Mechanism of ventricular rate control after radiofrequency modification of atrioventricular conduction in patients with atrial fibrillation. Circulation. 1996;94:2856-2864.

Markowitz SM, Christini DJ, Stein KM, Iwai S, Slotwiner DJ, Lerman BB. Time course and predictors of autonomic dysfunction after ablation of the slow atrioventricular nodal pathway. PACE. 2004;27:1638-1643.

Cardiac Resynchronization Therapy and Arrhythmias Triggers.
Key Faculty: Kenneth Stein, MD (Associate Professor), Rakesh Mishra, MD (Assistant Professor)

Analyzing the temporal pattern and autonomic triggers of ventricular arrhythmias to better understand the factors triggering a particular episode. We are participating in the Rethinq trial: a randomized double-blind multicenter trial sponsored by St. Jude Medical examining the use of CRT in patients with moderate-to-severely symptomatic congestive heart failure and a narrow QRS complex, but with echocardiographic evidence of ventricular dyssynchrony.

Selected References

KE Ellison, GE Hafley, K Hickey, J Kellen, J Coromilas, KM Stein, KL Lee, AE Buxton, for the MUSTT Investigators. Effect of Beta-blocking Therapy on Outcome in the Multicenter UnSustained Tachycardia Trial (MUSTT). Circulation. 2002;106:2694-9.

KM Stein, DE Euler, R Mehra, K Seidl, DJ Slotwiner, SM Markowitz, BB Lerman for the Jewel AF Worldwide Investigators. Do Atrial Tachyarrhythmias Beget Ventricular Tachyarrhythmias in Defibrillator Recipients? J Am Coll Cardiol. 2002;40:335-40.

Diagnostic Modalities for Novel Evaluation of Syncope and Arrhythmia.
Key Faculty: Kenneth Stein, MD (Associate Professor)

Noninvasive studies: We evaluated the yield of a widely used tilt table testing protocol in patients without structural heart disease who presented with syncope. We found that a similar yield could be obtained using an adenosine test protocol in a fraction of the time, thus reducing the procedure duration substantially for our patients. We then identified patient groups in whom the test was most likely to be useful.

Selected References

Stein KM, Markowitz SM, Slotwiner DJ, Rohatgi S, Lerman BB. Induction of neurally-mediated syncope with adenosine. Circulation. 1999;99(10): 1318-1324.

Stein KM, Markowitz SM, Iwai S, Guttigoli A, Lerman BB. A single-stage adenosine tilt test in patients with unexplained syncope. J Cardiovasc Electrophysiol. 2004;15:637-640.

Cheung JW, Stein KM, Markowitz SM, Iwai S, Guttigoli AB, Shah BK, Yarlagadda RK, Lerman BB. Significance of adenosine-induced atrioventricular block in patients with unexplained syncope. Heart Rhythm. 2004;1:664-668.

Invasive studies: We investigated the utility of electrophysiologic testing in patients with ischemic heart disease and depressed left ventricular function who presented with syncope. This research allowed us to make several important conclusions:

• Patients in whom sustained monomorphic ventricular tachycardia was not inducible had an excellent outcome.
• The induction of ventricular fibrillation alone did not impart an adverse long-term prognosis.
• In patients where sustained monomorphic ventricular tachycardia was inducible, those whose QRS duration was > 120 msec represented a particularly high risk group.

Selected References

Iwai S, Stein KM, Markowitz SM, Slotwiner DJ, Lerman BB. Long-term outcome of patients with unexplained syncope treated with an electrophysiologic-guided approach in the implantable cardioverter-defibrillator era. J Am Coll Cardiol. 1999;34(4):1082-1089.

Hao SC, Iwai S, Stein KM, Markowitz SM, Slotwiner DJ, Lerman BB. Significance of inducible ventricular fibrillation in patients with coronary artery disease and unexplained syncope. J Am Coll Cardiol 2001;38:371-376.

Guttigoli AB, Wilner BF, Stein KM, Markowitz SM, Iwai S, Shah BK, Yarlagadda RK, Lerman BB. Usefulness of prolonged QRS duration to identify high-risk ischemic cardiomyopathy patients with syncope and inducible ventricular tachycardia. Am J Cardiol. 2005;95:391-394.

Cardiac Tissue Engineering.
Key Faculty: Jay M. Edelberg, MD, PhD (Associate Professor)

Our present research program aims to develop cardiac cell-based biosensors from autologous stem cell sources, including bone marrow, as an approach to monitor intravascular pro-thrombotic activity in real-time.

Selected References

Christini DJ, Walden J, Edelberg JM. Direct biologically-based biosensing of dynamic physiological function. American Journal of Physiology. 2001;280: H2006-2010.

Edelberg JM, Jacobson JT, Gidseg DS, Tang L, Christini DJ. Enhanced myocyte-based biosensing of the blood-borne signals regulating chronotropy. Journal of Applied Physiology. 2002;92:581-585.

Tang L, Christini DJ, Edelberg JM. Genetically engineered biologically-based hemostatic biosensors. Annals of Biomedical Engineering. 2003;31:159-162.

Regulation of Potassium Channel Subunits.
Key Faculty: Geoffrey Abbott, PhD (Assistant Professor)

We are studying how one class of ancillary subunits, the MinK-related peptides (MiRPs), controls potassium channel function and pharmacology, with the ultimate goal being a better understanding of diseases such as cardiac arrhythmia and epilepsy. Using RNAi we are investigating the effects of endogenous Xenopus MiRPs on heterologous expression studies of human potassium channels in Xenopus oocytes. We have also recently discovered a new class of small molecule regulators of potassium channel function that has potential both for research and for therapy; we are currently working chemists to generate a comprehensive library of these molecules.

Selected References

McCrossan, Z.A., Lewis, A., Panaghie, G., Jordan, P.N., Christini, D.J., Lerner, D.J., & Abbott, G.W. MiRP2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. Journal of Neuroscience. 2003;23:8077-8091.

Lewis A., McCrossan Z.A., & Abbott, G.W. MinK, MiRP1 and MiRP2 diversify Kv3.1 and Kv3.2 potassium channel gating. J. Biol. Chem. 2004;279:7884-7892.

Abbott, G.W., Butler, M.H., Bendahhou, S., Dalakas, M.C., Ptacek, L.J., & Goldstein, S.A.N. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 2001;104:217-231.

Anantharam, A., Lewis, A., Panaghie, G., Gordon, E., McCrossan, Z.A., Lerner, D.J., & Abbott, G.W. RNA interference reveals that endogenous Xenopus MinK-related Peptides govern mammalian K+ channel function in oocyte expression studies. J Biol Chem. 2003;278:11739-11745

Anantharam, A., Markowitz, S.M. & Abbott, G.W. Pharmacogenetic considerations in diseases of cardiac ion channels. J. Pharm. Exp. Ther. 2003;307:831-838

Prediction and Control of Cardiac Arrhythmias.
Key Faculty: David Christini, PhD (Assistant Professor), Kenneth Stein, MD (Associate Professor), Bruce Lerman, MD (Professor)

We are using computational, large-animal in vivo, and clinical studies to investigate methods to predict the imminent onset of ventricular tachyarrhythmias and methods to prevent such onset once it is detected. The methods are aimed at improving the functionality of implantable cardioverter defibrillators.

Selected References

Christini DJ, Stein KM, Markowitz SM, Slotwiner DJ, Scheiner MA, Iwai S, and Lerman BB. Nonlinear-dynamical arrhythmia control in humans. Proceedings of the National Academy of Science. 2001;98:5827-5832.

Sinha S and Christini DJ. Termination of reentry in an inhomogeneous ring of model cardiac cells. Physical Review E. Statistical, Nonlinear, & Soft Matter Physics. 2002;66(6 Pt 1):061903.

Jordan PN and Christini DJ. Adaptive diastolic interval control of cardiac action potential duration alternans. Journal of Cardiovascular Electrophysiology. 2004;15:1177-1185.

Determination of the Molecular, Cellular, and Tissue Mechanisms Underlying Repolarization Alternans.
Key Faculty: David Christini, PhD (Assistant Professor)

We are using complementary computational modeling and in vitro optical mapping experiments to investigate the ion-channel to tissue-level mechanisms that lead to repolarization alternans. Given that alternans can trigger cardiac reentry, an improved understanding of their mechanism may help guide development of antiarrhythmic therapy.

Selected References

Maybhate A, Hao SC, Iwai S, Lee JU, Guttigoli AB, Stein KM, Lerman BB, and Christini DJ, "Detection of repolarization alternans with an implantable cardioverter defibrillator lead in a porcine model," IEEE Transactions on Biomedical Engineering, in press, (2005).

Jordan PN and Christini DJ. Determining the effects of memory and action potential duration alternans on cardiac restitution using a constant-memory restitution protocol. Physiological Measurement. 2004;25:1013-1024.

Hao SC, Christini DJ, Stein KM, Jordan PN, Iwai S, Bramwell O, Markowitz SM, and Lerman BB. Effect of beta adrenergic blockade on dynamic electrical restitution in vivo. 2004;American Journal of Physiology 2004;287:H390-H394.

Large-scale Computational Modeling of Cardiac Arrhythmias.
Key Faculty: David Christini, PhD (Assistant Professor)

We are using large-scale two- and three-dimensional computational modeling to investigate the dynamics of arrhythmias. We are focusing on atrial fibrillation and how it is triggered by abnormal electrical activity originating from the pulmonary veins.

Selected References

Gong Y and Christini DJ. Functional reentrant waves propagate outwardly in cardiac tissue. Physics Letters A. 2004;331:209-216.

Gong Y and Christini DJ. Antispiral waves in reaction-diffusion systems. Physical Review Letters. 2003;90:088302.