| Michael R. Rosen, M.D.
GUSTAVUS A. PFEIFFER PROFESSOR OF PHARMACOLOGY AND PROFESSOR OF PEDIATRICS
Developmental biology of the heart; Mechanisms for cardiac arrhythmias and their prevention and control with gene and cell therapies; Cardiac memory.
Our research involves three interdependent areas. In the first of these we study the developmental changes that occur in the mechanisms that control cardiac rhythm. The heart shows important changes in its normal physiology with growth and development that influence the normal heartbeat and the response of the individual to the interposition of cardiac disease. We perform research on animal models ranging in age from the fetus through the adult with a view towards understanding the changes in electrophysiologic properties and ionic fluxes that control the normal heartbeat, as well as the mechanisms responsible for developmental changes in the cardioactive agents.
Second, in collaboration with Drs. Richard Robinson, Ira Cohen and Peter Brink we have begun to use gene and cell therapies to build a biological pacemaker. We are doing this because as good as electronic pacemakers are, they remain palliative and not curative. The gene therapy strategy involves overexpressing HCN2 (a pacemaker gene in normal heart) to generate inward pacemaker current. This has provided stable ventricular rhythms having physiologically-acceptable rates and autonomic responsiveness in an animal model. We have also explored adult human mesenchymal stem cells (hMSCs) as a platform for biological pacemaking. hMSCs are multipotent, and can differentiate into a number of musculoskeletal and connective tissues. A property of hMSCs that makes them potentially attractive clinically is that in limited studies they have not elicited major immune responses. During heart block animals having hMSCs incorporating HCN2 injected into a small region of left ventricle develop effective pacemaker function. Moreover, histological studies reveal no rejection. Questions remaining to be answered include: do constructs or cells delivered remain localized or migrate elsewhere, do they persist as hMSCs or mature into other cell types, do they function as well in the heart long-term as in the model systems studied to date or evolve different functional characteristics, and can they can be engineered not to incorporate the risk of malignancy, infection and rejection. If the constructs used do not compete effectively with electronic pacemakers, if they are not as or more reliable and longer lasting, they should not become a clinical reality. But, whether or not the hMSC or another approach becomes a clinically-applicable biological pacemaker, the use of hMSCs and other cell types as platforms for gene and small molecule delivery will likely become a clinical reality.
The third area involves the study of cardiac memory. Cardiac memory describes an electrocardiographic T wave vector change, recorded during normal sinus rhythm that reflects the QRS complex vector during prior periods of ventricular pacing or arrhythmia. It is a readily-quantifiable phenomenon that permits us to relate repolarization changes in situ to their molecular, ion channel and cellular determinants. Hence its applicability to general knowledge regarding the regulation of cardiac repolarization is great, and it offers a unique window for relating molecular determinants of repolarization to their expression in the function of ion channels and in the electrophysiology of the heart. Understanding the steps that translate the molecular mechanisms for memory into clinical expression in this model facilitates our comprehension of the complex pathways that order normal cardiac repolarization as well as both physiologic and pathologic repolarization changes.
1. Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, Janse MJ, Brink PR, Cohen IS, Robinson RB, Danilo P Jr and Rosen MR: Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109:506-512, 2004. Abstract PDF File
2. Potapova I, Plotnikov A, Lu Z, Danilo P Jr, Valiunas V, Qu J, Doronin S, Zuckerman J, Shlapakova IN, Gao J, Pan Z, Herron AJ, Robinson RB, Brink PR, Rosen MR and Cohen IS: Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 94:952 959, 2004. Abstract PDF File
3. Plotnikov AN, Sosunov EA, Patberg KW, Anyukhovsky EP, Gainullin RZ, Shlapakova IN, Krishnamurthy G, Danilo P Jr and Rosen MR: Cardiac memory evolves with age in association with development of the transient outward current. Circulation 110:489 495, 2004. Abstract PDF File
4. Wecke L, Gadler F, Linde C, Lundahl G, Rosen MR and Bergfeldt L. Temporal characteristics of cardiac memory in humans: Vectorcardiographic quantification in a model of cardiac pacing. Heart Rhythm 2:28 34, 2005. Abstract
5. Shvilkin A, Ho KKL, Rosen MR and Josephson ME: T-Vector direction differentiates postpacing from ischemic T-wave inversion in precordial leads. Circulation 111:969 974, 2005. Abstract
6. Janse MJ , Sosunov EA, Coronel R, Opthof T, Anyukhovsky EP, de Bakker JMT, Plotnikov AN, Shlapakova IN, Danilo P Jr, Tijssen JGP and Rosen MR: Repolarization gradients in the canine left ventricle before and after induction of short-term cardiac memory. Circulation 112:1711 1718, 2005. Abstract
7. Patberg KW, Obreztchikova MN, Giardina SF, Symes AJ, Plotnikov AN, Qu J, Chandra P, McKinnon D, Liou SR, Rybin AV, Shlapakova I, Danilo, P Jr., Yang, J and Rosen MR: The cAMP response element binding protein modulates expression of the transient outward current: Implications for cardiac memory. Cardiovasc. Res. 68:259 267, 2005. Abstract
REVIEWS, CHAPTERS AND EDITORIALS
1. Rosen MR, Brink PR, Cohen IS and Robinson RB: Genes, stem cells and biological pacemakers. Cardiovasc. Res. 64:12-23, 2004. Abstract
2. Rosen, MR: Biological pacemaking: In our lifetime? Heart Rhythm 2:418-428, 2005.
3. Rosen MR and Cohen IS: Cardiac memory....new insights into molecular mechanisms. J. Physiol. in press, 2005.