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School of Medicine
The Tomaselli lab is focused on the fundamental basis of excitability in the heart. We study this problem at multiple levels of integration from molecules and cells to abnormalities of heart rhythm in patients.
At a molecular level, they seek to understand how ion channel proteins perform their essential tasks, in particular they are interested in a key paradox how these channels permit the flow of millions of ions a second, yet do this with exquisite selectivity (sodium channels allow sodium ions but not similarly sized and charged potassium ions).
More recently they have turned their attention to the regulation of sodium and potassium channels by important cellular signaling systems which are involved in not only in how the heart conducts electricity but also the force with which it contracts.
The diseased heart undergoes a series of changes, initially compensatory but ultimately maladaptive, that increase the risk of potentially lethal arrhythmias. These changes are commonly referred to as remodeling. Dr. Tomaselli’s group is studying the remodeling process in animal models of heart failure using gene expression, protein and ionic current measurements. They have developed a canine microarray for the broad-based study of gene expression in the failing canine heart.
At the ultimate level of integration they are examining the role of implanted defibrillators (ICDs) in patients with diseased, remodeled hearts. They have initiated a study referred to as PROSe-ICD (PRospective Observational Study of the ICD in the prevention of sudden death).
PROSe-ICD has enrolled nearly 800 patients all have undergone detailed clinical and electrocardiographic studies as well as having blood collected for performing genetic and proteomic analyses. Over 25% of this cohort has undergone detailed cardiac imaging (MR and CT) and spectroscopy to identify imaging based markers of risk of sudden death. The overarching goal is to better understand the mechanisms of sudden arrhythmic death and to develop better predictors of risk of this devastating outcome.
Donald W. Reynolds Center in Cardiovascular Clinical Research 2003 – 2010
Robert Weiss, Director, G.Tomaselli Co-Director and PI: PROSE –ICD
RO1 HL091062 (PI: Tomaselli) 2009 – 2014
“Fundamental Biology of Sudden Cardiac Death and Its Application to Identify Patient at Risk”
This grant will examine the role of genetic, protein and electrocardiographic markers measured longitudinally in predicting the risk of SCD and overall mortality in patients with implantable defibrillators placed for primary prevention.
R33 HL087363 (PI: Tomaselli) 2007 – 2010
“The System Biology of Sudden Cardiac Death”, Cluster Project 2
Cluster Project 2 will extend prior HF work to the tissue level by testing the hypothesis that regional (transmural) changes in the expression of SL ion channels, proteins involved in intracellular Ca2+-cycling and connex in proteins lead to regional heterogeneity of AP repolarization and thus increased risk for arrhythmia in the setting HF.
RO1 HL50411-14 (PI: Tomaselli) 2004 – 2010 NIH/NHLBI
“Cardiac Sodium Channel Function regulation of permeation and gating”
The goal is to understand the mechanism role of regulation of gating of the cardiac Na channel with a focus on structural motifs in the carboxy terminus. This grant is in a no-cost extension and a competitive renewal has been submitted.
1 PO1 HL077180 (PI: Kass) Role: PI Project 2, Co-Director Core C 2004 – 2010
“Pathobiology of Cardiac Dyssynchrony and Resynchronization”
Project 2, “Electrophysiology of Cardiac Dyssynchrony and CRT”
Core C: Cell/molecular/microscopy core
The study seeks to understand the cellular and molecular basis of electrical remodeling in HF and its correction by Cardiac Resynchronization Therapy (CRT). Ventricular myocytes and wedges of myocardium will be studied for remodeling of AP characteristics, ionic currents, calcium handling and tissue properties including conduction. In Core C studies of ion channel and Ca2+ handling proteins as well as mRNA expression profiling will be performed.
R37 HL54598-11 (PI: O’Rourke) Role: Co-Investigator 1996 – 2010
“Energetic Regulation of Cardiac Ion Channels”
The major goal of this project is to determine the role of the inner membrane mitochondrial anion channel in cardiac energetics and the integrated function of the myocyte.
R01 DK072367-01 (PI: Klag) Role: Co-Investigator 2007 – 2012
“Longitudinal Study of Dialysis”
This study will allow identification of dialysis-related risk factors that are unique to persons with ESRD for arrhythmias and SCD, setting the stage for clinical trials to test therapies to prevent SCD in a high risk population. In addition, this study will provide an infrastructure to answer, in future studies, a host of important questions related to the pathogenesis of morbidity and mortality in the ESRD population.
U54 MH084691 (PI: Li) Role: Co-Investigator 2008 – 2014
NIH Johns Hopkins Ion Channel Center
This center performs high throughput screening of chemical libraries for ion channel ligands and characterizes the biophysical effects of hits on their ion channel targets.
1RC1 HL099892 (PI: Tomaselli) 2009 – 2011
NIH ARRA, “Biomarkers of Sudden Death and Heart Failure Progression”
This study will examine the role of peripheral blood mRNA and microRNA markers of SCD and HF progression in a primary prevention HF population.
Current Lab Members:
- Subrata Biswas, PhD Research Associate (Projects 1 and 2)
- Andreas Barth, MD, PhD Post doctoral fellow (Projects 2 and 3)
- David Edwards MD, PhD Clinical Fellow in Cardiology (Projects 1 and 2)
- Rajesh Sekar PhD, Post doctoral fellow (Projects 2 and 3)
- Darshan Dalal MD, PhD, Assistant Professor of Medicine (Project 4)
- Debbie DiSilvestre Lab Manager (Projects 1-4)
- Peihong Gao, Senior Lab Technician (Projects 1-3)
- YanLi Tian, MD, Lab Technician (Projects 1-4)
- Victoria Halperin, Lab Technician (Projects 1-4)
- Barbara Butcher, RN Coordinator PROSE-ICD (Project 4)
- Sanaz Norgard, Technician (Project 4)
- Ami Kumordzie, Undergraduate Student
- Cardiac Ion Channel structure-function and regulation
- Na, K channels
- Cellular and Molecular Remodeling in the Diseased Heart
- Heart failure and CRT
- Mechanisms of Sudden Cardiac Death
Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 111:11-20, 2005.
Rose J, Armoundas AA, DiSilvestre D, Tian YL, Burysek M, Halperin V, O’Rourke B, Kass DA, Marbán E, Tomaselli GF. The molecular basis of altered expression of potassium currents in failing rabbit myocardium. Am J Physiol - Heart 288: 2077-2087, 2005.
Tsang SY, Tsushima RG, Tomaselli GF, Li RA, Backx PH. A multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor. Mol Pharmacol 67: 424-34, 2005.
Xiong W, Tian Y, DiSilvestre D, Tomaselli GF. Transmural heterogeneity of Na+-Ca2+ exchange: evidence for differential expression in normal and failing hearts. Circ Res 207-9, 2005.
Akar FG, Wu RC, Juang GJ, Tian Y, Burysek M, Disilvestre D, Xiong W, Armoundas AA, Tomaselli GF. Molecular mechanisms underlying K+ current down regulation in canine tachycardia-induced heart failure. Am J Physiol 288: H2887-96, 2005.
Shah M, Akar FG, Tomaselli GF. Molecular basis of arrhythmias.Circulation112: 2517-29 2005.
Gao Z, Xu H, DiSilvestre D, Halperin VL, Tunin R, Tian YL, Yu W, Winslow RL, Tomaselli GF. Transcriptomic profiling of the canine tachycardia-induced heart failure model: Global comparison to human and murine heart failure. J Mol Cell Cardiol 40:76-86, 2006.
Akar FG, Aon MA, Tomaselli GF, O’Rourke B. Mitochondrial origin of postischemic arrhythmias. J Clin Invest 115:3527-35, 2005.
Nazarian S, Bluemke DA, Lardo AC, Zviman MM, Watkins SP, Dickfeld TL, Meininger GR, Rougin A, Calkins HG, Tomaselli GF, Weiss RG, Berger RD, Lima JA, Halperin HR. Magnetic Resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 112:2821-5, 2005.
Piccini JP, Dalal D, Roguin A, Bomma C, Cheng A, Prakasa K, Dong J, Tichnell C, James C, Russell S, Crosson J, Berger RD, Marine JE, Tomaselli G, Calkins H. Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia. Heart Rhythm 2:1188-94, 2005.
Lickfett L, Calkins H, Nasir K, Dickfeld T, Eldadah Z, Jayam V, Leng C, Tomaselli G, Donahue K, Halperin H, Luderitz B, Berger R. Clinical prediction of cavotricuspid isthmus dependence in patients referred for catheter ablation of "typical" atrial flutter. J Cardiovasc Electrophysiol 16:969-73, 2005.
Bass AS, Tomaselli GF, Bullingham R III, Kinter LB. Drugs effects on ventricular repolarization: A critical evaluation of the strengths and weaknesses of current methodologies and regulatory practices. J Pharmacol Toxicol Methods 52:12-21, 2005.
Kittleson MM, Minhas KM, Irizarry RA, Ye SQ, Edness G, Breton E, Conte JV, Tomaselli G, Garcia JG, Hare JM. Gene expression in giant cell myocarditis: Altered expression of immune response genes. Int J Cardiol 102: 333-40, 2005.
Kittleson MM, Minhas KM, Irizarry RA, Ye SQ, Edness G, Breton E, Conte JV, Tomaselli G, Garcia JG, Hare JM. Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure. Physiol Genomics 21: 299-307, 2005.
Azene EM, Xue T, Marban E, Tomaselli GF, Li RA. Non-equilibrium behavior of HCN channels: Insights into the role of HCN channels in native and engineered pacemakers. Cardiovasc Res 67: 263-73, 2005.
Spragg DD, Akar FG, Helm RH, Tunin RS, Tomaselli GF, Kass DA. Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. Cardiovasc Res 67:77-86, 2005.
Akar FG and Tomaselli GF. Conduction Abnormalities in Nonischemic Dilated Cardiomyopathy: Basic Mechanisms and Arrhythmic Consequences. Trends in CV Medicine 15:259-64, 2005.
Akar FG and Tomaselli GF. Ion Channels as Novel Therapeutic Targets in Heart Failure. Annals of Medicine 37:1-12, 2005.
Tse H-F, Xue T, Lau C-P, Siu C-W, Wang K, Zhang Q-Y, Tomaselli GF, Akar FG, Li RA. Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation 114:1000-11, 2006.
Xiong W, Farukhi YZ, Tian Y, DiSilvestre D, Li RA, Tomaselli GF. A conserved ring of charge in mammalian Na channels: A molecular regulator of the outer pore conformation during slow inactivation. J Physiol 576:739-754, 2006.
Tomaselli GF. A failure to adapt: ankyrins in congenital and acquired arrhythmias. Circulation Jan 30;115(4):428-9, 2007.
Armoundas AA, Rose J, Aggarwal R, Stuyvers BD, O’Rourke B, Kass DA, Marbán E, Shorofsky SR, Tomaselli GF, Balke CW. Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol. 292(3):H1607-18, 2007.
Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marbán E, Tomaselli GF, Lima JA, Wu KC. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 115:2006-14, 2007.
Fernandes VR, Wu KC, Rosen BD, Schmidt A, Lardo AC, Osman N, Halperin HR, Tomaselli GF, Berger RD, Bluemke DA, Marban E, Lima JA. Enhanced infarct border zone function and altered mechanical activation predict inducibility of monomorphic ventricular tachycardia in patients with ischemic cardiomyopathy. Radiology 245:712-9, 2007.
Akar FG, Nass RD, Hahn S, Cingolani E, Shah M, Hesketh GG, DiSilvestre D, Tunin RS, Kass DA, Tomaselli GF. Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 293(2):H1223-H1230, 2007.
Henrikson CA, Spragg DD, Cheng A, Capps M, DeVaughn K, Marine JE, Calkins HG, Tomaselli GF, Berger RD. Evidence for electrical remodeling of the native conduction system with cardiac resynchronization therapy. Pacing Clin Electrophysiol. 30(5):591-5, 2007.
Marine JE, Tomaselli GF, Leng CT. Inappropriate implantable cardioverter-defibrillator discharge associated with a new ventricular tachycardia treatment algorithm. Heart Rhythm. 4(5):655-7, 2007.
Biswas S, Deschênes I, DiSilvestre D, Tian YL, Halperin VL, Tomaselli GF. Calmodulin regulation of NaV1.4 current: Role of binding to the carboxyl terminus. J Gen Physiol. 131:197-209, 2008.
Ouwerkerk R, Bottomley PA, Solaiyappan M, Spooner A, Tomaselli GF, Wu KC, Weiss RG. Tissue sodium concentration is elevated in human myocardial infarction: A quantitative 23NaMRI study. Radiology 248:88-96, 2008.
Chakir K, Daya SK, Tunin RS, Helm RH, Byrne MJ, Liang HY, Lardo AC, Abraham T, Tomaselli GF, Kass DA. Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization. Circulation. 117: 1369-77, 2008.
Deschênes I, Armoundas AA, Jones SP, Tomaselli GF. Post-transcriptional gene silencing of KChIP2 and Na(v)beta1 in neonatal rat cardiac myocytes reveals a functional association between Na and I(to) currents. J Mol Cell Cardiol 45(3):336-46, 2008.
Kostis WJ, Tedford RJ, Miller DL, Schulman SP, Tomaselli GF. Troponin-I elevation in a young man with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Interv Card Electrophysiol Jun;22(1):49-53, 2008.
Wu KC, Weiss RG, Thiemann DR, Kitagawa K, Schmidt A, Dalal D, Lai S, Bluemke DA, Gerstenblith G, Marbán E, Tomaselli GF, Lima JA. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol. 24;51(25): 2414-21. 2008.
Gao Z, Barth AS, Disilvestre D, Akar FG, Tian Y, Tanskanen A, Kass DA, Winslow RL, Tomaselli GF. Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. Physiol Genomics 2008 Sept 9 [epub ahead of print].
Nass RD, Aiba T, Tomaselli GF, Akar FG. Mechanisms of Disease: ion channel remodeling in the failing ventricle. Nat Clin Pract Cardiovasc Med. 5:196-207, 2008.
Loscalzo J, Tomaselli GF, Vaughan DE, Walsh RA. Task force 7: training in cardiovascular research. J Am Coll Cardiol 51:380-3, 2008.
Tomaselli GF, Aiba T. LQTS: Better with Age? J Cardiovasc Electrophysiol. 2008.
Josephson ME, Rosen MR, Tomaselli GF. The year in arrhythmias--2007: Part I. Heart Rhythm. 5(5):742-8, 2008.
Josephson ME, Rosen MR, Tomaselli GF. The year in arrhythmias 2007: Part II. Heart Rhythm. 5(6):867-71, 2008.
Aiba T, Barth A, Tomaselli GF. Deciphering gene expression profiling in cardiac resynchronization therapy. J Am Coll Cardiol50(14):1177, author reply 1177-8, 2008.
Bilchick KC, Dimaano V, Wu KC, Helm RH, Weiss RG, Lima JA, Berger RD, Tomaselli GF, Halperin HR, Kass DA, Abraham T, Lardo AC. Magnetic Resonance imaging myocardial tagging for circumferential mechanical dyssynchrony in heart failure: Prediction of cardiac resynchronization therapy response and comparison to tissue Doppler. J Am Coll Cardiol. Cardiovasc Imaging 1:561-8, 2008.
Aiba T, Hesketh GG, Barth AS, Liu T, Daya SK, Chakir K, Dimaano VL, Abraham T, O’Rourke B, Akar FG, Kass DA, Tomaselli GF. Electrophysiological Consequences of Dyssynchronous Heart Failure and its Restoration by Resynchronization Therapy. Circulation 119:1220-30, 2009.
Chakir K, Daya SK, Tunin RS, Liang H-Y, Abraham T, Lai, EW, Pacak K, Xiao R-P, Tomaselli GF, Kass DA. Mechanisms of Enhanced Beta-adrenergic Reserve From Cardiac Resynchronization Therapy. Circulation 119:1231-40, 2009.
Kao WH, Arking DE, Post WS, Rea TD, Sotoodehnia N, Prineas RJ, Bishe B, Doan BQ, Boerwinkle E, Psaty BM, Tomaselli GF, Coresh J, Siscovick DS, Marban E, Spooner PM, Burke GL, Chakravarti A. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. Circulation 119: 940-51, 2009.
Biswas S, DiSilvestre D, Tian YL, Halperin VL, Tomaselli GF. Latent modulation of cardiac sodium channel inactivation by dual mode calcium regulation. Circ Res 104:870-8, 2009.
Cheng A, Dalal D, Fetics BJ, Angkeow P, Spragg DD, Calkins H, Tomaselli GF, Berger RD. Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease. J Cardiovasc Electrophysiol20:873-9, 2009.
Yamaghishi T, Xiong W, Kondratiev A, Velez P, Mendez-Fitzwilliam A, Balser JR, Marban E, Tomaselli GF. Novel molecular determinants in the pore region of sodium channels regulate local anesthetic binding. Mol Pharm in press 2009.
Nazarian S, Dong J, Tomaselli GF, Marine JE. Profound hypotension due to slow atrioventricular nodal pathway conduction during atrial tachycardia. Pacing Clin Electrophysiol 32:278-80, 2009.
Barth AS, Aiba T, Halperin V, DiSilvestre D, Chakir K, Colantuoni C, Tunin RS, Dimaano VL, Yu W, Abraham TP, Kass DA, Tomaselli GF. Cardiac resynchronization therapy corrects dyssynchrony-induced regional gene expression changes on a genomic level. Circulation: Cardiovascular Genetics 2:371-8, 2009.
Hesketh GG, Van Eyk JE, Tomaselli GF. Mechanisms of Gap Junction Traffic in Health and Disease. J Cardiovasc Pharmacol in press 2009.