Contact the Lab
Vickas V. Patel, MD, PhD
Vickas Patel, MD, PhD
11-106 TSmillow Center for Translational Research
3400 Civic Center Boulevard, Bldg. 421
Philadelphia, PA 19104-5159
Nina Maschak, Administrative Assistant
Smillow Center for Translational Research
3400 Civic Center Boulevard, Bldg. 421
Philadelphia, PA 19104-5159
The Patel laboratory is focused upon elucidating the molecular mechanisms underlying cardiac arrhythmias and conduction disorders. Accordingly, the laboratory is creating and employing genetically engineered mice that model human arrhythmogenic disorders to investigate arrhythmia mechanisms at the level of the whole heart, cardiomyocyte and molecule. This integrative approach is accomplished using the murine in vivo electrophysiology technique in combination with the patch clamp technique, calcium flux imaging, molecular genetics and biochemical analysis.
Research Projects at the Patel Lab
The research projects presently ongoing at the Patel Laboratory, which are suitable for either students or post-doctoral fellows, are summarized below:
The function and regulation of a newly identified melanocyte-like cell population in the mouse and human pulmonary veins that may contribute to atrial arrhythmia triggers.
Atrial arrhythmias, in particular atrial fibrillation, are the most common clinical cardiac arrhythmias, and are associated with significant morbidity. While it is well accepted that ectopic beats arising from the pulmonary veins and atria initiate arrhythmias, the cellular source and mechanism underlying these beats remains largely unknown. The Patel Lab recently described a unique population of cells residing in the pulmonary veins and atria of both mice and humans. These cells express enzymes of the melanocyte lineage, including dopachrome tautomerase (Dct) and tyrosinase (Tyr). While melanocyte-like cells in the murine heart have been described by others, their contribution to atrial excitability remains unknown. Furthermore, human counterparts were previously not known to exist. Importantly, published data from the Patel Lab shows "cardiac melanocytes" are excitable and those lacking Dct have prolonged action potentials with after depolarizations. We have also found that cardiac melanocytes exist in close proximity to autonomic nerve terminals in the heart and contribute to atrial arrhythmia triggers in response to altered autonomic stimulation. The Patel Lab is currently carrying out studies investigating the ionic basis of triggered activity in cardiac melanocytes and their response to common stimuli that initiate atrial arrhythmias, such as changes in autonomic tone and reactive oxygen species.
The Patel Lab is also engineering mouse models with selective ablation of cardiac melanocytes driven by melanocyte-specific expression of diphtheria toxin A in order to better understand the contribution of these cells to atrial arrhythmias. In addition, the Lab is collaborating with Dr. Peng Chen's laboratory at Indiana University to investigate the mechanisms and frequency with which cardiac melanocytes initiate atrial arrhythmia triggers using ex vivo optical mapping in mouse atria. This work is funded through an NIH R01 grant.
The role of the transcription factors HopX, GATA-6 and T-box factors in cardiac conduction system development and function in genetically engineered mouse models.
The Patel Lab is investigating transcription factors involved with the development and maintenance of the cardiac conduction system, having discovered several years ago that expression of the homeodomain-only protein (HopX) is confined predominantly to the adult murine cardiac conduction system and that deletion of the HopX locus leads to infra-nodal conduction defects.
Surface ECG recordings and intracardiac electrograms from a HopX-null mouse and its wild-type littermate.
In the mature heart, HopX does not appear necessary for patterning of the cardiac conduction system, but conduction defects seem to be due to loss of connexin40, which is the major gap junction protein in the murine conduction system. Further studies showed HopX recruits class I histone deacetylases (HDACs), and current studies in the Patel Lab are focused upon investigating the role of HDACs in maintaining postnatal CCS function and structure. These investigations are being carried out using a novel MinKCre-inducible mouse line with which we can control the expression of Cre-recombinase within the cardiac conduction system and mice engineered with floxed HDAC alleles.
Serial frozen sections of newborn HopX+/- (A through C) and Hop-/- (D through F) hearts stained for β-galactosidase activity (A and D, blue) and connexin40 (B and C, E and F, green).
Recent studies in the Patel Lab have shown that cardiac-restricted deletion of the transcription factor GATA-6 induces specific deletion of HCN-4 positive cells in the compact atrioventricular (AV) node during development. This results in hypoplasia of the AV node with conduction defects that persist into postnatal life. In this case, it appears that proliferation of cardiac progenitors cells is increased within the AV node because the Id2 (inhibitor of DAN binding protein 2) is a direct transcriptional target of GATA-6, which otherwise suppresses cardiomyocyte proliferation. The Patel Lab is currently investigating the interactions between HopX, HDACs and GATA-6 in the AV node to determine the mechanism by which these factors interact to control AV node structure and function
The Lab is also collaborating with the group led by Drs. Ivan Moskowitz and Marcelo Nobrega at the University of Chicago to investigate the contribution of T-box factors to cardiac conduction system development and function. This work is funded through an NIH R01 to determine the contribution of Tbx3 and Tbx5 to maintaining nodal and infranodal cardiac conduction system function in the postnatal. These studies involve deleting floxed alleles of Tbx5 and/or Tbx3 from the cardiac conduction system using the MinKCre-inducible mouse engineered in Dr. Moskowitz's lab. The Patel Lab is assessing the functional affects of these deletions by in vivo electrophysiological analysis and the patch clamp technique.
In addition to the above investigations, the Patel Laboratory is elucidating the role and contribution of class I histone deacetylases to atrial fibrosis and arrhythmogenesis in genetically engineered mouse models with cardiac hypertrophy and the contribution of class I histone deacetylases to postnatal cardiac conduction system function.
Members of the Patel Lab of the Penn Cardiovascular Institute publish journal articles and book chapters that reflect the breadth of the laboratory's research.
- Rentschler S, Yen AH, Lu J, Petrenko NB, Lu MM, Manderfield LJ, Patel VV, Epstein JA. Myocardial notch signaling reprograms cardiomyocytes to a conduction-like phenotype. Circulation. 2012;126:1058-1066.
- Arnolds DE, Liu F, Smemo S, Schillinger KS, Fahrenbach JP, Kim GH, McNally EM, Nobrega MM, Patel VV, Moskowitz IP. A Tbx5-Scn5a molecular network modulates function of the murine adult cardiac conduction system. J Clin Invest. 2012;122:2509-2518.
- Kim TK, Sul JY, Peternko NB, Lee JH, Lee M, Patel VV, Kim J, Eberwine JH. Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes. P Natl Acad Sci USA. 2011;108:11918-11923.
- Rentschler S, Harris BS, Kuznekoff L, Jain R, Manderfield L, Lu MM, Morley GE, Patel VV, Epstein JA. Notch signaling regulates murine atrioventricular conduction and formation of accessory pathways. J Clin Invest. 121:525-533, 2011.
- Patel VV. Novel insights in the cellular basis of atrial fibrillation. Expert Rev Cardiovasc Ther. 2010;8:907-915.
- Levin MD, Lu MM, Petrenko NB, Hawkins BJ, Gupta TH, Lang D, Buckley PT, Jochems J, Liu F, Spurney CF, Yuan LJ, Jacobson JT, Brown CB, Huang L, Beermann F, Margulies KB, Muniswamy M, Eberwine JH, Epstein JA, Patel VV. Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest. 2009;119:3420-3436
- Wang D,* Patel VV,* Ricciottia E, Zhou R, Levin MD, Gao E, Yua Z, Ferrari VA, Lu MM, Xu J, Zhang H, Hui Y, Cheng Y, Petrenko N, Yu Y, FitzGerald GA. Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function. P Natl Acad Sci USA. 2009;106:7548-7552. *Equal contribution.
- Liu, F, Levin MD, N.B. Petrenko, Lu MM, Wang T, Yuan LJ, Stout AL, Epstein JA, Patel VV. Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Molecul Cell Cardiol. 2008;45:715-723.
- Ismat FA, Zhang M, Kook H, Huang B, Zhou R, Ferrari VA, Epstein JA, Patel VV. Homeobox protein Hop functions in the adult cardiac conduction system. Circ Res. 2005;96:898-903.