Research

Research in my laboratory focuses primarily on myocardial remodeling and myocardial responses to physiological and pathological stress with an emphasis on multilevel inquiries that balance the benefits and drawbacks of reductionism and integration. 

My laboratory has had a longstanding commitment to characterizing the human myocardium through physiological and molecular analyses of tissues obtained at the time of heart transplantation and organ donation.  Careful characterization of human myocardial biology permits insights into both the heterogeneity of myocardial adaptations to disease and identification of dominant mechanisms and responses.  Human tissue phenotyping also allows selection and validation of appropriate models that permit more mechanistic studies and preclinical inquiries.  Active studies utilizing human studies include integrated genetic, epigenetic and genomic inquiries designed to identify molecular mechanisms modifying disease susceptibility, preclinical pharmacologic assessments of novel therapeutics and multilevel characterization of recovery and repair process within human hearts.

My lab has had a longstanding interest in elucidating the responses of severely failing hearts to the mechanical unloading and neurohumoral changes that occur during circulatory assistance.  This phenomenology within human hearts and appropriate animal models yields new insights into mechanisms of myocardial plasticity, load-modulated signaling, and the biology of myocardial recovery.  Our long-term goal is to identify reliable biomarkers of recoverability and develop targeted therapeutic strategies to promote the recovery of failing hearts.

Our recent studies of cardiac stem/progenitor cells (S/PCs) have stimulated several new lines of research including several versatile in vitro models well-suited to studies of S/PC biology. Integrated use of multiparameter flow cytometry and cell sorting, cell culture, isolated-perfused hearts, and in vitro studies of cell and tissue mechanics models permit us to characterize mechanisms regulating S/PC homing, differentiation and maturation. These models are complemented by tissue engineering approaches that enable manipulation of the myocardial microenvironment, rigorous in vitro characterization of newly differentiated cardiac myocytes, and in vivo translational studies in humans.

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Publications

For all publications, click on

Latest Publications:

Jung AS, Kubo H, Wilson RM, Houser SP, Margulies KB, Modulation of Contractility by Myocyte-Derived Arginase in Normal and Hypertrophied Feline Myocardium. Am J Physiol Heart Circ Physiol. 290(5):H1756-62, 2006.

Grzywacz FW, Piacentino V III, Gaughan JP, Rothman SA, Margulies KB. Acute unloading via head-up tilt causes QTc prolongation in patients with advanced cardiomyopathy. Am J Cardiology 97:412-5, 2006.

Litvin J, Blagg A, Mu A, Matiwala S, Montgomery M, Berretta R, Houser S, Margulies KB. Periostin and periostin-like factor in the human heart: possible therapeutic targets. Cardiovasc Pathol. 15(1):24-32, 2006.

Petre RE, Qualie MP, Rossman EI, Ratcliffe SJ, Bailey BA, Houer SR, Margulies KB. Sex-based differences in myocardial contractile reserve. Am J Physiol Heart Circ Physiol. 292:R810-8, 2007.

Maybaum S, Mancini D, Xydas S, Starling R, Aaronson K, Pagani FD, Miller LW, Margulies K, McRee S, Frazier OH, Torre-Amione G. Cardiac Improvement During Mechanical Circulatory Support: A Prospective, Multi-center Study of the LVAD Working Group. Circulation 115:2497-505, 2007.

McGinley JC, Berretta RM, Chaudhary K, Rossman E, Bratinov GD, Gaughan JP, Houser S, Margulies KB. Impaired contractile reserve in severe mitral valve regurgitation with a preserved ejection fraction. Eur J Heart Fail. 2007 Jun 25; [Epub ahead of print]

Quaile MP, Rossman EI, Berretta RM, Bratinov G, Kubo H, Houser SR, Margulies KB. Reduced sarcoplasmic reticulum Ca2+ load mediates impaired contractile reserve in right ventricular pressure overload. J Mol Cell Cardiol. 43:552-63, 2007.

Kubo J, Jaleel N, Kumarapeli A, Beretta R, Bratinov G, Shan X, Wang H, Houser SR, Margulies KB. Increased Cardiac Myocyte Progenitors in Failing Human Hearts. Circulation 118:649-57, 2008.

Shan X, Wang H, Margulies KB. Apoptosis signal-regulating kinase 1 attenuated atrial natriuretic peptide secretion. Biochemistry 47:10041-8, 2008.

Matkovich SJ, Van Booven DJ, Youker KA, Torre-Amione G, Diwan A, Eschenbacher WH, Dorn LE, Watson MA, Margulies KB, Dorn GW 2nd. Reciprocal Regulation of Myocardial microRNAs and Messenger RNA in Human Cardiomyopathy and Reversal of the microRNA Signature by Biomechanical Support. Circulation 119: 1263-71, 2009.

Quaile MP, Kubo H, Kimbrough CL, Douglas SA, Margulies KB. Direct Inotropic Effects of Exogenous and Endogenous Urotensin-II: Divergent Actions in Failing and Nonfailing Human Myocardium. Circulation Heart Failure 2:39-46, 2009.

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Reagents and Protocols

Cardiac Myocyte Core

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Contact

Ken Margulies, MD
608 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104

Email: ken.margulies@uphs.upenn.edu
Phone: 215-573-2980
Fax: 215-898-3473

Chrisine Malloy, Administrative Assistant

Email: Christine.Malloy@uphs.upenn.edu
Phone: 215-573-2999
Fax: 215-898-3473

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Lab Members and Contact Information

Ken Margulies, MD, kenb@mail.med.upenn.edu

George Bratinov, bratinov@mail.med.upenn.edu

Judy Marble, judith.marble@uphs.upenn.edu

Anbin Mu, anbinmu@yahoo.com

Mike Quaile, quaile@temple.edu

Xiaoyin Shan, xiaoyins@mail.med.upenn.edu

Hongmei Wang, hongmeiw@mail.med.upenn.edu

 

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Useful Links

• Cardiac Myocyte Core

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