Jeffery Saffitz Lab
Research in my laboratory is focused on cell-cell communication via gap junctions in the heart. Our long-term goals are to elucidate molecular and structural determinants of normal and abnormal intercellular coupling and to define the role of altered expression of connexins (gap junction channel proteins) and remodeling of gap junctions in the pathogenesis of lethal ventricular arrhythmias. We use mouse models and in vitro preparations to delineate mechanisms regulating formation and function of gap junctions and define how altered coupling contributes to conduction abnormalities. Much of our work has focused on the role of gap junction remodeling in arrhythmogenesis in acute and chronic ischemic heart disease. However, we have also characterized the molecular pathology of human cardiomyopathies caused by mutations in genes encoding proteins that form desmosomes. These diseases (Naxos disease, Carvajal syndrome, ARVC Type 8 and plakophilin-related cardiomyopathies) have clinical phenotypes of arrhythmogenic right ventricular cardiomyopathy (ARVC) and/or dilated cardiomyopathy (DCM) associated with a particularly high risk of malignant ventricular arrhythmias and sudden cardiac death (SCD). We have developed a unifying hypothesis that genetic defects in cell-cell adhesion junctions and resultant discontinuities between mechanical junctions and the cytoskeleton cause contractile dysfunction by interfering with force transmission and also create anatomic substrates of sudden death by remodeling gap junctions and altering electrical conduction. We have substantiated this hypothesis in various mouse models of these human cardiomyopathies and in studies in vitro in which cardiac myocytes are subjected to defined mechanical load and changes in expression of cell-cell junction proteins are rigorously analyzed in a defined system.
Members of The Lab
Karen Yee, PhD - Lab Manager
Kiyomi Yamada Hames, MD, PhD - Post-doc Fellow
Weihui Li, PhD - Post-doc Fellow
Angeliki Asimaki - Graduate Student
Nathan Norton, Research Assistant
Selected Recent Publications
Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis, A, Prost Squarcione C, McKenna WJ, Thiene G, Basso C, Brousse N, Fontaine G, Saffitz JE: Remodeling of gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 2004; 1:3-11
Yamada K, Green KG, Samarel AM, Saffitz JE: Distinct pathways regulate expression of cardiac electrical and mechanical junction proteins in response to stretch. Circ. Res., 2005; 97:346-353.
Saffitz JE: Adhesion molecules: why they are important to the electrophysiologist. (Molecular Perspectives) J Carviovasc Electrophysiol, 2006; 17:225-229.
Saffitz, JE: The biology and pathobiology of cardiac connexins - from cell to bedside. Heart Rhythm, 2006; 3:102-107.
Beauchamp P, Yamada KA, Baertschi AJ, Green K, Kanter EM, Saffitz JE, Kléber AG: Relative contributions of connexin40 and connexin43 to atrial impulse propagation synthetic strands of neonatal and fetal murine cardiomyocytes. Circ Res, in press.