Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 28, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp164
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Cardiac Fibroblast Paracrine Factors Alter Impulse Conduction and Ion Channel Expression of Neonatal Rat Cardiomyocytes
Biomedical Engineering Department, Duke University, Durham, NC 27708
* Corresponding author: Nenad Bursac, PhD, Assistant Professor, Department of Biomedical Engineering, Duke University, Hudson Hall 136, Durham, NC 27708, Phone: 919-660-5510, FAX: 919-684-4488, Email: nbursac{at}duke.edu
Aims: The pathologic proliferation of cardiac fibroblasts in response to heart injury results in fibrosis, which correlates with arrhythmia generation and heart failure. Here we systematically examined the effect of fibroblast-derived paracrine factors on electrical propagation in cardiomyocytes.
Methods: Neonatal rat cardiac monolayers were exposed for 24 h to media conditioned by cardiac fibroblasts. Optical mapping, sharp microelectrode recordings, quantitative RT-PCR and immunostaining were used to assess changes in the propagation and shape of the action potential and underlying changes in gene and protein expression.
Results: The fibroblast paracrine factors produced a 52% reduction in cardiac conduction velocity, a 217% prolongation of action potential duration, a 64% decrease of maximum capture rate, a 21% increase in membrane resting potential, and an 80% decrease of action potential upstroke velocity. These effects were dose-dependent and partially reversible with removal of the conditioned media. No fibroblast proliferation, cardiomyocyte apoptosis, or decreased connexin-43 expression, phosphorylation and function were found in conditioned cardiac cultures. In contrast, the expression of the fast sodium, inward rectifying potassium and transient outward potassium channels were respectively reduced 3.8-fold, 6.6-fold, and to undetectable levels. The expression of β-myosin heavy chain increased 17.4-fold. No electrophysiological changes were observed from media conditioned by cardiac fibroblasts in the presence of cardiomyocytes.
Conclusions: Paracrine factors from neonatal cardiac fibroblasts alone produced significant electrophysiological changes in neonatal rat cardiomyocytes resembling those found in several cardiac pathologies.
Time for primary review: 29 Days
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