Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express α-smooth muscle actin (αSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [θ] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to αSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected θ and dV/dtmax in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both θ and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), θ fell <200 mm/s. This biphasic dependence of θ and dV/dtmax on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from -78 mV to -50 mV as measured using microelectrode recordings. These findings suggest that myofibroblasts, apart from their role in structural remodeling, might contribute to arrhythmogenesis by direct electrotonic modulation of conduction and that prevention of their appearance might represent an antiarrhythmic therapeutic target. © 2006 American Heart Association, Inc.

Electrotonic modulation of cardiac impulse conduction by myofibroblasts / Miragoli, Michele; Gaudesius, Giedrius; Rohr, Stephan. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 98:6(2006), pp. 801-810. [10.1161/01.RES.0000214537.44195.a3]

Electrotonic modulation of cardiac impulse conduction by myofibroblasts

MIRAGOLI, MICHELE;
2006-01-01

Abstract

Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express α-smooth muscle actin (αSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [θ] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to αSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected θ and dV/dtmax in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both θ and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), θ fell <200 mm/s. This biphasic dependence of θ and dV/dtmax on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from -78 mV to -50 mV as measured using microelectrode recordings. These findings suggest that myofibroblasts, apart from their role in structural remodeling, might contribute to arrhythmogenesis by direct electrotonic modulation of conduction and that prevention of their appearance might represent an antiarrhythmic therapeutic target. © 2006 American Heart Association, Inc.
Electrotonic modulation of cardiac impulse conduction by myofibroblasts / Miragoli, Michele; Gaudesius, Giedrius; Rohr, Stephan. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 98:6(2006), pp. 801-810. [10.1161/01.RES.0000214537.44195.a3]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2817821
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