Electrotonic modulation of cardiac impulse conduction by myofibroblasts.
Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express alpha-smooth muscle actin (alphaSMA) 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 [theta] 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 alphaSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected theta 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 theta and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), theta fell <200 mm/s. This biphasic dependence of theta 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.
Department of Physiology, University of Bern, Bern, Switzerland.
Michele
M
Miragoli
Giedrius
G
Gaudesius
Stephan
S
Rohr
D000818:Animals; D002478:Cells, Cultured; D018031:Connexin 43 / Q000032:analysis; D017630:Connexins / Q000032:analysis; D005347:Fibroblasts / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology
D018031:Connexin 43; D017630:Connexins; C487370:Gja3 protein, rat; D013779:Tetrodotoxin; D011188:Potassium