Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts

Abstract

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 ␣-smooth muscle actin (␣SMA) 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 [] and maximal upstroke velocity [dV/dt max ]) 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 ␣SMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected and dV/dt max in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both and dV/dt max , which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio Ͼ20:100), fell Ͻ200 mm/s. This biphasic dependence of and dV/dt max on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from Ϫ78 mV to Ϫ50 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. Key Words: electrophysiology Ⅲ slow conduction Ⅲ cardiac myofibroblasts Ⅲ fibrosis Ⅲ gap junctions T wo thirds of the cells of normal hearts are noncardiomyocytes, with fibroblasts constituting the largest fraction. At 2 months of age, fibroblasts outnumber cardiomyocytes by a factor of Ϸ2 in human hearts. [1][2][3] Under physiological conditions, fibroblasts are responsible for providing cardiomyocytes with a mechanical scaffold, which integrates the contractile activity of individual cells so as to result in the coordinated pump function of the organ. Accordingly, fibroblasts are found throughout the myocardium, where they form a 3D cellular network surrounding groups of cardiomyocytes. 4 The integrity of this structure is adversely affected by a large number of cardiac diseases ranging from volume to pressure overload and to myocardial infarction. Under these pathological conditions, complex reactions involving changes in extracellular matrix production, cell proliferation, and cell death cause structural remodeling of the ventricular wall, which compromises pump function and predisposes the heart to arrhythmias. 5 Moreover, it has been shown that these disease states are associated with the appearan...

Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

“…For fibroblasts, previous studies using myocytefibroblast co-culture models have shown that the fibroblasts depolarized electrotonically coupled myocytes (Miragoli et al, 2006;MacCannell et al, 2007;Jacquemet and Henriquez, 2008;Maleckar et al, 2009). Our simulations also showed a depolarizing effect of coupled fibroblasts on the resting membrane potential of ventricular myocytes.…”

“…In an experimental study, Miragoli et al (2006) found a biphasic effect on CV when endogeneous fibroblasts proliferated with myocytes. In a modeling study, Xie et al (2009a) showed that fibroblasts, whether coupled to myocytes or not, slowed conduction by creating zigzag conduction pathways.…”

“…Therefore, the functional roles of the fibroblasts in cardiac electrical and mechanical activities have attracted increasing interest, and have been explored in experimental studies (Miragoli et al, 2007;Zlochiver et al, 2008) and computational models (MacCannell et al, 2007;Tanaka et al, 2007;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008;Sachse et al, 2009). Both experimental and computational studies (Miragoli et al, 2006;Jacquemet and Henriquez, 2008;Zlochiver et al, 2008) have illustrated that non-monotonic changes in conduction velocity (CV) are caused by increasing the fibroblast population. ten Tusscher and Panfilov (2007) showed that CV decreased from 0.7 to 0.3 m/s as the percentage of fibroblast proliferous cells rose from 0 to 40% in two-dimensional (2D) tissue.…”

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Four whole-istic aspects of schistosome granuloma biology: fractal arrangement, internal regulation, autopoietic component and closure

“…Connexins are integral membrane proteins that form communicating junctions, or gap junctions. Connexin-43 was localized in hepatocytes, activated rat hepatic stellate cells, hematopoietic stroma cells, smooth muscle cells, fibroblasts (Ibuki et al 2002), myofibroblasts (Miragoli et al 2006), macrophages, thymocytes, and thymic epithelial cells. In our material (data not shown), double stains to connexin-43 combined with eosinophils or thy-1 or MAC-1 or B-220, showed that connexin-43 was expressed mainly by the middle or fibroblastic-like zone (myofibroblastic cells?)…”