Fibroblasts: modulating the rhythm of the heart

Abstract

Cardiac fibroblasts have been implicated in arrhythmia initiation and maintenance affecting electrical propagation through slow, discontinuous conduction. Fibroblasts are unexcitable cells, their resting membrane potential is more depolarized than that of myocytes and their membrane resistance is higher. These characteristics suggest that, if coupled to myocytes, fibroblasts may function as current sinks and/or sources for electrical charge and as shortand long-range conductors. Abnormal accumulation of fibroblasts occurs in the heart under pathological conditions and ageing, which may alter normal cardiac function. Most clinical, experimental and numerical studies have regarded fibroblasts and fibrosis as electrically insulating obstacles. However, recent suggest that when coupled to cardiac myocytes, fibroblasts could influence impulse propagation not only by acting as passive transducers but also by influencing excitability of neighbouring myocytes (Miragoli et al. 2007). Compared to the atria and ventricles, the sinoatrial (SA) node contains a relatively higher amount of fibroblasts, which can be electrically coupled to pacemaker cells. Electrical coupling through gap junctions in the SA node is important for achieving pacemaker synchronization (Jalife, 1984). Pacemaker cells in the intact SA node beat at a common frequency but when isolated they show large variations in intrinsic beating frequency. Functional electrical coupling of SA nodal pacemaker cells through connexins forming gap junctions has been demonstrated in several species. However, the connexin isotypes expressed in the SA node vary somewhat depending on the species. Cx43, the most abundant connexin in the heart, has also been found in the SA node of rabbit, hamster and guinea pig although it is less abundant than other connexins. Interestingly, Cx43 was not detected in rat, cow or human nodal tissue. Recently, Kreuzberg et al. (2005) demonstrated that the mouse SA node expresses Cx30.2. Further studies using Cx30.2-knock-out mice suggest that Cx30.2 provides higher intercellular resistance and slower conductance due to a relatively small unitary conductance (∼9 pS). Nevertheless, the role of gap junctions in heterocellular tissue in the SA node remains unknown. The study by Fahrenbach et al. (2007) provides indirect evidence toward addressing this question. They investigated the mechanism through which non-excitable cells influence the spontaneous activity of pacemaker cells using heterocellular monolayers of HL-1 cells, a cell line derived from murine atrial myocyte tumour lineage AT-1, and fibroblasts that were isolated from neonatal rat and mouse ventricular tissue. The influence of fibroblasts on frequency of spontaneous activity, conduction velocity and interbeat interval variability were studied by co-culturing fibroblasts and myocytes at varying ratios.