Human atrial fibroblasts and their contribution to supraventricular arrhythmia.

The healthy heart is heavily populated with fibroblasts. The mouse heart contains 56% cardiomyocytes, 27% fibroblasts, 7% endothelial cells, and 10% vascular smooth muscle cells, based on a study where hearts were enzymatically digested and the cells immunolabeled and sorted according to fluorescence, FACS (Banerjee et al. 2007). Another study from rat heart reports only 30–35% cardiomyocytes and 65–70% nonmuscle cells (Nag 1980). Despite their high numbers, the fibroblasts constitute less than 25% of the mass of the heart, and the majority of the mass comprised cardiomyocytes (Vliegen et al. 1991). The relative size of the fibroblasts is small; cell sizes measured as electrical capacitance are approximately 15 pF for freshly isolated fibroblasts (Poulet et al. 2016) compared to 90 pF atrial cells and 190 pF of ventricular cells (Calloe et al. 2013). The cardiac fibroblasts secrete the majority of the extracellular matrix proteins, like collagens, laminin, proteoglycans, and fibronectin, and are pivotal for keeping the three-dimensional structure of the heart. Myofibroblasts are fibroblasts that are expressing actin and myosin. Fibroblasts are continuously adapting to their environment, and especially mechanical stimuli will modulate the expression of these contractile proteins. Not all agree on a sharp separation between the fibroblast and the myofibroblast and take the view that the fibroblast is a dynamic cell type that can express various amounts of actin and myosin, suggesting that the transition into myofibroblast is not a differentiation of the cell. Myofibroblasts are not found in the healthy heart, but they play a key role in the reparative fibrosis and scarring after myocardial infarction (Souders et al. 2009). Fibroblasts secrete the extracellular matrix and can thereby affect cardiac electrophysiology by separating strands of cardiomyocytes with interstitial fibrosis. This causes a regionally reduced conduction velocity. Functional coupling between fibroblasts and cardiomyocytes has not been shown in human tissue; however, in animal models and cell cultures, it has been demonstrated that fibroblasts and cardiomyocytes can couple electrically to each other (Camelliti et al. 2004). This can affect the electrical properties of the cardiomyocytes, both passively and actively. The passive effects are due to the resistive and capacitive load on the cardiomyocyte. Fibroblasts are electrically nonexcitable (i.e., they do not make action potentials), but they have a high membrane resistance, and efficient coupling to a cardiomyocyte causes a dilution of the current density when membrane area increases without an increase in the number of ion channels. Moreover, fibroblasts may actively affect the action potential shape in cardiomyocytes (Camelliti et al. 2005; Kakkar and Lee 2010). Compared to cardiomyocytes, the fibroblasts have a less negative membrane potential ( 50 to 10 mV; Kohl and Gourdie 2014), so when the fibroblasts are coupled to cardiomyocytes, depolarization of the cardiomyocytes will generate a flow of gap junctional current into the fibroblasts. This causes activation of voltage gated outward K currents in the fibroblasts, which may shorten the action potential in the cardiomyocyte. The less negative potential of the fibroblasts can in turn depolarize the coupled cardiomyocyte during diastole. The effect of this depolarization on cardiomyocyte excitability is complex. A slight depolarization can bring the potential closer to threshold for action potential firing, resulting in triggered activity, but will more likely result in sodium channel inactivation and thereby slow depolarization during the action potential. The increased capacitive load after coupling will also contribute to diluting the depolarization force of the cardiomyocyte. Thus, the fibroblasts may be an important component of the cardiac syncytium in disease, where fibroblast–cardiomyocyte coupling will reduce conduction velocity and potentially render the cardiomyocytes unexcitable. The impact of fibroblasts on cardiac electrophysiology depends on (1) how well the cells are coupled; and (2) the electrical properties of the fibroblast. Yet, all these parameters are not fully investigated in vivo, and the functional importance of fibroblast–cardiomyocyte coupling still needs to be established in both healthy and diseased human hearts.