Tbx18 and the generation of a biological pacemaker. Are we there yet?

Keywords: Sinus node Gene program Calcium clock Membrane clock Transcriptional control, repressor Biological pacemaker A group of approximately 10,000 cells in the sinoatrial node (SAN), which is located at the entry of the right superior caval vein into the right atrium, is responsible for regular heart beating under different physiological conditions [1]. While the SAN is reliably working for most of our life, in the elderly, sick sinus syndrome (SSS), or sinus node dysfunction (SND) is prevalent [2] and responsible for 30 to 50% of all electronic pacemaker implantations [3]. Moreover, SSS is also often associated with the development of atrial fibrillation [4]. A fraction of the SSS cases is familial and has a genetic basis. Moreover, several null mutants in mice display bradyarrhythmias during postnatal life and may serve as animal models of SSS. SSS is also the result of intrinsic and extrinsic factors causing fibrosis and other structural impairments [4]. Treatment options are currently limited to the implantation of an electronic pacemaker. While being effective, the electronic pacemaker is insensitive to hormonal stimulation, has the hazards of infections, and possibly the replacement of the pacemaker may be required. Thus, there is demand to develop a biological pacemaker, which may overcome these problems. The SAN makes up an extensive area of the intercaval myocardium. Transitory cells are surrounding the primary nodal cells, which display both pacemaking abilities and fast conduction [5]. The SAN is densely innervated by the autonomic nervous system. It is separated from the working myocardium by connective tissue, which functions as electrical insulation and may protect the SAN from getting hyperpolarized. Optical mapping revealed the presence of exit pathways in the human SAN via which impulses are propagated into surrounding atrial muscle [6]. SAN myocytes are poorly coupled due to the presence of small amounts of slow conducting gap junctions consisting of connexin (Cx) 45 and Cx30.2 [7]. There are significant morphological differences between SAN myocytes and chamber myocytes (Fig. 1A). Sinus node cells have a small cell body and long thin cellular extensions [8]. The myofibrillar content in SAN myocytes is low, they lack T-tubules, but contain larger amounts of caveolae in comparison to atrial myocytes [9,10]. The ability of the SAN cells to act as the pacemaker of the heart depends on two oscillatory mechanisms, the Ca 2+-clock and the membrane clock that are interlinked by the release of calcium from the sarcoplasmatic reticulum …