Biologic Pacemaker - Role of Gene and Cell Therapy in Cardiac Arrhythmias

Abstract

In mammalian heart, the sino-atrial (SA) node is the pacemaker region, which contains a family of ionic currents that contributes to the pacemaker potential. Using SA nodal cells, experiments have shown that dysrhythmias are easily elicited under conditions involving calcium overload that occur during ischemia and cardiac failure. Clinically these SA nodal dysfunctions cause bradyarrhythmias in general and are associated with syncope but rarely with death. To initiate pacemaker function an inward current (If) carried by sodium through a family of channels that are hyperpolarization-activated and cyclic nucleotide-gated (HCN channels) (Biel et al 2002). Recent advances in molecular and cellular biology, specifically in the areas of stem cell biology and tissue engineering have initiated the development of a new field in molecular biology, regenerative medicine, seeks to develop new biological solutions, using the mobilization of endogenous stem cells or delivery of exogenous cells to replace or modify the function of diseased, absent, or malfunctioning tissue. As far as adult cardiomyocytes have limited regenerative capacity it represents an attractive candidate for these emerging technologies. Therefore, dysfunction of the specialized electrical conduction system may result in inefficient rhythm initiation or impulse conduction leading to significant bradycardia that may require the implantation of a permanent electronic pacemaker. Replacement of the dysfunctional myocardium by implantation of external heart muscle cells is emerging as a novel paradigm for restoration of the myocardial electromechanical properties, but has been significantly limited by the paucity of cell sources for human heart cells and by the relatively limited evidence for functional integration between grafted and host cells. Human embryonic stem cell lines may provide a possible solution for the cell sourcing problem. Although electronic pacing is an excellent therapy, still have disadvantage like the need for monitoring and replacement, indwelling catheter-electrodes in the heart, possibility of infection, and lack of autonomic responsiveness, geometric limitations with respect to pediatric patients make it warrant a search for better alternatives (Rosen et al 2004). The biological pacemaker, a tissue that spontaneously or via engineering confers pacemaker properties to regions of the heart, is an exciting alternative. Several approaches have been