Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering

Abstract

Kurata Y, Matsuda H, Hisatome I, Shibamoto T. Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering. Am J Physiol Heart Circ Physiol 292: H701-H718, 2007. First published September 22, 2006; doi:10.1152/ajpheart.00426.2006.-A cardiac biological pacemaker (BP) has been created by suppression of the inward rectifier K ϩ current (IK1) or overexpression of the hyperpolarization-activated current (Ih). We theoretically investigated the effects of incorporating Ih, T-type Ca 2ϩ current (ICa,T), sustained inward current (Ist), and/or low-voltage-activated L-type Ca 2ϩ channel current (ICa,LD) on 1) creation of BP cells, 2) robustness of BP activity to electrotonic loads of nonpacemaking (NP) cells, and 3) BP cell ability to drive NP cells. We used a single-cell model for human ventricular myocytes (HVMs) and also coupled-cell models composed of BP and NP cells. Bifurcation structures of the model cells were explored during changes in conductance of the currents and gap junction. Incorporating the pacemaker currents did not yield BP activity in HVM with normal IK1 but increased the critical IK1 conductance for BP activity to emerge. Expressing Ih appeared to be most helpful in facilitating creation of BP cells via IK1 suppression. In the coupled-cell model, Ist significantly enlarged the gap conductance (GC) region where stable BP cell pacemaking and NP cell driving occur, reducing the number of BP cells required for robust pacemaking and driving. In contrast, Ih enlarged the GC region of pacemaking and driving only when IK1 of the NP cell was relatively low. ICa,T or ICa,LD exerted effects similar to those of I st but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing I st most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle. mathematical model; bifurcation analysis; computer simulation A CARDIAC BIOLOGICAL PACEMAKER (BP) has recently been created by genetic suppression of the inward rectifier K ϩ current (I K1 ) in guinea pig ventricular myocytes (28) or overexpression of the hyperpolarization-activated current (I h ) in canine atrial or Purkinje myocytes (32, 36), suggesting possible development of the functional BP as a therapeutic alternative to the electronic pacemaker (8, 37).A first step for creation of the functional BP would be engineering of single BP cells, which requires deep understanding of the BP mechanisms. By bifurcation analyses of a mathematical model for human ventricular myocytes (HVMs), we have elucidated (22) the dynamical mechanisms of BP generation in I K1 -downregulated HVMs and the roles of individual sarcolemmal currents in HVM pacemaking. We have suggested that 1) BP activity can be developed by reducing I K1 alone in HVMs as in guinea pig ventricular myocytes (41), 2) the instability of an equilibrium point (EP) with depolarized potentials is essentially important for BP gener...

Roles of hyperpolarization-activated current If in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models

“…Thus we first examined the influences of I f on stability and bifurcation of EPs during I bias applications, i.e., whether I f enlarges the unstable V E (and I bias ) region in the I bias -V E curve, for the model cells. This approach would reveal the contributions of I f to EP (V E ) instability, as well as robustness against hyperpolarizing and depolarizing loads (22)(23)(24)(25)52). Figure 1 shows the effects of increasing g f on stability and bifurcation during I bias applications of the Kurata et al central (21) and peripheral (25) Bifurcation points on the I bias -V E curve were determined with changing g f and plotted as functions of g f on both the potential (V E ) and current (I bias ) coordinates.…”

“…In our laboratory's previous studies, bifurcation structures (i.e., ways of changes in the number or stability of equilibrium and periodic states) of ventricular or SAN model systems were investigated for elucidating the dynamic mechanisms of normal and abnormal pacemaker activities (22)(23)(24)(25). These theoretical works indicate that the initiation and cessation of pacemaker activity are considered as bifurcation phenomena, and that the mathematical approach-bifurcation analysis-provides a convenient way of understanding how individual currents contribute to pacemaker activities.…”

Different distribution of Cav3.2 and Cav3.1 transcripts encoding T-type Ca2+ channels in the embryonic heart of mice

“…T-type Ca 2+ channels are further classified into 2 subtypes, Ni 2+ -insensitive (α1G) and -sensitive (α1H) channels, encoded by Cav3.1 and Cav3.2, respectively (8). They regulate intracellular calcium concentrations and contribute to cardiac automaticity (6). Their expression in the heart is regulated developmentally, being high in embryonic and neonatal hearts (12).…”

Effect of hyperpolarization-activated current If on robustness of sinoatrial node pacemaking: theoretical study on influence of intracellular Na+ concentration

“…For instance, I CaLD , which activates in the pacemaker potential range but is not present in the rabbit SAN, may contribute to enhancement of SAN cell robustness and emergence of I f -dependent pacemaking in the mouse SAN; indeed, I f at lower conductance (physiological densities) enhanced robustness of the Na i -variable system modified by incorporating I CaLD to simulate mouse SAN cell pacemaking (data not shown). Requirement of the combined effects of I f and other inward currents such as I st and I CaLD was also suggested for enhancement of biological pacemaker functions (23). In fact, the combined action of I f and I CaLD or I CaT as a requisite to generation of spontaneous rhythmic firings has been suggested for mouse atrioventricular cells (36) and ES cell-derived cardiomyocytes (55).…”