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

A cardiac biological pacemaker (BP) has been created by suppression of the inward rectifier K+ current ( IK1) or overexpression of the hyperpolarization-activated current ( Ih). We theoretically investigated the effects of incorporating Ih, T-type Ca2+ current ( ICa,T), sustained inward current ( Ist), and/or low-voltage-activated L-type Ca2+ 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 Ist but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing Ist most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle.

PROGRESS AND GAPS IN UNDERSTANDING THE ELECTROPHYSIOLOGICAL PROPERTIES OF MORPHOLOGICALLY NORMAL CELLS FROM THE CARDIAC ATRIOVENTRICULAR NODE

The atrioventricular node (AVN) is a small but critically important component of the cardiac electrical conduction system and is located at the junction between right atrium and right ventricle of the heart. It plays important roles in normal and abnormal impulse propagation. Mathematical models of the conduction properties of the AVN have been made, but detailed in silico reconstruction of AVN electrophysiology lags behind that of other cardiac regions. One important facet of detailed reconstruction of AVN electrical activity is the development of comprehensive, ionic conductance-based models of single cell electrophysiology. With a view to facilitating the construction of such models, this article reviews progress made regarding single AVN cell electrophysiological data during the last decade, predominantly focusing on that derived from morphologically normal AVN cells. Properties and potential roles of a range of currents are discussed: including L-type and T-type calcium currents (I Ca,L and I Ca,T respectively), background current, hyperpolarization-activated current (I f ), delayed and transient outward potassium currents (I Kr and I to , respectively), sodium–calcium exchanger current (I NaCa ), the sustained inward current (I st ) and acetylcholine-activated potassium current (I KACh ).

A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction

Mutations in the gene ( SCN5A) encoding the α-subunit of the cardiac Na+ channel cause congenital long QT syndrome (LQT-3). Here we describe a novel LQT-3 mutation I1768V (I1768V) located in the sixth transmembrane spanning segment of domain IV. This mutation is unusual in that it is located within a transmembrane spanning domain and does not promote the typically observed sustained inward current corresponding to a gain of channel function (bursting). Rather, I1768V increases the rate of recovery from inactivation and increases the channel availability, observed as a positive shift of the steady-state inactivation curve (+7.6 mV). Using a Markovian model of the cardiac Na+ channel, we simulated these changes in gating behavior and demonstrated that a small increase in the rate of recovery from inactivation is sufficient to explain all of the experimentally observed current changes. The effect of these alterations in channel gating results in an increase in window current that may act to disrupt cardiac repolarization.

Norepinephrine-induced sustained inward current in brown fat cells: α1-mediated by nonselective cation channels

The nature of the sustained norepinephrine-induced depolarization in brown fat cells was examined by patch-clamp techniques. Norepinephrine (NE) stimulation led to a whole cell current response consisting of two phases: a first inward current, lasting for only 1 min, and a sustained inward current, lasting as long as the adrenergic stimulation was maintained. The nature of the sustained current was here investigated. It could be induced by the α1-agonist cirazoline but not by the β3-agonist CGP-12177A. Reduction of extracellular Cl− concentration had no effect, but omission of extracellular Ca2+ or Na+ totally eliminated it. When unstimulated cells were studied in the cell-attached mode, some activity of ≈30 pS nonselective cation channels was observed. NE perfusion led to a 10-fold increase in their open probability (from ≈0.002 to ≈0.017), which persisted as long as the perfusion was maintained. The activation was much stronger with the α1-agonist phenylephrine than with the β3-agonist CGP-12177A, and with the Ca2+ionophore A-23187 than with the adenylyl cyclase activator forskolin. We conclude that the sustained inward current was due to activation of ≈30 pS nonselective cation channels via α1-adrenergic receptors and that the effect may be mediated via an increase in intracellular free Ca2+ concentration.