Recreating an artificial biological pacemaker: Insights from a theoretical model

Background

Normal cardiac rhythm is critically dependent on the sinoatrial (SA) node, the natural biological pacemaker. Although recent studies have focused on the development of “artificial” biological pacemakers using gene transfer, less is known about the functional consequences of such interventions.

Objective

The purpose of this study was to investigate the electrophysiological consequences of two approaches used to create a biological pacemaker: overexpression of the hyperpolarization-activated cyclic nucleotide gated channel (HCN “pacemaker” channels) and suppression of the inward-rectifier potassium current, I_K1.

Methods

We used a linear multicellular Luo-Rudy (LRd) AP model consisting of 130 ventricular cells connected by resistive gap junctions. To induce automaticity, I_K1 current was reduced or I_f (HCN) current was introduced in endocardial and midmyocardial (M) cells.

Results

Similar to the previously published results for a single LRd model, myocyte I_K1 suppression induced automaticity in the fiber. While introduction of I_f also resulted in automaticity, the main differences between I_K1 suppression and I_f expression were (1) a relatively more gradual phase 4 depolarization with HCN expression, (2) stabilization of cycle lengths during I_K1 suppression, but not during HCN expression, and (3) responsiveness to β-adrenergic stimulation during HCN expression, but not during I_K1 suppression. Upon further investigation, we found that cycle length instability during HCN expression was primarily due to a gradual reduction of intracellular potassium ([K⁺]_i) from its baseline value of 142 mM to 120 mM in 600 beats and subsequent alteration of potassium-dependent ionic currents. A twofold increase in HCN expression also led to a similar behavior. We attribute this decrease in [K⁺]_i to a large I_K1 during phase 4 depolarization. When intracellular [K⁺]_i loss was minimized, cycle lengths stabilized during HCN expression.

Conclusions

Our results help to further understand the electrophysiologic consequences as well as some of the challenges associated with the creation of biological pacemakers using HCN and I_K1 gene transfer strategies.

Keywords:  Computer modeling , Pacemaker , Gene therapy , Inward rectifier , Pacemaker channel