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Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells.

ABSTRACT: The intrinsic heterogeneity of electrical action potential (AP) properties between Purkinje fibers (PFs) and the ventricular wall, as well as within the wall, plays an important role in ensuring successful excitation of the ventricles. It can also be proarrhythmic due to nonuniform repolarization across the Purkinje-ventricular junction. However, the ionic mechanisms that underlie the marked AP differences between PFs and ventricular cells are not fully characterized. We studied such mechanisms by developing a new family of biophysically detailed AP models for rabbit PF cells and three transmural ventricular cell types. The models were based on and validated against experimental data recorded from rabbit at ionic channel, single cell, and tissue levels. They were then used to determine the functional roles of each individual ionic channel current in modulating the AP heterogeneity at the rabbit Purkinje-ventricular junction, and to identify specific currents responsible for the differential response of PFs and ventricular cells to pharmacological interventions.

SUBMITTER: Aslanidi OV

PROVIDER: S-EPMC2877343 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells.

Aslanidi Oleg V OV Sleiman Rakan N RN Boyett Mark R MR Hancox Jules C JC Zhang Henggui H

Biophysical journal 20100601 11

The intrinsic heterogeneity of electrical action potential (AP) properties between Purkinje fibers (PFs) and the ventricular wall, as well as within the wall, plays an important role in ensuring successful excitation of the ventricles. It can also be proarrhythmic due to nonuniform repolarization across the Purkinje-ventricular junction. However, the ionic mechanisms that underlie the marked AP differences between PFs and ventricular cells are not fully characterized. We studied such mechanisms ...[more]

PMID: 20513385

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Project description:AimsCardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.Methods and resultsAPD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK.ConclusionModelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.

Project description:RationaleA chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I(to)) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I(to) and that its overexpression might specifically alter PF I(to) properties and repolarization.ObjectiveTo assess the potential role of DPP6 in PF I(to).Methods and resultsClinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I(to) had similar density, but PF I(to) differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K(+)-channel interacting β-subunit K(+)-channel interacting protein type-2, essential for normal expression of I(to) in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I(to); I(to) amplitude was greatly enhanced by coexpression with K(+)-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K(+)-channel interacting protein type-2 failed to alter I(to) compared with Kv4.3/K(+)-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I(to) composition) greatly enhanced I(to) compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization.ConclusionsThese results point to a previously unknown central role of DPP6 in PF I(to), with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.

Dataset Information

Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells.

Publications

Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells.

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