Abstract
Cardiac 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. APD 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. Modelling 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.
Highlights
The ventricular action potential (AP) waveform is the crucial first step in excitation–contraction (E-C) coupling
Modelling 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
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
Summary
The ventricular action potential (AP) waveform is the crucial first step in excitation–contraction (E-C) coupling. The time-course and magnitude of AP Phases 0–3 are a consequence of a complex pattern of transsarcolemmal current flow mediated by ion channels, electrogenic exchangers, and pumps. Any change to the dynamic balance of ionic currents caused by environmental (e.g. drugs) or genetic factors (e.g. single nucleotide polymorphisms) affects the AP waveform and can have fatal pro-arrhythmic consequences.[1] The timing of repolarization in the left ventricle (LV), and the QT interval, is key to stable ventricular electrophysiology. The average corrected QT value (QTc) in humans is close to 400 ms [e.g. 408 ± 27 ms, mean ± standard deviation (SD)],2 with variation across a population quantified by an SD of 30–35 ms.[3] Individuals with shorter or longer than normal QTc values are at higher risk of death from cardiovascular causes.[1] Genetic variation within the human population is thought to account for about 50% of the QT variation,[4] presumably through variations in expression and activity/kinetics of ion channels associated with the AP. Computational studies have shown that this large inter-individual variation in ion channel activity can be tolerated through functional overlap and specific correlations between ion channels.[8,9] This concept is established in neuroscience[10,11,12] and evidence is emerging of similar key relationships in cardiac-specific mRNA levels from molecular studies in humans.[7]
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