Cardiovasc Res. 2022 Jan 10:cvab375. doi: 10.1093/cvr/cvab375. Online ahead of print.
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 APDs.
AIMS: 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 RESULTS: 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 ± 25ms (mean±SD) in 17 hearts with a mean inter-quartile range (IQR) of 53 ± 17ms. 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 4,471 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.
CONCLUSIONS: 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 repolarisation despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.
TRANSLATIONAL PERSPECTIVE: We show that single myocytes from the same region of a heart have highly variable electrophysiology and different responses to ion-channel blocking drugs because of even higher inter-cell variation in ion-channel activity. Our data demonstrate that it is the relative activity of a single ion channel comparted to others that determines electrophysiological stability in the heart. Therefore, predisposition to arrhythmias from genetic or environmental causes is not due to up- or down-regulation of single ion-channels, but instead disrupted patterns of co-expression. An alternative treatment strategy therefore is to manipulate other ion-channels in the network to restore a stable co-expression pattern.
PMID:35020837 | DOI:10.1093/cvr/cvab375
