Abstract
AimHypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification.MethodsLeft ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K+]o) solutions. Corresponding K+ currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes.ResultsHypokalaemia prolonged epicardial action potential durations (APD) from mean APD90s of 37.2 ± 1.7 ms (n = 7) to 58.4 ± 4.1 ms (n =7) and 66.7 ± 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K+]o respectively. Endocardial APD90s correspondingly increased from 51.6 ± 1.9 ms (n = 7) to 62.8 ± 2.8 ms (n = 7) and 62.9 ± 5.9 ms (n = 11) giving reductions in endocardial–epicardial differences, ΔAPD90, from 14.4 ± 2.6 to 4.4 ± 5.0 and −3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K+]o with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K+]o respectively. Early outward K+ current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K+]o).ConclusionsHypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD90 suggesting arrhythmogenic substrate on the other.
Highlights
S (APD) from mean APD90s of 37.2 Æ 1.7 ms (n 1⁄4 7) to 58.4 Æ 4.1 ms (n 1⁄4 7) and 66.7 Æ 2.1 ms (n 1⁄4 11) at 5.2, 4 and 3 mm [K+]o respectively
The experiments sought to investigate the intrinsic arrhythmogenicity induced by hypokalaemia by recording left ventricular epicardial and endocardial monophasic action potentials (MAPs) from isolated, perfused mouse hearts, and to determine whether arrhythmogenicity was associated with the occurrence of repolarization abnormalities such as early afterdepolarizations (EADs) and triggered beats, an altered transmural gradient of repolarization or a combination of the two
Experimental data were initially obtained from recordings of MAPs from isolated, perfused WT mouse hearts under normokalaemic conditions (5.2 mm [K+]o) to establish the control phenotype
Summary
S (APD) from mean APD90s of 37.2 Æ 1.7 ms (n 1⁄4 7) to 58.4 Æ 4.1 ms (n 1⁄4 7) and 66.7 Æ 2.1 ms (n 1⁄4 11) at 5.2, 4 and 3 mm [K+]o respectively. Endocardial APD90s correspondingly increased from 51.6 Æ 1.9 ms (n 1⁄4 7) to 62.8 Æ 2.8 ms (n 1⁄4 7) and 62.9 Æ 5.9 ms (n 1⁄4 11) giving reductions in endocardial–epicardial differences, DAPD90, from 14.4 Æ 2.6 to 4.4 Æ 5.0 and )3.4 Æ 6.0 ms respectively. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K+]o respectively.
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