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Separation of early afterdepolarizations from arrhythmogenic substrate in the isolated perfused hypokalaemic murine heart through modifiers of calcium homeostasis
Author(s) -
Killeen M. J.,
Gurung I. S.,
Thomas G.,
Stokoe K. S.,
Grace A. A.,
Huang C. L.H.
Publication year - 2007
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2007.01715.x
Subject(s) - afterdepolarization , nifedipine , medicine , repolarization , cardiology , ventricular tachycardia , channel blocker , endocardium , chemistry , electrophysiology , calcium
Aims: We resolved roles for early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in Langendorff‐perfused hypokalaemic murine hearts paced from the right ventricular epicardium. Methods: Left ventricular epicardial and endocardial monophasic action potentials (MAPs) and arrhythmogenic tendency were compared in the presence and absence of the L‐type Ca 2+ channel blocker nifedipine (10 n m –1 μ m ) and the calmodulin kinase type II inhibitor KN‐93 (2 μ m ). Results: All the hypokalaemic hearts studied showed prolonged epicardial and endocardial MAPs, decreased epicardial‐endocardial APD 90 difference, EADs, triggered beats and ventricular tachycardia (VT) ( n = 6). In all spontaneously beating hearts, 100 (but not 10) n m nifedipine reduced both the incidence of EADs and triggered beats from 66.9 ± 15.7% to 28.3 ± 8.7% and episodes of VT from 10.8 ± 6.3% to 1.2 ± 0.7% of MAPs ( n = 6 hearts, P < 0.05); 1 μ m nifedipine abolished all these phenomena ( n = 6). In contrast programmed electrical stimulation (PES) still triggered VT in six of six hearts with 0, 10 and 100 n m but not 1 μ m nifedipine. 1 μ m nifedipine selectively reduced epicardial (from 66.1 ± 3.4 to 46.2 ± 2.5 ms) but not endocardial APD 90 , thereby restoring ΔAPD 90 from −5.9 ± 2.5 to 15.5 ± 3.2 ms, close to normokalaemic values. KN‐93 similarly reduced EADs, triggered beats and VT in spontaneously beating hearts to 29.6 ± 8.9% and 1.7 ± 1.1% respectively ( n = 6) yet permitted PES‐induced VT ( n = 6), in the presence of a persistently negative ΔAPD 90 . Conclusions: These findings empirically implicate both EADs and triggered beats alongside arrhythmogenic substrate of ΔAPD 90 in VT pathogenesis at the whole heart level.