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Cytosolic Ca 2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome
Author(s) -
Choi BumRak,
Burton Francis,
Salama Guy
Publication year - 2002
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2002.024570
Subject(s) - afterdepolarization , torsades de pointes , long qt syndrome , cytosol , medicine , cardiology , rabbit (cipher) , qt interval , chemistry , electrophysiology , repolarization , biochemistry , enzyme , statistics , mathematics
The role of intracellular Ca 2+ (Ca 1 2+ ) in triggering early afterdepolarizations (EADs), the origins of EADs and the mechanisms underlying Torsade de Pointes (TdP) were investigated in a model of long QT syndrome (Type 2). Perfused rabbit hearts were stained with RH327 and Rhod‐2/AM to simultaneously map membrane potential ( V m ) and Ca 1 2+ with two photodiode arrays. The I Kr blocker E4031 (0.5 μM) together with 50% reduction of [K + ] o and [Mg 2+ ] o elicited long action potentials (APs), V m oscillations on AP plateaux (EADs) then ventricular tachycardia (VT). Cryoablation of both ventricular chambers eliminated Purkinje fibres as sources of EADs. E4031 prolonged APs (0.28 to 2.3 s), reversed repolarization sequences (base→apex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of I Kr . At low [K + ] o and [Mg 2+ ] o , E4031 elicited spontaneous Ca 1 2+ and V m spikes or EADs (3.5 ± 1.9 Hz) during the AP plateau ( n = 6). EADs fired ‘out‐of‐phase’ from several sites, propagated, collided then evolved to TdP. Phase maps (Ca 1 2+ vs . V m ) had counterclockwise trajectories shaped like a ‘boomerang’ during an AP and like ellipses during EADs, with V m preceding Ca 1 2+ by 9.2 ± 1.4 ( n = 6) and 7.2 ± 0.6 ms ( n = 5/6), respectively. After cryoablation, EADs from surviving epicardium (∼1 mm) fired at the same frequency (3.4 ± 0.35 Hz, n = 6) as controls. At the origins of EADs, Ca 1 2+ preceded V m and phase maps traced clockwise ellipses. Away from EAD origins, V m coincided with or preceded Ca 1 2+ . In conclusion, overload elicits EADs originating from either ventricular or Purkinje fibres and ‘out‐of‐phase’ EAD activity from multiple sites generates TdP, evident in pseudo‐ECGs.