Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome.
The role of intracellular Ca2+ (Ca2+i) 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 Ca2+i with two photodiode arrays. The I(Kr) blocker E4031 (0.5 microM) together with 50 % reduction of [K+]o and [Mg2+]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 (baseapex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of I(Kr). At low [K+]o and [Mg2+]o, E4031 elicited spontaneous Ca2+iand 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 (Ca2+ivs. V(m)) had counterclockwise trajectories shaped like a 'boomerang' during an AP and like ellipses during EADs, with V(m) preceding Ca2+iby 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, Ca2+ipreceded V(m) and phase maps traced clockwise ellipses. Away from EAD origins, V(m) coincided with or preceded Ca2+i. 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.
University of Pittsburgh, School of Medicine, Department of Cell Biology and Physiology, Pittsburgh, PA 15261, USA.
Bum-Rak
BR
Choi
Francis
F
Burton
Guy
G
Salama
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016477:Artifacts; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003452:Cryosurgery; D003600:Cytosol / Q000378:metabolism; D005260:Female; D007700:Kinetics; D008133:Long QT Syndrome / Q000378:metabolism* / Q000503:physiopathology*; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008856:Microscopy, Fluorescence / Q000295:instrumentation / Q000379:methods; D009068:Movement; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D016171:Torsades de Pointes / Q000378:metabolism* / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D008274:Magnesium; D011188:Potassium; D002118:Calcium