In a rabbit model of type 2 long QT syndrome, intracellular calcium overload elicited early afterdepolarizations from ventricular or Purkinje fibers, generating Torsade de Pointes.
Does intracellular Ca2+ overload trigger early afterdepolarizations and Torsade de Pointes in a rabbit model of type 2 long QT syndrome?
Intracellular calcium overload triggers early afterdepolarizations originating from ventricular or Purkinje fibers, leading to Torsade de Pointes in a model of 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.
Choi et al. (Fri,) conducted a other in Type 2 long QT syndrome (rabbit model) (n=12). E4031 with reduced [K+]o and [Mg2+]o was evaluated on Membrane potential (V(m)) and intracellular Ca2+ (Ca2+i) mapping during early afterdepolarizations and Torsade de Pointes. In a rabbit model of type 2 long QT syndrome, intracellular calcium overload elicited early afterdepolarizations from ventricular or Purkinje fibers, generating Torsade de Pointes.