TY - JOUR
T1 - Drug-Induced Torsade de Pointes Arrhythmias in the Chronic AV Block Dog Are Perpetuated by Focal Activity
AU - Boulaksil, Mohamed
AU - Jungschleger, Jerome G.
AU - Antoons, Gudrun
AU - Houtman, Marien J. C.
AU - de Boer, Teun P.
AU - Wilders, Ronald
AU - Beekman, Jet D. M.
AU - Maessen, Jos G.
AU - van der Hulst, Ferenc F.
AU - van der Heyden, Marcel A. G.
AU - van Veen, Toon A. B.
AU - van Rijen, Harold V. M.
AU - de Bakker, Jacques M. T.
AU - Vos, Marc
PY - 2011/8
Y1 - 2011/8
N2 - Background-The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored. Methods and Results-Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current (I-Na) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV. I-Na was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal I-Na. Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45 +/- 25 to 120 +/- 65 ms; P90%) of beats were focal; reentry was observed only occasionally. Conclusions-Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP. (Circ Arrhythm Electrophysiol. 2011;4:566-576.)
AB - Background-The electrically remodeled canine heart after chronic AV block (CAVB) has a high susceptibility for drug-induced torsade de pointes (TdP) arrhythmias. Although focal mechanisms have been considered for initiation, there is still controversy about whether reentry is the dominant mechanism for perpetuation of TdP. In this animal model with known nonuniform prolongation of repolarization, the mechanism of perpetuation of TdP arrhythmia was explored. Methods and Results-Seventeen TdP-sensitive CAVB and 10 sinus rhythm (SR) dogs were studied. In 6 animals, 66 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Activation times and activation recovery intervals were determined before and during ibutilide-induced TdP. In 12 CAVB and 9 SR dogs, left ventricular (LV) and right ventricular (RV) epicardial electrograms were recorded with a 208-point multiterminal grid electrode allowing conduction velocity (CV) and ventricular effective refractory period (VERP) measurements. Biopsy specimens were processed for connexin43 (Cx43) expression and collagen content. Ventricular myocytes were isolated to determine sodium current (I-Na) density and cell dimensions. Computer simulations were used to assess the effects of changes therein. In CAVB, VERP and ARI were increased, whereas CV was unaltered in LV. Transversal but not longitudinal CV was increased in RV. I-Na was reduced by 37% in LV but unaltered in RV. LV and RV cell size were increased, but collagen and Cx43 content remained unchanged. Simulations showed increase in CV of RV as a consequence of increased cell size at normal I-Na. Ibutilide increased ARI, ERP, and maximal transmural dispersion of ERP (45 +/- 25 to 120 +/- 65 ms; P90%) of beats were focal; reentry was observed only occasionally. Conclusions-Focal activity is the dominant mechanism involved in perpetuation of ibutilide-induced TdP in CAVB dogs based on detailed 3D mapping. This conclusion is in line with unaltered conduction and documented increase in VERP. (Circ Arrhythm Electrophysiol. 2011;4:566-576.)
KW - mechanisms of arrhythmia
KW - conduction
KW - ion channels
KW - long-QT syndrome
KW - torsade de pointes
U2 - 10.1161/CIRCEP.110.958991
DO - 10.1161/CIRCEP.110.958991
M3 - Article
C2 - 21622813
SN - 1941-3149
VL - 4
SP - 566-U275
JO - Circulation-Arrhythmia and Electrophysiology
JF - Circulation-Arrhythmia and Electrophysiology
IS - 4
ER -