In rabbits, 3-week bradypacing prolonged QT intervals by approximately 50% (P<0.01) and caused spontaneous TdP in 75%, whereas tachypacing caused isolated ectopy but lethal TdP upon IKr blockade.
Long-term bradycardia and tachycardia produce distinct patterns of potassium channel subunit remodeling, with bradycardia specifically suppressing IKr and promoting spontaneous torsade de pointes.
p-value: p=<0.01
BACKGROUND: Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits. METHODS AND RESULTS: We evaluated mRNA and protein expression of subunits underlying rapid (IKr) and slow (IKs) delayed-rectifier and transient-outward K+ currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by approximately 50% at 60 bpm; P<0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced and tachypaced rabbits, whereas ERG was significantly downregulated in bradypaced rabbits only. Kv4.3 and Kv1.4 were downregulated by tachypacing only. Patch-clamp experiments showed that IKs was reduced in both but IKr was decreased in bradypaced rabbits only. Continuous monitoring revealed spontaneous TdP in 75% of bradypaced but only isolated ventricular ectopy in tachypaced rabbits. Administration of dofetilide (0.02 mg/kg) to mimic IKr downregulation produced ultimately lethal TdP in all tachypaced rabbits. CONCLUSIONS: Sustained tachycardia and bradycardia downregulate IKs subunits, but bradycardia also suppresses ERG/IKr, causing prominent repolarization delays and spontaneous TdP. Susceptibility of tachycardia/heart failure rabbits to malignant tachyarrhythmias is induced by exposure to IKr blockers. These results point to a crucial role for delayed-rectifier subunit remodeling in TdP susceptibility associated with rate-related cardiac remodeling.
Tsuji et al. (Mon,) conducted a other in Heart rate abnormalities (tachycardia and bradycardia). Ventricular pacing (bradypacing or tachypacing) vs. Sinus rhythm control was evaluated on QT intervals and spontaneous torsade de pointes (TdP) (p=<0.01). In rabbits, 3-week bradypacing prolonged QT intervals by approximately 50% (P<0.01) and caused spontaneous TdP in 75%, whereas tachypacing caused isolated ectopy but lethal TdP upon IKr blockade.