Dose-Related Shortening of Ventricular Tachycardia Cycle Length After Administration of the KATP Channel Opener Bimakalim in a 4-Day-Old Chronic Infarct Anesthetized Pig Model

Abstract

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K( ATP) channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.

Evaluation of Index of Cardio‐Electrophysiological Balance (iCEB) as a New Biomarker for the Identification of Patients at Increased Arrhythmic Risk

“…[3][4][5] To address these limitations we hypothesized that QT/QRS might serve as a readily measurable local estimate of cardiac wavelength and called this parameter the "index of cardio-electrophysiological balance." [3][4][5] To address these limitations we hypothesized that QT/QRS might serve as a readily measurable local estimate of cardiac wavelength and called this parameter the "index of cardio-electrophysiological balance."…”

“…Only limited in vitro data are available on cardiac wavelength as a risk stratifier, mainly due to the invasive nature to measure it. [3][4][5] To address these limitations we hypothesized that QT/QRS might serve as a readily measurable local estimate of cardiac wavelength and called this parameter the "index of cardio-electrophysiological balance." It is generally accepted that QRS duration in the absence of a clear bundle branch block is inversely proportional to conduction velocity in the cardiac ventricle.…”

“…2 The rationale for this parameter is that iCEB, measured as QT interval divided by QRS duration, might serve as an ECG-based derivative of cardiac wavelength λ, which plays an important role in arrhythmogenesis: drugs that increase wavelength tend to increase the risk for TdP while agents that decrease the wavelength tend to increase the risk for non-TdP VT or VF. [3][4][5] Cardiac wavelength λ is the distance travelled by the depolarization wave during the functional refractory period. A local estimate of λ is determined by the product of conduction velocity (CV) and effective refractory period (ERP).…”

Transmural dispersion of repolarization and cardiac remodeling in ventricles of rabbit with right ventricular hypertrophy

“…This difference in duration reflects increased heterogeneity of repolarization, another electrophysiological substrate predisposing to arrhythmia. Finally it has been suggested that changes in cardiac wavelength λ [λ = effective refractory period (ERP) × conduction velocity (CV)] promote reentrant arrhythmias (Aidonidis et al, 2009). Since changes in APDs reflect the changes in ERP, therefore, agents that prolong APDs tend to increase the risk for torsades de pointes while agents that shorten APDs tend to increase the risk for ventricular fibrillation (Hondeghem, 2008;Hondeghem, Dujardin, Hoffmann, Dumotier, & De clerk, 2011).…”

Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: A potential anti-arrhythmic agent

“…In addition, increased oxidation directly activates SarcKATP (sarcolemmal-ATPdependent potassium) channels (Tokube et al, 1996(Tokube et al, , 1998 and changes the inactivation kinetics of L-type calcium channels (Belevych et al, 2009). SarcKATP channels opening reduces the action potential duration and effective refractory period (Aidonidis et al, 2009;Ferrier & Howlett, 2005) which in turn increases the incidence of cardiac arrhythmia (Billman, 2008;Billman et al, 2004). There is credible evidence that during reperfusion, production of oxygen free radicals increase in ischemic tissue (Bolli et al, 1989;Manning et al, 1988) and the use of ROS (reactive oxygen species) scavengers is associated with successful decrease in the reperfusion-induced arrhythmias (Cho et al, 2007;Hicks et al, 2007;Konya et al, 1992).…”