A quantitative analysis of the effect of cycle length on arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Abstract

The clinically established proarrhythmic effect of bradycardia and antiarrhythmic effect of lidocaine (10 μM) were reproduced in hypokalaemic (3.0 mM K + ) Langendorffperfused murine hearts paced over a range (80-180 ms) of baseline cycle lengths (BCLs). Action potential durations (at 90% repolarization, APD 90 s), transmural conduction times and ventricular effective refractory periods (VERPs) were then determined from monophasic action potential records obtained during a programmed electrical stimulation procedure in which extrasystolic stimuli were interposed following regular stimuli at successively decreasing coupling intervals. A novel graphical analysis of epicardial and endocardial, local and transmural relationships between APD 90 , corrected for transmural conduction time where appropriate, and VERP yielded predictions in precise agreement with the arrhythmogenic findings obtained over the entire range of BCLs studied. Thus, in normokalaemic (5.2 mM K + ) hearts a statistical analysis confirmed that all four relationships were described by straight lines of gradients not significantly (P>0.05) different from unity that passed through the origin and thus subtended constant critical angles, θ with the abscissa (45.8°±0.9°, 46.6°±0.5°, 47.6°±0.5°and 44.9°± 0.8°, respectively). Hypokalaemia shifted all points to the left of these reference lines, significantly (P<0.05) increasing θ at BCLs of 80-120 ms where arrhythmic activity was not observed (∼63°, ∼54°, ∼55°and ∼58°, respectively) and further significantly (P<0.05) increasing θ at BCLs of 140-180 ms where arrhythmic activity was observed (∼68°, ∼60°, ∼61°and ∼65°, respectively). In contrast, the antiarrhythmic effect of lidocaine treatment was accompanied by a significant (P<0.05) disruption of this linear relationship and decreases in θ in both normokalaemic (∼40°, ∼33°, ∼39°and ∼41°, respectively) and hypokalaemic (∼40°, ∼44°, ∼50°and ∼48°, respectively) hearts. This extended a previous approach that had correlated alterations in transmural repolarization gradients with arrhythmogenicity in murine models of the congenital long QT syndrome type 3 and hypokalaemia at a single BCL. Thus, the analysis in terms of APD 90 and VERP provided a more sensitive indication of the effect of lidocaine than one only considering transmural repolarization gradients and may be particularly applicable in physiological and pharmacological situations in which these parameters diverge.

Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β−/− hearts: effects of age

“…The measurements of d V /d t max and RMPs would not have been available with the monophasic action potential electrode methods used on previous occasions (Sabir et al . , ). The incremental pacing protocols applied cycles of 100 regular pacing stimuli at successively decremented BCLs.…”

“…They have been described in experimental conditions as alternating variations in temporal properties of AP excitation and/or recovery that occur with varying heart rates in analyses of pro‐arrhythmic tendencies associated with ventricular arrhythmogenesis (Sabir et al . , ). We sought to analyse whether such phenomena are important in atrial arrhythmogenesis.…”

“…These included maximal AP upstroke rates (dV/dt max ), AP latencies, defined as the time interval between the pacing spike of each AP and the maximal deflection, or peak, of the AP, AP durations at 90% recovery (APD 90 ), and resting membrane potentials (RMPs). The measurements of dV/dt max and RMPs would not have been available with the monophasic action potential electrode methods used on previous occasions (Sabir et al 2007a(Sabir et al , 2008a. The incremental pacing protocols applied cycles of 100 regular pacing stimuli at successively decremented BCLs.…”

“…Reduced temporal heterogeneities in atrial AP characteristics in aged Pgc1β −/− hearts Instabilities in characteristics of successive APs, often taking the form of episodes of alternans, presage major ventricular arrhythmias in clinical situations. They have been described in experimental conditions as alternating variations in temporal properties of AP excitation and/or recovery that occur with varying heart rates in analyses of pro-arrhythmic tendencies associated with ventricular arrhythmogenesis (Sabir et al 2007a(Sabir et al , 2008a. We sought to analyse whether such phenomena are important in atrial arrhythmogenesis.…”

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

“…Sustained arrhythmia may require both triggering events and arrhythmic substrate to maintain the resulting abnormal electrical activity . Arrhythmic substrate arises either from slowed myocardial AP conduction or activation, exemplified by Brugada Syndrome, or altered AP recovery, reflected in altered AP duration and/or refractoriness, exemplified by long QT syndrome . Arrhythmic risk is also associated with dysregulated intracellular Ca 2+ homeostasis.…”