92 research outputs found
A quantitative analysis of the effect of cycle length on arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts
The clinically established proarrhythmic effect of bradycardia and antiarrhythmic effect of lidocaine (10Β ΞΌM) were reproduced in hypokalaemic (3.0Β mM K+) Langendorff-perfused murine hearts paced over a range (80β180Β ms) of baseline cycle lengths (BCLs). Action potential durations (at 90% repolarization, APD90s), 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 APD90, 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 (5.2Β mM K+) hearts a statistical analysis confirmed that all four relationships were described by straight lines of gradients not significantly (Pβ>β0.05) different from unity that passed through the origin and thus subtended constant critical angles, ΞΈ with the abscissa (45.8Β°βΒ±β0.9Β°, 46.6Β°βΒ±β0.5Β°, 47.6Β°βΒ±β0.5Β° and 44.9Β°βΒ±β0.8Β°, respectively). Hypokalaemia shifted all points to the left of these reference lines, significantly (Pβ<β0.05) increasing ΞΈ at BCLs of 80β120Β ms where arrhythmic activity was not observed (βΌ63Β°, βΌ54Β°, βΌ55Β° and βΌ58Β°, respectively) and further significantly (Pβ<β0.05) increasing ΞΈ at BCLs of 140β180Β ms where arrhythmic activity was observed (βΌ68Β°, βΌ60Β°, βΌ61Β° and βΌ65Β°, respectively). In contrast, the antiarrhythmic effect of lidocaine treatment was accompanied by a significant (Pβ<β0.05) disruption of this linear relationship and decreases in ΞΈ in both normokalaemic (βΌ40Β°, βΌ33Β°, βΌ39Β° and βΌ41Β°, respectively) and hypokalaemic (βΌ40Β°, βΌ44Β°, βΌ50Β° and βΌ48Β°, 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 APD90 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
Empirical correlation of triggered activity and spatial and temporal re-entrant substrates with arrhythmogenicity in a murine model for Jervell and Lange-Nielsen syndrome
KCNE1 encodes the Ξ²-subunit of the slow component of the delayed rectifier K+ current. The Jervell and Lange-Nielsen syndrome is characterized by sensorineural deafness, prolonged QT intervals, and ventricular arrhythmogenicity. Loss-of-function mutations in KCNE1 are implicated in the JLN2 subtype. We recorded left ventricular epicardial and endocardial monophasic action potentials (MAPs) in intact, Langendorff-perfused mouse hearts. KCNE1β/β but not wild-type (WT) hearts showed not only triggered activity and spontaneous ventricular tachycardia (VT), but also VT provoked by programmed electrical stimulation. The presence or absence of VT was related to the following set of criteria for re-entrant excitation for the first time in KCNE1β/β hearts: Quantification of APD90, the MAP duration at 90% repolarization, demonstrated alterations in (1) the difference, βAPD90, between endocardial and epicardial APD90 and (2) critical intervals for local re-excitation, given by differences between APD90 and ventricular effective refractory period, reflecting spatial re-entrant substrate. Temporal re-entrant substrate was reflected in (3) increased APD90 alternans, through a range of pacing rates, and (4) steeper epicardial and endocardial APD90 restitution curves determined with a dynamic pacing protocol. (5) Nicorandil (20Β Β΅M) rescued spontaneous and provoked arrhythmogenic phenomena in KCNE1β/β hearts. WTs remained nonarrhythmogenic. Nicorandil correspondingly restored parameters representing re-entrant criteria in KCNE1β/β hearts toward values found in untreated WTs. It shifted such values in WT hearts in similar directions. Together, these findings directly implicate triggered electrical activity and spatial and temporal re-entrant mechanisms in the arrhythmogenesis observed in KCNE1β/β hearts
The Electrophysiological Basis of Arrhythmogenicity of QT/T Alternants in the Long QT Syndrome
Tachycardia-dependent QT/T alternans (A) occurs in patients with the congenital or idiopathic form of long QT syndrome (LQTS) and may presage the onset of polymorphic ventricular tachyarrhythmias (VT). We studied the electrophysiological basis of arrhythmogenicity of QT/T A in the anthopleurin-A model of LQTS, a surrogate for LQT3. in 7 anesthetized mongrel puppies, tridimensional repolarization and activation patterns were analyzed from 256-384 unipolar electrograms. Cardiac repolarization was evaluated as activation-recovery interval (ARI) of local electrograms. To induce QT/T A, the pacing cycle length (CL) was abruptly shortened in steps of 50 msec from a basic drive of 1000 msec. ARIs were calculated at epicardial (Epi), midmyiocardial (Mid), and endocardial (End) sites. ARI restitution at each site was assessed using single premature stimulation delivered after the basic drive. ARI A occurred at longer CLs at Mid sites compared to End and Epi sites and the magnitude of A at Mid sites was greater. This was due to differences in restitution kinetics at Mid sites, characterized by larger deltaARI and a slower time constant , and differences in diastolic intervals resulting in differetn input to restitution. The arrhythmogenicity of QT/T A was primarily due to the greater degree of spatial dispersion of repolarization during A compared to slower rates not associated with A. In 3 of 7 sxperiments, this resulted in funcional conduction block and reentrant VT during the fixed drive associated with
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