Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a^+/− hearts

Abstract

Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a+/− murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a+/− hearts. Recordings were obtained from right (RV) and left (LV) ventricular, epicardial and endocardial surfaces during incremental pacing, before and following flecainide or quinidine challenge. Conduction velocities (θ′), action potential wavelengths (λ′= APD ×θ′), and their corresponding alternans depended non-linearly upon diastolic interval (DI). Maximum θ′ was lower in Scn5a+/− RV epicardium than endocardium. Flecainide further reduced θ′, accentuating this RV conduction block. Quinidine reduced maximum θ′ in WT and caused earlier conduction failure in the RV of both Scn5a+/− and WT. Use of recovery wavelengths (λ′0= DI ×θ′) rather than DI, provided novel λ restitution plots of λ′ against λ′0, which sum to a basic cycle distance permitting feedback analysis. λ′ restitution gradient better correlated with alternans magnitude than either APD or θ restitution gradient. The large differences in θ′ and APD restitution contrasted with minor differences in maximum λ′ between epi- and endocardia of untreated hearts, and quinidine-treated WT hearts. Strikingly, all regions and conditions converged to a common instability point, implying a conserved relationship. Flecainide or quinidine decreased the pacing rates at which this occurred, through reducing basic cycle distance, in the Scn5a+/− RV epicardium, directly predictive of its arrhythmic phenotype.

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

“…These were quantified by active wavelengths (λ) derived from conduction velocity [reflected by 1/(AP latency)] and APD terms (given by APD 90 ; Matthews et al . ), and resting wavelengths (λ 0 ) comprising DI 90 and AP latency terms (Matthews et al . ; Ning et al .…”

“…), and resting wavelengths (λ 0 ) comprising DI 90 and AP latency terms (Matthews et al . ; Ning et al . ).…”

Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

“…These preparations replicated the clinically observed arrhythmic tendencies and attributed these to compromised AP conduction particularly following extrasystolic stimuli, findings that correlate with biophysical observations of a reduced peak I Na (Martin et al , , ). Flecainide challenge also reproduced clinical observations, as it increased these ventricular arrhythmic tendencies (Stokoe et al , ; Martin et al , ; Matthews et al , ). The altered balance between inward I Na and outward I to mediating early AP repolarization would also be expected to increase the likelihood of pro‐arrhythmic phase II re‐entry phenomena (Lukas and Antzelevitch, ), although these would be made less likely as flecainide also increases effective refractory periods (Martin et al , ).…”

From channels to systems: Ca2+‐sensitive K+ currents, alternans and cardiac arrhythmia

“…The unity slope instability criterion in the resulting λ(λ 0 ) plot ( Bd; dashed tangent) now encompasses AP propagation in addition to recovery characteristics (Matthews et al . ), and offers one of many possible developments of this elegant approach.…”