Nonlinearity between action potential alternans and restitution, which both predict ventricular arrhythmic properties inScn5a^+/−and wild-type murine hearts

Abstract

Electrocardiographic QT- and T-wave alternans, presaging ventricular arrhythmia, reflects compromised adaptation of action potential (AP) duration (APD) to altered heart rate, classically attributed to incomplete Na(v)1.5 channel recovery prior to subsequent stimulation. The restitution hypothesis suggests a function whose slope directly relates to APD alternans magnitude, predicting a critical instability condition, potentially generating arrhythmia. The present experiments directly test for such correlations among arrhythmia, APD alternans and restitution. Mice haploinsufficient in the Scn5a, cardiac Na(+) channel gene (Scn5a(+/-)), previously used to replicate Brugada syndrome, were used, owing to their established arrhythmic properties increased by flecainide and decreased by quinidine, particularly in right ventricular (RV) epicardium. Monophasic APs, obtained during pacing with progressively decrementing cycle lengths, were systematically compared at RV and left ventricular epicardial and endocardial recording sites in Langendorff-perfused Scn5a(+/-) and wild-type hearts before and following flecainide (10 μM) or quinidine (5 μM) application. The extent of alternans was assessed using a novel algorithm. Scn5a(+/-) hearts showed greater frequencies of arrhythmic endpoints with increased incidences of ventricular tachycardia, diminished by quinidine, and earlier onsets of ventricular fibrillation, particularly following flecainide challenge. These features correlated directly with increased refractory periods, specifically in the RV, and abnormal restitution and alternans properties in the RV epicardium. The latter variables were related by a unique, continuous higher-order function, rather than a linear relationship with an unstable threshold. These findings demonstrate a specific relationship between alternans and restitution, as well as confirming their capacity to predict arrhythmia, but implicate mechanisms additional to the voltage feedback suggested in the restitution hypothesis.

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

“…,b), then associated pro‐arrhythmic instabilities with increasing limiting slopes in APD 90 versus DI 90 plots with shortening DI 90 (Matthews et al . ). Attainment of unity gradient presaged waxing AP alternans and arrhythmia.…”

“…; Matthews et al . , ) increasing the steepness of restitution curve plots of APD 90 against DI 90 at short BCLs. The consequent APD 90 instabilities would increase frequencies and amplitudes of alternans, culminating in arrhythmic substrate (Huang, ).…”

“…The present experiments, likewise, looked for the presence of arrhythmic phenotypes provoked by the imposition of extrasystolic S2 stimuli at differing S1S2 intervals following trains of regular S1 pacing as well as steady-state pacing at progressively decreased basic cycle lengths (BCLs). The findings were then matched to results from simultaneous determinations of AP activation and recovery, as well as temporal instabilities in the form of AP alternans (Matthews et al 2010), APD-diastolic interval (DI) restitution relationships (Kim et al 2002;Matthews et al 2012) and spatiotemporal indicators of AP wavelength. This study represents the first to make such measurements in murine atria.…”

“…; Matthews et al . ) and spatiotemporal indicators of AP wavelength. This study represents the first to make such measurements in murine atria.…”

Andrew Fielding Huxley (1917–2012)

“…Even when he had ceased active laboratory work, Huxley himself encouraged the recent studies of genetically modified murine cardiac models for Na + channelopathies in Cambridge (Papadatos et al 2002; Sabir et al 2008; Killeen et al 2008). These demonstrated the importance of their consequently altered Na + channel activation and recovery properties in producing sino‐atrial pacemaker (Lei et al 2005) and atrial and ventricular arrhythmic disorders, findings applicable to the human arrhythmogenic Brugada and long QT3 syndromes (Martin et al 2012; Matthews et al 2012), with implications for management of patients with sinus node dysfunction, atrial fibrillation and at risk of sudden cardiac death (Martin et al 2011). Finally, the electrical circuit theory formulations describing the ionic hypothesis prompted subsequent realistic mathematical simulations of the effects upon cellular homeostasis of not only electrogenic but also electroneutral and osmotic fluxes (Fraser & Huang, 2004).…”