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Spatial and temporal heterogeneities are localized to the right ventricular outflow tract in a heterozygotic Scn5a mouse model.

Martin CA, Grace AA, Huang CL - Am. J. Physiol. Heart Circ. Physiol. (2010)

Bottom Line: This was accentuated by flecainide, but reduced by quinidine, in parallel with their respective pro- and anti-arrhythmic effects.We attribute the arrhythmic tendency within the RVOT to the greater spatial heterogeneities in baseline electrophysiological properties.Our findings may contribute to future work investigating possible pharmacological treatments for a disease in which the current mainstay of treatment is implantable cardioverter defibrillator implantation.

View Article: PubMed Central - PubMed

Affiliation: Physiological Laboratory, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK. clairemartin@gmail.com

ABSTRACT
Ventricular tachycardia (VT) in Brugada Syndrome patients often originates in the right ventricular outflow tract (RVOT). We explore the physiological basis for this observation using murine whole heart preparations. Ventricular bipolar electrograms and monophasic action potentials were recorded from seven epicardial positions in Langendorff-perfused wild-type and Scn5a+/- hearts. VT first appeared in the RVOT, implicating it as an arrhythmogenic focus in Scn5a+/- hearts. RVOTs showed the greatest heterogeneity in refractory periods, response latencies, and action potential durations, and the most fractionated electrograms. However, incidences of concordant alternans in dynamic pacing protocol recordings were unaffected by the Scn5a+/- mutation or pharmacological intervention. Conversely, particularly at the RVOT, Scn5a+/- hearts showed earlier and more frequent transitions into discordant alternans. This was accentuated by flecainide, but reduced by quinidine, in parallel with their respective pro- and anti-arrhythmic effects. Discordant alternans preceded all episodes of VT. The RVOT of Scn5a+/- hearts also showed steeper restitution curves, with the diastolic interval at which the gradient equaled one strongly correlating with the diastolic interval at which discordant alternans commenced. We attribute the arrhythmic tendency within the RVOT to the greater spatial heterogeneities in baseline electrophysiological properties. These, in turn, give rise to a tendency to drive concordant alternans phenomena into an arrhythmogenic discordant alternans. Our findings may contribute to future work investigating possible pharmacological treatments for a disease in which the current mainstay of treatment is implantable cardioverter defibrillator implantation.

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Related in: MedlinePlus

A–C: traces from the position RV1 and RV2 (labeled 1 and 2) of an Scn5a+/− heart first transitioning from regular action potentials (APs) to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Transition points are arrowed. Dotted lines along the AP peaks are included to emphasize the change in morphology, although transition points were quantified in the form of APDs and not AP amplitudes. D: graph showing the transition from normal APs to alternans on changing to a shorter basic cycle length (BCL).
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Figure 5: A–C: traces from the position RV1 and RV2 (labeled 1 and 2) of an Scn5a+/− heart first transitioning from regular action potentials (APs) to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Transition points are arrowed. Dotted lines along the AP peaks are included to emphasize the change in morphology, although transition points were quantified in the form of APDs and not AP amplitudes. D: graph showing the transition from normal APs to alternans on changing to a shorter basic cycle length (BCL).

Mentions: Figure 5, A–C shows typical traces from positions RV1 and RV2 of an Scn5a+/− heart first transitioning from regular APs to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Figure 5D displays graphically the change from normal APs to alternans on changing to a shorter BCL. Table 1 shows the proportion of runs in adjacent cardiac regions in WT and Scn5a+/− hearts that resulted in either concordant alternans or discordant alternans. Figure 6, A–C, shows the mean values of BCL at which hearts transitioned from normal APs to concordant alternans, and then to discordant alternans both before drug (A) and after flecainide (B) or quinidine (C). Results from two simultaneous recordings of each of the adjacent regions in WT (solid squares) and Scn5a+/− (shaded squares) hearts are shown.


Spatial and temporal heterogeneities are localized to the right ventricular outflow tract in a heterozygotic Scn5a mouse model.

Martin CA, Grace AA, Huang CL - Am. J. Physiol. Heart Circ. Physiol. (2010)

A–C: traces from the position RV1 and RV2 (labeled 1 and 2) of an Scn5a+/− heart first transitioning from regular action potentials (APs) to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Transition points are arrowed. Dotted lines along the AP peaks are included to emphasize the change in morphology, although transition points were quantified in the form of APDs and not AP amplitudes. D: graph showing the transition from normal APs to alternans on changing to a shorter basic cycle length (BCL).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044044&req=5

Figure 5: A–C: traces from the position RV1 and RV2 (labeled 1 and 2) of an Scn5a+/− heart first transitioning from regular action potentials (APs) to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Transition points are arrowed. Dotted lines along the AP peaks are included to emphasize the change in morphology, although transition points were quantified in the form of APDs and not AP amplitudes. D: graph showing the transition from normal APs to alternans on changing to a shorter basic cycle length (BCL).
Mentions: Figure 5, A–C shows typical traces from positions RV1 and RV2 of an Scn5a+/− heart first transitioning from regular APs to concordant alternans (A), from concordant alternans to discordant alternans (B), and from discordant alternans into VT (C). Figure 5D displays graphically the change from normal APs to alternans on changing to a shorter BCL. Table 1 shows the proportion of runs in adjacent cardiac regions in WT and Scn5a+/− hearts that resulted in either concordant alternans or discordant alternans. Figure 6, A–C, shows the mean values of BCL at which hearts transitioned from normal APs to concordant alternans, and then to discordant alternans both before drug (A) and after flecainide (B) or quinidine (C). Results from two simultaneous recordings of each of the adjacent regions in WT (solid squares) and Scn5a+/− (shaded squares) hearts are shown.

Bottom Line: This was accentuated by flecainide, but reduced by quinidine, in parallel with their respective pro- and anti-arrhythmic effects.We attribute the arrhythmic tendency within the RVOT to the greater spatial heterogeneities in baseline electrophysiological properties.Our findings may contribute to future work investigating possible pharmacological treatments for a disease in which the current mainstay of treatment is implantable cardioverter defibrillator implantation.

View Article: PubMed Central - PubMed

Affiliation: Physiological Laboratory, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK. clairemartin@gmail.com

ABSTRACT
Ventricular tachycardia (VT) in Brugada Syndrome patients often originates in the right ventricular outflow tract (RVOT). We explore the physiological basis for this observation using murine whole heart preparations. Ventricular bipolar electrograms and monophasic action potentials were recorded from seven epicardial positions in Langendorff-perfused wild-type and Scn5a+/- hearts. VT first appeared in the RVOT, implicating it as an arrhythmogenic focus in Scn5a+/- hearts. RVOTs showed the greatest heterogeneity in refractory periods, response latencies, and action potential durations, and the most fractionated electrograms. However, incidences of concordant alternans in dynamic pacing protocol recordings were unaffected by the Scn5a+/- mutation or pharmacological intervention. Conversely, particularly at the RVOT, Scn5a+/- hearts showed earlier and more frequent transitions into discordant alternans. This was accentuated by flecainide, but reduced by quinidine, in parallel with their respective pro- and anti-arrhythmic effects. Discordant alternans preceded all episodes of VT. The RVOT of Scn5a+/- hearts also showed steeper restitution curves, with the diastolic interval at which the gradient equaled one strongly correlating with the diastolic interval at which discordant alternans commenced. We attribute the arrhythmic tendency within the RVOT to the greater spatial heterogeneities in baseline electrophysiological properties. These, in turn, give rise to a tendency to drive concordant alternans phenomena into an arrhythmogenic discordant alternans. Our findings may contribute to future work investigating possible pharmacological treatments for a disease in which the current mainstay of treatment is implantable cardioverter defibrillator implantation.

Show MeSH
Related in: MedlinePlus