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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

VERP values (A) and VERP gradients (B) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In B, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.
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Figure 3: VERP values (A) and VERP gradients (B) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In B, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.

Mentions: Data of the kind illustrated in Fig. 2A also permitted comparisons of VERP recordings obtained from the S1S2 intervals in stimulus cycles that last triggered APs following the S2 stimulus. These demonstrated that, in both the WT and Scn5a+/− hearts, there was a gradient of refractory period existing along the long axis of both the RVs and the LVs, such that the VERP was larger at the apex than the base (Fig. 3A) (e.g., 37.2 ± 3.0 ms at apex compared with 34.9 ± 2.3 ms at the base for RV in WT hearts, P = 0.05, n = 16). These VERP gradients were slightly, but not significantly, larger in the LV than the RV in WT hearts. However, this pattern was reversed in the Scn5a+/− hearts, where the gradient was significantly larger in the RV than the LV (Fig. 3B) (e.g., 3.7 ± 0.8 ms in LV1–2 compared with 8.0 ± 0.8 ms in RV1–2, P = 0.0007, n = 16). Thus VERP gradients were larger in Scn5a+/− hearts than WT only in the RV.


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)

VERP values (A) and VERP gradients (B) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In B, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: VERP values (A) and VERP gradients (B) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In B, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.
Mentions: Data of the kind illustrated in Fig. 2A also permitted comparisons of VERP recordings obtained from the S1S2 intervals in stimulus cycles that last triggered APs following the S2 stimulus. These demonstrated that, in both the WT and Scn5a+/− hearts, there was a gradient of refractory period existing along the long axis of both the RVs and the LVs, such that the VERP was larger at the apex than the base (Fig. 3A) (e.g., 37.2 ± 3.0 ms at apex compared with 34.9 ± 2.3 ms at the base for RV in WT hearts, P = 0.05, n = 16). These VERP gradients were slightly, but not significantly, larger in the LV than the RV in WT hearts. However, this pattern was reversed in the Scn5a+/− hearts, where the gradient was significantly larger in the RV than the LV (Fig. 3B) (e.g., 3.7 ± 0.8 ms in LV1–2 compared with 8.0 ± 0.8 ms in RV1–2, P = 0.0007, n = 16). Thus VERP gradients were larger in Scn5a+/− hearts than WT only in the RV.

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