Limits...
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.

Show MeSH

Related in: MedlinePlus

A: typical monophasic action potential (MAP) recording from the RV of an Scn5a+/− heart, showing action potential duration (APD) and latency measurements. B: typical MAP recordings taken from the 7 recording positions in the RV and LV of a Scn5a+/− heart. C and D: APD to 90% repolarization (APD90) values (C) and APD90 gradients (D) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In D, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3044044&req=5

Figure 4: A: typical monophasic action potential (MAP) recording from the RV of an Scn5a+/− heart, showing action potential duration (APD) and latency measurements. B: typical MAP recordings taken from the 7 recording positions in the RV and LV of a Scn5a+/− heart. C and D: APD to 90% repolarization (APD90) values (C) and APD90 gradients (D) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In D, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.

Mentions: Figure 4A shows a typical MAP recording, demonstrating APD and latency measurements. Response latencies were larger in Scn5a+/− than WT hearts (32.1 ± 2.9 vs. 15.6 ± 2.1 ms, P < 0.0001, n = 112 as a total of recordings from all regions). They were increased by flecainide in WT (to 26.2 ± 2.0 ms, P = 0.0019, n = 56) and Scn5a+/− (to 44.1 ± 4.0 ms, P = 0.025, n = 56), and by quinidine in WT hearts (to 23.3 ± 3.2 ms, P = 0.04, n = 56), but not Scn5a+/−. There was no obvious difference in mean response latency between different regions of the RV and LV; however, our method would be unlikely to detect subtle changes in latency, as it measures the entire conduction path between stimulating and recording electrode. It is impossible to keep this distance constant to each recording electrode, as the detailed three-dimensional conduction pathway in the heart is likely to be different in different regions. However, on closer examination of traces recorded from the RV1 position in Scn5a+/− hearts, i.e., at the base of the RV closest to the RVOT, while the overall mean response latency was not significantly different from other regions, some traces had noticeably longer response latencies than the surrounding tissue. This was reflected in the larger standard deviation of values (14.3 in RVOT vs. 9.8 in rest of RV for Scn5a+/− hearts). This effect was accentuated in the presence of flecainide (SD = 16.9).


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: typical monophasic action potential (MAP) recording from the RV of an Scn5a+/− heart, showing action potential duration (APD) and latency measurements. B: typical MAP recordings taken from the 7 recording positions in the RV and LV of a Scn5a+/− heart. C and D: APD to 90% repolarization (APD90) values (C) and APD90 gradients (D) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In D, 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 4: A: typical monophasic action potential (MAP) recording from the RV of an Scn5a+/− heart, showing action potential duration (APD) and latency measurements. B: typical MAP recordings taken from the 7 recording positions in the RV and LV of a Scn5a+/− heart. C and D: APD to 90% repolarization (APD90) values (C) and APD90 gradients (D) between 7 recording regions of the heart, in both WT and Scn5a+/− hearts, before and after the addition of flecainide and quinidine. In D, for example, “1–2” denotes the difference in VERP between recording positions 1 and 2.
Mentions: Figure 4A shows a typical MAP recording, demonstrating APD and latency measurements. Response latencies were larger in Scn5a+/− than WT hearts (32.1 ± 2.9 vs. 15.6 ± 2.1 ms, P < 0.0001, n = 112 as a total of recordings from all regions). They were increased by flecainide in WT (to 26.2 ± 2.0 ms, P = 0.0019, n = 56) and Scn5a+/− (to 44.1 ± 4.0 ms, P = 0.025, n = 56), and by quinidine in WT hearts (to 23.3 ± 3.2 ms, P = 0.04, n = 56), but not Scn5a+/−. There was no obvious difference in mean response latency between different regions of the RV and LV; however, our method would be unlikely to detect subtle changes in latency, as it measures the entire conduction path between stimulating and recording electrode. It is impossible to keep this distance constant to each recording electrode, as the detailed three-dimensional conduction pathway in the heart is likely to be different in different regions. However, on closer examination of traces recorded from the RV1 position in Scn5a+/− hearts, i.e., at the base of the RV closest to the RVOT, while the overall mean response latency was not significantly different from other regions, some traces had noticeably longer response latencies than the surrounding tissue. This was reflected in the larger standard deviation of values (14.3 in RVOT vs. 9.8 in rest of RV for Scn5a+/− hearts). This effect was accentuated in the presence of flecainide (SD = 16.9).

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