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 BEG traces from RV apex or RVOT of wild-type (WT) and Scn5a+/− hearts, either before drug or after treatment with either flecainide or quinidine. The arrows denote stimulus artifacts, the first in each trace from an S1 stimulus and the second from an S2 stimulus. B–D: comparison of conduction curves from the base of the RV in a WT heart and in an Scn5a+/− heart (B), and at the base of an Scn5a+/− heart before and after flecainide (C) or quinidine (D). E: electrogram duration (EGD) ratios calculated from WT and Scn5a+/− hearts in 7 positions across the heart, before and after the addition of flecainide or quinidine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: A: typical BEG traces from RV apex or RVOT of wild-type (WT) and Scn5a+/− hearts, either before drug or after treatment with either flecainide or quinidine. The arrows denote stimulus artifacts, the first in each trace from an S1 stimulus and the second from an S2 stimulus. B–D: comparison of conduction curves from the base of the RV in a WT heart and in an Scn5a+/− heart (B), and at the base of an Scn5a+/− heart before and after flecainide (C) or quinidine (D). E: electrogram duration (EGD) ratios calculated from WT and Scn5a+/− hearts in 7 positions across the heart, before and after the addition of flecainide or quinidine.

Mentions: Figure 2A compares typical BEG traces from the RV apex or RVOT of WT and Scn5a+/− hearts, either before or after treatment with either flecainide or quinidine. It displays BEG deflections obtained in response to the last S2 stimulus that elicited APs and the immediately preceding S1 stimulus. Each trace contains deflections arising successively from the S1 stimulus artifact (arrowed), its BEG response, and the S2 stimulus artifact (arrowed), and its BEG response.


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 BEG traces from RV apex or RVOT of wild-type (WT) and Scn5a+/− hearts, either before drug or after treatment with either flecainide or quinidine. The arrows denote stimulus artifacts, the first in each trace from an S1 stimulus and the second from an S2 stimulus. B–D: comparison of conduction curves from the base of the RV in a WT heart and in an Scn5a+/− heart (B), and at the base of an Scn5a+/− heart before and after flecainide (C) or quinidine (D). E: electrogram duration (EGD) ratios calculated from WT and Scn5a+/− hearts in 7 positions across the heart, before and after the addition of flecainide or quinidine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: A: typical BEG traces from RV apex or RVOT of wild-type (WT) and Scn5a+/− hearts, either before drug or after treatment with either flecainide or quinidine. The arrows denote stimulus artifacts, the first in each trace from an S1 stimulus and the second from an S2 stimulus. B–D: comparison of conduction curves from the base of the RV in a WT heart and in an Scn5a+/− heart (B), and at the base of an Scn5a+/− heart before and after flecainide (C) or quinidine (D). E: electrogram duration (EGD) ratios calculated from WT and Scn5a+/− hearts in 7 positions across the heart, before and after the addition of flecainide or quinidine.
Mentions: Figure 2A compares typical BEG traces from the RV apex or RVOT of WT and Scn5a+/− hearts, either before or after treatment with either flecainide or quinidine. It displays BEG deflections obtained in response to the last S2 stimulus that elicited APs and the immediately preceding S1 stimulus. Each trace contains deflections arising successively from the S1 stimulus artifact (arrowed), its BEG response, and the S2 stimulus artifact (arrowed), and its BEG response.

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