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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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A: typical mouse heart, showing the 7 recording regions: 3 in the right ventricle (RV) and 4 in the left ventricle (LV). B: typical peak and trough bipolar electrogram (BEG) data obtained in the course of a programmed electrical stimulation (PES) procedure (bottom) and resulting conduction curve constructed using an experimental paced electrogram fractionation analysis (PEFA) procedure (top) (see methods for details). C: typical trace showing simultaneous recording from the RV outflow tract (RVOT) and LV outflow tract (LVOT) at the initiation of ventricular tachycardia (VT), showing earlier onset in the RVOT. Vertical markings denote timings of the pacing (S1) and the extra-systolic (S2) stimuli (arrowed). VERP, ventricular effective refractory period.
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Figure 1: A: typical mouse heart, showing the 7 recording regions: 3 in the right ventricle (RV) and 4 in the left ventricle (LV). B: typical peak and trough bipolar electrogram (BEG) data obtained in the course of a programmed electrical stimulation (PES) procedure (bottom) and resulting conduction curve constructed using an experimental paced electrogram fractionation analysis (PEFA) procedure (top) (see methods for details). C: typical trace showing simultaneous recording from the RV outflow tract (RVOT) and LV outflow tract (LVOT) at the initiation of ventricular tachycardia (VT), showing earlier onset in the RVOT. Vertical markings denote timings of the pacing (S1) and the extra-systolic (S2) stimuli (arrowed). VERP, ventricular effective refractory period.

Mentions: Measurements were made from three positions on the RV and four positions on the LV, evenly spaced at 10-mm intervals from base to apex, with the stimulating electrode at 10 mm from each. These positions were kept constant through all experiments. This distance allowed the hearts to be placed into the rig, with the stimulating electrode coming into contact with the septum and the recording electrodes coming into contact with the LV and RV. As the clamp was secure throughout experiments, this distance was constant to ∼0.5 mm, i.e., 5% of the distances between stimulating and recording electrodes. Figure 1A illustrates a typical mouse heart, showing the seven recording regions, three in the RV and four in the LV. Region 1 in the RV was at its base, as close as possible on the epicardial surface to the underlying RVOT. Region 3 in the RV and region 4 in the LV were positioned as apically as possible. While the direct absolute distance between electrodes would not necessarily reflect the path through which the electrical signal would be conducted in the spherical whole heart, the fact that the distance was maintained between experiments allowed consistent measurements of response latencies. For each run, two simultaneous recordings were made from adjacent regions of the heart. For example, recordings from regions RV1 and RV2 were made concurrently, and then recordings made from regions RV2 and RV3. In addition, some recordings were made simultaneously from the RVOT and base of the LV.


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 mouse heart, showing the 7 recording regions: 3 in the right ventricle (RV) and 4 in the left ventricle (LV). B: typical peak and trough bipolar electrogram (BEG) data obtained in the course of a programmed electrical stimulation (PES) procedure (bottom) and resulting conduction curve constructed using an experimental paced electrogram fractionation analysis (PEFA) procedure (top) (see methods for details). C: typical trace showing simultaneous recording from the RV outflow tract (RVOT) and LV outflow tract (LVOT) at the initiation of ventricular tachycardia (VT), showing earlier onset in the RVOT. Vertical markings denote timings of the pacing (S1) and the extra-systolic (S2) stimuli (arrowed). VERP, ventricular effective refractory period.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A: typical mouse heart, showing the 7 recording regions: 3 in the right ventricle (RV) and 4 in the left ventricle (LV). B: typical peak and trough bipolar electrogram (BEG) data obtained in the course of a programmed electrical stimulation (PES) procedure (bottom) and resulting conduction curve constructed using an experimental paced electrogram fractionation analysis (PEFA) procedure (top) (see methods for details). C: typical trace showing simultaneous recording from the RV outflow tract (RVOT) and LV outflow tract (LVOT) at the initiation of ventricular tachycardia (VT), showing earlier onset in the RVOT. Vertical markings denote timings of the pacing (S1) and the extra-systolic (S2) stimuli (arrowed). VERP, ventricular effective refractory period.
Mentions: Measurements were made from three positions on the RV and four positions on the LV, evenly spaced at 10-mm intervals from base to apex, with the stimulating electrode at 10 mm from each. These positions were kept constant through all experiments. This distance allowed the hearts to be placed into the rig, with the stimulating electrode coming into contact with the septum and the recording electrodes coming into contact with the LV and RV. As the clamp was secure throughout experiments, this distance was constant to ∼0.5 mm, i.e., 5% of the distances between stimulating and recording electrodes. Figure 1A illustrates a typical mouse heart, showing the seven recording regions, three in the RV and four in the LV. Region 1 in the RV was at its base, as close as possible on the epicardial surface to the underlying RVOT. Region 3 in the RV and region 4 in the LV were positioned as apically as possible. While the direct absolute distance between electrodes would not necessarily reflect the path through which the electrical signal would be conducted in the spherical whole heart, the fact that the distance was maintained between experiments allowed consistent measurements of response latencies. For each run, two simultaneous recordings were made from adjacent regions of the heart. For example, recordings from regions RV1 and RV2 were made concurrently, and then recordings made from regions RV2 and RV3. In addition, some recordings were made simultaneously from the RVOT and base of the LV.

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