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Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/- mouse model.

Martin CA, Guzadhur L, Grace AA, Lei M, Huang CL - Am. J. Physiol. Heart Circ. Physiol. (2011)

Bottom Line: In contrast, Scn5a+/- hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT.This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits.The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

View Article: PubMed Central - PubMed

Affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK. clairemartin@gmail.com

ABSTRACT
Two major mechanisms have been postulated for the arrhythmogenic tendency observed in Brugada Syndrome (BrS): delays in conduction or increased heterogeneities in repolarization. We use a contact mapping system to directly investigate the interacting roles of these two mechanisms in arrhythmogenesis using a genetic murine model for BrS for the first time. Electrograms were obtained from a multielectrode recording array placed against the left ventricle and right ventricle (RV) of spontaneously beating Langendorff-perfused wild type (WT) and Scn5a+/- mouse hearts. Scn5a+/- hearts showed activation waves arriving at the epicardial surface consistent with slowed conduction, which was exacerbated in the presence of flecainide. Lines of conduction block across the RV resulting from premature ventricular beats led to the formation of reentrant circuits and polymorphic ventricular tachycardia. WT hearts showed an inverse relationship between activation times and activation recovery intervals measured at the epicardial surface, which resulted in synchronicity of repolarization times. In contrast, Scn5a+/- hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT. Isochronal maps showed that their normal activation recovery interval gradients at the epicardial surface were disrupted, leading to heterogeneity in repolarization times. We thus directly demonstrate the initiation of arrhythmia in the RV of Scn5a+/- hearts. This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits. The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

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A and B: maps of ARIs in the RV of WT (A) and Scn5a+/− (B) hearts from the same runs as Fig. 3, A and B, measured relative to the shortest ARI in the array. C: graph of paired ARI and AT measurements, relative to the shortest ARI or earliest AT in the array, at each of 64 points on the 8 × 8 electrode grid for the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B. Graphs of ARIs (D) and ARI differences (E). Significant differences: *: effect of drug; #: effect of genotype; x: effect of cardiac ventricle.
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Figure 5: A and B: maps of ARIs in the RV of WT (A) and Scn5a+/− (B) hearts from the same runs as Fig. 3, A and B, measured relative to the shortest ARI in the array. C: graph of paired ARI and AT measurements, relative to the shortest ARI or earliest AT in the array, at each of 64 points on the 8 × 8 electrode grid for the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B. Graphs of ARIs (D) and ARI differences (E). Significant differences: *: effect of drug; #: effect of genotype; x: effect of cardiac ventricle.

Mentions: The ARI is a measure of the RT course, as indicated by the initial studies comparing unipolar electrogram recordings with MAP recordings (see Fig. 2, A and B). Figure 2, C and D, shows variation in the ARIs within recordings and among different experimental conditions of ventricle, genotype, and drug treatment. Figure 5, A and B, demonstrates maps of ARIs, measured relative to the shortest ARI in the array in the RV of WT and Scn5a+/− hearts from the same experimental runs as Fig. 3, A and B. Figure 5C, again using the data from the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B, plots each ARI measurement in the array relative to the shortest ARI in the array, against the corresponding AT relative to the earliest AT in the array, for each of 64 points on the 8 × 8 electrode grid.


Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/- mouse model.

Martin CA, Guzadhur L, Grace AA, Lei M, Huang CL - Am. J. Physiol. Heart Circ. Physiol. (2011)

A and B: maps of ARIs in the RV of WT (A) and Scn5a+/− (B) hearts from the same runs as Fig. 3, A and B, measured relative to the shortest ARI in the array. C: graph of paired ARI and AT measurements, relative to the shortest ARI or earliest AT in the array, at each of 64 points on the 8 × 8 electrode grid for the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B. Graphs of ARIs (D) and ARI differences (E). Significant differences: *: effect of drug; #: effect of genotype; x: effect of cardiac ventricle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094090&req=5

Figure 5: A and B: maps of ARIs in the RV of WT (A) and Scn5a+/− (B) hearts from the same runs as Fig. 3, A and B, measured relative to the shortest ARI in the array. C: graph of paired ARI and AT measurements, relative to the shortest ARI or earliest AT in the array, at each of 64 points on the 8 × 8 electrode grid for the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B. Graphs of ARIs (D) and ARI differences (E). Significant differences: *: effect of drug; #: effect of genotype; x: effect of cardiac ventricle.
Mentions: The ARI is a measure of the RT course, as indicated by the initial studies comparing unipolar electrogram recordings with MAP recordings (see Fig. 2, A and B). Figure 2, C and D, shows variation in the ARIs within recordings and among different experimental conditions of ventricle, genotype, and drug treatment. Figure 5, A and B, demonstrates maps of ARIs, measured relative to the shortest ARI in the array in the RV of WT and Scn5a+/− hearts from the same experimental runs as Fig. 3, A and B. Figure 5C, again using the data from the experimental runs depicted in Fig. 3, A and B, and Fig. 5, A and B, plots each ARI measurement in the array relative to the shortest ARI in the array, against the corresponding AT relative to the earliest AT in the array, for each of 64 points on the 8 × 8 electrode grid.

Bottom Line: In contrast, Scn5a+/- hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT.This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits.The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

View Article: PubMed Central - PubMed

Affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK. clairemartin@gmail.com

ABSTRACT
Two major mechanisms have been postulated for the arrhythmogenic tendency observed in Brugada Syndrome (BrS): delays in conduction or increased heterogeneities in repolarization. We use a contact mapping system to directly investigate the interacting roles of these two mechanisms in arrhythmogenesis using a genetic murine model for BrS for the first time. Electrograms were obtained from a multielectrode recording array placed against the left ventricle and right ventricle (RV) of spontaneously beating Langendorff-perfused wild type (WT) and Scn5a+/- mouse hearts. Scn5a+/- hearts showed activation waves arriving at the epicardial surface consistent with slowed conduction, which was exacerbated in the presence of flecainide. Lines of conduction block across the RV resulting from premature ventricular beats led to the formation of reentrant circuits and polymorphic ventricular tachycardia. WT hearts showed an inverse relationship between activation times and activation recovery intervals measured at the epicardial surface, which resulted in synchronicity of repolarization times. In contrast, Scn5a+/- hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT. Isochronal maps showed that their normal activation recovery interval gradients at the epicardial surface were disrupted, leading to heterogeneity in repolarization times. We thus directly demonstrate the initiation of arrhythmia in the RV of Scn5a+/- hearts. This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits. The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

Show MeSH
Related in: MedlinePlus