Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Michael Brunner, Xuwen Peng, Xin Liu Gong, Xiao Qin Ren, Ohad Ziv, Bum Rak Choi, Rajesh Mathur, Mohammed Hajjiri, Katja E. Odening, Eric Steinberg, Eduardo J. Folco, Ekatherini Pringa, Jason Centracchio, Roland R. Macharzina, Tammy Donahay, Lorraine Schofield, Naveed Rana, Malcolm Kirk, Gary F. Mitchell, Athena PoppasManfred Zehender, Gideon Koren

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Abstract

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I Ks and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Original languageEnglish (US)
Pages (from-to)2246-2259
Number of pages14
JournalJournal of Clinical Investigation
Volume118
Issue number6
DOIs
StatePublished - Jun 2 2008

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Long QT Syndrome
Sudden Death
Cardiac Arrhythmias
Sudden Cardiac Death
Rabbits
Ventricular Tachycardia
Down-Regulation
Transgenes
Cardiac Myocytes
Genes
Action Potentials
Electrocardiography
Up-Regulation
Phenotype
Peptides
Mutation
Incidence

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Brunner, Michael ; Peng, Xuwen ; Gong, Xin Liu ; Ren, Xiao Qin ; Ziv, Ohad ; Choi, Bum Rak ; Mathur, Rajesh ; Hajjiri, Mohammed ; Odening, Katja E. ; Steinberg, Eric ; Folco, Eduardo J. ; Pringa, Ekatherini ; Centracchio, Jason ; Macharzina, Roland R. ; Donahay, Tammy ; Schofield, Lorraine ; Rana, Naveed ; Kirk, Malcolm ; Mitchell, Gary F. ; Poppas, Athena ; Zehender, Manfred ; Koren, Gideon. / Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 6. pp. 2246-2259.
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abstract = "Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90{\%} of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I Ks and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50{\%} at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.",
author = "Michael Brunner and Xuwen Peng and Gong, {Xin Liu} and Ren, {Xiao Qin} and Ohad Ziv and Choi, {Bum Rak} and Rajesh Mathur and Mohammed Hajjiri and Odening, {Katja E.} and Eric Steinberg and Folco, {Eduardo J.} and Ekatherini Pringa and Jason Centracchio and Macharzina, {Roland R.} and Tammy Donahay and Lorraine Schofield and Naveed Rana and Malcolm Kirk and Mitchell, {Gary F.} and Athena Poppas and Manfred Zehender and Gideon Koren",
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Brunner, M, Peng, X, Gong, XL, Ren, XQ, Ziv, O, Choi, BR, Mathur, R, Hajjiri, M, Odening, KE, Steinberg, E, Folco, EJ, Pringa, E, Centracchio, J, Macharzina, RR, Donahay, T, Schofield, L, Rana, N, Kirk, M, Mitchell, GF, Poppas, A, Zehender, M & Koren, G 2008, 'Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome', Journal of Clinical Investigation, vol. 118, no. 6, pp. 2246-2259. https://doi.org/10.1172/JCI33578

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. / Brunner, Michael; Peng, Xuwen; Gong, Xin Liu; Ren, Xiao Qin; Ziv, Ohad; Choi, Bum Rak; Mathur, Rajesh; Hajjiri, Mohammed; Odening, Katja E.; Steinberg, Eric; Folco, Eduardo J.; Pringa, Ekatherini; Centracchio, Jason; Macharzina, Roland R.; Donahay, Tammy; Schofield, Lorraine; Rana, Naveed; Kirk, Malcolm; Mitchell, Gary F.; Poppas, Athena; Zehender, Manfred; Koren, Gideon.

In: Journal of Clinical Investigation, Vol. 118, No. 6, 02.06.2008, p. 2246-2259.

Research output: Contribution to journalArticle

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T1 - Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

AU - Brunner, Michael

AU - Peng, Xuwen

AU - Gong, Xin Liu

AU - Ren, Xiao Qin

AU - Ziv, Ohad

AU - Choi, Bum Rak

AU - Mathur, Rajesh

AU - Hajjiri, Mohammed

AU - Odening, Katja E.

AU - Steinberg, Eric

AU - Folco, Eduardo J.

AU - Pringa, Ekatherini

AU - Centracchio, Jason

AU - Macharzina, Roland R.

AU - Donahay, Tammy

AU - Schofield, Lorraine

AU - Rana, Naveed

AU - Kirk, Malcolm

AU - Mitchell, Gary F.

AU - Poppas, Athena

AU - Zehender, Manfred

AU - Koren, Gideon

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N2 - Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I Ks and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

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