Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model
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Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model. / Lemoine, Marc D; Duverger, James Elber; Naud, Patrice; Chartier, Denis; Qi, Xiao Yan; Comtois, Philippe; Fabritz, Larissa; Kirchhof, Paulus; Nattel, Stanley.
In: CARDIOVASC RES, Vol. 92, No. 1, 01.10.2011, p. 67-74.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model
AU - Lemoine, Marc D
AU - Duverger, James Elber
AU - Naud, Patrice
AU - Chartier, Denis
AU - Qi, Xiao Yan
AU - Comtois, Philippe
AU - Fabritz, Larissa
AU - Kirchhof, Paulus
AU - Nattel, Stanley
PY - 2011/10/1
Y1 - 2011/10/1
N2 - AIMS: Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes).METHODS AND RESULTS: Peak and late Na(+) current (I(NaP) and I(NaL)) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I(NaL) was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I(NaP) was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD(90) at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I(NaL) (50% inhibitory concentration: 12.5 vs. 151.8 µM for I(NaP)) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD(90) at 0.5 Hz to 122 ± 4 ms, P= 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P< 0.05).CONCLUSION: This study implicates increased I(NaL) in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications.
AB - AIMS: Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes).METHODS AND RESULTS: Peak and late Na(+) current (I(NaP) and I(NaL)) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I(NaL) was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I(NaP) was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD(90) at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I(NaL) (50% inhibitory concentration: 12.5 vs. 151.8 µM for I(NaP)) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD(90) at 0.5 Hz to 122 ± 4 ms, P= 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P< 0.05).CONCLUSION: This study implicates increased I(NaL) in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications.
KW - Acetanilides/pharmacology
KW - Action Potentials
KW - Animals
KW - Arrhythmias, Cardiac/etiology
KW - Disease Models, Animal
KW - Heart Atria/physiopathology
KW - Long QT Syndrome/physiopathology
KW - Male
KW - Mice
KW - NAV1.5 Voltage-Gated Sodium Channel
KW - Piperazines/pharmacology
KW - Ranolazine
KW - Sodium Channels/genetics
U2 - 10.1093/cvr/cvr166
DO - 10.1093/cvr/cvr166
M3 - SCORING: Journal article
C2 - 21672931
VL - 92
SP - 67
EP - 74
JO - CARDIOVASC RES
JF - CARDIOVASC RES
SN - 0008-6363
IS - 1
ER -