INTRACELLULAR CA2+ (CAI) OSCILLATIONS AND T-WAVE LABILITY (TWL) PRECEDE TORSADE DE POINTES (TDP) IN A RABBIT MODEL OF LONG QT TYPE 2 (LQT2)

Introduction: Long QT syndrome (LQTS) is a genetic disorder associated with abnormal ventricular repolarization and a predisposition for torsade de pointes and sudden cardiac death. Identification of markers to elucidate high risk patients is of major practical importance. Our aim was to use a novel, automated quantitative T wave analysis program to distinguish symptomatic from asymptomatic LQTS patients. Methods: We analyzed a genotyped cohort of 420 patients (22 ± 15.7years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using novel software that we created to automatically detect subtle changes in T wave morphology. Symptomatic patients were defined as those with a history of syncope or resuscitated cardiac arrest that was suspected of being LQTS triggered. Classification was performed using the top three T wave features in a linear discriminant classifier by 10x10 cross-validation. Results: Symptomatic LQT1 patients have a greater QTc duration in lead aVF (437 msec vs 416 msec, p <0.0001), a greater T wave center of gravity on the x axis (COGx) in lead V2 (0.304 vs 0.280, p <0.0001) and longer Tpeak-Tend/QT in lead II (0.208 vs 0.188, p < 0.0001) than asymptomatic patients with LQT1. Use of these 3 features enabled classification of symptomatic status in 72% of LQT1 cases, compared to 68% when QTc was used to classify alone. Symptomatic LQT2 patients had a longer QTc in Lead 1 (460 vs 418 msec, p < 0.0001), COGx in 4th segment of T wave was greater in lead V5 (0.399 vs 0.350, p<0.0001), and the Tpeak-Tend interval in V2 was longer (126 vs 99 msec, P =0.0004). Use of these 3 features enabled correct classification in 73% of LQT2 cases, compared to 67% when QTc was used alone. Conclusions: Application of an automated T wave analysis program was able to identify T wave features that distinguished the patients who presented as symptomatic LQTS, associated with syncope or resuscitated cardiac arrest. Use of these features could help assess arrhythmic risk and guide management strategies for patients with LQTS.

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Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome

EP Europace ◽

10.1093/europace/eum252 ◽

2007 ◽

Vol 10 (1) ◽

pp. 112-113 ◽

Cited By ~ 14

Author(s):

F. T. Wegener ◽

J. R. Ehrlich ◽

S. H. Hohnloser

Keyword(s):

Long Qt Syndrome ◽

Torsade De Pointes ◽

Long Qt ◽

T Wave ◽

T Wave Alternans ◽

Qt Syndrome

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Architectural T-Wave Analysis and Identification of On-Therapy Breakthrough Arrhythmic Risk in Type 1 and Type 2 Long-QT Syndrome

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.117.005648 ◽

2017 ◽

Vol 10 (11) ◽

Cited By ~ 2

Author(s):

Alan Sugrue ◽

Ram K. Rohatgi ◽

Peter A. Noseworthy ◽

Vaclav Kremen ◽

J. Martijn Bos ◽

...

Keyword(s):

Long Qt Syndrome ◽

Wave Analysis ◽

Long Qt ◽

T Wave ◽

Qt Syndrome

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Late I Na Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.118.006875 ◽

2020 ◽

Vol 13 (8) ◽

Author(s):

Jungmin Hwang ◽

Tae Yun Kim ◽

Dmitry Terentyev ◽

Mingwang Zhong ◽

Anatoli Y. Kabakov ◽

...

Keyword(s):

Action Potential ◽

Long Qt Syndrome ◽

Rabbit Model ◽

Syndrome Type ◽

Long Qt ◽

Repolarization Reserve ◽

Action Potential Plateau ◽

Qt Syndrome ◽

Potential Plateau

Background: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I NaL ) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs. Methods: We tested the effects of the selective I NaL blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca 2+ imaging, and computer modeling. Results: GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca 2+ -mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca 2+ imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca 2+ transient duration via accelerating Na + /Ca 2+ exchanger (I NCX )-mediated Ca 2+ efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I NaL potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na + (Na i ) that decreases the depolarizing I NCX thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K + channels (I Ks ), suggesting important roles of I NaL in regulating Na i . Conclusions: Selective I NaL blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na i . Graphic Abstract: A graphic abstract is available for this article.

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Alternating Cycle Lengths Increases Dispersion of Action Potential Durations (APD) in Transgenic Rabbit Model of Long QT Syndrome Type 2

Biophysical Journal ◽

10.1016/j.bpj.2011.11.2948 ◽

2012 ◽

Vol 102 (3) ◽

pp. 539a-540a

Author(s):

Tae Yun Kim ◽

Paul Jeng ◽

Chantel Taylor ◽

JungMin Hwang ◽

Xuwen Peng ◽

...

Keyword(s):

Action Potential ◽

Long Qt Syndrome ◽

Rabbit Model ◽

Syndrome Type ◽

Long Qt ◽

Transgenic Rabbit ◽

Cycle Lengths ◽

Qt Syndrome

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Cytosolic Ca 2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome

The Journal of Physiology ◽

10.1113/jphysiol.2002.024570 ◽

2002 ◽

Vol 543 (2) ◽

pp. 615-631 ◽

Cited By ~ 170

Author(s):

Bum‐Rak Choi ◽

Francis Burton ◽

Guy Salama

Keyword(s):

Long Qt Syndrome ◽

Torsade De Pointes ◽

Long Qt ◽

Early Afterdepolarizations ◽

Qt Syndrome

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Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model

Scientific Reports ◽

10.1038/s41598-019-51230-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Tae Yun Kim ◽

Paul Jeng ◽

JungMin Hwang ◽

Zachary Pfeiffer ◽

Divyang Patel ◽

...

Keyword(s):

Short Term Memory ◽

Rabbit Model ◽

Polymorphic Ventricular Tachycardia ◽

Rate Variation ◽

Short Term ◽

Long Qt ◽

Term Memory ◽

Transgenic Rabbit ◽

Cycle Lengths

Abstract The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.

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