Nicorandil Suppresses a Hump on the Monophasic Action Potential and Torsade de Pointes in a Patient with Idiopathic Long QT Syndrome.

Cardiac I Kr is a critical repolarizing current in the heart and a target for inherited and acquired long QT syndrome. Biochemical studies show that native I Kr channels are heteromers composed of both hERG 1a and 1b subunits, yet our current understanding of I Kr functional properties derives primarily from studies of homo-oligomers of the original hERG 1a isolate. The hERG 1a and 1b subunits are identical except at the amino (NH2) terminus, which in hERG 1b is much shorter and has a unique primary sequence. We compared the biophysical properties of currents produced by hERG 1a and 1a/1b channels expressed in HEK-293 cells at near-physiological temperatures. We found that heteromeric hERG 1a/1b currents are much larger than hERG 1a currents and conduct 80% more charge during an action potential. This surprising difference corresponds to a two-fold increase in the apparent rates of activation and recovery from inactivation, which reduces rectification and facilitates current rebound during repolarization. Kinetic modeling shows these gating differences account quantitatively for the differences in current amplitude between the two channel types. Depending on the action potential model used, loss of 1b predicts an increase in action potential duration of 27 ms (7%) or 41 ms (17%), respectively. Drug sensitivity was also different. Compared to homomeric 1a channels, heteromeric 1a/1b channels were inhibited by E-4031 with a slower time course and a corresponding four-fold positive shift in the IC 50 . Differences in current kinetics and drug sensitivity were modeled by “NH2 mode” gating with conformational states bound by the amino terminus in hERG 1a homomers but not 1a/1b heteromers. The importance of hERG 1b in vivo is supported by the identification of a 1b-specific A8V missense mutation in 1/269 unrelated genotype-negative LQTS patients and absent in 400 control alleles. Mutant 1bA8V expressed alone or with hERG 1a in HEK-293 cells nearly eliminated 1b protein. Thus, mutations specifically disrupting hERG 1b function are expected to reduce cardiac I Kr , prolong QT interval and enhance drug sensitivity, thus representing a potential mechanism underlying inherited or acquired LQTS.

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Bupivacaine Destabilizes Action Potential Duration in Cellular and Computational Models of Long QT Syndrome 1

Anesthesia & Analgesia ◽

10.1213/ane.0b013e3182323245 ◽

2011 ◽

Vol 113 (6) ◽

pp. 1365-1373 ◽

Cited By ~ 2

Author(s):

Alexander P. Schwoerer ◽

Roman Zenouzi ◽

Heimo Ehmke ◽

Patrick Friederich

Keyword(s):

Action Potential ◽

Long Qt Syndrome ◽

Action Potential Duration ◽

Computational Models ◽

Long Qt ◽

Qt Syndrome

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Acquired long QT syndrome and torsade de pointes

Pacing and Clinical Electrophysiology ◽

10.1111/pace.13296 ◽

2018 ◽

Vol 41 (4) ◽

pp. 414-421 ◽

Cited By ~ 15

Author(s):

Nabil El-Sherif ◽

Gioia Turitto ◽

Mohamed Boutjdir

Keyword(s):

Long Qt Syndrome ◽

Torsade De Pointes ◽

Long Qt ◽

Acquired Long Qt Syndrome ◽

Qt Syndrome

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Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.119.008082 ◽

2020 ◽

Vol 13 (5) ◽

Cited By ~ 4

Author(s):

Sarah Strand ◽

Janette F. Strasburger ◽

Bettina F. Cuneo ◽

Ronald T. Wakai

Keyword(s):

Atrioventricular Block ◽

Long Qt Syndrome ◽

De Novo ◽

Perinatal Death ◽

Torsade De Pointes ◽

Fetal Loss ◽

Long Qt ◽

Premature Ventricular Contractions ◽

Fetal Magnetocardiography ◽

Qt Syndrome

Background: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. Methods: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). Results: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. Conclusions: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03047161.

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