scholarly journals Tetrodotoxin-sensitive Navs contribute to early and delayed afterdepolarizations in long QT arrhythmia models

2018 ◽  
Vol 150 (7) ◽  
pp. 991-1002 ◽  
Author(s):  
Megan Koleske ◽  
Ingrid Bonilla ◽  
Justin Thomas ◽  
Naveed Zaman ◽  
Stephen Baine ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Action Potential ◽  
Qt Interval ◽  
Torsades De Pointes ◽  
Cellular Level ◽  
Polymorphic Ventricular Tachycardia ◽  
Wild Type ◽  
Long Qt ◽  
Delayed Afterdepolarizations

Recent evidence suggests that neuronal Na+ channels (nNavs) contribute to catecholamine-promoted delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The newly identified overlap between CPVT and long QT (LQT) phenotypes has stoked interest in the cross-talk between aberrant Na+ and Ca2+ handling and its contribution to early afterdepolarizations (EADs) and DADs. Here, we used Ca2+ imaging and electrophysiology to investigate the role of Na+ and Ca2+ handling in DADs and EADs in wild-type and cardiac calsequestrin (CASQ2)-null mice. In experiments, repolarization was impaired using 4-aminopyridine (4AP), whereas the L-type Ca2+ and late Na+ currents were augmented using Bay K 8644 (BayK) and anemone toxin II (ATX-II), respectively. The combination of 4AP and isoproterenol prolonged action potential duration (APD) and promoted aberrant Ca2+ release, EADs, and DADs in wild-type cardiomyocytes. Similarly, BayK in the absence of isoproterenol induced the same effects in CASQ2-null cardiomyocytes. In vivo, it prolonged the QT interval and, upon catecholamine challenge, precipitated wide QRS polymorphic ventricular tachycardia that resembled human torsades de pointes. Treatment with ATX-II produced similar effects at both the cellular level and in vivo. Importantly, nNav inhibition with riluzole or 4,9-anhydro-tetrodotoxin reduced the incidence of ATX-II–, BayK-, or 4AP-induced EADs, DADs, aberrant Ca2+ release, and VT despite only modestly mitigating APD prolongation. These data reveal the contribution of nNaVs to triggered arrhythmias in murine models of LQT and CPVT-LQT overlap phenotypes. We also demonstrate the antiarrhythmic impact of nNaV inhibition, independent of action potential and QT interval duration, and provide a basis for a mechanistically driven antiarrhythmic strategy.

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype

2003 ◽  
Vol 285 (1) ◽  
pp. H194-H203 ◽  
Author(s):  
Michael Brunner ◽  
Sodikdjon A. Kodirov ◽  
Gary F. Mitchell ◽  
Peter D. Buckett ◽  
Katsushi Shibata ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Qt Interval ◽  
Direct Injection ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Long Qt ◽  
Dispersion Of Repolarization ◽  
Surface Ecg

Mutations in cardiac voltage-gated K+channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3–10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

Polymorphic ventricular tachycardia, ischaemic ventricular fibrillation, and torsade de pointes: importance of the QT and the coupling interval in the differential diagnosis

2021 ◽  
Author(s):  
Raphael Rosso ◽  
Aviram Hochstadt ◽  
Dana Viskin ◽  
Ehud Chorin ◽  
Arie Lorin Schwartz ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Fibrillation ◽  
Qt Interval ◽  
Torsade De Pointes ◽  
Polymorphic Ventricular Tachycardia ◽  
Ectopic Beat ◽  
Long Qt ◽  
Drug Induced ◽  
Long Qt Interval ◽  
Coupling Interval

Abstract Aims Distinctive types of polymorphic ventricular tachycardia (VT) respond differently to different forms of therapy. We therefore performed the present study to define the electrocardiographic characteristics of different forms of polymorphic VT. Methods and results We studied 190 patients for whom the onset of 305 polymorphic VT events was available. The study group included 87 patients with coronary artery disease who had spontaneous polymorphic VT triggered by short-coupled extrasystoles in the absence of myocardial ischaemia. This group included 32 patients who had a long QT interval but nevertheless had their polymorphic VT triggered by ectopic beats with short coupling interval, a subcategory termed ‘pseudo-torsade de pointes] (TdP). For comparison, we included 50 patients who had ventricular fibrillation (VF) during acute myocardial infarction (‘ischaemic VF’ group) and 53 patients with drug-induced TdP (‘true TdP’ group). The QT of patients with pseudo-TdP was (by definition) longer than that of patients with polymorphic VT and normal QT (QTc 491.4 ± 25.2 ms vs. 447.3 ± 55.6 ms, P < 0.001). However, their QT was significantly shorter than that of patients with true TdP (QTc 564.6 ± 75.6 ms, P < 0.001). Importantly, the coupling interval of the ectopic beat triggering the arrhythmia was just as short during pseudo-TdP as during polymorphic VT with normal QT (359.1 ± 38.1 ms vs. 356.6 ± 39.4 ms, P = 0.467) but was much shorter than during true TdP (581.2 ± 95.3 ms, P < 0.001). Conclusions The coupling interval helps discriminate between polymorphic VT that occurs despite a long QT interval (pseudo-TdP) and polymorphic arrhythmias striking because of a long QT (true TdP).

scholarly journals Qtc Prolongation as Prognostic Marker in Organophosphate Poisoning

2021 ◽  
Vol 8 (04) ◽  
pp. 5317-5337
Author(s):  
Dr. Digbijay Kumar Thakur ◽  
Dr. Dhruba Gaire ◽  
Dr. Siddi Datri Jha ◽  
Dr. Rameshwar Mahaseth
Keyword(s):  
Ventricular Tachycardia ◽  
Qt Interval ◽  
Torsades De Pointes ◽  
Polymorphic Ventricular Tachycardia ◽  
K Channel ◽  
Organophosphate Poisoning ◽  
Ca Channel ◽  
Corrected Qt Interval ◽  
Normal Limits ◽  
Increased Risk

Background The long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia, a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes. A rate related corrected QT interval (QTc) can be calculated as QT/√RR and normally is ≤0.44s. Some references given QTc upper normal limits as 0.43s in men and 0.45s in female. OP compound supposed to block K+ channel and Na+/Ca++ channel and hence causing prolongation of QT interval. As we know that prolongation of QT interval may precipitate polymorphic ventricular tachycardia and sudden cardiac death, so it become important in case of OP poisoning and related mortality. In this study, I calculated corrected QT interval in diagnosed cases of OP poisoning admitted at Bir Hospital and compared QTc among those with complications and without complication. I also tried to evaluate QTc as a predictor for duration of hospital stays, ICU admission, vasopressor and mechanical ventilation requirement, higher POP score and low GCS.

scholarly journals Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

2013 ◽  
pp. 127-136
Author(s):  
Gianluca Airoldi
Keyword(s):  
Heart Rate ◽  
Qt Interval ◽  
Physical Restraint ◽  
Safety Data ◽  
Surrogate Marker ◽  
Diagnostic Procedures ◽  
Torsades De Pointes ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

scholarly journals Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

2021 ◽  
Vol 10 (13) ◽  
pp. 2821
Author(s):  
Giulia Borile ◽  
Tania Zaglia ◽  
Stephan E. Lehnart ◽  
Marco Mongillo
Keyword(s):  
Ventricular Tachycardia ◽  
Single Cells ◽  
Tissue Level ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Adrenergic Stimulation ◽  
Release Channel ◽  
Multiphoton Imaging ◽  
Delayed Afterdepolarizations ◽  
Multiple Cells

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.

scholarly journals Prolonged QTc: "Mind the Gap"

2014 ◽  
Vol 2 (1) ◽  
pp. 44-45
Author(s):  
Ahmad Mursel Anam ◽  
Raihan Rabbani ◽  
Farzana Shumy ◽  
M Mufizul Islam Polash ◽  
M Motiul Islam ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Long Qt Syndrome ◽  
Qt Interval ◽  
Torsades De Pointes ◽  
Junior Doctors ◽  
Long Qt ◽  
Acquired Long Qt Syndrome ◽  
Prolonged Qt Interval ◽  
Prolonged Qt ◽  
Qt Syndrome

We report a case of drug induced torsades de pointes, following acquired long QT syndrome. The patient got admitted for shock with acute abdomen. The initial prolonged QT-interval was missed, and a torsadogenic drug was introduced post-operatively. Patient developed torsades de pointes followed by cardiac arrest. She was managed well and discharged without complications. The clinical manifestations of long QT syndromes, syncope or cardiac arrest, result from torsades de pointes. As syncope or cardiac arrest have more common differential diagnoses, even the symptomatic long QT syndrome are commonly missed or misdiagnosed. In acquired long QT syndrome with no prior suggestive feature, it is not impossible to miss the prolonged QT-interval on the ECG tracing. We share our experience so that the clinicians, especially the junior doctors, will be more alert on checking the QT-interval even in asymptomatic patients. DOI: http://dx.doi.org/10.3329/bccj.v2i1.19970 Bangladesh Crit Care J March 2014; 2 (1): 44-45

scholarly journals Functional Calsequestrin-1 Is Expressed in the Heart and Its Deficiency Is Causally Related to Malignant Hyperthermia-Like Arrhythmia

Circulation ◽  
2021 ◽  
Author(s):  
Zhipeng Sun ◽  
Luqi Wang ◽  
Lu Han ◽  
Yue Wang ◽  
Yuan Zhou ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ventricular Tachycardia ◽  
Malignant Hyperthermia ◽  
Ex Vivo ◽  
Heat Stroke ◽  
Time Lapse ◽  
Underlying Mechanism ◽  
Neonatal Rat ◽  
Polymorphic Ventricular Tachycardia

Background: Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca 2+ and regulate its release in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in CASQ1 or CASQ2 include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often suffer from arrhythmia for which the underlying mechanism remains unknown. Methods: Working hearts from conventional ( Casq1 -KO) and cardiac-specific ( Casq1 -CKO) Casq1 knockout mice were monitored in vivo and ex vivo by electrocardiogram and electrical mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca 2+ activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes (NRVMs) with knockdown, over-expression or truncation of the Casq1 gene. Conformational change in both Casqs was determined by crosslinking Western blot analysis. Results: Like MH/EHS patients, Casq1 -KO and Casq1 -CKO mice had faster basal heart rate, and ventricular tachycardia upon exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electrical triggering also occurred in Casq1 -KO hearts ex vivo . Accordingly, the ventricular cardiomyocytes from Casq1 -CKO mice displayed dantrolene-sensitive increased Ca 2+ waves and diastole premature Ca 2+ transients/oscillations upon isoflurane. NRVMs with Casq1-knockdown had enhanced spontaneous Ca2+ sparks/transients upon isoflurane, while cells over-expressing Casq1 exhibited decreased Ca2+ sparks/transients that were absent in cells with truncation of 9 amino acids at the C-terminus of Casq1. Structural evaluation showed that most of the Casq1 protein was present as a polymer and physically interacted with RyR2 in the ventricular SR. The Casq1 isoform was also expressed in human myocardium. Mechanistically, exposure to 2% isoflurane or heating at 41ºC induced Casq1 oligomerization in mouse ventricular and skeletal muscle tissues, leading to a reduced Casq1/RyR2 interaction and increased RyR2 activity in the ventricle. Conclusions: Casq1 is expressed in the heart, where it regulates SR Ca 2+ release and heart rate. Casq1 deficiency independently causes MH/EHS-like ventricular arrhythmia by trigger-induced Casq1 oligomerization and a relief of its inhibitory effect on RyR2-mediated Ca 2+ release, thus revealing a new inherited arrhythmia and a novel mechanism for MH/EHS arrhythmogenesis.

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