scholarly journals A systematic review of utilisation of diurnal timing information in clinical trial design for Long QT syndrome

2020 ◽  
Author(s):  
Lydia M Seed ◽  
Timothy J Hearn
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Long Qt Syndrome ◽  
Cardiac Electrophysiology ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Time Of Day ◽  
Long Qt ◽  
Timing Information ◽  
Qt Syndrome

Diurnal oscillations in human cardiac electrophysiology are thought to be under the control of the endogenous circadian clock. The incidence of arrhythmic events in patients with Long QT syndrome (LQTS) varies diurnally. The diurnal variation in QT interval has previously been identified as a potential for error in clinical trials which utilise ECG measurement. We performed a systematic review of clinical trials for LQTS to identify practice around specification of timing information for point electrocardiogram (ECG) measurements, analysis of continual ECG recordings ≥24 hours, and drug delivery. Despite guidelines having been issued around the analysis of 24-hour ECG recordings, we identify a lack of usage of detailed time of day information in trial design for LQTS studies, which has the potential to affect the interpretation of the results of drug trials. We identify that, in contrast, clinical trials for QT prolonging drugs demonstrate increased incorporation of time of day information of both QT analysis and drug dosing. We provide a visual portal to allow trial designers and clinicians to better understand timing of common cardiac-targeting drugs, and to bear this concept in mind in the design of future clinical trials.

scholarly journals Fetal Presentation of Long QT Syndrome – Evaluation of Prenatal Risk Factors: A Systematic Review

2013 ◽  
Vol 33 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Satoshi Ishikawa ◽  
Takashi Yamada ◽  
Tomoyuki Kuwata ◽  
Mamoru Morikawa ◽  
Takahiro Yamada ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
Prenatal Risk ◽  
Prenatal Risk Factors ◽  
Qt Syndrome

scholarly journals Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome

2021 ◽  
Vol 11 ◽  
Author(s):  
Kyle E. Simpson ◽  
Ravichandra Venkateshappa ◽  
Zhao Kai Pang ◽  
Shoaib Faizi ◽  
Glen F. Tibbits ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Cardiac Electrophysiology ◽  
Toxicological Screening ◽  
Long Qt ◽  
Zebrafish Model ◽  
Qt Syndrome ◽  
Organ Models ◽  
Whole Heart ◽  
Herg Channels

Long-QT Syndrome (LQTS) is a cardiac electrical disorder, distinguished by irregular heart rates and sudden death. Accounting for ∼40% of cases, LQTS Type 2 (LQTS2), is caused by defects in the Kv11.1 (hERG) potassium channel that is critical for cardiac repolarization. Drug block of hERG channels or dysfunctional channel variants can result in acquired or inherited LQTS2, respectively, which are typified by delayed repolarization and predisposition to lethal arrhythmia. As such, there is significant interest in clear identification of drugs and channel variants that produce clinically meaningful perturbation of hERG channel function. While toxicological screening of hERG channels, and phenotypic assessment of inherited channel variants in heterologous systems is now commonplace, affordable, efficient, and insightful whole organ models for acquired and inherited LQTS2 are lacking. Recent work has shown that zebrafish provide a viable in vivo or whole organ model of cardiac electrophysiology. Characterization of cardiac ion currents and toxicological screening work in intact embryos, as well as adult whole hearts, has demonstrated the utility of the zebrafish model to contribute to the development of therapeutics that lack hERG-blocking off-target effects. Moreover, forward and reverse genetic approaches show zebrafish as a tractable model in which LQTS2 can be studied. With the development of new tools and technologies, zebrafish lines carrying precise channel variants associated with LQTS2 have recently begun to be generated and explored. In this review, we discuss the present knowledge and questions raised related to the use of zebrafish as models of acquired and inherited LQTS2. We focus discussion, in particular, on developments in precise gene-editing approaches in zebrafish to create whole heart inherited LQTS2 models and evidence that zebrafish hearts can be used to study arrhythmogenicity and to identify potential anti-arrhythmic compounds.

scholarly journals EP14.05: Arrhythmias in fetal long QT syndrome: a systematic review – PROSPERO registration (10,527–)

2019 ◽  
Vol 54 (S1) ◽  
pp. 313-313
Author(s):  
S.B. Clur ◽  
P. Peltenburg ◽  
A.S. Vink ◽  
C.E. Limpens ◽  
B. Cuneo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals A Systematic Review on the Cost-Effectiveness of Genetic and Electrocardiogram Testing for Long QT Syndrome in Infants and Young Adults

2015 ◽  
Vol 18 (5) ◽  
pp. 700-708 ◽  
Author(s):  
Fernando Matias Gonzalez ◽  
Maria Assunta Veneziano ◽  
Anna Puggina ◽  
Stefania Boccia
Keyword(s):  
Systematic Review ◽  
Young Adults ◽  
Cost Effectiveness ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
Qt Syndrome ◽  
The Cost

scholarly journals Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice

2014 ◽  
Vol 307 (12) ◽  
pp. H1777-H1785 ◽  
Author(s):  
Elizabeth A. Schroder ◽  
Don E. Burgess ◽  
Cody L. Manning ◽  
Yihua Zhao ◽  
Arthur J. Moss ◽  
...  
Keyword(s):  
Heart Rate ◽  
Long Qt Syndrome ◽  
Time Of Day ◽  
Restricted Feeding ◽  
Light Phase ◽  
Long Qt ◽  
Qt Intervals ◽  
Qt Syndrome ◽  
Time Of Feeding ◽  
Type 3

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice ( Scn5a+/ΔKPQ). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a+/ΔKPQ mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a+/ΔKPQ mice, light phase-restricted feeding shifted the RR and QT rhythms ∼12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ∼10%. In contrast to WT mice, the QTc interval in Scn5a+/ΔKPQ mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a+/ΔKPQ mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.

scholarly journals Beneficial electrophysiologic effects of sacubitril in different arrhythmia syndromes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
G Frommeyer ◽  
D Dimanski ◽  
C Ellermann ◽  
J Wolfes ◽  
L Eckardt
Keyword(s):  
Long Qt Syndrome ◽  
Cardiac Electrophysiology ◽  
Torsade De Pointes ◽  
Additional Treatment ◽  
Long Qt ◽  
Beneficial Effects ◽  
Dispersion Of Repolarization ◽  
Qt Syndrome ◽  
The Impact ◽  
Antiarrhythmic Effects

Abstract Background Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. The aim of the presents study was to assess the impact of sacubitril in different arrhythmia models. Methods and results In 12 isolated rabbit hearts, sacubitril was infused in rising concentrations (3, 5, 10μM) after obtaining baseline data. In 12 further hearts, erythromycin was administered to simulate long QT syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long QT syndrome-3 (LQT3). Both LQT groups were treated with sacubitril (5μM). Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol (ACH/ISO) and sacubitril (5μM) was added afterwards. With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarization (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD and SDR in the LQT2-group (APD: −21 ms, p<0.05; SDR: −8 ms, p=ns) and did not alter APD but reduced SDR in the LQT3-group (APD: +2 ms, p=ns; SDR: −9 ms, p<0.05). Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril treatment or under baseline conditions in any group. Erythromycin provoked 43 episodes of TdP (p<0.05). Additional treatment with sacubitril significantly suppressed TdP (3 episodes, p<0.05). With veratridine, 16 episodes of TdP (p=0.07) occurred. Further treatment with sacubitril did not reduce TdP (10 episodes, p=ns) significantly. Infusion of ACH/ISO led to an increased inducibility of atrial fibrillation (31 vs. 7 episodes). Additional infusion of sacubitril increased atrial ERP (+21ms, p<0.05) and reduced inducibility of AF (9 episodes). Conclusion Sacubitril abbreviated APD and was not proarrhythmic. SDR is a major pathomechanism of TdP and was reduced by sacubitril in both LQT groups. Thereby, sacubitril exhibits antiarrhythmic effects in LQT2 and may be beneficial in LQT3. Furthermore, sacubitril suppressed AF by prolonging aERP. Our results indicate beneficial effects of sacubitril on cardiac electrophysiology. Funding Acknowledgement Type of funding source: None

scholarly journals A Systematic Review on the Role of Βeta-Blockers in Reducing Cardiac Arrhythmias in Long QT Syndrome Subtypes 1-3

Cureus ◽  
2021 ◽  
Author(s):  
Terry R Went ◽  
Waleed Sultan ◽  
Alisha Sapkota ◽  
Hajra Khurshid ◽  
Israa A Qureshi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Long Qt Syndrome ◽  
Cardiac Arrhythmias ◽  
Long Qt ◽  
Qt Syndrome

scholarly journals Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

2019 ◽  
Vol 8 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Luca Sala ◽  
Massimiliano Gnecchi ◽  
Peter J Schwartz
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Long Qt Syndrome ◽  
Pluripotent Stem Cells ◽  
Cardiac Electrophysiology ◽  
Clinical Decision Making ◽  
Long Qt ◽  
Qt Syndrome ◽  
Induced Pluripotent

Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS in vitro include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies. In 2010, human-induced pluripotent stem cells (hiPSCs) revolutionised the field and allowed scientists to study in vitro some of the disease traits of LQTS on hiPSC-derived cardiomyocytes (hiPSC-CMs) from LQTS patients. In this concise review we present how the hiPSC technology has been used to model three main forms of LQTS and the severe form of LQTS associated with mutations in calmodulin. We also introduce some of the most recent challenges that must be tackled in the upcoming years to successfully shift hiPSC-CMs from powerful in vitro disease modelling tools into assets to improve risk stratification and clinical decision-making.

scholarly journals Molecular Pathophysiology of Congenital Long QT Syndrome

2017 ◽  
Vol 97 (1) ◽  
pp. 89-134 ◽  
Author(s):  
M. S. Bohnen ◽  
G. Peng ◽  
S. H. Robey ◽  
C. Terrenoire ◽  
V. Iyer ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
Clinical Management ◽  
Cardiac Electrophysiology ◽  
Channel Structure ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

scholarly journals Long QT syndrome type 2: mechanism-based therapies

2021 ◽  
Author(s):  
Kofi Oliver Taylor Cox ◽  
Brian Xiangzhi Wang
Keyword(s):  
Long Qt Syndrome ◽  
Cardiac Electrophysiology ◽  
Current Treatment ◽  
Delayed Rectifier ◽  
Adrenergic Blockade ◽  
Syndrome Type ◽  
Long Qt ◽  
Life Threatening ◽  
Qt Syndrome

Long QT syndrome type 2 is a life-threatening disorder of cardiac electrophysiology. It can lead to sudden cardiac death as a result of QT prolongation and can remain undetected until it presents clinically in the form of life-threatening cardiac arrythmias. Current treatment relies on symptom management largely through the use of β-adrenergic blockade and presently no mechanism-based therapies exist to treat the dysfunction in the hERG channels responsible for the rapid delayed rectifier K+ current which is the pathological source of long QT syndrome type 2. We review the pathophysiology, diagnosis and current management of this life-threatening condition and also analyze some promising potential mechanism-based therapies.

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