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Frontiers in Cardiovascular Medicine 2024Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has... (Review)
Review
Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na current (I) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na channel Na1.8-mediated I may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.
PubMed: 38504714
DOI: 10.3389/fcvm.2024.1363848 -
Circulation Research Apr 2024Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys...
BACKGROUND
Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys (cysteine)-to-Cys disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys-to-Cys disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.
METHODS
We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1 variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments.
RESULTS
Kir2.1 mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1 cardiomyocytes showed significantly reduced inwardly rectifier K+ (I) and inward Na+ (I) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1 mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and Na1.5 proteins.
CONCLUSIONS
The extracellular Cys-to-Cys disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the Na1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.
Topics: Humans; Mice; Animals; Andersen Syndrome; Mutation; Myocytes, Cardiac; Cardiac Conduction System Disease; Disulfides; Phosphatidylinositols
PubMed: 38497220
DOI: 10.1161/CIRCRESAHA.123.323895 -
International Journal of Chronic... 2024To assess the diagnostic accuracy of a purpose-designed QTc-scoring algorithm versus the established hand-scoring in patients with chronic obstructive pulmonary disease...
STUDY OBJECTIVES
To assess the diagnostic accuracy of a purpose-designed QTc-scoring algorithm versus the established hand-scoring in patients with chronic obstructive pulmonary disease (COPD) undergoing sleep studies.
METHODS
We collected 62 overnight electrocardiogram (ECG) recordings in 28 COPD patients. QT-intervals corrected for heart rate (QTc, Bazett) were averaged over 1-min periods and quantified, both by the algorithm and by cursor-assisted hand-scoring. Hand-scoring was done blinded to the algorithm-derived results. Bland-Altman statistics and confusion matrixes for three thresholds (460, 480, and 500ms) were calculated.
RESULTS
A total of 32944 1-min periods and corresponding mean QTc-intervals were analysed manually and by computer. Mean difference between manual and algorithm-based QTc-intervals was -1ms, with limits of agreement of -18 to 16ms. Overall, 2587 (8%), 357 (1%), and 0 QTc-intervals exceeding the threshold 460, 480, and 500ms, respectively, were identified by hand-scoring. Of these, 2516, 357, and 0 were consistently identified by the algorithm. This resulted in a diagnostic classification accuracy of 0.98 (95% CI 0.98/0.98), 1.00 (1.00/1.00), and 1.00 (1.00/1.00) for 460, 480, and 500ms, respectively. Sensitivity was 0.97, 1.00, and NA for 460, 480, and 500ms, respectively. Specificity was 0.98, 1.00, and 1.00 for 460, 480, and 500ms, respectively.
CONCLUSION
Overall, 8% of nocturnal 1-min periods showed clinically relevant QTc prolongations in patients with stable COPD. The automated QTc-algorithm accurately identified clinically relevant QTc-prolongations with a very high sensitivity and specificity. Using this tool, hospital sleep laboratories may identify asymptomatic patients with QTc-prolongations at risk for malignant arrhythmia, allowing them to consult a cardiologist before an eventual cardiac event.
Topics: Humans; Long QT Syndrome; Pulmonary Disease, Chronic Obstructive; Electrocardiography; Arrhythmias, Cardiac; Algorithms
PubMed: 38495216
DOI: 10.2147/COPD.S445412 -
Kardiologia Polska 2024In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help...
BACKGROUND
In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help identify relatives at risk and prevent further events but is more difficult if an autopsy has not been performed.
AIMS
We aimed to assess the diagnostic value of clinical and genetic screening in relatives of young non-autopsied sudden unexplained death (SUD) victims.
MATERIAL AND METHODS
Eighty-seven relatives of 65 young non-autopsied SUD victims from 39 families were evaluated from 2016 to 2019. The relatives underwent extensive noninvasive cardiac workup. Genetic examinations were performed in 39 families.
RESULTS
The definite diagnoses were made in 17 of 39 (44%) families. Cardiomyopathies were identified in 10 families (5 hypertrophic, 4 dilated, and 1 arrhythmogenic), followed by long QT syndrome (5 families). In 3 families, probable diagnoses were made, whereas in 20 families no diagnosis was achieved. In total, definite and probable diagnoses were made in 18 and 5 patients, respectively. All affected relatives were offered medical management, one of them died of heart failure and one underwent transplantation during the median follow-up of 3 years. Disease-causing variants were found in 7 of 39 (18%) probands; all in families with a definite diagnosis. Variants of unknown significance were found in 2 probands.
CONCLUSION
Screening of relatives of SUD victims is warranted and may save lives, even if it is not guided by autopsy results. Genetic testing in families without the disease phenotype has little effectiveness.
Topics: Humans; Female; Male; Death, Sudden, Cardiac; Genetic Testing; Adult; Young Adult; Adolescent; Middle Aged; Child; Genetic Predisposition to Disease; Long QT Syndrome
PubMed: 38493454
DOI: 10.33963/v.phj.99617 -
Journal of Acute Medicine Mar 2024A 53-year-old presented to the emergency department following a fall and was found to have recurrent episodes of torsades de pointes and pulseless ventricular...
A 53-year-old presented to the emergency department following a fall and was found to have recurrent episodes of torsades de pointes and pulseless ventricular tachycardia on cardiac monitoring. He had been abusing nimetazepam for sleep issues over the preceding one month. Despite correction of electrolytes, the arrhythmias were persistent which necessitated temporary overdrive pacing. The patient made an uneventful recovery and the temporary pacing was successfully removed with no recurrence of the malignant arrhythmias prior to discharge.
PubMed: 38487758
DOI: 10.6705/j.jacme.202403_14(1).0006 -
Frontiers in Cardiovascular Medicine 2024The use of SGLT-2 inhibitors has revolutionized heart failure therapy. Evidence suggests a reduced incidence of ventricular and atrial arrhythmias in patients with...
BACKGROUND
The use of SGLT-2 inhibitors has revolutionized heart failure therapy. Evidence suggests a reduced incidence of ventricular and atrial arrhythmias in patients with dapagliflozin or empagliflozin treatment. It is unclear to what extent the reduced arrhythmia burden is due to direct effects of the SGLT2 inhibitors or is solely a marker of improved cardiac function.
METHODS
One hundred five rabbit hearts were allocated to eight groups and retrogradely perfused, employing a Langendorff setup. Action potential duration at 90% of repolarization (APD), QT intervals, effective refractory periods, conduction velocity, and dispersion of repolarization were obtained with monophasic action potential catheters. A model for tachyarrhythmias was established with the I blocker erythromycin for QT prolongation associated proarrhythmia as well as the potassium channel opener pinacidil for a short-QT model. An atrial fibrillation (AF) model was created with isoproterenol and acetylcholine. With increasing concentrations of both SGLT2 inhibitors, reductions in QT intervals and APD were observed, accompanied by a slight increase in ventricular arrhythmia episodes. During drug-induced proarrhythmia, empagliflozin succeeded in decreasing QT intervals, APD, and VT burden whereas dapagliflozin demonstrated no significant effects. In the presence of pinacidil induced arrhythmogenicity, neither SGLT2 inhibitor had a significant impact on cardiac electrophysiology. In the AF setting, perfusion with dapagliflozin showed significant suppression of AF in the course of restitution of electrophysiological parameters whereas empagliflozin showed no significant effect on atrial fibrillation incidence.
CONCLUSION
In this model, empagliflozin and dapagliflozin demonstrated opposite antiarrhythmic properties. Empagliflozin reduced ventricular tachyarrhythmias whereas dapagliflozin showed effective suppression of atrial arrhythmias.
PubMed: 38455723
DOI: 10.3389/fcvm.2024.1369250 -
Cardiovascular Research May 2024While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent...
AIMS
While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes.
METHODS AND RESULTS
We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (μM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6-391.6, n = 7] in population cells vs. 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 μM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs and markedly prolonged APD90.
CONCLUSION
Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.
Topics: KCNQ1 Potassium Channel; Humans; Myocytes, Cardiac; Action Potentials; Induced Pluripotent Stem Cells; Moxifloxacin; Phenethylamines; Sulfonamides; Jervell-Lange Nielsen Syndrome; Potassium Channel Blockers; Fluoroquinolones
PubMed: 38442735
DOI: 10.1093/cvr/cvae042 -
Journal of Pharmacological and... 2024A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a...
BACKGROUND AND PURPOSE
A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint.
EXPERIMENTAL APPROACH
Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron.
KEY RESULTS
Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms.
CONCLUSION AND IMPLICATIONS
Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation.
Topics: Humans; Dose-Response Relationship, Drug; Electrocardiography; Fluoroquinolones; Heart Rate; Long QT Syndrome; Moxifloxacin; Ondansetron; Phenethylamines; Sulfonamides; Verapamil
PubMed: 38432528
DOI: 10.1016/j.vascn.2024.107498 -
Sensors (Basel, Switzerland) Feb 2024In the rapidly evolving landscape of continuous electrocardiogram (ECG) monitoring systems, there is a heightened demand for non-invasive sensors capable of measuring... (Review)
Review
In the rapidly evolving landscape of continuous electrocardiogram (ECG) monitoring systems, there is a heightened demand for non-invasive sensors capable of measuring ECGs and detecting heart rate variability (HRV) in diverse populations, ranging from cardiovascular patients to sports enthusiasts. Challenges like device accuracy, patient privacy, signal noise, and long-term safety impede the use of wearable devices in clinical practice. This scoping review aims to assess the performance and safety of novel multi-channel, sensor-based biopotential wearable devices in adults. A comprehensive search strategy was employed on four databases, resulting in 143 records and the inclusion of 12 relevant studies. Most studies focused on healthy adult subjects ( = 6), with some examining controlled groups with atrial fibrillation (AF) ( = 3), long QT syndrome ( = 1), and sleep apnea ( = 1). The investigated bio-sensor devices included chest-worn belts ( = 2), wrist bands ( = 2), adhesive chest strips ( = 2), and wearable textile smart clothes ( = 4). The primary objective of the included studies was to evaluate device performance in terms of accuracy, signal quality, comparability, and visual assessment of ECGs. Safety findings, reported in five articles, indicated no major side effects for long-term/continuous monitoring, with only minor instances of skin irritation. Looking forward, there are ample opportunities to enhance and test these technologies across various physical activity intensities and clinical conditions.
Topics: Adult; Humans; Wearable Electronic Devices; Electrocardiography; Heart Rate; Monitoring, Physiologic; Atrial Fibrillation
PubMed: 38400474
DOI: 10.3390/s24041318 -
Journal of Pharmacological Sciences Mar 2024An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was...
An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and T-T, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating I inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na or Ca channel inhibition in vivo. Peramivir prolonged T-T and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.
Topics: Humans; Dogs; Animals; Torsades de Pointes; Isoflurane; Influenza, Human; Heart; Long QT Syndrome; Electrocardiography; Acids, Carbocyclic; Guanidines
PubMed: 38395523
DOI: 10.1016/j.jphs.2024.02.002