Long QT Interval Research Articles

Hydroxychloroquine induces long QT syndrome by blocking hERG channel

Abstract Objective In March 2022, more than 600 million cases of Corona Virus Disease 2019 (COVID-19) and about 6 million deaths have been reported worldwide. Unfortunately, while effective antiviral therapy has not yet been available, chloroquine (CQ)/hydroxychloroquine (HCQ) has been considered an option for the treatment of COVID-19. While many studies have demonstrated the potential of HCQ to decrease viral load and rescue patients’ lives, controversial results have also been reported. One concern associated with HCQ in its clinical application to COVID-19 patients is the potential of causing long QT interval (LQT), an electrophysiological substrate for the induction of lethal ventricular tachyarrhythmias. Yet, the mechanisms for this cardiotoxicity of HCQ remained incompletely understood. Materials and methods Adult New Zealand white rabbits were used for investigating the effects of HCQ on cardiac electrophysiology and expression of ion channel genes. HEK-293T cells with sustained overexpression of human-ether-a-go-go-related gene (hERG) K+ channels were used for whole-cell patch-clamp recordings of hERG K+ channel current (IhERG). Quantitative RT-PCR analysis and Western blot analysis were employed to determine the expression of various genes at mRNA and protein levels, respectively. Results electrocardiogram (ECG) recordings revealed that HCQ prolonged QT and RR intervals and slowed heart rate in rabbits. Whole-cell patch-clamp results showed that HCQ inhibited the tail current of hERG channels and slowed the reactivation process from inactivation state. HCQ suppressed the expression of hERG and hindered the formation of the heat shock protein 90 (Hsp90)/hERG complex. Moreover, the expression levels of connexin 43 (CX43) and Kir2.1, the critical molecular/ionic determinants of cardiac conduction thereby ventricular arrythmias, were decreased by HCQ, while those of Cav1.2, the main Ca2+ handling proteins, remained unchanged and SERCA2a was increased. Conclusion HCQ could induce LQT but did not induce arrhythmias, and whether it is suitable for the treatment of COVID-19 requires more rigorous investigations and validations in the future.

Prevention, management and emergency treatment of children with long QT interval syndrome and its advanced Torsades de Pointes

Long QT interval syndrome(LQTS) is an ion channelopathy disease which holds the characteristics of the prolongation of QT interval on electrocardiogram(ECG) and ventricular arrhythmia(VT). The occurrence of this disease is associated with mutations among potassium channel protein, sodium channel protein, calcium channel related factor, and membrane adaptation protein.Now, there were 13 genes that their mutation results in LQTS.The clinical feature is mainly manifested on the abnormal prolongation of QT interval, the giant T wave alternans on the ECG and the syncope or cardiac sudden death resulted from torsades de pointes(TdP) ventricular tachycardia.Arrhythmic events are closely related with the gene type involved.On LQTS1, the arrhythmia was normally triggered by sports and emotional excitement, and LQTS2 was by loud noises.The emergency treatment is required when the TdP occurred, because it will result in rapid deterioration of circulatory perfusion and sudden death.The emergency treatment includes intravenous administration of magnesium sulfate, synchronized or nonsynchronized DC shock for cardioversion, correcting internal environmental disturbance such as hypokalemia, and terminating the use of certain drugs which could cause the prolongation of QT interval.The long term management of LQTS includes lifestyle intervention, oral administration of β-blockers, implantation of implantable cardioverter defibrillator(ICD), left cardiac sympathetic denervation and certain target drugs. Key words: Long QT interval syndrome; Torsades de Pointes; Prevention; Management,

Alterations in the carnitine cycle in a mouse model of Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disease that leads to intellectual deficit, motor disability, epilepsy and increased risk of sudden death. Although in up to 95% of cases this disease is caused by de novo loss-of-function mutations in the X-linked methyl-CpG binding protein 2 gene, it is a multisystem disease associated also with mitochondrial metabolic imbalance. In addition, the presence of long QT intervals (LQT) on the patients’ electrocardiograms has been associated with the development of ventricular tachyarrhythmias and sudden death. In the attempt to shed light on the mechanism underlying heart failure in RTT, we investigated the contribution of the carnitine cycle to the onset of mitochondrial dysfunction in the cardiac tissues of two subgroups of RTT mice, namely Mecp2+/− NQTc and Mecp2+/− LQTc mice, that have a normal and an LQT interval, respectively. We found that carnitine palmitoyltransferase 1 A/B and carnitine acylcarnitine translocase were significantly upregulated at mRNA and protein level in the heart of Mecp2+/− mice. Moreover, the carnitine system was imbalanced in Mecp2+/− LQTc mice due to decreased carnitine acylcarnitine transferase expression. By causing accumulation of intramitochondrial acylcarnitines, this imbalance exacerbated incomplete fatty acid oxidation, which, in turn, could contribute to mitochondrial overload and sudden death.

ECG Response: August 20, 2013

HomeCirculationVol. 128, No. 8ECG Response: August 20, 2013 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBECG Response: August 20, 2013 Originally published20 Aug 2013https://doi.org/10.1161/CIRCULATIONAHA.113.005120Circulation. 2013;128:869ECG Challenge: A 67-year-old man recently underwent radical neck surgery for pharyngeal cancer. Three days later, he developed severe muscle twitching and spasms and sharp chest pain. An ECG was obtained.The rhythm is regular at a rate of 78 bpm. There is a P wave (+) before each QRS complex with a stable PR interval (0.16 second). The P waves are positive in leads I, II, aVF, and V4 through V6. Hence, this is a normal sinus rhythm. The QRS complex duration is normal (0.08 second) and has a normal axis (between 0° and 90°, positive QRS complex in leads I and aVF). The QRS complex has a normal morphology, although there is poor R-wave progression in leads V1 and V2. This is likely a normal variant, although an old anteroseptal myocardial infarction should be considered. The QT/QTc intervals are prolonged (480/540 milliseconds). There are 2 different patterns for QT prolongation. The first is delayed repolarization in which the long-QT interval is the result of a long ST segment (^) and the T wave is normal in duration. This pattern is seen with either hypocalcemia or hypomagnesemia, which results in a prolongation in phase 2 of the action potential and hence a delay in the onset of repolarization. This type of QT prolongation is not associated with any cardiac abnormalities; specifically, it is not associated with torsade des pointes. The second pattern is called prolonged repolarization in which there is a widening of the T wave (prolongation in the T-wave duration). This is often the result of a slow efflux of potassium during phase 3 of the action potential, which prolongs repolarization or the refractoriness of the membrane. This is a long-QT pattern that is associated with the development of torsade des pointes, or a long-QT syndrome. The long-QT interval in this situation may be acquired, a result of therapy with a drug that interferes with the efflux of potassium during repolarization (eg, the class III antiarrhythmic drugs), or congenital, a result of a channelopathy that causes a prolongation in membrane refractoriness. In this ECG, the pattern is one of delayed repolarization as there is a long ST segment (^) and a normal T wave. The patient likely developed hypocalcemia as a result of hypoparathyroidism due to the recent neck surgery.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails August 20, 2013Vol 128, Issue 8 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.005120PMID: 23960258 Originally publishedAugust 20, 2013 PDF download Advertisement SubjectsElectrocardiology (ECG)

Recurrent Syncope Due to Torsades de Pointes in a 41-Year-Old Woman With an Empty Sella, Anterior Pituitary Insufficiency, and a Long-QT Interval

A 41-year-old woman was admitted to our emergency room (ER) because of recurrent syncope. ECG monitoring in the ER showed episodes of sustained but self-limiting torsades de pointes ventricular tachycardia (Figure 1). Two more episodes of syncope occurred in the ER. Intravenous magnesium was administered. Echocardiography revealed a severely impaired left ventricular (LV) function (online-only Data Supplement Movie I). The patient was immediately transferred to the cardiac catheterization laboratory for further assessment. Coronary artery disease was excluded by coronary angiography. LV angiography confirmed global hypokinesia (online-only Data Supplement Movie II). The calculated LV ejection fraction was 30%. During the procedure a temporary pacemaker was placed in the right ventricle. Pacing was initiated at a rate of 80 bpm, and the patient was transferred to the coronary care unit. No more episodes …

Genotyping Has a Minor Role in Selecting Therapy for Congenital Long-QT Syndromes at Present

Genotyping has led to enormous advances in understanding the phenotype and clinical course of the congenital long-QT syndromes (LQTS). In the most common LQTS forms, LQT1, LQT2, and LQT3, genotyping a clearly affected person in each family provides the ability to easily identify family members with reduced penetrance of the QTc and symptoms phenotypes, thus, providing also the opportunity to prevent sudden death and cardiac arrest by administering presymptomatic therapy. Response by Moss and Goldberg see p 227 The role of genotyping in selecting the therapy for LQTS is, on the other hand, unclear. Data from the literature and from the Salt Lake City LQTS database will be presented to show that genotyping has only a minor role in selecting therapy for LQTS. The discussion will primarily address the LQT1, LQT2, and LQT3 forms (caused by mutations of the LQT1, 2, 3, 5, and 6 genes)1 and the rare LQT4, LQT7, and LQT8 forms will be discussed briefly, and because so little is known about the new LQT9-11 forms they are not ready for a discussion of genotyping for therapy decisions. The pleural term “Long-QT syndromes” is indeed now very appropriate because of the diversity (both molecular and phenotype) of the conditions caused by the 11 accepted or proposed LQTS genes. The idea of genotype-based therapy has been discussed for some time, being encouraged by the experimental findings with mexiletine and flecainide in LQT3 and potassium supplementation in LQT2, plus other laboratory findings.2–8 The concept has received additional attention recently as some details outlining the complexity of the molecular substrate of LQTS are being reported.9–18 There are several concepts that are important for the discussion of this controversy. First, what we really want to accomplish by treatment is to prevent sudden death and aborted cardiac arrest. Most …

Electrocardiographic Evaluation of Cardiovascular Status

The electrocardiogram (ECG) is indispensable for the diagnosis and management of patients with a wide variety of cardiac and noncardiac diseases. The purpose of this paper is focused on recent research that used ECG, specifically the long-QT interval and microvolt T wave alternans, for the evaluation of life-threatening ventricular arrhythmias. Although remaining to be validated, QT prolongation along with other emerging electrocardiographic indices such as T wave morphology, T peak-to-T end time, or beat-to-beat QT variability may be sensitive indicators of malignant polymorphic ventricular tachyarrhythmia, torsade de pointes. Microvolt T wave alternans may provide important information in identifying a low-risk group with left ventricular dysfunction who is unlikely to benefit from unnecessary prophylactic implantable cardioverter defibrillator therapy. These ECG markers have the potential to aid in the safe administration of individualized medications, avoidance of sudden cardiac death, and provision of a noninvasive strategy to identify patients who are most and least likely to benefit from expensive prophylactic implantable cardioverter defibrillator placement.

Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias

Recent reports have highlighted the importance of a family history of sudden death as a risk for ventricular fibrillation (VF) in patients experiencing acute myocardial infarction (AMI), pointing to the possibility of a genetic predisposition. This report briefly reviews 2 recent studies designed to examine the hypothesis that there is a genetic predisposition to the development of arrhythmias associated with AMI. Ventricular tachycardia and VF (VT/VF) complicating AMI as well as arrhythmias associated with Brugada syndrome, a genetic disorder linked to SCN5A mutations, have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI in patients developing VF during AMI. A missense mutation in SCN5A was found in a patient who developed an arrhythmic electrical storm during an evolving myocardial infarction. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. G400A mutation and H558R polymorphism were on the same allele, and functional expression in TSA201 demonstrated loss of function of sodium channel activity. These results suggest that a subclinical mutation in SCN5A resulting in a loss of function may predispose to life-threatening arrhythmias during acute ischemia. In another cohort of patients who developed long-QT intervals and torsade de pointes arrhythmias in days 2 to 11 after an AMI, a genetic screening of all long-QT genes was performed. Of 8 patients in this group, 6 (75%) displayed the same polymorphism in KCNH2, which encodes the α-subunit of the rapidly activating delayed rectifier potassium current, I Kr. The K897T polymorphism was detected in only 3 of 14 patients with uncomplicated myocardial infarction and has been detected in 33% of the white population. Expression of this polymorphism has previously been shown to cause a loss of function in HERG current consistent with the long-QT phenotype. These observations suggest a genetic predisposition to the development of long-QT intervals and torsade de pointes in the days after an AMI. These preliminary studies provide support for the hypothesis that there is a genetic predisposition to the type and severity of arrhythmias that develop during and after an AMI, and that additional studies are warranted.

Left Ventricular Epicardial Activation Increases Transmural Dispersion of Repolarization in Healthy, Long QT, and Dilated Cardiomyopathy Dogs

Benefits of cardiac resynchronization therapy (CRT) are well established. However, less is understood concerning its effects on myocardial repolarization and the potential proarrhythmic risk. Healthy dogs (n = 8) were compared to a long QT interval (LQT) model (n = 8, induced by cesium chloride, CsCl) and a dilated cardiomyopathy with congestive heart failure (DCM-CHF, induced by rapid ventricular pacing, n = 5). Monophasic action potential (MAP) recordings were obtained from the subendocardium, midmyocardium, subepicardium, and the transmural dispersion of repolarization (TDR) was calculated. The QT interval and the interval from the peak to the end of the T wave (T(p-e)) were measured. All these characteristics were compared during left ventricular epicardial (LV-Epi), right ventricular endocardial (RV-Endo), and biventricular (Bi-V) pacing. In healthy dogs, TDR prolonged to 37.54 ms for Bi-V pacing and to 47.16 ms for LV-Epi pacing as compared to 26.75 ms for RV-Endo pacing (P < 0.001), which was parallel to an augmentation in T(p-e) interval (Bi-V pacing, 64.29 ms; LV-Epi pacing, 57.89 ms; RV-Endo pacing, 50.29 ms; P < 0.01). During CsCl exposure, Bi-V and LV-Epi pacing prolonged MAPD, TDR, and T(p-e) interval as compared to RV-Endo pacing. The midmyocardial MAPD (276.30 ms vs 257.35 ms, P < 0.0001) and TDR (33.80 ms vs 27.58 ms, P=0.002) were significantly longer in DCM-CHF dogs than those in healthy dogs. LV-Epi and Bi-V pacing further prolonged the MAPD and TDR in this model. LV-Epi and Bi-V pacing result in prolongation of ventricular repolarization time, and increase of TDR accounted for a parallel augmentation of the T(p-e) interval, which provides evidence that T(p-e) interval accurately represents TDR. These effects are magnified in the LQT and DCM-CHF canine models in addition to their intrinsic transmural heterogeneity in the intact heart. This mechanism may contribute to the development of malignant ventricular arrhythmias, such as torsades de pointes (TdP) in congestive heart failure (CHF) patients treated with CRT.

Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome.

This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events. Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the Tpeak-Tend interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to register on the ECG. The morphology of the T wave appeared to be due to currents flowing down voltage gradients on either side of the M region during phase 2 and phase 3 of the ventricular action potential. The interplay between these opposing forces determined the height of the T wave as well as the degree to which the ascending or descending limb of the T wave was interrupted, giving rise to bifurcated T waves and "apparent T-U complexes" under LQT conditions. Spontaneous and stimulation-induced polymorphic ventricular tachycardia with characteristics of torsade de pointes (TdP) developed in the presence of dl-sotalol. Our results provide the first direct evidence that opposing voltage gradients between epicardium and the M region and endocardium and the M region contribute prominently to the inscription of the ECG T wave under normal conditions and to the widened or bifurcated T wave and long-QT interval observed under LQT conditions. Our data suggest that the "pathophysiological U" wave observed in acquired or congenital LQTS is more likely to be a second component of an interrupted T wave, and argue for use of the term T2 in place of U to describe this event.