QT-related Arrhythmias Research Articles

Antioxidants in Arrhythmia Treatment-Still a Controversy? A Review of Selected Clinical and Laboratory Research.

Antioxidants are substances that can prevent damage to cells caused by free radicals. Production of reactive oxygen species and the presence of oxidative stress play an important role in cardiac arrhythmias. Currently used antiarrhythmic drugs have many side effects. The research on animals and humans using antioxidants (such as vitamins C and E, resveratrol and synthetic substances) yields many interesting but inconclusive results. Natural antioxidants, such as vitamins C and E, can reduce the recurrence of atrial fibrillation (AF) after successful electrical cardioversion and protect against AF after cardiac surgery, but do not affect the incidence of atrial arrhythmias in critically ill patients with trauma. Vitamins C and E may also effectively treat ventricular tachycardia, ventricular fibrillation and long QT-related arrhythmias. Another natural antioxidant—resveratrol—may effectively treat AF and ventricular arrhythmias caused by ischaemia–reperfusion injury. It reduces the mortality associated with life-threatening ventricular arrhythmias and can be used to prevent myocardial remodelling. Statins also show antioxidant activity. Their action is related to the reduction of oxidative stress and anti-inflammatory effect. Therefore, statins can reduce the post-operative risk of AF and may be useful in lowering its recurrence rate after successful cardioversion. Promising results also apply to polyphenols, nitric oxide synthase inhibitors and MitoTEMPO. Although few clinical trials have been conducted, the use of antioxidants in treating arrhythmias is an interesting prospect.

QTc prolongation in adolescents with acute alcohol intoxication

In adults, alcohol intoxication is associated with prolongation of the QT interval corrected for heart rate (QTc). The QTc is influenced by age and sex. Although alcohol intoxication is increasingly common in adolescents, there are no data on the prevalence of QTc prolongation in adolescents with alcohol intoxication. This study aimed to determine the prevalence of QTc prolongation in adolescents with alcohol intoxication and identify at-risk adolescents. In this observational study including adolescents aged 10–18 years, heart rate and QT interval were automatically assessed from an electrocardiogram (ECG) at alcohol intoxication using a validated algorithm. The QTc was calculated using both the Bazett formula (QTcB) and Fridericia formula (QTcF). If present, an ECG recorded within 1 year of the date of admission to the emergency department was obtained as a reference ECG. A total of 317 adolescents were included; 13.3% had a QTcB and 7.9% a QTcF longer than the sex- and age-specific 95th-percentile. None of the adolescents had a QTcB or QTcF > 500 ms, but 11.8% of the adolescents with a reference ECG had a QTcB prolongation of > 60 ms, while no adolescents had a QTcF prolongation of > 60 ms. QTc prolongation was mainly attributable to an increase in heart rate rather than QT prolongation, which underlies the differences between QTcB and QTcF. Male sex and hypokalaemia increased the likelihood of QTc prolongation.Conclusion: QTc prolongation was seen in approximately 10% of the adolescents presenting with alcohol intoxication, and although no ventricular arrhythmias were observed in this cohort, QTc prolongation increases the potential for malignant QT-related arrhythmias. Clinicians must be aware of the possibility of QTc prolongation during alcohol intoxication and make an effort to obtain an ECG at presentation, measure the QT interval, and give an adequate assessment of the findings. We advocate admitting adolescents with alcohol intoxication and QTc prolongation. During hospital admission, we recommend limiting exposure to QTc-prolonging medication, increasing potassium levels to a high-normal range (4.5–5.0 mmol/L) and obtaining a reference ECG at discharge.What is Known:• One out of five deaths in adolescents is alcohol-related. Alcohol intoxication has been related to cardiac arrhythmias and sudden cardiac death.•In adults, alcohol intoxication is associated with QTc prolongation.What is New:•Approximately 10% of the adolescents with alcohol intoxication had a QTc longer than the age- and sexspecific cut-off. In contrast to adults, in adolescents with alcohol intoxication, QTc prolongation is attributable to an increase in heart rate, rather than a prolongation of the QT interval.•Especially males and adolescents with hypokalaemia are at risk of QTc prolongation.

Arrhythmic safety of hydroxychloroquine in COVID-19 patients from different clinical settings.

AimsThe aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings.Methods and resultsCOVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36–72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9–16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting.ConclusionHCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.

Clinicians\u2019 adherence to clinical practice guidelines for cardiac function monitoring during antipsychotic treatment: a retrospective report on 434 patients with severe mental illness

BackgroundSevere mental illness (SMI) has considerable excess morbidity and mortality, a proportion of which is explained by cardiovascular diseases, caused in part by antipsychotic (AP) induced QT-related arrhythmias and sudden death by Torsade de Point (TdP). The implementation of evidence-based recommendations for cardiac function monitoring might reduce the incidence of these AP-related adverse events. To investigate clinicians’ adherence to cardiac function monitoring before and after starting AP, we performed a retrospective assessment of 434 AP-treated SMI patients longitudinally followed-up for 5 years at an academic community mental health center.MethodsWe classified antipsychotics according to their risk of inducing QT-related arrhythmias and TdP (Center for Research on Therapeutics, University of Arizona). We used univariate tests and multinomial or binary logistic regression model for data analysis.ResultsUnivariate and multinomial regression analysis showed that psychiatrists were more likely to perform pre-treatment electrocardiogram (ECG) and electrolyte testing with AP carrying higher cardiovascular risk, but not on the basis of AP pharmacological class. Univariate and binomial regression analysis showed that cardiac function parameters (ECG and electrolyte balance) were more frequently monitored during treatment with second generation AP than with first generation AP.ConclusionsOur data show the presence of weaknesses in the cardiac function monitoring of AP-treated SMI patients, and might guide future interventions to tackle them.

Dan Roden: learn, apply, evolve.

As a scientist, Dan Roden grew up as clinical electrophysiology did. Widely recognized for his research into mechanisms behind abnormal heart rhythms and drug responses, Roden was on the front lines in the 1980s and 1990s as new antiarrhythmic drugs were tested, the ability to use catheters to study drug actions evolved, and the specialty of clinical electrophysiology arose. From his first publication, appearing in the New England Journal of Medicine in 1980,1 Roden set a tone for a career focused on variable action of antiarrhythmic therapies and genetic determinants of that variation. Much of his current work focuses on individual cardiac ion channel mutations and their role in variable responses to drug therapy, and applications of genomics to healthcare. Among his achievements, Roden is credited with developing the idea of reduced repolarization reserve leading to acquired long QT intervals and arrhythmias2–4 and was one of the first to suggest that early afterdepolarizations cause long QT-related arrhythmias.5,6 As leader of Vanderbilt University’s pharmacogenomics project PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care & Treatment)—which pre-emptively enhances individuals’ electronic medical records with personalized information about genetic variants that could guide drug therapy—Roden and colleagues7 have demonstrated multiple advantages of preemptive genotyping. Meanwhile Vanderbilt’s massive BioVU DNA bank, which includes ≈175 000 human DNA samples and which Roden pioneered and directs, is similarly showing the power of incorporating genomic data into electronic medical records, for research purposes.7–11 Roden, who initially flirted with a future in journalism, described to Circulation Research some of his interests beginning as a child of immigrants in Montreal and leading to not just 1 career as an investigator, but a series of interlinked careers—in clinical pharmacology, cellular electrophysiology, molecular genetics, and population science. The paradigm for his progress, …

Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: potential significance in arrhythmogenesis and antiarrhythmic therapy.

Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion. The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model. Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp. KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias. Induction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to enhance repolarization reserve in long QT syndrome.

Female gender: risk factor for congenital long QT-related arrhythmias

This editorial refers to ‘Increased late sodium current contributes to long QT-related arrhythmia susceptibility in female mice’ by J.S. Lowe et al ., doi:10.1093/cvr/cvs160. Congenital long-QT syndrome (LQTS) is a genetic cardiac channelopathy in which patients exhibit delayed ventricular repolarization that appears as a prolongation of the corrected QT (QTc) interval on the electrocardiogram.1 More than 200 mutations have been found in 13 different genes encoding ion channels, accessory beta subunits, and regulatory proteins.2 Most cases of congenital LQTS are the consequence of the dominant inheritance of a given mutation.2 Kv11.1 mutations are the most frequent ones (45%), followed by those found in Kv7.1 (42%), Nav1.5 (8%), KCNE1 (3%), and KCNE2 (2%).3 In addition, another type of LQTS, the ‘acquired’ LQTS, has been described, mostly as the consequence of drugs able to prolong the cardiac action potential duration.4,5 This lengthening of the cardiac action potential can produce the development of early afterdepolarizations (EADs) and the genesis of a ventricular polymorphic arrhythmia called torsades de pointes …

Increased late sodium current contributes to long QT-related arrhythmia susceptibility in female mice

Female gender is a risk factor for long QT-related arrhythmias, but the underlying mechanisms remain uncertain. Here, we tested the hypothesis that gender-dependent function of the post-depolarization 'late' sodium current (I(Na-L)) contributes. Studies were conducted in mice in which the canonical cardiac sodium channel Scn5a locus was disrupted, and expression of human wild-type SCN5A cDNA substituted. Baseline QT intervals were similar in male and female mice, but exposure to the sodium channel opener anemone toxin ATX-II elicited polymorphic ventricular tachycardia in 0/9 males vs. 6/9 females. Ventricular I(Na-L) and action potential durations were increased in myocytes isolated from female mice compared with those from males before and especially after treatment with ATX-II. Further, ATX-II elicited potentially arrhythmogenic early afterdepolarizations in myocytes from 0/5 male mice and 3/5 female mice. These data identify variable late I(Na) as a modulator of gender-dependent arrhythmia susceptibility.

Non-Genomic Regulation of K+ and Ca2+ Channels by Sex Hormones

QT interval and risk of long QT-related arrhythmias exhibit gender difference: however, underlying mechanisms are not fully understood. We examined the acute effects of sex hormones on cardiac ion channels, and the underlying molecular mechanisms. Testosterone, progesterone, and high concentration of estrogen shortened action potential duration (APD) by activating IKs in the basal condition, and inhibited ICa,L in cAMP-stimulated condition, both via nitric oxide (NO) produced through the non-genomic pathway. IKs activation was due to s-nitrosylation of KCNQ1 in the C-terminus in a calmodulin-dependent manner, while ICa,L inhibition via cGMP-dependent activation of phosphodiesterase and cAMP breakdown. The non-genomic generation of NO occurred in a signal pathway localized in lipid raft/caveola. N-terminal truncated from of sex hormone receptors appeared to be involved. High concentration of estrogen prolonged APD by directly inhibiting IKr independent of estrogen receptor. Incorporation of these effects in a computer simulation model recapitulated longer QT interval and higher incidence of torsade de pointes (TdP) in women, especially in luteal phase of menstrual cycle. Thus, the non-genomic regulation of cardiac K+ and Ca2+ channels by sex hormones may be involved, at least in part, in gender difference in long QT-related arrhythmias.

Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome

Enhanced dispersion of repolarization has been proposed as an important mechanism in long QT related arrhythmias. Dispersion can be dynamic and can be augmented with the occurrence of spatially out-of-phase action potential duration (APD) alternans (discordant alternans; DA). We investigated the role of tissue heterogeneity in generating DA using a novel transgenic rabbit model of type 2 long QT syndrome (LQT2). Littermate control (LMC) and LQT2 rabbit hearts (n = 5 for each) were retrogradely perfused and action potentials were mapped from the epicardial surface using di-4-ANEPPS and a high speed CMOS camera. Spatial dispersion (Delta APD and Delta slope of APD restitution) were both increased in LQT2 compared to LMC (Delta APD: 34 +/- 7 ms vs. 23 +/- 6 ms; Delta slope: 1.14 +/- 0.23 vs. 0.59 +/- 0.19). Onset of DA under a ramp stimulation protocol was seen at longer pacing cycle length (CL) in LQT2 compared to LMC hearts (206 +/- 24 ms vs. 156 +/- 5 ms). Nodal lines between regions with APD alternans out of phase from each other were correlated with conduction velocity (CV) alternation in LMC but not in LQT2 hearts. In LQT2 hearts, larger APD dispersion was associated with onset of DA at longer pacing CL. At shorter CLs, closer to ventricular fibrillation induction (VF), nodal lines in LQT2 (n = 2 out of 5) showed persistent complex beat-to-beat changes in nodal line formation of DA associated with competing contribution from CV restitution and tissue spatial heterogeneity, increasing vulnerability to conduction block. In conclusion, tissue heterogeneity plays a significant role in providing substrate for ventricular arrhythmia in LQT2 rabbits by facilitating DA onset and contributing to unstable nodal lines prone to reentry formation.

Larger dispersion of INa in female dog ventricle as a mechanism for gender-specific incidence of cardiac arrhythmias

Women have a higher incidence of long QT-related arrhythmias, whereas men exhibit a higher incidence of Brugada syndrome (BrS). The cardiac sodium current (I(Na)) is associated with arrhythmias in BrS and long QT-syndrome (LQTS) and conduction disease. Although a great deal of work has been performed to explain how heterogeneous distribution of repolarizing currents triggers arrhythmias, the transmural distribution of I(Na) within the cardiac ventricle and its contribution to generate the arrhythmogenic substrate remain unknown. We undertook to determine whether I(Na) was heterogeneously distributed within the ventricular wall of canine heart, an animal model close to humans. Using patch-clamp and molecular biology techniques, we tested whether gender differences exist in the ventricular distribution and amplitude of I(Na) in the canine heart model. Our results show that the I(Na) amplitude is smaller in the female epicardial and endocardial layers of the left ventricle, but similar to male in the mid-myocardium. Exposure of female cardiomyocytes to testosterone increased the amplitude of I(Na) to levels similar to male in epicardium, but had no effects in mid-myocardial and endocardial cells. Castrated male dogs displayed I(Na) amplitudes similar to what was found in female hearts. The larger dispersion of I(Na) amplitude within the female cardiac ventricle may contribute to the higher risk of arrhythmias in females. Testosterone modulates this dispersion. By decreasing the transmural dispersion of I(Na), testosterone may exert a protective effect against LQTS-related arrhythmias in males.

Development of torsade de pointes caused by exacerbation of QT prolongation during clipping of cerebral artery aneurysm in a patient with subarachnoid haemorrhage

We report the case of a 79-yr-old woman with subarachnoid haemorrhage (SAH) in whom torsade de pointes (TdP) caused by worsening the QT prolongation occurred during clipping of cerebral artery aneurysm. This patient shows a potential risk of occurrence of life-threatening tachyarrhythmia, TdP by prolonging the QT interval during surgery in patients with SAH even with no additional factors that predispose to TdP. Therefore, a proper monitoring of the QT interval is necessary as a predictor of TdP. When ventricular tachyarrhythmia occurs, recognition of TdP is important because antiarrhythmic drug therapy for TdP is different from that for ventricular tachyarrhythmias that is not TdP.

Droperidol, when used for sedation during ERCP, may prolong the QT interval

Droperidol is a known effective adjunctive agent for sedation/analgesia during endoscopic procedures, particularly in patients who are difficult to sedate with narcotics and benzodiazepines alone. However, the Food and Drug Administration (FDA) warning about potential droperidol-related fatal cardiac arrhythmias, issued in December 2001, led to concern about its safety in current clinical practice. In this study, we evaluated the effects of droperidol on the Bazett's corrected QT interval (QTcB) administered to patients undergoing ERCP and frequency of cardiac arrhythmias. We retrospectively reviewed the medical records of patients who, at our institute, underwent ERCP while under sedation/analgesia and who received droperidol. Our protocol for patients who are considered to be candidates for droperidol use includes obtaining an ECG before and 1 to 3 hours after the procedure. From April 2002 to October 2004, 6292 ERCPs were performed, of which 3113 patients with normal baseline QTcB (2001 women, 1112 men) received droperidol. Mean dosages were 4.3 mg (range, 1.25-10 mg) in women and 4.5 mg (range, 1.25-13.75 mg) in men. A total of 233 patients (7.48%; 133 women, 100 men) developed QTcB prolongation. Mean increases of the QTcB above the upper limit of normal were 16 milliseconds in women (range, 1-194 milliseconds) and 22 milliseconds in men (range, 1-310 milliseconds). Of these, 15 patients (0.48%; 8 women, 7 men) had marked prolongation of the QTcB (defined QTcB, >500 milliseconds). No serious dysrhythmias occurred. Droperidol at usual doses during sedation/analgesia may precipitate QTcB prolongation above the normal range. However, no QT-related arrhythmias were noted in this study. Clinically significant cardiac events are probably rare with droperidol, despite documented QTcB effects. Baseline electrocardiogram for excluding patients with prolonged baseline QTcB and 1 to 3 hours afterward monitoring appears adequate when using droperidol. The study is still too small to detect very infrequent arrhythmia events.

Drug Challenge with Epinephrine or Isoproterenol for Diagnosing a Long QT Syndrome: Should We Try This at Home?

Diagnosing a congenital long QT syndrome (LQTS) is straightforward when a prolonged QT is present in a patient with arrhythmia-related symptoms and documented torsade de pointes.1 More often, however, a clear-cut diagnosis is not possible because: (1) QT-related arrhythmias are only rarely documented (except for patients with arrhythmic storms), and cannot be reliably and safely provoked. (2) Accurate measurement of the QT interval is not always easy2 and the presence of respiratory sinus arrhythmia complicates the estimation of the rate corrected QTc because the response of the QT interval to heart rate oscillations is not instantaneous. Consequently, the QTc calculated during heart rate deceleration will be shorter than the QTc calculated, only a few beats later, when the heart rate accelerates.3 (3) The QTc intervals of healthy individuals and that of patients with genetically proven LQTS overlap to such extent that one third of LQTS gene carriers and a similar number of healthy individuals have “borderline QT,” that is, a QTc between 430 and 460 ms.4 (4) Genetic testing is obviously useful when mutations are found but, with present technology, no mutations are identified in ≥25% of patients with LQTS. Furthermore, genetic analysis is only available in selected centers and often takes months to perform. Therefore, diagnostic and therapeutic decisions are still based, at least initially, on clinical grounds. Since symptoms in the common types of LQTS are commonly triggered by stress, it is only logical to use sympathetic stimulation, in the form of adrenaline or isoproterenol infusion, as a challenge test to unravel a LQTS in questionable cases. In fact, physicians have used such tests sporadically without rigorous control.5 Two groups of investigators finally evaluated the effects of an epinephrine challenge in LQTS patients in a controlled fashion.6-8 First, Ackerman6 studied 37 patients with LQTS (19 with LQT1, 15 with LQT2, and 3 with LQT3) as well as 27 healthy controls. Epinephrine was started at “low doses” (0.05 μg/kg/min) and the infusion rate was gradually increased to a “high dose” of 0.3 μg/kg/min. The absolute (uncorrected) QT interval increased in all patients with LQT1, decreased in LQT2/3 and increased or decreased in different controls. Since epinephrine also increased the heart rate, the rate-corrected QTc actually increased in all patient groups. This increment in QTc was greatest for LQT1 patients, intermediate for controls and smallest for LQT2/3 patients. Yet, there was significant overlap between the QTc

Sulfonylureas blockade of neural and cardiac HERG channels

The human ether-a-go-go-related gene ( herg) encodes a K + current ( I HERG) which plays a fundamental role in heart excitability and in neurons by contributing to action potential repolarization and to spike-frequency adaptation, respectively. In this paper we show that I HERG, recorded in neuroblastoma cells and guinea-pig ventricular myocytes, was reversibly inhibited by the K ATP channel blocker glibenclamide (IC 50=74 μM). The voltage and use dependence of glibenclamide blockade were also evaluated. Another sulfonylurea, glimepiride, had less effective results in blocking I HERG. The findings of this study are relevant to the interpretation of glibenclamide effects on cellular electrophysiology and suggest that oral antidiabetic therapy with sulfonylureas may contribute to iatrogenic QT prolongation and related arrhythmias.

Magnesium treatment of ventricular arrhythmias

The association between marked hypomagnesemia and arrhythmias, particularly those associated with digitalis intoxication, has long been recognized. More recently, acute intervention with magnesium in patients who are not hypomagnesemic has demonstrated arrhythmia suppression in 3 settings: digitalis intoxication, long QT-related arrhythmias and arrhythmias after acute myocardial infarction. Although the electrophysiologic effects of magnesium are not clearly understood, magnesium treatment is emerging as an important adjunct in managing certain serious ventricular arrhythmias.