Incidences, risk factors, and clinical correlates of severe QT prolongation after the use of quetiapine or haloperidol.

BACKGROUND: Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes. OBJECTIVE: The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users. METHODS: This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression. RESULTS: Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66). CONCLUSION: More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP.

Life-Threatening Cardiac Arrhythmias in a Case of Undetected Myxedema Coma: Importance of Early Detection and Medication Adherence.

BACKGROUND Myxedema coma is a rare, life-threatening condition caused by a severe form of hypothyroidism. The dangerously low levels of circulating thyroid hormone can lead to progressive mental status changes and numerous organ dysfunctions, including serious cardiac abnormalities. CASE REPORT We present a case of a 59-year-old woman who presented with altered mental status and fall who was originally thought to have a cerebrovascular accident but was later diagnosed with myxedema coma, after multiple cardiac arrests. It was discovered that the patient had not been taking any of her medications for the last several weeks, after her primary care provider retired from practice. Initial laboratory evaluation was significant for a TSH level of 159.419 mIU/L and an undetectable free T4 level. Complications of the myxedema coma resulted in QTC interval prolongation, causing torsades de pointes and sustained polymorphic ventricular tachycardia, requiring cardioversion. CONCLUSIONS This case demonstrates the importance of early detection and treatment of myxedema coma, as it can cause life-threatening cardiac arrhythmias. It also emphasizes the need to ensure proper medication adherence in patients with chronic medical conditions, as non-compliance can result in dire consequences.

Coeliac axis thrombosis and acute hepatic failure in a patient with dilated cardiomyopathy.

We present the case of a female patient in her 40s who presented with jaundice, orthopnoea, paroxysmal nocturnal dyspnoea and bilateral pedal oedema. After extensive investigations, she was diagnosed with hepatic dysfunction, dilated cardiomyopathy (DCM) and coeliac axis thrombosis. Her case was further complicated with episodes of torsades de pointes due to metabolic disturbance, with consequent sudden cardiac arrest. In this case report, we explore the clinical features, pathophysiology and treatment of acute hepatic failure and coeliac axis thrombosis, secondary to DCM and alcoholic liver disease.

Prolonged QT Interval in Cirrhosis: Twisting Time?

Approximately 30% to 70% of patients with cirrhosis have QT interval prolongation. In patients without cirrhosis, QT prolongation is associated with an increased risk of ventricular arrhythmias, such as torsade de pointes (TdP). In cirrhotic patients, there is likely a significant association between the corrected QT (QTc) interval and the severity of liver disease, and possibly with increased mortality. We present a stepwise overview of the pathophysiology and management of acquired long QT syndrome in cirrhosis. The QT interval is mainly determined by ventricular repolarization. To compare the QT interval in time it should be corrected for heart rate (QTc), preferably by the Fridericia method. A QTc interval >450 ms in males and >470 ms in females is considered prolonged. The pathophysiological mechanism remains incompletely understood, but may include metabolic, autonomic or hormonal imbalances, cirrhotic heart failure and/or genetic predisposition. Additional external risk factors for QTc prolongation include medication (IKr blockade and altered cytochrome P450 activity), bradycardia, electrolyte abnormalities, underlying cardiomyopathy and acute illness. In patients with cirrhosis, multiple hits and cardiac-hepatic interactions are often required to sufficiently erode the repolarization reserve before long QT syndrome and TdP can occur. While some risk factors are unavoidable, overall risk can be mitigated by electrocardiogram monitoring and avoiding drug interactions and electrolyte and acidbase disturbances. In cirrhotic patients with prolonged QTc interval, a joint effort by cardiologists and hepatologists may be useful and significantly improve the clinical course and outcome.

The genetics of drug-induced QT prolongation: evaluating the evidence for pharmacodynamic variants.

Drug-induced long QT syndrome (diLQTS) is an adverse effect of many commonly prescribed drugs, and it can increase the risk for lethal ventricular arrhythmias. Genetic variants in pharmacodynamic genes have been associated with diLQTS, but the strength of the evidence for each of those variants has not yet been evaluated. Therefore, the purpose of this review was to evaluate the strength of the evidence for pharmacodynamic genetic variants associated with diLQTS using a novel, semiquantitative scoring system modified from the approach used for congenital LQTS. KCNE1-D85N and KCNE2-T8A had definitive and strong evidence for diLQTS, respectively. The high level of evidence for these variants supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.

Prolonged ST segment and T-wave alternans with torsade de pointes secondary to hypocalcemia due to hypoparathyroidism: A case report.

Hypoparathyroidism predisposes patients to hypocalcemia. Patients with hypoparathyroidism are thus at risk of electrocardiographic abnormalities, including T-wave alternans. T-wave alternans is poorly understood and lacks uniform diagnostic criteria. Its presence suggests myocardial electrical instability, and it has become an important sign for identifying patients at high risk of malignant arrhythmias and sudden cardiac death. We report a rare case of T-wave alternans with torsade de pointes due to hypocalcemia. The etiology of T-wave alternans may easily be overlooked. It should thus be thoroughly investigated to avoid misdiagnosis and poor outcomes.

What accounts for the high mortality of anorexia nervosa?

The exact medical complications, leading to the well-known high risk of death in patients with anorexia nervosa (AN), remain elusive. Such deaths are often abrupt with no satisfactory explanation. Suspected causes include cardiac QTc prolongation and, in turn, torsade de pointes (TdP). Psychotropic medications often prescribed to these patients are linked to QTc prolongation. AN is also presumed to cause heart failure due to malnutrition with increased susceptibility to QTc prolongation, and TdP, resulting in sudden cardiac death. Recent literature, however, is conflicting, and the likely cause of death may involve other cardiac abnormalities, such as low heart rate, abnormal heart rate variability, or increased QT dispersion. With an ongoing gap in research explaining the high mortality rate in AN, a compelling need to define the exact proximate causes of death in these patients remains. Because low serum potassium is the most common trigger for TdP, we postulate the early signal of sudden cardiac death, especially in patients with AN who purge, is hypokalemia. We also speculate that hypoglycemia could be a major factor in the sudden death of patients with AN as well as bradycardia or sinus arrest. A path forward to elucidate potential causes is offered.

Empirical Antimicrobial Therapy and QTc Interval Prolongation in Emergency Medicine.

BACKGROUND: QTc prolongation is common in dangerous clinical conditions, associated with an increased risk of life-threatening arrhythmia torsades de pointes. The goal of this short communication is to evaluate the principal causes of risk of QTc prolongation that are observed in an emergency department and discuss the differences between drug- and non-drug-associated factors. METHODS: The retrospective analysis was carried out on 130 patients that presented a QTc prolongation (>480 ms for man and >470 for female, respectively), admitted to the emergency department of a single Italian hospital. Patients with pace-maker (22) were excluded from this study. For each patient, a minimum of 3 ECGs (12 leads) were recorded. Attention was paid on electrolytes disturbances and to the pharmacotherapy, with a particular emphasis to the use of antibiotics. RESULTS: Mean age of the patients was 79.6 years (SD=11.3) and females and males were almost equally present (46.6% F, 53.7% M). The average QTc value was 492.2 ms (493.3 ms F, 492.8 M). The patients were divided in those with electrolytes disturbances (24.0%), antimicrobial therapy (35.2%), both antimicrobial therapy and electrolytes disturbances (24.1%), and other causes of QTc prolongation (16.7%). CONCLUSION: This analysis shows the relevance of the empirical therapy established at the admission, in particular for infective diseases, as an important risk factor for the prolongation of QTc. Other factors that can increase the risk are electrolytes alterations, advanced age, cardiovascular diseases, and drug-drug interaction.

A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca2+ handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.

Critical repolarization gradients determine the induction of reentry-based torsades de pointes arrhythmia in models of long QT syndrome.

BACKGROUND: Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization. OBJECTIVE: The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance. METHODS: Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N = 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart. RESULTS: pVTs (n = 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with T-wave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations. CONCLUSION: pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.

Global electrical heterogeneity associated with drug-induced torsades de pointes.

BACKGROUND: Drugs belonging to diverse therapeutic classes can prolong myocardial refractoriness or slow conduction. These drugs may be effective and well-tolerated, but the risk of sudden cardiac death from torsades de pointes (TdP) remains a major concern. The corrected QT interval has significant limitations when used for risk stratification. Measurement of global electrical heterogeneity (GEH) could help identify the substrate vulnerable to drug-induced ventricular arrhythmias. OBJECTIVE: The purpose of this study was to improve risk stratification for drug-induced TdP by measuring GEH on the electrocardiogram (ECG). METHODS: We analyzed ECG data from a case-control study of patients with a history of drug-induced TdP as well as age- and sex-matched controls. Vectorcardiograms were constructed from ECGs. GEH was measured via the spatial ventricular gradient (SVG) vector (magnitude, azimuth, and elevation). Log odds coefficients for TdP were estimated using multivariable logistic regression. RESULTS: Among 17 cases (47% male; age 58.9 ± 12.5 years) and 17 controls (29% male; age 61.0 ± 12.2 years), 34 ECGs were analyzed. SVG azimuth was significantly different between cases and controls (3.4 vs 22.0 degrees, respectively; P = 0.02). After adjusting for sex and QTc interval, odds of TdP increased by a factor of 3.2 for each 1 SD change in SVG azimuth from the control group mean (95% confidence interval 1.07-9.14; P = .04). QTc was not significant in the multivariable analysis (P = .20). CONCLUSION: SVG azimuth is correlated with a history of drug-induced TdP independent of QTc. GEH measurement may help identify patients at high risk for drug-induced arrhythmias.

[CME ECC 66: Torsade de Pointes: The Danger of a Rotating Heart Axis]. / CME-EKG 66: Torsade de pointes: die Gefahr der rotierenden Herzachse.

CME ECC 66: Torsade de Pointes: The Danger of a Rotating Heart Axis Abstract. Torsade de pointes tachycardia is a potentially life-threatening heart rhythm disorder, caused by prolongation of the QT-interval resulting in triggered activity. This QT-prolongation can be congenital or acquired. If acquired, it is mainly caused by pharmacological therapy. The hallmark of torsade de pointes is an undulating QRS axis with a twist of the QRS complex around the ECG's baseline. Often, this polymorphic ventricular tachycardia is self-limiting, but degeneration into ventricular fibrillation is possible, which makes torsade de pointes tachycardia dangerous. This article aims to provide insights into etiology, diagnostics, prevention and management of this heart rhythm disorder.

QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients.

OBJECTIVE: To evaluate the prevalence of torsades de pointes and to identify risk factors associated with QTc prolongation of ≥500 milliseconds in hospitalized pediatric oncology patients. A QTc prolongation of ≥500 milliseconds is associated with higher mortality in hospitalized adults but has not been demonstrated in pediatrics. STUDY DESIGN: A single-center, retrospective review of all hospitalized oncology patients ≤21 years of age was performed from 2014 to 2016. Patients with long/short QT syndrome or a QRS interval of ≥120 ms were excluded. Rapid response events were reviewed to determine the prevalence of torsades. In patients with ECGs for review, data were compared between patients with a QTc of <500 and ≥500 ms via logistic regression. RESULTS: There were 1934 hospitalized patients included. Rapid response events occurred in 90 patients (4.7%) with 2 torsades events (0.1%). There were 1412 electrocardiograms performed in 287 unique patients (10.6 ± 6.3 years of age; 43% female). The mean QTc was 448 ± 31 ms; 25 patients (8.7%) had ≥1 ECG with a QTc of ≥500 ms. The prevalence of torsades was greater in patients with a QTc of ≥500 ms (8% vs 0%; P<.01). In multivariate analysis, factors associated with a QTc of ≥500 ms included female sex, (OR 2.95) and ≥2 QT-prolonging medications (OR, 2.95). CONCLUSIONS: The prevalence of torsades in hospitalized pediatric oncology patients was low (0.1%), although the risk was significantly greater in patients with a QTc of ≥500 ms. Routine monitoring of electrocardiograms and electrolytes is essential in patients with risk factors predisposing to QTc prolongation.

Recurrent Torsades with Refractory QT Prolongation in a 54-Year-Old Man.

BACKGROUND QT prolongation is a common, easily overlooked clinical problem with potentially dire consequences. Drug-induced and congenital forms are not mutually exclusive, but are treated differently. Here, we present a case of cryptogenic underlying congenital long QT syndrome (cLQTS) successfully treated with isoproterenol, a drug contraindicated in most congenital forms of this condition. CASE REPORT We present the case of a 54-year-old man who experienced severe QT prolongation after drug administration followed by recurrent episodes of torsade de pointes (TdP) with subsequent ventricular fibrillation (VF) arrest unresponsive to typical therapy. After failing electrolyte repletion, magnesium, amiodarone, and lidocaine, the patient was started on an isoproterenol drip to achieve a heart rate of at least 90 beats per minute (bpm). Isoproterenol resulted in an immediate near-normalization of his QT interval and cessation of his recurrent TdP. The patient was subsequently found to have a mutation of undetermined significance in the KCNQ1 gene, which is implicated in long QT syndrome type 1 (LQT1). Although isoproterenol is contraindicated in LQT1, our patient had an astonishingly therapeutic benefit. CONCLUSIONS After reviewing the electrophysiology of the delayed rectifier potassium current as it relates to long QT syndrome, we propose a mechanism by which our patient's specific mutation may have allowed him to derive benefit from isoproterenol treatment. We believe that there are patients with variants of LQT1 who can be safely treated with isoproterenol.

Management of anaphylaxis and allergies in patients with long QT syndrome: A review of the current evidence.

OBJECTIVE: To develop a treatment algorithm for patients with long QT syndrome (LQTS) in case they need antiallergic medications for allergic reactions, including asthma and anaphylaxis. DATA SOURCES: A literature review was performed to assess safety and to develop antiallergic treatment strategies for patients with LQTS. STUDY SELECTIONS: LQTS is a heterogeneous group of myocardial repolarization disorders characterized by prolongation of the QT interval that potentially results in life-threatening torsades de pointes tachycardia. Data on pharmacologic treatment in case of anaphylaxis in LQTS are sparse. For this narrative review, all currently available articles on the use of antiallergic drugs for allergic reactions, anaphylaxis, and asthma in patients with LQTS were used. RESULTS: Local allergic symptoms can be safely treated primarily with fexofenadine, levocetirizine, desloratadine, or cetirizine and, if needed, a short course of corticosteroids. In case of systemic symptoms, epinephrine should be administered. It may be less effective in patients with LQTS treated with ß-blockers, necessitating the use of glucagon as add-on treatment. In case of lower airway obstruction, ipratropium bromide should be used, but if not effective, inhaled ß2-adrenergic agents may be used. Continuous cardiac monitoring is indicated with the use of epinephrine and inhaled ß2-adrenergic agents. The use of the latter also warrants intense monitoring of serum potassium levels. Clemastine and dimetindene should be avoided in patients with LQTS. CONCLUSION: Patients with LQTS have a higher risk of life-threatening complications during the treatment of their allergic reactions because of the underlying disease and concomitant treatment with ß-blockers. Treatment algorithms will certainly decrease these complications.

Takotsubo cardiomyopathy-related complete heart block and torsades de pointes.

Takotsubo cardiomyopathy (TCM) is a relatively recently recognised clinical entity. It frequently mimics acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. TCM is a reversible condition, and the prognosis is usually well. However, in rare instances, it can be associated with life-threatening arrhythmic complications. Herein, we report the case of a patient with TCM who developed complete atrioventricular block followed by QT prolongation and torsades de pointes. Furthermore, we undertook a literature review of this rare complication of TCM and discussed the formidable therapeutic challenge encountered in such patients.

Evaluation and Management of Athletes With Long QT Syndrome.

CONTEXT: The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia, torsades de pointes (TdP). TdP can lead to syncope or sudden death and is often precipitated by triggers such as physical exertion or emotional stress. Given that athletes may be at particular risk for adverse outcomes, those suspected of having LQTS should be evaluated, risk stratified, treated, and receive appropriate counseling by providers with sufficient expertise according to the latest guidelines. EVIDENCE ACQUISITION: The following keywords were used to query MEDLINE and PubMed through 2016: LQTS, LQT1, LQT2, LQT3, long QT, long QTc, prolonged QT, prolonged QTc, QT interval, QTc interval, channelopathy, channelopathies, athletes, torsades de pointes, and sudden cardiac death. Selected articles within this primary search, in addition to relevant references from those articles, were reviewed for relevant information and data. Articles with pertinent information regarding pathophysiology, evaluation, diagnosis, genetic testing, treatment, and guidelines for athletes were included, particularly those published in the prior 2 decades. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Diagnosis of LQTS involves eliciting the patient's family history, clinical history, and evaluation of electrocardiographic findings. Genetic testing for common mutations can confirm suspected cases. ß-Blockers represent the mainstay of treatment, though interventions such as implantable cardioverter-defibrillator placement or left cardiac sympathetic denervation may be required. Properly evaluated and treated athletes with LQTS have a low risk of cardiac events. CONCLUSION: Detection and management of LQTS in the athletic population is crucial given the possibility of adverse outcomes with the stress of athletic participation. Preparticipation screening examinations should include a thorough clinical and family history. Screening electrocardiograms may display key findings consistent with LQTS while genetic testing can confirm the diagnosis. Formerly considered a strict contraindication to athletic participation, LQTS is now an increasingly manageable entity with proper evaluation and treatment by qualified and experienced providers.

Torsade de pointes / Torsades de pointes

Presentamos el caso de un varón tratado por convulsiones con diazepam en varias ocasiones. Finalmente se demuestra un síndrome de QT largo adquirido que le predisponía a torsades de pointes manifestándose con convulsiones y, por tanto, tratado erróneamente. Se repasa el síndrome del QT largo, describiendo las diferentes causas tanto congénitas como adquiridas, diagnóstico electrocardiográfico, la medición corregida del intervalo QT según la frecuencia cardiaca y tratamiento (AU)

The present is the case of a male treated on several occasions for seizures with diazepam. Eventually, an acquired long QT syndrome was demonstrated which predisposed him to torsades de pointes, manifesting as seizures and henceforth treated erroneously. The long QT syndrome is reviewed, describing the different causes of long QT interval, both congenital and acquired, electrocardiographic diagnosis, according to heart rate and treatment (AU)