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Acquired long QT syndrome: Definitions, pathophysiology, and causes

Acquired long QT syndrome: Definitions, pathophysiology, and causes
Charles I Berul, MD
Section Editor:
Samuel Asirvatham, MD
Deputy Editor:
Nisha Parikh, MD, MPH
Literature review current through: Nov 2022. | This topic last updated: Sep 21, 2022.

INTRODUCTION — Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) (waveform 1). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia (VT) and a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (TdP) (waveform 2A-B).

LQTS may be either congenital or acquired. There is potential overlap between these two etiologies, as some people with acquired LQTS can have underlying pathogenic variants but do not meet all the clinical criteria for congenital LQTS. (See 'Underlying pathogenic variant in a long QT syndrome gene' below.)

Acquired LQTS usually results from drug therapy, although a number of patient-specific and medication-related factors can enhance the risk of drug-induced LQTS. Other causes of acquired LQTS include electrolyte abnormalities, eating disorders, coronary artery disease, and bradyarrhythmias.

In this topic, we review the definition, causes, and pathophysiology of acquired LQTS. The clinical manifestations, diagnosis, and management of congenital and acquired LQTS, as well as the genetics of congenital LQTS, are discussed elsewhere. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management" and "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Congenital long QT syndrome: Diagnosis" and "Congenital long QT syndrome: Treatment" and "Congenital long QT syndrome: Pathophysiology and genetics".)


Normal QT interval – The normal range for the rate-corrected QT interval (QTc) is similar in males and females from birth until the start of adolescence, while after puberty and in adults, females have slightly longer QT intervals than males. Before puberty, a QTc <450 ms is considered normal, between 450 and 459 borderline, and ≥460 prolonged. After puberty in males, a QTc between 460 and 469 is borderline and ≥470 is considered prolonged. In post-pubertal females, 460 to 479 is borderline and ≥480 ms is considered prolonged. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'ECG findings'.)

Polymorphic VT – Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute in adults with frequent variations of the QRS axis, morphology, or both [1,2].

Torsades de pointes – Torsades de pointes (TdP) is a form of polymorphic VT that classically occurs in the setting of acquired or congenital QT interval prolongation and typically has a rate between 160 and 250 beats per minute [1,3]. In the specific case of TdP, these variations take the form of a progressive, sinusoidal, and cyclic alteration of the QRS axis (waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points."

Typical features of TdP include an antecedent prolonged QT interval, particularly in the last beat preceding the onset of the arrhythmia. The stereotypical short-long-short sequence is an important trigger for initiation of TdP. Additional typical features include a ventricular rate of 160 to 250 beats per minute, irregular RR intervals, and a cycling of the QRS axis through 180 degrees every 5 to 20 beats [1,2]. TdP is usually short-lived and typically terminates spontaneously. However, most patients experience multiple episodes of the arrhythmia. These episodes of TdP can recur in rapid succession, potentially degenerating to ventricular fibrillation and sudden cardiac death (SCD) [1,2].

Potassium channels – IKr is the delayed rectifier cardiac potassium channel present in cardiac myocytes. Many QT-prolonging drugs block the IKr channel, which leads to prolonged myocardial repolarization. Some medications can also impact the IKs channel and late sodium current, which may be important in the genesis of TdP.

INCIDENCE — The incidence of acquired LQTS is uncertain because most available studies rely on selected cohorts rather than population-based studies. Additionally, the incidence of QT prolongation without torsades de pointes (TdP) is likely much higher than the incidence of TdP itself. Determining the absolute and comparative risk of the many drugs associated with QT prolongation is difficult, since most available data come from case reports or small observational series. Where available, drug-specific incidences are presented below. (See 'Drugs that prolong the QT interval' below.)

Hospitalized patients – In one retrospective review of over 41,649 hospital admissions over six months, 0.7 percent of patients had a QTc >500 milliseconds. Of these, less than 6 percent had severe QT prolongation, syncope, or a life-threatening arrhythmia [4]. In a separate study of patients in a tertiary-care hospital, the risk of TdP ranged from 0.1 to 0.3 percent per year; 46 percent of cases were from drug-induced TdP [5].

People with SCD – Medication-related acquired LQTS may underlie a substantial proportion of SCD in the United States; SCD accounts for 5 to 15 percent of annual deaths in the United States. In a study of 525 autopsy-confirmed, non-traumatic sudden deaths from San Francisco County, over half of the individuals had been taking at least one QT-prolonging medication [6]. In this study, one-third of people who had experienced a drug overdose as a cause of SCD were taking a QT-prolonging medication.

In contrast, a study from the Netherlands suggested a lower contribution of QT-prolonging medications in SCD cases. Among over 500,000 people, 775 cases of SCD were identified over a period of nine years. Among persons with SCD, 3.1 percent were using a QT-prolonging drug [7]. Current use of any noncardiac QT-prolonging drug was associated with a significantly increased risk of SCD (adjusted odds ratio [OR] 2.7), and the highest risk was associated with antipsychotic drugs (adjusted OR 5.0).

Possible reasons for the differences between these two studies are population differences in causes of SCD, differences in accuracy of SCD definitions between the studies (the former had direct autopsy confirmation of SCD cases), and a 15-year difference between the studies, during which more QT-prolonging medications have been recognized.

PATHOPHYSIOLOGY — Acquired LQTS is most often due to drugs (table 1). The proposed mechanism for drug-induced torsades de pointes (TdP) is the development of early afterdepolarizations and triggered activity resulting from prolonged repolarization [8]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Triggered activity'.)

There are thought to be pathophysiologic differences between congenital and acquired LQTS, though these differences are not absolute. Pathophysiologic mechanisms of acquired LQTS and some differences with the congenital syndrome are discussed here. The pathophysiologies of both types of LQTS are described in more detail separately. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Pathophysiology'.)

KCNH2 blockade – Nearly all drugs that produce LQTS do so by blocking the IKr current, which is mediated by a potassium channel in myocardial cells. This potassium channel is encoded by the KCNH2 gene [9-28]. KCNH2 pathogenic genetic variants are common in both drug-induced LQTS and in some forms of congenital LQTS. (See "Congenital long QT syndrome: Pathophysiology and genetics".)

The relationship between the degree of drug-induced KCNH2 blockade and the risk of ventricular arrhythmias and SCD was described in a study of over 280,000 cases of reported adverse drug reactions from the International Drug Monitoring Program of the World Health Organization [29]. For 54 medications associated with QT prolongation and TdP, the investigators studied the association between medication-specific degree of KCNH2 blockade and a composite endpoint of cardiac arrest, sudden death, TdP, VT, and ventricular fibrillation.

The medications with the greatest chance of toxicity based on KCNH2 blockade were cisapride, sparfloxacin, quinidine, ibutilide, and thioridazine.

There was a linear relationship between the measure of toxicity in this study and the reported incidence of a composite endpoint of cardiac arrest, sudden death, TdP, VT, and ventricular fibrillation.

Reverse use dependence The association between bradycardia and antiarrhythmic drug-induced TdP is thought to be related to a property of some of these drugs called "reverse use dependence," which is defined as the inverse correlation between the heart rate and QT interval [30]. As a result, the QT interval decreases as the heart rate increases and lengthens as the heart rate slows. This explains why drug-induced TdP is more commonly seen with bradycardia or immediately following sinus pauses. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)

Whereas TdP in acquired LQTS is triggered by bradycardia and pauses, some forms of congenital LQTS can follow a sudden adrenergic surge (eg, exercise, emotional stress, or arousal). This can be a typical clinical presentation in congenital LQTS type 1 and, to a lesser degree, type 2 (figure 1). (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.)

Reverse use dependence may be mediated at least in part by changes in the extracellular potassium concentration. Virtually all of the drugs that produce LQTS act by blocking the outward IKr current, which is mediated by the potassium channel encoded by the KCNH2 gene [9-28]. Lower heart rates result in less potassium moving out of the cell during repolarization (before subsequent reuptake by the Na-K-ATPase pump), since there are fewer repolarizations. The associated reduction in extracellular potassium concentration enhances the degree of drug-induced inhibition of IKr, increasing the QT interval [11]. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Perturbations in ion channels'.)

Pause dependence Polymorphic VT in acquired LQTS is commonly precipitated by short-long RR intervals (ie, a short RR interval followed by a long RR interval). The short-long interval is typically caused by a premature ventricular contraction followed by compensatory pause (waveform 2B). Polymorphic VT also can occur in association with bradycardia or frequent pauses; this is sometimes referred to as "pause-dependent” LQTS [31].

Patients with congenital LQTS can also have pause-dependent TdP. This was illustrated in an observational study of 15 patients with congenital LQTS in which pause-dependent TdP was noted in 14 of 15 patients [32].

RISK FACTORS FOR DRUG-INDUCED LONG QT SYNDROME — Acquired LQTS usually results from drug therapy (table 1), although a number of patient-specific demographic, regimen-related, and ECG-related factors can enhance the risk of drug-induced LQTS [9,33,34].

Demographic — The most prevalent risk factor for drug-induced torsades de pointes (TdP) is female sex [35-38]. Between 55 and 70 percent of people with drug-induced TdP are female, regardless of whether TdP is caused by a cardiac or noncardiac medication [36,39,40]. Compared with males, females have a longer QTc, a lower repolarization reserve, and a higher risk of TdP with drugs that even mildly block IKr [37]. Furthermore, sex steroids may affect ion channel expression, leading to sex differences in the QT interval [41]. Estrogen potentiates bradycardia-induced QT prolongation and arrhythmia. By contrast, androgens shorten the QT interval and make it less susceptible to drug-induced prolongation [37].

Advanced age is another risk factor for prolonged QT [34].

Underlying pathogenic variant in a long QT syndrome gene — In some patients, drug-associated LQTS appears to represent a concealed form of congenital LQTS in which a pathogenic variant in one of the LQTS genes is clinically inapparent until the patient is exposed to a particular drug or other predisposing factor (eg, hypokalemia or hypomagnesemia) [42-45]. In these individuals, the alteration in repolarizing currents is insufficient to prolong the QT interval at rest. This may be due to a redundancy in repolarizing currents (called repolarization reserve) [9]. This topic is discussed in detail elsewhere. (See "Congenital long QT syndrome: Pathophysiology and genetics".)

However, individuals with concealed congenital LQTS and their affected offspring might be at risk for TdP if they are exposed to drugs that can prolong the QT interval. Supporting evidence includes a case series of 92 patients with drug-induced TdP (77 percent of patients took antiarrhythmic drugs). Pathogenic variants in LQT1, LQT2, or LQT3 were identified in five patients (5.4 percent), and genetic variants that possibly contribute to risk were identified in up to 10 percent [45]. Furthermore, unaffected family members may carry clinically silent mutations in LQTS pathogenic variants with low penetrance [44,46-48]. This was illustrated in a study of nine families with sporadic cases of LQTS; 15 of 46 family members (33 percent) who were felt to be unaffected based upon clinical criteria were gene carriers [47].

Structural heart disease — Heart failure, diastolic dysfunction, myocardial ischemia, and left ventricular hypertrophy are common risk factors for drug-induced TdP. In persons with structural heart disease, antiarrhythmic drugs and diuretic-induced hypokalemia and/or hypomagnesemia may contribute to proarrhythmia. Individuals with structural heart disease may have other non-medication-related factors that can lead to acquired LQTS, including a lower creatinine clearance [49,50]. Whether or not structural heart disease is an independent risk factor for TdP in the absence of the medications is not known.

Specific drug regimen

Rapid infusion This has been linked with TdP in animal models; however, equivalent studies in humans have not been performed [34,51]. It is likely that rapid infusion leads to supratherapeutic drug concentrations in cardiac tissues.

High drug doses or concentration – For example, thioridazine doses of ≥600 mg/day should generally be avoided [52]; however, doses <600 mg/day (less than 3 mg/kg/day in pediatric patients) may also be unsafe in the presence of other cardiac risks [53].

Some drugs, such as quinidine, can cause idiosyncratic QT prolongation and do not cause QT prolongation in a dose-dependent way; in such cases, QT prolongation is likely due to intracellular handling of the drug.

Use of medications that inhibit hepatic cytochrome P450 (CYP45) enzymes – Concurrent use of these medications can slow metabolism of other QT-prolonging drugs and/or directly cause QT prolongation (table 2). Examples of CYP3A4 inhibitors are erythromycin (which both slows drug metabolism and directly causes QT prolongation) [17,18,22,54] and cimetidine [55]. Grapefruit juice also inhibits CYP3A4 and can increase the QT interval by two possible mechanisms: slowed metabolism of other drugs and direct inhibition of the IKr channel by flavonoids in grapefruit juice, thereby increasing parent drug concentrations [56].

Diuretics – Diuretics can cause electrolyte abnormalities or can directly block the potassium current [34]. Diuretics are also commonly given for heart failure; these individuals are already predisposed to LQTS. (See 'Structural heart disease' above.)

Medications to treat COVID-19 Several medications that prolong the QT interval have been suggested as treatment for severe COVID-19 infection. Hydroxychloroquine (and chloroquine), alone or given in combination with azithromycin for concomitant pneumonia treatment, were shown to compound the effect on IKr block, causing QT prolongation and TdP [57-59]. (See "COVID-19: Arrhythmias and conduction system disease", section on 'Patients receiving therapies that prolong the QT interval'.)

Electrocardiographic abnormalities — Several ECG findings can enhance a person's risk of developing drug-induced LQTS. These include:

Baseline QT prolongation (either sporadic or due to known genetic variants) – In a 2016 study of patients with acquired LQTS and TdP, approximately one-third had pathogenic variants in one of the known LQTS genes [60]. (See 'Underlying pathogenic variant in a long QT syndrome gene' above.)

Baseline T-wave lability Aperiodic repolarization lability can be quantified from ECGs, and T-wave lability can be quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. Repolarization lability may be provoked with exercise [61,62].

Development of specific ECG changes during drug therapy – These include marked QT prolongation (eg >500 milliseconds), T-wave lability, or T-wave morphologic changes (such as LQT2-type repolarization [notching, long T peak-T end]). (See "Congenital long QT syndrome: Diagnosis", section on 'Other ECG features' and "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 2 LQTS (LQT2)'.)

Bradycardia – Bradycardia may cause a fall in local extracellular potassium concentration, leading to enhanced drug-induced inhibition of IKr [11]. Specific bradyarrhythmias that lead to increased risk of TdP include sinus bradycardia, heart block, incomplete heart block with pauses, and premature complexes leading to short-long-short cycles. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Bradycardia-induced ventricular arrhythmias'.)

Metabolic factors — Electrolyte disturbances, especially hypokalemia and hypomagnesemia, and less often hypocalcemia, are risk factors for drug-induced LQTS. The risk for developing TdP in the presence of hypokalemia and/or hypomagnesemia is greatest in patients taking antiarrhythmic drugs [45,63-66]. In a series of 92 patients with drug-induced LQTS, 27 percent had hypokalemia or hypomagnesemia [45]. Virtually all of the drugs that produce LQTS act by blocking the IKr current mediated by the potassium channel encoded by the KCNH2 gene [9-22,25]. The increase in risk with hypokalemia may be related to enhanced drug blockade of IKr [11]. Acidosis is another risk factor for drug-induced LQTS [67]. (See 'Metabolic abnormalities' below.)

Patients with anorexia may be predisposed to an acquired long QTc because of catabolic metabolism, psychotropic medications, and electrolyte disturbances. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.)

Impaired hepatic and/or renal function are additional risk factors due to decreased metabolism leading to increased drug exposure [68,69].

Multiple risk factors — Most patients who have drug-induced TdP have one or more risk factors, and having multiple risk factors confers a greater risk than having one risk factor [34]. In a review of 249 published cases of patients with TdP associated with noncardiac drugs, 97 percent had at least one, and 71 percent had at least two risk factors [39]. Risk factors included:

Female sex – 71 percent

History of heart disease – 41 percent

Concurrent use of another QT-prolonging drug – 39 percent

Hypokalemia – 28 percent

High drug dose – 19 percent

Prior history of LQTS - 18 percent


Overview — Drugs that can prolong the QT interval and cause torsades de pointes (TdP) include prescription medications (either taken as prescribed or misused) and over-the-counter medications or supplements (including herbal medications).

A 2020 scientific statement from the American Heart Association details drugs associated with TdP [70].

Many medications are known to cause acquired LQTS, and more continue to be identified [44,71,72].

Several major classes of drugs prolong the QT interval. Medications along with their class and level of risk are detailed in a table (table 1) [33,45,72-75]. Among drugs still commonly available, some of the best data on incidence of TdP come from studies of antiarrhythmic drugs, particularly class IA and III drugs, and from psychotropic medications. Data are not as readily available on the incidence of TdP with drugs other than antiarrhythmic medications, most of which are used for noncardiac reasons and in much less controlled settings than antiarrhythmic drugs

Some drugs have been taken off the market in the United States and other countries, specifically because of concerns that they increase the risk of TdP (eg, cisapride, terfenadine, astemizole). The drugs that are most frequently implicated in prolonging the QT interval are discussed here. A more complete list of specific drugs that prolong the QT interval is available at

Specific recommendations for the administration and monitoring of QT-prolonging drugs are discussed in UpToDate topics and Lexicomp monographs for individual drugs.

Antiarrhythmic drugs — Use of these medications may be the most common cause of drug-induced LQTS since many of these medications can induce arrhythmia (this is sometimes referred to as being "proarrhythmic"). In a review of 92 patients from the United States with drug-induced TdP, antiarrhythmic drugs were responsible in 77 percent of cases [45]. Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the most common drug was sotalol (17 percent) [72]. In patients with atrial fibrillation on QT-prolonging antiarrhythmic drugs, there is a greater risk of QT prolongation and TdP shortly after cardioversion than before or some time after [76-78].

Sotalol Sotalol (class II and III) causes QT prolongation and TdP in approximately 4 percent of women and 2 percent of men in a dose-dependent relationship [35,79,80]. As a result, sotalol therapy is often initiated in a hospital with facilities for cardiac rhythm monitoring and assessment. The need to do this is controversial and is discussed separately. (See "Clinical uses of sotalol", section on 'Initiation of therapy' and "Clinical uses of sotalol", section on 'Proarrhythmia'.)

Intravenous sotalol is available for acute tachyarrhythmia conversion and/or for those patients who transiently cannot tolerate enteral sotalol administration (such as perioperatively).

Dofetilide – This is a class III agent associated with increased risk of TdP, generally within the first three days of therapy; this is when QT interval increase peaks [81,82]. Patients must be hospitalized for dofetilide initiation at a facility that can provide measurement of creatinine clearance, cardiac monitoring, and resuscitation. Patients who are on dofetilide and convert from atrial fibrillation to sinus rhythm have greater risks of QT prolongation and TdP than patients who are started on dofetilide when in sinus rhythm [78]. Dofetilide has a high risk of drug-drug interactions. (See "Clinical use of dofetilide" and "Clinical use of dofetilide", section on 'Safety'.)

Ibutilide – Proarrhythmia is the most common toxic reaction with intravenous ibutilide, a class III medication used for acute termination of atrial tachyarrhythmia. Sustained polymorphic VT occurs in 1.7 percent of patients [83,84]. When ibutilide is administered, it is done so in a carefully monitored setting with continuous telemetry to identify potential polymorphic VT. (See "Therapeutic use of ibutilide", section on 'Proarrhythmia'.)

Amiodarone – This class III antiarrhythmic medication can markedly prolong the QT interval. However, in contrast to the other class III antiarrhythmic drugs, amiodarone is rarely associated with TdP, except when used concomitantly with a class IA agent or when hypokalemia is present [85]. This is because amiodarone prolongs repolarization in a more homogeneous manner, with less transmural dispersion of refractoriness than other class III agents. Other factors contributing to the rare occurrence of TdP with amiodarone use are lack of reverse-use dependence, concurrent blockade of the L-type calcium channels, and less heterogeneity of ventricular repolarization (also called QT dispersion). The estimated incidence of TdP is less than 1 percent overall [86], and in a review of 738 patients in randomized trials of low-dose therapy (≤400 mg/day for at least one year), there were no cases of TdP [87]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.)

Quinidine – This is a class IA (table 3) sodium channel blocking agent with potassium channel blocking function at slow heart rates. It has historically been the most frequently implicated cause of drug-induced TdP; however, it is now less often prescribed when implantable defibrillators are a viable option [63]. Most cases occur within 48 hours of initiating drug therapy; associated factors are hypokalemia and excessive bradycardia. The incidence may be reduced by correction of hypokalemia or hypomagnesemia before therapy and discontinuation of drug therapy if QT prolongation occurs [88]. Although quinidine-induced QT prolongation and TdP ("quinidine syncope") often are dose related, these abnormalities may represent an idiosyncratic reaction, occurring when drug dose and serum concentrations are low. (See "Major side effects of class I antiarrhythmic drugs", section on 'Proarrhythmia and ventricular arrhythmias'.)

Disopyramide and procainamide – Although TdP occurs with disopyramide and procainamide (also class IA), the reported incidence is lower than with quinidine [89,90]. With procainamide therapy, QT prolongation and TdP result from the major metabolite of the drug N-acetylprocainamide, which has class III potassium channel-blocking activity and thereby causes QT prolongation [91]. (See "Major side effects of class I antiarrhythmic drugs", section on 'Electrocardiographic and proarrhythmic effects' and "Major side effects of class I antiarrhythmic drugs", section on 'QT interval'.)

Psychotropic medications

Haloperidol – This is an antipsychotic agent. The U S Food and Drug Administration (FDA) issued an alert for haloperidol in September of 2007 based upon the observation that QT prolongation and TdP have been observed in patients, especially when administered intravenously or in higher doses than recommended. Because of the potential confounding influence of other QT-prolonging factors, the magnitude of the risk associated with or attributable to haloperidol cannot be determined from the case reports upon which this advisory was based. However, a direct effect is likely since in vitro studies have shown that haloperidol is a high-potency blocker of the KCNH2 channel, which is blocked by virtually all drugs that cause LQTS [27]. (See 'Pathophysiology' above.)

Particular caution should be exercised in treating patients with haloperidol who have any of the following characteristics:

Electrolyte abnormalities (particularly hypokalemia or hypomagnesemia)

Use of other drugs known to prolong the QT interval

Congenital LQTS

Underlying cardiac abnormalities


Although typical antipsychotic drugs like haloperidol and thioridazine have received particular attention with regard to risk of arrhythmia and sudden death, there is evidence that several atypical antipsychotic medications can prolong the QT interval and cause TdP [92]. In addition, a large retrospective cohort study found that treatment with typical and atypical antipsychotics was associated with similar increases in the risk of sudden death in patients with psychosis [93]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

Antidepressants – Antidepressants that can prolong the QTc and can cause drug-induced TdP include selective serotonin reuptake inhibitors, tricyclics, mirtazapine, and others (table 1). This is discussed separately. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Cardiac' and "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Side effects' and "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Cardiac'.)

Opioids — Some synthetic opioids are increasingly recognized as a cause of QT prolongation, leading to TdP and sudden cardiac death [94]. Natural opioids have not been shown to prolong the QT interval. Opioid medications that prolong QTc and have been associated with TdP include methadone, levacetylmethadol, and loperamide.

Methadone often increases the QTc interval and is a cause of TdP. Concern regarding the proarrhythmic potential of methadone prompted a clinician safety alert from the FDA in 2006, as well as a manufacturer's black-box warning. These issues, as well as safety recommendations for prescribing methadone, are discussed elsewhere [95]. (See "Medication for opioid use disorder", section on 'Prolonged QTc and cardiac arrhythmias'.)

Gastrointestinal medications — Cisapride, which is not easily available in the United States, was previously one of the most common causes of acquired TdP not due to antiarrhythmic drugs [72,96]. Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the second most common drug was cisapride (13 percent), after sotalol [72].

This has become much less frequent since it was taken off the general market (ie, available only through a limited access program), along with awareness of the potential for QT prolongation, particularly when used concomitantly with other QT-prolonging drugs.

The antiemetic agents droperidol and ondansetron have a moderate risk of prolonging the QTc and do so more commonly when given in an intravenous rather than oral formulation. (See "Arrhythmias during anesthesia", section on 'Medications that may prolong the QT interval'.)

Antimicrobials — QT-prolonging antimicrobial medications include macrolide and fluoroquinolone antibiotics and some antifungal and antiviral drugs.

Macrolide antibiotics (eg, erythromycin, azithromycin, clarithromycin), fluoroquinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, etc.), and antifungal drugs (eg, fluconazole, itraconazole, ketoconazole, etc.) can prolong the QT interval. Users of erythromycin in one report had a twofold increased risk of SCD over nonusers [54]. In addition, because erythromycin is metabolized by the CYP3A4 system, medications that inhibit CYP3A4 cause a further increase in risk when used with erythromycin (table 2). (See "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events' and "Fluoroquinolones", section on 'QT interval prolongation'.)

Arsenic — Arsenic trioxide is used in the treatment of patients with acute promyelocytic leukemia and other advanced malignancies. It appears to be associated with a very high rate of QT prolongation but a lower rate of TdP [97-99]. The unusually high incidence of QT prolongation with arsenic trioxide may be a consequence of a unique effect on potassium flux. Most of the drugs that produce LQTS act by blocking the IKr current. However, arsenic trioxide blocks both IKr and IKs, an effect comparable to the combined effects of genetic LQT1 and LQT2 [100].

Tyrosine kinase inhibitors — Tyrosine kinase inhibitors inhibit angiogenesis and are used to treat a variety of solid tumors. Potential toxicities of some tyrosine kinase inhibitors are QT prolongation and TdP. This is discussed in detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.)


Metabolic abnormalities — Hypokalemia and hypomagnesemia can predispose to torsades de pointes (TdP) even in the absence of QT-prolonging drugs. As discussed above, electrolyte abnormalities can predispose to TdP. Multiple electrolyte abnormalities can coexist; hypomagnesemia directly causes hypokalemia. Hypocalcemia alone or induced by hypomagnesemia is a less common cause [101-103]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)

The risk of hypokalemia itself may also be related to decreased IKr activity [104].

Further support for the importance of hypomagnesemia is the beneficial effect of magnesium administration in the acute therapy of TdP. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Initial management'.)

Impaired hepatic and/or renal function can also cause a prolonged QTc, independent of drug administration [68,69].

Patients with anorexia may be predisposed to a long QTc because of catabolic metabolism, electrolyte disturbances, psychotropic medications, or other physiologic changes. This is discussed separately. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Functional changes'.)

Ischemia — QTc prolongation may be common during the early phase of ischemia. In a series of 74 patients undergoing serial ECGs during angioplasty, all patients developed QT prolongation during balloon inflation [105]. In addition, some patients with acute myocardial infarction (8 of 434 consecutive patients in one series) develop progressive QT interval prolongation that is maximal at days 3 to 11 during the healing phase of the infarct [106]. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features", section on 'Polymorphic VT'.)

Bradyarrhythmias — The likelihood of developing QT prolongation and TdP in patients taking antiarrhythmic drugs is increased by bradycardia due to reverse use dependency [11]. It is less clear whether bradycardia alone causes TdP [107,108]. This issue was addressed in a report of 14 patients with complete atrioventricular block, six of whom had a history of TdP [107]. The two groups did not differ with respect to the rate of the escape rhythm; however, the corrected QT interval was significantly longer in those who had experienced TdP (0.59 versus 0.48 seconds). After pacemaker placement, the corrected QT interval was also longer in patients who had TdP, with pacemaker set to 50 beats per minute (QTc 0.70 versus 0.53 seconds).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Cardiac implantable electronic devices".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Long QT syndrome (The Basics)")


Background – The long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) (waveform 1). This syndrome is associated with an increased risk of polymorphic ventricular tachycardia and a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (TdP) (waveform 2A-B). (See 'Definitions' above.)

There is potential overlap between acquired and congenital LQTS, as some people with acquired LQTS can have underlying pathogenic genetic variants but do not meet all the clinical criteria for congenital LQTS. (See 'Underlying pathogenic variant in a long QT syndrome gene' above and "Congenital long QT syndrome: Pathophysiology and genetics".)

Pathophysiology – Nearly all drugs that produce LQTS do so by blocking the IKr current; this is mediated by a potassium channel in myocardial cells. This potassium channel is encoded by the KCNH2 gene. (See 'Pathophysiology' above.)

Medication-induced LQTS

Risk factors Several patient-specific and medication-related factors can enhance the risk of drug-induced LQTS. (See 'Risk factors for drug-induced long QT syndrome' above.)

-Drug-induced LQTS is more common in females, and the prevalence increases with age. Other risk factors include metabolic disturbances such as hypokalemia, hypomagnesemia, impaired hepatic and/or renal function, underlying heart disease, and recent conversion from atrial fibrillation

-Drug regimen associated risk factors for TdP (including rapid infusion high drug concentrations), concurrent use of other drugs that can prolong the QT interval or that slow drug metabolism due to inhibition of cytochrome P450 enzymes, or concurrent intake of grapefruit juice.

-Electrocardiogram (ECG)-related factors predisposing to drug-induced LQTS include baseline QT prolongation or T-wave lability, development of marked QT prolongation, or T-wave changes during therapy and bradycardia.

Specific medications Acquired LQTS is usually secondary to drug therapy. (See 'Drugs that prolong the QT interval' above.)

Common medications include antiarrhythmics (sotalol is the most common), psychotropic medications (antidepressants, antipsychotics), synthetic opioids (eg, methadone), gastrointestinal medications (cisapride and the antiemetics droperidol and ondansetron), and antimicrobials (including macrolide antibiotics and fluoroquinolones, antifungals and antivirals).

Other causes – Causes of acquired LQTS other than drugs include electrolyte abnormalities, structural and ischemic heart disease, and bradyarrhythmias. (See 'Other causes' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Stephen Seslar MD, PhD, and the late Mark E. Josephson, MD, who contributed to an earlier version of this topic review.

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