INTRODUCTION — 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, a characteristic life-threatening cardiac arrhythmia also known as torsades de pointes (waveform 2A-B). The primary symptoms in patients with LQTS include palpitations, syncope, seizures, and sudden cardiac death.

LQTS may be either congenital or acquired. These two primary syndromes (congenital and acquired LQTS) may be related, as some patients who develop acquired LQTS may have an inherited predisposition with abnormalities in repolarization that represent the forme fruste of LQTS. Acquired LQTS usually results from drug therapy (table 1), although hypokalemia, hypomagnesemia, and bradycardia can increase the risk of drug-induced LQTS. (See 'Mutations in LQTS genes' below.)

The definition, causes, and pathophysiology of acquired LQTS will be reviewed here. 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".)

DEFINITIONS

Normal QT interval — The normal range for the rate-corrected QT interval (QTc) is similar in males and females from birth until adolescence, while in teenagers and adults, females have slightly longer QT intervals than males. Overall, the average QTc in healthy persons during infancy is 400±20 milliseconds and increases slightly after puberty to 420±20 milliseconds. In general, the 99th percentile QTc values are 460 milliseconds (prepuberty), 470 milliseconds in postpubertal males, and 480 milliseconds in postpubertal females. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'ECG findings'.)

Torsades de pointes — Polymorphic ventricular tachycardia (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 (TdP) is a form of polymorphic VT that 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 heart beat preceding the onset of the arrhythmia, 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, and episodes can recur in rapid succession, potentially degenerating to ventricular fibrillation and sudden cardiac death [1,2].

INCIDENCE — 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. Additionally, the incidence of QT prolongation without torsades de pointes (TdP) is likely much higher than the incidence of TdP itself. In one retrospective review of all hospital admissions to a single center over a six-month period, 293 out of 41,649 patients (0.7 percent) were noted to have a QTc ≥500 milliseconds, but less than 6 percent of those with severe QT prolongation experienced syncope or a life-threatening arrhythmia [4].

In an observational study of 500,000 persons in the Netherlands, from which 775 cases of sudden cardiac death (SCD) were identified over a period of slightly less than nine years (with each case matched to up to 10 controls), 24 of 775 patients with SCD (3.1 percent) were currently using a QT-prolonging drug [5]. 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).

Although these results suggest that drug-induced TdP may be more common than documented cases suggest, the absolute number of events is still low and represents a small proportion of SCD events (24 of 775 patients with SCD [3.1 percent] were currently using a QT-prolonging drug).

PATHOPHYSIOLOGY — The proposed mechanism for drug-induced torsades de pointes (TdP) is the development of early afterdepolarizations and triggered activity resulting from prolonged repolarization [6]. The pathophysiology of LQTS is described in detail elsewhere.

There are thought to be pathophysiologic differences between the acquired and congenital forms of LQTS:

●The polymorphic ventricular tachycardia (VT) in the acquired form of LQTS is most commonly precipitated by short-long RR intervals. This interval typically is caused by a premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) followed by a compensatory pause (waveform 2B). Polymorphic VT also can occur in association with bradycardia or frequent pauses; as a result, the acquired form of LQTS is sometimes called "pause-dependent" LQTS [7].

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 [8]. 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".)

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].

●In contrast to the association with bradycardia and pauses seen in acquired LQTS, arrhythmias in some forms of congenital LQTS tend to follow a sudden adrenergic surge (due, for example, to exercise, emotional stress, or arousal), particularly 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'.)

However, these distinctions between acquired and congenital LQTS are not absolute. This was illustrated in an observational study of 15 patients with congenital LQTS in which "pause-dependent" TdP, which is more characteristic of the acquired form, was noted in 14 of 15 patients [29].

MUTATIONS IN ACQUIRED LQTS — Long QT syndrome can also be an acquired disorder, most often due to drugs (table 1). Virtually all of the drugs that produce LQTS act by blocking the IKr current mediated by the potassium channel encoded by the KCNH2 gene. As noted above, mutations in KCNH2 are responsible for LQT2. (See 'Importance of KCNH2 blockade' below.)

In some patients, drug-associated LQTS appears to represent a "forme fruste" of congenital LQTS in which a mutation or polymorphism in one of the LQTS genes is clinically concealed, therefore it is diagnostically inapparent until the patient is exposed to a particular drug or other predisposing factor [30-33]. It has been suggested that there is a redundancy in repolarizing currents that has been called repolarization reserve [9]. This could explain why a given mutation might be associated with clinical disease only when an additional insult, such as that mediated by a drug, hypokalemia, or hypomagnesemia, is superimposed.

The frequency with which patients with drug-associated LQTS and TdP have an underlying predisposition to such events has been evaluated in a variety of studies [31,34-38]. In one series of 92 patients, in which the culprit drugs were antiarrhythmic drugs (eg, quinidine and sotalol) in 77 percent and nonantiarrhythmic drugs in 23 percent, mutations in LQT1, LQT2, or LQT3 were identified in five patients (5.4 percent) and gene polymorphisms that might contribute to risk were identified in another 5 to 10 percent [33]. Additionally, 82 of the 92 patients had an underlying risk factor for TdP (eg, heart failure, left ventricular hypertrophy, hypokalemia, and/or hypomagnesemia). Unaffected family members may carry silent mutations in LQTS genes (ie, they are carriers of mutated genes with low penetrance) [32,34,39,40]. 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 [39]. In such individuals, the LQTS mutations may produce an alteration in repolarizing currents that is insufficient to prolong the QT interval at rest. However, these silent gene carriers and their affected offspring might be at risk for unexpected TdP if exposed to drugs that can prolong the QT interval.

CAUSES OF ACQUIRED QT PROLONGATION

Medications — Medications are a common cause of acquired LQTS and torsades de pointes (TdP). Many medications have been implicated, and additional medications continue to be identified [32,41,42]. A 2020 scientific statement from the American Heart Association details drugs associated with Torsades de pointes [43]. (See 'Torsades de pointes' above.)

The major classes of drugs that prolong the QT interval include (table 1) [33,42,44-47]:

●Antiarrhythmic drugs

●Certain older nonsedating antihistamines (eg, terfenadine and astemizole) that are no longer available to prescribe in most countries

●Certain antimicrobials (eg, macrolide and fluoroquinolone antibiotics, some antifungal and antiviral drugs, etc)

●Certain psychotropic medications

●Certain gastric motility agents (eg, cisapride, which has limited availability)

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). A more complete list of specific drugs that prolong the QT interval is available at www.crediblemeds.org/.

The relative frequency of the different causes of drug-induced TdP will vary with the population studied and the drugs that are available (eg, cisapride is not easily available in the United States but is available in some other countries). The range of findings can be illustrated by the following observations:

●Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the most common drugs were sotalol and cisapride (17 and 13 percent) [42].

●In a review of 92 patients from the United States with drug-induced TdP, antiarrhythmic drugs were responsible in 71 (77 percent) [33].

Among drugs still commonly available, some of the best data on incidence of TdP come from studies of antiarrhythmic drugs, particularly class IA and class III drugs, and psychotropic medications.

Antiarrhythmic drugs

●Quinidine, a class IA (table 2) sodium channel blocking agent with potassium channel blocking function at slow heart rates, has historically been the most frequently implicated cause of drug-induced TdP; however, it is now rarely prescribed [48]. Most cases occur within 48 hours of initiating drug therapy; associated factors are hypokalemia and excessive bradycardia. The incidence may be reduced by careful attention to correction of hypokalemia or hypomagnesemia before therapy and discontinuation of drug therapy if QT prolongation occurs [49]. 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.

●Although TdP occurs with disopyramide and procainamide (also class IA), the incidence is substantially lower than with quinidine [50,51]. With procainamide therapy, QT prolongation and TdP result from the major metabolite of the drug, N-acetylprocainamide (NAPA), which has class III potassium channel blocking activity and thereby causes QT prolongation [52].

●Sotalol (class II and III) causes QT prolongation and TdP in approximately 2 percent of men and 4 percent of women in a dose-dependent relationship [53-55]. As a result, sotalol therapy should typically be initiated in a hospital with facilities for cardiac rhythm monitoring and assessment. (See "Clinical uses of sotalol".)

●Dofetilide (class III) was associated with increased risk of TdP generally within the first three days of therapy, the time of peak increase in the QT interval [56,57]. Patients must be hospitalized for dofetilide initiation at a facility that can provide measurement of creatinine clearance, cardiac monitoring, and resuscitation. (See "Clinical use of dofetilide".)

●Proarrhythmia is the most common toxic reaction with intravenous ibutilide (class III) when utilized for acute termination of atrial tachyarrhythmias; such ventricular proarrhythmias include nonsustained polymorphic ventricular tachycardia (VT; 2.7 percent of patients), sustained polymorphic VT (1.7 percent), nonsustained monomorphic VT (4.9 percent), and sustained monomorphic VT (0.2 percent) [58,59].

●Amiodarone (class III) markedly prolongs 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 [60], as it prolongs repolarization in a more homogeneous manner than other class III agents. The estimated incidence of TdP is less than 1 percent overall [61] 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 [62]. Several factors contribute to the rarity of TdP with amiodarone: lack of reverse use dependence, concurrent blockade of the L-type calcium channels, and less heterogeneity of ventricular repolarization (less QT dispersion). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.)

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 (table 1).

Psychotropic medications

●Haloperidol was the topic of a US Food and Drug Administration (FDA) alert in September 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 'Importance of KCNH2 blockade' below.)

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

•Hypothyroidism

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 [63]. 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 [64]. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

●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. Other narcotic agents such as fentanyl have similar impact on repolarization with QT prolongation [65]. (See "Medication for opioid use disorder", section on 'Methadone: Opioid agonist' and "Medication for opioid use disorder" and "Medication for opioid use disorder", section on 'Adverse effects'.)

Other 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 [42,66]. 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.

●Macrolide antibiotics (eg, erythromycin, azithromycin, clarithromycin), fluoroquinolone antibiotics (eg, ciprofloxacin, gatifloxacin, levofloxacin, etc.), and antifungal drugs (eg, fluconazole, itraconazole, ketoconazole, etc.) similarly impact metabolism and potentially prolong the QT interval. Users of erythromycin in one report had a twofold increased risk of sudden cardiac death (SCD) over nonusers [67]. 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 3).

●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 [68-70]. 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 [71].

Risk factors — Although drug-induced TdP is sometimes regarded as an idiosyncratic event, a number of risk factors have been identified [9,44,72] in addition to the genetic susceptibility. Patients with multiple risk factors may face the greatest risk [72]. These factors can be classified as follows.

With respect to the drug regimen:

●High drug doses or concentrations of QT-prolonging drugs (quinidine is an exception); for example, thioridazine doses of ≥600 mg/day should generally be avoided [73]; 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 [74].

●Rapid intravenous infusion of QT-prolonging drug.

●Concurrent use of more than one drug that can prolong the QT interval or use of a QT-prolonging drug with one that slows drug metabolism due to inhibition of hepatic cytochrome P450 enzymes (table 3), such as erythromycin (which also directly causes QT prolongation) [17,18,22,67] and cimetidine [75]; in addition, concurrent intake of grapefruit juice, which inhibits CYP3A4, 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 [76].

●Diuretic treatment may be a risk factor due to its correlation with electrolyte abnormalities and heart failure (HF) or due to the direct blockade of potassium current by some diuretics [72].

With respect to ECG abnormalities:

●Baseline QT prolongation or T wave lability.

●The development of marked QT prolongation (eg, QTc >500 milliseconds), T wave lability, or T wave morphologic changes (such as LQT2-type repolarization: notching, long T peak-T end) during therapy.

●Bradycardia which may be related to a fall in local extracellular potassium concentration, leading to enhanced drug-induced inhibition of IKr [11].

•Sinus bradycardia, heart block, incomplete heart block with pauses

•Premature complexes leading to short-long-short cycles

●Congenital LQTS or "silent" mutations in LQTS genes. In a 2016 study of patients with acquired LQTS and TdP, approximately one-third had mutations in one of the known LQTS genes identified [77]. (See 'Mutations in LQTS genes' below.)

With respect to metabolic factors:

●Electrolyte disturbances, especially hypokalemia and hypomagnesemia and less often hypocalcemia

●Impaired hepatic and/or renal function

Other risk factors [72,78,79]:

●Occult (latent) congenital LQTS

●Genetic polymorphisms (reduced repolarization reserve)

●Underlying heart disease, particularly HF, myocardial infarction (MI), and left ventricular hypertrophy (LVH) (see 'Structural heart disease' below)

●Female sex [79]

●Advanced age [72]

Most patients who have drug-induced TdP have one or more risk factors. In a literature review including 249 patients with TdP associated with noncardiac drugs, 97 percent had at least one risk factor, and 71 percent had at least two [80]. These included female sex in 71 percent, a history of heart disease in 41 percent, concurrent use of another QT-prolonging drug in 39 percent, hypokalemia in 28 percent, high drug dose in 19 percent, and a prior history of LQTS in 18 percent.

The most frequent risk factor for drug-induced TdP is female sex [54,79,81,82]. In a literature review of 332 patients with TdP associated with cardiovascular drugs, 70 percent were female [79], similar to the 71 percent incidence associated with noncardiac drugs [80]. A female preponderance for symptomatic disease has also been noted in patients with congenital LQTS [83]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".)

Compared with males, females have a longer QTc and greater response to drugs that block IKr, potentiating the development of TdP [81]. This may be mediated by the effect of sex steroids on ion channel expression. Estrogen potentiates QT prolongation induced by bradycardia and the development of arrhythmia. By contrast, androgens shorten the QT interval and make it less responsive to drugs.

Mutations in LQTS genes — In some patients, drug-associated LQTS appears to represent a concealed form of congenital LQTS in which a mutation in one of the LQTS genes is clinically inapparent until the patient is exposed to a particular drug or other predisposing factor. It has been suggested that there is a redundancy in repolarizing currents that has been called repolarization reserve [9]. This could explain why a given mutation might be associated with clinical disease only when another insult, such as a drug, hypokalemia, or hypomagnesemia, is superimposed. This topic is discussed in detail elsewhere. (See "Congenital long QT syndrome: Pathophysiology and genetics".)

The frequency with which patients with drug-associated LQTS and TdP have an underlying predisposition to such events has been evaluated in a variety of studies [31,33-38].

●In one series of 92 patients, in which the culprit drugs were antiarrhythmic drugs (eg, quinidine and sotalol) in 77 percent and nonantiarrhythmic drugs in 23 percent, mutations in LQT1, LQT2, or LQT3 were identified in five patients (5.4 percent), and gene polymorphisms that might contribute to risk were identified in another 5 to 10 percent [33]. Additionally, 82 of the 92 patients had an underlying risk factor for TdP (HF, LVH, hypokalemia, and hypomagnesemia).

●In a series of nine families with sporadic cases of LQTS, 15 of 46 family members (33 percent) who were felt to be unaffected with congenital LQTS based upon clinical criteria were gene carriers [39]. In such individuals, the LQTS mutations may produce an alteration in repolarizing currents that is insufficient to prolong the QT interval at rest. However, these silent gene carriers and their affected offspring might be at risk for unexpected TdP if exposed to drugs that can prolong the QT interval.

●It is important to balance the need for medications, such as psychotropic drugs, versus the risk of QT prolongation when managing patients with serious psychiatric disorders and not deprive patients of necessary treatments [84].

Importance of KCNH2 blockade — The majority of drugs that produce acquired LQTS predominantly act by blocking the IKr current mediated by the potassium channel encoded by the KCNH2 gene [9-28]. In addition, one of the forms of congenital LQTS, LQTS type 2, is due to mutations in KCNH2. (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 report from the International Drug Monitoring Program of the World Health Organization [85]. For 54 medications associated with QT prolongation and TdP, the investigators compared the plasma concentrations achieved during usual clinical use, defined as the effective free therapeutic plasma concentration (ETCP), with the in vitro concentration of the drug that inhibits 50 percent of potassium channels (IC50). The ratio of these values (ETCP/IC50) is considered a measure of the therapeutic/toxic window. The following findings were reported:

●The ETCP/IC50 ratio ranged from 0.00003 for nifedipine (indicating that drug levels in general clinical use are substantially lower than levels required to block potassium channels) to 29.7 for thioridazine (indicating that usual drug levels have significant potassium channel blocking activity).

●Medications with a ratio >1, indicating a greater chance of toxicity at usual clinical doses, included cisapride, sparfloxacin, quinidine, ibutilide, and thioridazine.

●There was a linear relationship between the ETCP/IC50 ratio and the reported incidence of a composite end point of cardiac arrest, sudden death, TdP, VT, and ventricular fibrillation.

●Tertiary hospitalized patients have risk of TdP ranging from 0.1 to 0.3 percent per year, most commonly due to known QT-prolonging medication use [86].

Other causes of TdP

Hypokalemia, hypomagnesemia, and hypocalcemia — Hypokalemia and hypomagnesemia can predispose to TdP. These disorders can occur together since hypomagnesemia directly causes hypokalemia. Hypocalcemia, alone or induced by hypomagnesemia, is a less common cause [87-89]. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)

The risk for developing TdP in the presence of hypokalemia and/or hypomagnesemia is greatest in patients taking antiarrhythmic drugs [33,48,90-92]. In another series of 92 patients with drug-induced LQTS, 27 percent had hypokalemia or hypomagnesemia [33]. 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]. The risk of hypokalemia itself may also be related to decreased IKr activity [93].

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 'Management'.)

Structural heart disease — Heart failure, diastolic dysfunction, myocardial ischemia, and LVH are common risk factors for drug-induced TdP. Antiarrhythmic drugs and hypokalemia and/or hypomagnesemia associated with diuretic therapy may all contribute to proarrhythmia. Creatinine clearance may be an additional clinical risk factor in patients receiving diuretics and antiarrhythmic agents [94,95]. It is not clear if there is an increased risk of LQTS or TdP with either type of heart disease alone.

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 [96]. In addition, some patients with acute MI (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 [97]. (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 [98,99]. This issue was addressed in a report of 14 patients with complete atrioventricular block, six of whom had a history of TdP [98]. 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 again significantly longer in those patients who had had TdP when the pacemaker was set at 60 beats per minute (0.55 versus 0.50 seconds) or 50 beats per minute (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 5^th to 6^th 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 10^th to 12^th 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)")

SUMMARY AND RECOMMENDATIONS

●Acquired long QT syndrome (LQTS) usually results from drug therapy, hypokalemia, and/or hypomagnesemia (table 1). Some patients with acquired LQTS have an underlying "forme fruste" of congenital LQTS. (See 'Introduction' above.)

●Torsades de pointes (TdP) is a form of polymorphic ventricular tachycardia (VT) that occurs in the setting of acquired or congenital QT interval prolongation. TdP is usually short-lived and terminates spontaneously. However, most patients experience multiple episodes of the arrhythmia, and episodes can recur in rapid succession, potentially degenerating to ventricular fibrillation and sudden cardiac death. (See 'Torsades de pointes' above.)

●Acquired LQTS is commonly associated with bradycardia and pauses, in contrast to some forms of congenital LQTS (particularly types 1 and 2) (figure 1) in which arrhythmias often follow a sudden adrenergic surge. (See 'Pathophysiology' above and "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Triggers of arrhythmia'.)

●Drugs that prolong the QT interval include antiarrhythmic drugs (classes IA and III), macrolide antibiotics, and certain psychotropic medications (see www.crediblemeds.org/). (See 'Incidence' above.)

●Risk factors for drug-induced TdP include high concentrations (quinidine is an exception), concurrent use of other drugs that can prolong the QT interval or that slow drug metabolism due to inhibition of cytochrome P450 enzymes, concurrent intake of grapefruit juice, baseline QT prolongation or T wave lability, development of marked QT prolongation or T wave changes during therapy, bradycardia, electrolyte disturbances (particularly hypokalemia and hypomagnesemia), impaired hepatic and/or renal function, underlying heart disease, recent conversion from atrial fibrillation, and female sex. (See 'Risk factors' 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.