Measurement of the QT interval on a surface electrocardiogram (ECG) has garnered more attention and gained clinical importance in the last several decades. The cardiac action potential is governed by several ion membrane channels, including the sodium, calcium, and potassium channels.1 The QT interval is a relative measure of both ventricular depolarization and repolarization of the action potential which, when prolonged, indicates an increased risk of serious ventricular arrhythmias and sudden cardiac death.2–4 While QT interval prolongation may be either congenital or acquired, the focus of this article will be to evaluate acquired causes of QT prolongation.
Specialized proteins known as ion channels exist within the cardiac myocyte.5 Ventricular depolarization, and subsequent repolarization, are governed by ion channel movement of the electrically charged ions sodium (Na+), calcium (Ca+), and potassium (K+). The resting action potential (phase 4) of a cardiac myocyte is approximately −90 mV and is largely determined by the potassium equilibrium across the cell membrane. As cardiac myocytes are electrically stimulated (typically by an adjacent cell) fast Na+ channels open leading to rapid depolarization (phase 0). As fast Na+ channels close and K+ shifts transiently outward phase 1 of the action potential occurs. The plateau phase (phase 2) occurs as the inward movement of Ca+, and to a lesser extent delayed Na+, is balanced against outward K+ movement. Repolarization of the cardiac myocyte occurs as Ca+ and Na+ channels close, while outward K+ channels remain open (phase 3) (Figure 1). The primary determinants of cardiac action potential duration, and therefore QT interval duration, are the ionic currents of phase II (plateau) and phase III (repolarization).1,5–7
Derangements in cardiac ion movement may result in prolongation of the cardiac action potential. These derangements can include an increase in inward currents (Ca+, Na+), a decrease in outward currents (K+), or both.5 The predominant cause of acquired action potential prolongation, and hence QT prolongation, is decreased outward K+ movement secondary to blockade of outward rectifying K+ channels (IK).8 Abnormal repolarization delays the inactivation of ion channels responsible for the inward movement of depolarizing currents (Ca+, Na+) leading to early after depolarizations (EADs).9 These EADs are partially responsible for the tachyarrhythmias associated with action potential and QT prolongation. The most concerning of these tachyarrhythmias is torsades de pointes (TdP) which may degenerate into ventricular fibrillation and sudden cardiac death.6,10
The QT interval is a surrogate marker of action potential duration, and therefore is utilized to estimate risk of ventricular tachyarrhythmias and TdP. The QT interval on the surface ECG is measured from the beginning of the QRS complex (ventricular depolarization) to the end of the T wave (ventricular repolarization) (Figure 2).5,7,9 This measurement is subject to variability including diurnal variation, method and technique of ECG recording, patient environment, and intraobserver and interobserver variability.7 In addition, the QT interval is affected by heart rate (adrenergic tone) with the interval prolonged at slower heart rates and shortened at faster heart rates. Several formulas exist which aim to standardize the QT interval based on heart rate (QTC). The Bazett formula is the most commonly used, though it may be inaccurate at faster heart rates.11,12 The QT interval is most often considered prolonged when the QTC exceeds 440 ms (men) and 460 ms (women), with a QT interval >500 ms associated with a higher risk of TdP.9,13
QT prolongation is typically classified as either congenital (primary) or acquired (secondary).14 In congenital (primary) QT prolongation, mutations in genes encoding for Na+ or K+ ion channels alter ionic currents and result in prolongation of the action potential and QT interval.15,16 These patients may present with baseline QT prolongation in the absence of acquired causes (eg QT prolonging medications). While the focus of this article is acquired QT prolongation, it is important to note that unrecognized genetic mutations may predispose individuals to acquired QT prolongation.7 The acquired (secondary) form of QT prolongation results from electrolyte abnormalities, medical conditions, and drug therapy.
The predominant mechanism of drug-induced QT prolongation is blockade of outward K+ movement resulting in delayed repolarization and prolonged action potential duration. In addition to these direct effects, drugs which inhibit CYP3A4 metabolism of QT prolonging agents have also been associated with QT prolongation.17 The list of drugs associated with QT prolongation is extensive, though broad categories include antiarrhythmics, anti-infectives, antihistamines, and psychotropics (Table I). More complete, up to date lists of drugs associated with QT prolongation are available at http://www.torsades.org or http://www.azcert.org
Antiarrhythmics, specifically class Ia and class III, are associated with QT prolongation and risk of TdP. Class Ia antiarrhythmics (eg quinidine, disopyramide, and procainamide) are predominantly thought of as Na+ channel blockers, though they also exhibit reverse use blockade of K+ channels, leading to prolongation of the action potential. Reverse-use dependence is characterized by a greater block of K+ channels at slower heart rates. As a result of this reverse-use dependence, QT prolongation with class Ia antiarrhythmics is more pronounced with bradycardia.5 Like class Ia agents, class III antiarrhythmics (eg sotalol, dofetilide, ibutilide, and amiodarone) as a group demonstrate reverse-use dependence. However, unlike class Ia, the primary antiarrhythmic mechanism of class III agents is blockade of K+ channels and prolongation of phase III of the action potential. While the QT prolonging effect of class Ia agents tend not to be dose related, the QT prolongation and proarrhythmic effects of class III antiarrhythmics are dose dependent.9 It should be noted that while amiodarone is associated with QT prolongation, it demonstrates a lower risk for TdP than other class III agents. This property of amiodarone is related to its concurrent blockade of Ca+ channels, lack of reverse-use dependence, and more homogenous ventricular repolarization.5,18
Specific classes of anti-infectives also demonstrate QT prolongation. Macrolide antibiotics block K+ channels and inhibit CYP3A4 metabolism of other QT prolonging drugs. Erythromycin is the macrolide most associated with QT prolongation, followed by clarithromycin and azithromycin.19 Fluoroquinolones also exhibit QT prolongation related to K+ channel blockade. Two agents, sparfloxacin and grepafloxacin, which were withdrawn from the US market, block K+ channels to a much greater degree than currently available fluoroquinolones.14,19 Though cases of TdP have been reported with most fluoroquinolones, the remaining available agents appear safe from a QT prolongation standpoint. Precaution, however, is still warranted in patients receiving concomitant QT prolonging agents. In addition to macrolides and fluoroquinolones, azole antifungals (eg ketoconazole, fluconazole, and itraconazole) demonstrate K+ channel blockade and QT prolongation. Also, like macrolide antibiotics, these antifungal agents inhibit CYP3A4 metabolism of other QT prolonging drugs. Fluconazole demonstrates less CYP3A4 inhibition, and therefore results in less drug interactions, than the other agents in this class.20
Two nonsedating antihistamines (terfenadine and astemizole) have been associated with QT prolongation and TdP.9,14 These agents, removed from the US market in 1998 and 1999, respectively, illicit K+ channel blockade though these effects were generally seen in the presence of other predisposing factors (e.g. drug interactions, impaired liver function). Newer agents in this class (eg loratadine and cetirizine) have lower to no K+ channel blockade and have not been conclusively shown to cause arrhythmias.14,21
Psychotropic agents including tricyclic antidepressants (TCAs), certain antipsychotics, and selective serotonin reuptake inhibitors (SSRIs) have also been associated with QT prolongation. TCAs such as amitriptyline, doxepin, and nortriptyline, appear to prolong the QT interval through K+ channel blockade.5 Likewise, select antipsychotics such as haloperidol, thioridazine, and ziprasidone exhibit QT prolongation.9 Although case reports have linked SSRIs with QT prolongation this association is likely secondary to drug interactions with other QT prolonging drugs.22
In addition to drug therapy, electrolyte abnormalities including hypokalemia, hypomagnesemia, and hypocalcemia have been associated with QT prolongation.23–25 Hypokalemia is by far the most common metabolic cause of QT prolongation and is related to decreased activity and enhanced drug blockade of K+ channels.9 Hypomagnesemia also induces QT prolongation though this is the result of the direct association of hypomagnesemia with hypokalemia. Hypocalcemia may also result in QT prolongation as reduced Ca+ concentrations prolong the plateau phase (phase 2) thereby prolonging the action potential duration and QT interval.
Development of acquired QT prolongation is often dependent on the presence of other predisposing factors (Table II).14,17 Presence of these factors should be considered when initiating patients on QT prolonging medications. Upon drug initiation baseline ECGs should be obtained with routine ECGs monitored during the course of therapy. The arrhythmogenic potential of a drug at a given QT interval varies from patient to patient. As a result, no consensus exists on the degree of QT prolongation that requires drug discontinuation.7 When clinically concerning QT prolongation is identified, the offending agent should be removed and any electrolyte abnormalities corrected. Along with drug removal and electrolyte correction additional interventions may be required if arrhythmias such as TdP are identified. Treatment of TdP consists of intravenous (IV) magnesium and temporary ventricular pacing to maintain heart rate >100 beats per minute. IV isoproterenol titrated to maintain heart rate >100 beats per minute can also be used, but is generally a temporizing measure until temporary pacing can be implemented.5–7,9 Another mode of TdP therapy is atropine, an anticholinergic agent that accelerates heart rate which is expected to shorten the QT interval and suppress arrhythmias. Atropine, however, often fails to maintain rapid heart rate and may induce paradoxical bradycardia, increasing the risk of TdP.26 Urgent cardioversion may be required in patients with hemodynamically unstable TdP.
|Advanced age (>65 y)|
|Baseline QT prolongation|
|Concomitant QT prolonging drugs|
|Congenital long QT|
|Congestive heart failure|
|Ischemic heart disease|
The true incidence of acquired QT prolongation is difficult to define as identification of predisposing factors, association with individual agents, and provider recognition continue to evolve. Torsade de pointe was the most common reason for drug withdrawal from the market in the past decade.27 Examples of withdrawn drugs include the antihistamines terfenadine and astemizole, the antibiotic grepafloxacin, the antipsychotic sertindole, and the gastrointestinal motility agent cisapride. Each of these agents was associated with TdP in postmarketing case reports and with voluntary adverse drug reaction reporting. Owing to the small study populations evaluated and relatively infrequent occurrence of QT prolongation and TdP, this serious adverse effect may not be identified during drug development.7,17 In 2005, the Food and Drug Administration (FDA) published recommendations for the preclinical evaluation of the QT prolongation potential of drugs.28 These nonmandatory guidelines suggest that investigators evaluate in vivo and in vitro (animal) effects of drugs in development, specifically focusing on the potential for K+ channel blockade. Increased FDA regulation of preclinical testing may lead to decreased postmarketing revelation of QT prolongation and TdP.
Acquired QT prolongation and resultant ventricular arrhythmias are serious, potentially life-threatening effects that may be secondary to drug therapy, medical conditions, or electrolyte abnormalities. Identification of predisposing factors for QT prolongation is vital when weighing the risk-benefit profile of drug therapy. Close ECG monitoring and prompt identification of QT prolongation are essential in the management of patients on QT prolonging drug therapy. Immediate discontinuation of offending agents, correction of electrolyte abnormalities, and appropriate adjunctive medical therapy can improve patient outcomes. Improved drug development regulation is likely to reduce, but not eliminate, the identification of postmarketing QT prolongation and TdP.