On the relationship among QT interval, atrial fibrillation, and torsade de pointes

The uncommon congenital syndromes of QT prolongation associated with a high risk of sudden death (SD) were first described in the 1950s and 1960s, 1–3 and the term torsade de pointes (TdP) was coined in the mid-1960s to describe the peculiar polymorphic ventricular tachycardia that can arise at slow heart rates when the QT is very long. 4 The notion that drugs could produce a very similar clinical syndrome, with striking QT prolongation and polymorphic tachycardia, was first noted in the same era, 5 , 6 and became increasingly well recognized with antiarrhythmic therapies during the 1970s and 1980s. The idea that ‘non-cardiovascular’ drugs could prolong the QT interval, and trigger TdP (or even SD), remained an arrhythmia curiosity until the initial report of terfenadine-associated TdP in the late 1980s. 7 Review of the extant safety data, and a series of clinical and in vitro mechanistic studies, identified inhibition of CYP3A4-mediated terfenadine biotransformation to an antihistamine metabolite (fexofenadine) as the major mechanism. 8–10 Terfenadine itself turned out to be a very potent QT prolonging agent, and that is now well recognized as a reflection of its ability to block the rapid component of the cardiac delayed rectifier IKr . Indeed, block of IKr , or in occasional instances reduction of the current by other mechanisms, 11 , 12 is the major mechanism underlying virtually all forms of drug-induced TdP. 13 The reason the terfenadine incident proved so important for drug development was not only the elucidation of underlying mechanisms, but also the recognition that even a small risk of a very serious side effect, such as drug-induced TdP, could upset the balance between risk and benefit that goes into the prescription of any drug. In the case of terfenadine, regulatory agencies viewed the benefit as a reduction of relatively mild symptoms, and thus even a small risk of TdP was viewed as quite ominous. A series of regulatory opinions over the last decade and half has now culminated in a consensus view that all new drug entities should be evaluated for QT prolonging potential usually through a ‘thorough QT’ trial, and that drug-induced QT prolongation of as little as 0.006 s (6 ms) may indicate that the new drug in question will receive greater regulatory scrutiny. 14 , 15 The notion that a 6 ms change in QT interval in an individual, or even in a population, could possibly have any physiological or regulatory significance seems far-fetched until one recognizes that this is exactly the degree of QT prolongation seen with usual doses of terfenadine. 16 Thus, the 6 ms ‘signal’ is an indication for regulators and drug developers to examine further the likelihood that subgroups at special risk, such as those with underlying cardiovascular disease or those receiving interacting drugs, may be exposed. This concept has led to a series of debates during Food and Drug Administration hearings and other settings around new antipsychotic, antibiotic, and urological drugs (to name a few) in which the relative risks are weighed against the potential benefits of new drug entities. These debates are inevitably characterized by discussion of the risk imposed by a given degree of QT prolongation within the population, since new drug studies are only conducted in several thousand patients at most, and even the riskiest of ‘non-cardiovascular’ drugs producing QT prolongation will not generate even a single episode of TdP in such a small data set. That is, the ‘acceptable’ incidence of TdP with non-cardiovascular therapies is not well defined, but is certainly <1 in 10 000 or more in exposed patients. In contrast, it is well recognized that antiarrhythmic drugs such as sotalol, dofetilide, ibutilide, and quinidine carry a TdP risk of 1% or more. 17–21 The mechanisms whereby these drugs produce TdP seem no different from others, and so one must assume that the increased incidence reflects enhanced risk among patients with certain forms of cardiovascular disease likely to be treated with these agents. Thus, although many risk factors have been described for drug-associated TdP (female gender, hypokalaemia, slow heart rates and complete heart block, and DNA variants in ion channel or other genes), the presence of concomitant heart disease that is itself an indication for antiarrhythmic therapy seems a very powerful risk factor as well. Some clinical trials suggest that congestive heart failure 18 , 22 also contributes to this risk, and this would further help explain the higher incidence of TdP during antiarrhythmic therapy, compared with non-cardiovascular therapy that also blocks IKr . The mechanisms whereby some patients seem to be at much higher risk than others remain incompletely understood. We have proposed the idea of ‘repolarization reserve’, which suggests that multiple mechanisms contribute to normal repolarization, 23 , 24 so that removal of any one of these (by disease, subclinical mutation or polymorphism in an ion channel or other gene, etc.) may be without consequence until a drug is added at which point the ‘reduced repolarization reserve’ becomes evident by marked QT prolongation and TdP. Atrial fibrillation (AF) is the current primary indication for antiarrhythmic drug therapy. 25 To date, drugs used to maintain sinus rhythm in patients with AF fall into one of the three broad categories. The first includes drugs whose electrophysiological toxicity is characterized by QT prolongation and TdP. The second, exemplified by flecainide and perhaps propafenone, has sodium channel block as its major mechanism of action, and electrophysiological toxicity due to excess sodium channel block is a risk with these agents; such toxicity can include atrial flutter with 1:1 atrio-ventricular conduction (also seen with other antiarrhythmics), as well as sustained ventricular tachycardia and an increase in SD in patients with coronary disease and recent myocardial infarction. 26 , 27 The third ‘category’ of drugs used in the treatment of AF comprises those with mixed pharmacological actions exemplified by amiodarone, which despite producing both sodium channel block and marked QT prolongation, does not produce much in the way of serious drug-related proarrhythmia. The mechanisms whereby amiodarone can produce such striking QT prolongation and yet produce a small risk of TdP are incompletely understood; likely explanations include block of some inward arrhythmogenic current such as that through calcium channels or sodium–calcium exchange, or decreased heterogeneity of action potential durations across the ventricular wall. The important point is that this experience demonstrates there is not a consistent link between the extent of QT prolongation and the risk of serious QT-related proarrhythmia. 28 One common clinical observation is that TdP often (but not always 21 ) occurs in patients with AF after conversion to sinus rhythm. 29 This may reflect the decrease in heart rate that often accompanies such conversion, but studies that we conducted in the late 1990s indicated that the mechanisms must be more complicated. In a small study, we examined the extent of QT prolongation by intravenous dofetilide during AF and shortly after conversion to sinus rhythm. Despite the fact that dofetilide did not change heart rate, the extent of QT prolongation was much greater in the sinus rhythm setting than in the AF setting. 30 Indeed, more recently, we have shown that QT-RR slopes are extraordinarily flat during AF (i.e. even with long pauses, the QT interval does not prolong), and steepen very sharply, to greater than normal values, shortly after conversion to sinus rhythm. 31 We infer that AF itself may exert a heretofore poorly understood influence on the QT interval both during arrhythmia and shortly after its conversion to normal rhythm. Understanding the mechanisms underlying such an effect would be an important step towards understanding the increased risk of TdP when an IKr blocker is used in a patient with AF. Detailed examination of the relationships among IKr block, action potential prolongation, heterogeneity of repolarization times, perturbed intracellular calcium control, TdP, and its potential degeneration to ventricular fibrillation have provided a superb model for translational science. Advances have been made by scientists at all levels of this ‘chain of evidence’ that links IKr block to SD, from basic and clinical geneticists and electrophysiologists to experts in regulatory science. Proarrhythmia and other forms of serious drug-related toxicity are the Achilles’ heel of drug therapy in AF. The development of new compounds with different targets of action and perhaps mixed drug effects (like amiodarone) may therefore represent an advance in the field, assuming efficacy can be demonstrated and no serious toxicity arises in clinical trials or in post-marketing surveillance; AZD7009 is one example of a series of drugs under development with this rationale. In this supplement, the science around this chain of evidence is examined in a series of manuscripts. Charles Antzelevitch reviews the ionic, molecular, and cellular bases of QT prolongation and TdP. Ahmad and Dorian probe the question of whether there is an inevitable relationship between QT prolongation and proarrhythmia. Darpö describes the problems in identifying cases of drug-induced arrhythmias, and finally Shantsila, Watson, and Lip examine the relationship between QT prolongation and TdP in the setting of treatment for AF. It is clear that new drugs lacking proarrhythmic or other serious toxicity potential would provide important new tools to practitioners who are seeing large numbers of patients with symptomatic AF for whom currently available therapies are unsuitable. Conflict of interest : D.M.R. reports receiving consulting income for activities related to safety of new drugs, including their QT-prolonging potential; these have been from CV Therapeutics, Sanofi-Aventis Therapeutics, Pfizer, Avanir, Novartis, and AstraZeneca.