THE ACQUIRED BRUGADA SYNDROME AND THE PARADOX OF CHOICE

The “paradox of choice” in drug-induced channelopathies

Consider the following two patients: The first is female, asymptomatic, and develops marked QT prolongation while receiving intravenous procainamide for atrial fibrillation. The second is male, also asymptomatic, and develops coved-type ST-segment elevation in the right precordial leads while receiving intravenous flecainide during a diagnostic test. Most physicians would simply recommend discontinuation of procainamide, and avoidance of QT-prolonging medications in the future, as the only therapeutic measures needed for the first patient. In contrast, the same physicians would likely perform electrophysiologic studies and, if positive, move on to implant a defibrillator to the second patient.¹ How did we end-up choosing such disparate recommendations for patients with drug-induced long QT syndrome (LQTS) and Brugada syndrome?

Part of the answer is that “timing is everything.” The LQTS was first recognized as a congenital disorder half a century ago.^2-4 Soon thereafter, description of “quinidine syncope”⁵ led to the recognition of acquired (drug-induced) LQTS. For many years, congenital and acquired LQTS were viewed as two different entities with intriguing similarities.⁶ It would take 40 years to finally realize that loss of function of the same potassium channels -- responsible for the rapidly activating delayed rectifier current (I_Kr) -- may be caused by either genetic mutations or medications.⁷ The realization that some patients with drug-induced LQTS have underlying subclinical genetic mutations that become clinically manifest when treated by QT-prolonging medications, was made only in the year 2000.⁸ Finally, the diagnostic use of I_Kr-channel blockers to identify patients with underlying LQTS mutations was not formally proposed until recently.^9,10

The history of the Brugada syndrome unfolded in a different order. Its original description in 1992¹¹ was soon followed by in-vitro studies describing this disease as a ion-channel disorder¹² and by genetic studies confirming an inborn loss-of-function of the cardiac sodium channel (I_Na) as the cause.¹³ All this prompted the use of drugs that block I_Na to unravel Brugada syndrome.¹⁴ It so happened that the use of sodium-channel blockers became a widespread means for identifying patients with underlying Brugada syndrome¹⁵ before the idea of acquired (drug-induced) Brugada syndrome was accepted. Ironically, back in 1991, the Cardiac Arrhythmia Suppression Trial (CAST) showed that patients with asymptomatic ventricular arrhythmias after myocardial infarction have increased mortality when treated with sodium-channel blockers.¹⁶ Since CAST was published one year before the description of Brugada syndrome,¹¹ the possibility that an “acquired Brugada syndrome” was behind this increased mortality was never contemplated.

Beware of drugs dot com

Although the fact that patients with LQTS are at increased risk for developing arrhythmias when treated with QT-prolonging medications is well known, the sheer size of that risk is not appreciated. In a retrospective study, 1 of every 2 patients with congenital LQTS receiving a QT-prolonging medication had cardiac arrest!¹⁷ It is therefore imperative that all patients with LQTS, including those with suspected but unconfirmed diagnosis, avoid QT prolonging medications at all times. The internet provides up-to-date information on such drugs. For example, www.QTdrugs.org, a reliable website maintained by the Arizona Center for Education and Research on Therapeutics), had more than one million visits only last year (Woosley R.L., Personal Communication). In this issue of Heart Rhythm, Postema¹⁸ reports, on behalf of an outstanding group of experts, the creation of a similar website for Brugada syndrome: www.brugadadrugs.org

Postema et al¹⁸ performed the formidable task of reviewing a vast amount of literature into a concise page with drugs that should be “definitively avoided” or “preferably avoided” by patients at risk for Brugada syndrome. Importantly, www.QTdrugs.org now includes an electronic link to www.brugadadrugs.org. Thus, physicians will soon make recommendations based on a quick look at this new website instead of personally performing a thorough literature search. However, physicians making decisions based on what appears (and does not appear) in www.brugadadrugs.org should remember that behind this website are enthusiastic investigators that will have to cope with an exponentially increasing number of publications. Physicians should also realize that in contrast to the safety evaluation that newly-developed drugs undergo for their “torsadogenic potential,” limited data is collected for their “Brugadogenic potential” (see below). Even more limited data are available for medications already on the market. For example, methadone has been used to treat opiate-addiction for almost 50 years,¹⁹ but the fact that methadone is an I_Kr-channel blocker that can provoke TdP was discovered only recently.²⁰ The dictum “if it's not on the website it is not a problem” will not always be correct.

Patients with Brugada syndrome should avoid all drugs listed as risky in www.brugadadrugs.org even if they have implanted defibrillators. This is because drugs may precipitate arrhythmic-storms with multiple VF episodes.¹⁸ Conversely, every patient presenting with ventricular arrhythmias while receiving such medications should be evaluated for the presence of underlying congenital Brugada syndrome.¹⁸

Safety evaluation of newly developed drugs: The worst is yet to come

Identification of a new drug's propensity to provoke arrhythmias is a critical issue in drug development. The main focus has been on identifying the drugs' potential for blocking I_Kr and prolonging the QT interval.²¹ New drugs are tested for these effects at the level of the ion channel, cardiac tissues and whole animals.²² Guidelines have been developed for both non-clinical and clinical assays (www.ich.org). The International Conference on Harmonization E14 document deals with non-cardiac drugs in development, defining a need for almost all compounds to undergo a thorough QT study in healthy volunteers to test for QT/QTc prolongation. If the study is positive, extensive further evaluation is required both at the non-clinical and clinical levels. Yet, in the case of drugs, QT prolongation per se may be a poor surrogate of proarrhythmia.²³

Complicating matters further, it is now clear that, in addition to I_Kr-mediated QT prolongation, different drug-induced ion-channel actions may predispose to arrhythmias. These include I_Ks-mediated QT prolongation²⁴ as well as several forms of QT abbreviation.^25,26 Drug-induced inhibition of the I_Na and I_Ca²⁷ as well as drug-induced augmentation of the transient outward potassium current²⁸ contribute to the development of the substrate and triggers for ventricular fibrillation (VF) in experimental Brugada syndrome.

Because formulas used for QT correction by heart rate are less than perfect,²⁹ clinical evaluation of the QT-prolonging effects of medications is difficult. Clinical appraisal of “potentially Brugadogenic” new drugs will be even harder. The degree of ST-segment elevation in Brugada syndrome may be transient or fluctuating and is influenced by multiple factors, including the position of the recording electrodes³⁰ and ingestion of heavy meals.³¹ Thus, to maximize the likelihood of detecting Brugada-like changes during investigation of new drugs, one could argue in favor of Holter recordings using electrodes placed at elevated intercostal spaces.³² How much of this testing is really necessary is far from clear.

Born to be “wild-type” or born to loose

Identification of patients at risk for proarrhythmia should ideally occur before they receive the first dose of the drug. Studies to identify genetic variants that contribute to susceptibility for drug-induced TdP require large numbers of cases and controls. Investigators have used datasets generated by referral centers and, more recently, from networks of such centers (http://allianceagainstscd.org/leducq.php). Larger networks to accumulate cases are being planned (Roden DM: personal communication).

In the meantime, the baseline QT/QTc remains an important – albeit imprecise – tool for predicting risk from QT-prolonging drugs. Even borderline QTc prolongation is an exclusion criterion in clinical trials evaluating new medications with I_Kr-blockade properties. However, as explained elsewhere,³³ it is impractical in clinical practice to perform electrocardiographic screening prior to administration of medications with non-cardiac indications except when several risk factors are present (Table 1). Until more is known about the drug-induced Brugada syndrome, it is reasonable to use a similar approach for the drugs listed in www.brugadadrugs.org.

Table 1.

Risk factors for proarrhythmic events.

Risk factor	Drug-induced long QT syndrome from IKr− blockers.34	Drug-induced Brugada syndrome from INa or ICa blockers.
Gender	Female	Male (?)
Baseline ECG	Long QT Borderline-long QT (?)	Coved-type ST elevation. RBBB (?) rSr' in V1-V2 (?)
Heart disease	Yes	Probably
Excessive drug effects:	1) Combination of more than one IKr− blocker. 2) Combination with a drug that impairs the metabolism of the IKr− blocker. 3) Kidney/liver failure.	1) Combined use of INa and ICa blockers. 2) Combination with a drug that impairs the metabolism of the INa or ICa blockers. 3) Kidney/liver failure.
Electrolyte imbalance	Hypokalemia	Hypokalemia (?) Hyperkalemia (?)