EDITORIAL COMMENT
Potassium andlong QT syndrome
A new look at an old therapy*
Elizabeth Bisinov, MD*,
James H. Mitchell, MD* and
Craig T. January, MD, PhD, FACC*,*
* Section of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA
* Reprint request and correspondence: Dr. Craig T. January, University of Wisconsin–Madison, Room H6/354, CSC, 600 Highland Avenue, Madison, Wisconsin, USA 53792.
CTJ{at}medicine.wisc.edu
In this issue of the Journal, the study by Etheridge et al. (1) reports results of a clinical trial of raising the serum potassium concentration as a novel approach to QT interval shortening in patients with congenital long QT syndrome (LQTS). The investigators studied patients with Human Ether-a-go-go-Related Gene (HERG or KNCH2) potassium channel mutations, which is the most commonly affected gene in LQTS. These investigators found that raising the serum potassium concentration an average of 1.2 mEq/l caused nearly a 100-ms decrease in the QTc interval and reduced QT dispersion. The QT interval shortening occurred in each of eight patients with six different HERG mutations. This was achieved by having patients take remarkable amounts of oral spironolactone and potassium. For the four-week duration of the trial, the therapy appeared to work and was well tolerated by the patients. The trial did not address long-term tolerability or potential side effects: it lacked a control group, and it was not powered to test for arrhythmia or mortality reduction. Furthermore, the investigators did not address how much shortening of the QT interval and QT dispersion might be desirable. The current report serves as an initial study for a longer-term trial.
The use of potassium to suppress cardiac arrhythmias and its effect on the QT interval is not new. Indeed, beginning nearly 100 years ago it was recognized that potassium supplementation could have arrhythmia-suppressing properties (2,3), and nearly 50 years ago it was shown directly to shorten underlying cardiac action potentials (4). The principal use of potassium was in correcting hypokalemia, yet it was recognized that increasing the potassium concentration within the normal range, or even above normal, occasionally diminished arrhythmias and could even treat experimental ventricular fibrillation successfully (5). In congestive heart failure (CHF), aldosterone causes myocardial and vascular fibrosis, direct vascular damage, baroreceptor dysfunction, and inhibition of uptake of norepinephrine by myocardium; blockade of these effects reduces morbidity and mortality in patients with class III and IV heart failure. The RALES trial studied 1,663 patients with an ejection fraction  35% who were randomized to receive spironolactone versus placebo. Almost all were taking angiotensin-converting enzyme inhibitors, loop diuretics, and digoxin, but only 10% of the patients were on a beta-blocker. In patients receiving spironolactone, there was a reduction in blood pressure, a lower incidence of hypokalemia, and an overall reduction of mortality by 30%. A large proportion of the deaths were sudden, and potentially an increase in serum potassium may have played a large role in reducing the incidence of malignant ventricular arrhythmias (6). Other clinical trials in CHF have shown that amiloride, also a potassium-sparing diuretic, raises serum potassium, shortens the QT interval, and reduces ventricular ectopy (7).
The treatment of LQTS patients by increasing the serum potassium concentration is founded in modern molecular electrophysiology. Originating from the identification of human analogues of a drosophilia (fruit fly) ion-channel gene (HERG) (8), HERG was shown to encode an ion channel with properties similar to the native rapidly activating delayed rectifier potassium channel (IKr) found in the human heart (9,10). One observation was its "paradoxical" response to increased extracellular potassium. In several laboratories it was shown that increasing extracellular potassium, which decreases the driving force for potassium ion movement across heart and other cell membranes, in fact caused the IKr amplitude to "paradoxically" increase, which will shorten action potentials.
Potassium as a chronic therapy for LQTS has obvious potential risks. It has a relatively narrow therapeutic margin of safety, and as long-term therapy it will require careful patient follow-up. Not every patient will easily tolerate the daily intake of large doses of potassium. Spironolactone has long-term side effects that potentially may limit its utility. Indeed, 10% of patients in the RALES trial developed gynecomastia. Nonetheless, this promising approach has the potential advantage of spanning the different gene defects involved in LQTS. It requires that HERG channels be intact and responsive to increased extracellular potassium.
As the molecular mechanisms causing congenital LQTS are understood, other novel clinical therapies may emerge into clinical practice. In patients with sodium channel mutations (LQT3, causing a persistent late inward current), sodium channel-blocking drugs such as flecainide cause QT interval shortening (11). This approach is limited to selected LQT3 patients. In contrast, in Brugada syndrome patients, where sodium current is reduced, flecainide therapy potentially may worsen the disease. The drug nicorandil, an adenosine triphosphate-sensitive potassium channel opener, has been shown to decrease slightly the QT interval in patients with LQTS, although it prolonged refractoriness (12). In LQT2 (HERG) channel mutations the "pharmacological rescue" of functional channels has been shown experimentally by the therapeutically available drug fexofenadine (13). This approach may offer a potentially well-tolerated treatment, but it will likely be gene-specific (HERG) and mutation-specific (protein trafficking-defective mutations). A novel benzodiazepine drug, L3, has been described that selectively increases the slowly activating delayed rectifier potassium current (IKs, defective in LQT1) to shorten action potentials and suppress triggered activity (14). As with the combination of potassium and spironolactone, L3 has the potential of spanning the different gene defects involved in LQTS; however, it is a new compound whose clinical development is uncertain. Finally, overexpression of HERG channels has been shown experimentally to shorten ventricular action potentials and suppress triggered activity (but also prolongs refractoriness) in a model of acquired LQTS (15). The clinical development of potentially exciting new and novel therapies is hampered, however, by our incomplete understanding of the complex polygenetic and molecular mechanisms of LQTS, and by diminished interest within the pharmaceutical industry for relatively rare congenital ion-channel diseases.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol 2003;42:1777–82
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