Author + information
- Received December 12, 2002
- Revision received July 6, 2003
- Accepted July 7, 2003
- Published online November 19, 2003.
- Susan P Etheridge, MD, FACC*,* (, )
- Steven J Compton, MD, FACC†,
- Martin Tristani-Firouzi, MD* and
- Jay W Mason, MD, FACC‡
- ↵*Reprint requests and correspondence:
Dr. Susan P. Etheridge, University of Utah and Primary Children's Medical Center, 100 North Medical Drive, Salt Lake City, Utah 84113, USA.
Objectives We sought to determine whether oral potassium supplementation safely increases serum K+and results in sustained improvement of repolarization parameters in long QT syndrome type 2 (LQT2) subjects.
Background Mutations in HERG(LQT2), the gene encoding the rapid delayed rectifier K+current IKr, account for a significant proportion of congenital long QT syndrome (LQTS). The magnitude of IKris paradoxically increased by an increase in extracellular K+. We tested the hypothesis that long-term oral potassium supplementation results in a mild, sustainable increase in serum K+that improves repolarization abnormalities in subjects with LQT2.
Methods After an initial evaluation consisting of electrocardiography, electrolytes, blood urea nitrogen, and creatinine, escalating doses of potassium chloride (KCl) and spironolactone were administered to eight subjects with six distinct HERGmutations. Medications were continued for four weeks, at which time, the final evaluation was undertaken. Beta-adrenergic blocking therapy was maintained.
Results The subjects ranged in age from 11 to 52 years. The average daily KCl and spironolactone dose was 3.3 ± 1.5 mEq/kg and 3.5 ± 1.2 mg/kg, respectively, and this regimen resulted in an increase in serum K+from 4.0 ± 0.3 to 5.2 ± 0.3 mEq/l. There were no serious complications associated with therapy. The increase in serum K+resulted in a decrease in the corrected QT interval from 526 ± 94 to 423 ± 36 ms (mean ± SD; lead V2). Both QT dispersion and T-wave morphology improved in most subjects.
Conclusions Long-term oral potassium administration increases serum K+in patients with LQT2. This can be achieved safely and results in improvement in repolarization. Further studies are warranted to determine whether this will reduce the incidence of life-threatening events in LQTS patients.
Congenital long QT syndrome (LQTS) is an inherited disorder of myocellular repolarization characterized by electrocardiographic (ECG) abnormalities, syncope, and sudden death (1). Mortality may approach 50% in untreated, symptomatic individuals (2). Although beta-adrenergic blocking drugs are the mainstay of therapy, their use has only been validated by observational and retrospective studies (3,4). Other therapies for LQTS include permanent pacing, left cardiac sympathetic denervation, and defibrillator implantation (1). None of these therapies addresses the fundamental differences in the molecular pathogenesis of LQTS. Molecular genetic studies have revealed that LQTS is a heterogeneous disorder caused by mutations in several cardiac ion channel genes (5). Mutations in HERG(LQTS type 2, or LQT2) account for 45% of the LQTS mutations identified to date (6). HERGencodes the channel that underlies the cardiac rapidly activating delayed rectifier K+current, IKr(7,8). Modulation by extracellular potassium is a hallmark of IKrin myocytes and heterologously expressed HERGchannels (7,9). Outward current is paradoxically increased, despite a decrease in the electrochemical gradient, by increasing extracellular K+within the physiologic range. With this in mind, we hypothesized that impaired IKrchannel function could be improved by exogenously administered potassium, resulting in increased outward K+current and shortening of repolarization. Indeed, an early increase in serum K+by intravenous potassium chloride (KCl) and oral spironolactone resulted in a reduction in the resting corrected QT interval (QTc) and normalization of QT dispersion and the QT/RR slope in subjects with HERGmutations (10).
The aim of this study was to determine the safety, feasibility, and efficacy of long-term oral potassium supplementation in LQT2 subjects. Therapy with KCl and spironolactone resulted in a sustained, mild increase in serum K+from 4.0 ± 0.3 to 5.2 ± 0.3 mEq/l, with no adverse events. The increase in serum K+was associated with a decrease in QTc from 526 ± 94 to 423 ± 36 ms (lead V2). QT dispersion also improved in all eight subjects. This study underscores the potential benefit of potassium supplementation as a novel treatment strategy for LQTS. Our findings serve as the basis for a larger study powered to determine the effect of this therapy on the improvement in cardiac event rates.
The study was reviewed and approved by the University of Utah's Institutional Review Board. Written, informed consent was obtained. We prospectively studied eight patients from six families with HERGmutations. No subject had structural heart disease. No changes were made in the study participant's prior therapy while taking part in this protocol. Six subjects, including four children, were taking beta-blockers. One adult had a permanent atrial pacemaker in place due to intolerance of beta-blockers. A 52-year-old asymptomatic patient was not receiving therapy.
Baseline testing included an ECG, 24-h Holter monitor, exercise treadmill study (standard Bruce protocol), serum pregnancy test, serum electrolytes, blood urea nitrogen, and creatinine. After the baseline evaluation was completed, oral KCl and spironolactone therapy was initiated. The starting dose of KCl was 1.5 mEq/kg (maximum starting dose 20 mEq) every 12 h and spironolactone 1.5 mg/kg (maximum 100 mg) every 12 h. The KCl dose was increased by 0.5-mEq/kg increments alternating with 0.5-mg/kg increases in the dose of spironolactone every 48 to 72 h. The target serum K+level was 1.5 mEq/l above baseline. Serum electrolytes, blood urea nitrogen, and creatinine levels were obtained every 48 to 72 h and before increases in the medication dose. Once the target serum K+level was reached and maintained at steady-state for three consecutive determinations over a six- to nine-day period, the frequency of blood testing was decreased to weekly for the four-week maintenance period. At the conclusion of the four-week maintenance phase of the study, the blood tests and ECG were repeated.
The ECGs were analyzed manually in a blinded fashion. The QT interval was defined as the intersection of a tangent to the steepest down-slope of the dominant repolarization wave with the isoelectric baseline. The T waves were rated as biphasic when two distinct components of opposite polarity were present. The T-wave morphology was rated as notched when a second positive deflection interrupted the descending phase of the T wave. QT dispersion was defined as the difference between the longest and shortest QT interval (11)and was measured in a minimum of eight ECG leads.
Statistical analysis was performed using the Student two-tailed ttest (SigmaStat version 2.03, SPSS Inc., Chicago, Illinois) and a linear mixed model analysis (S-Plus version 6.0, Insightful, Seattle, Washington). A p value <0.05 was required for statistical significance. Data are presented as the mean ± SD.
Table 1describes the HERGnucleotide substitution, coding effect, and functional effect of the mutation in the eight subjects. Figure 1depicts the location of the mutations within the HERGchannel subunit. Functional characterization has been reported for six of eight mutations, with the majority of mutations causing dominant-negative effects by altering protein processing and trafficking. Demographic data, medication and genetic information, and serum K+levels are detailed in Table 2. The average doses of KCl and spironolactone required to attain the target serum K+were 3.3 ± 1.5 mEq/kg and 3.5 ± 1.2 mg/kg, respectively, resulting in a mean increase in serum K+of 1.2 mEq/l. Serum K+values ≥6 mEq/l occurred on three occasions in three patients, with the maximum measured level of 6.2 mEq/l. No complications were described. Overall, the therapy was well tolerated without significant side effects. One subject complained of mild muscle cramps, and another experienced orthostatic dizziness that improved with increased fluid intake. Renal function measurements remained stable throughout the trial.
An increase in serum K+resulted in a decrease in the resting QTc in all subjects (Fig. 2). The three subjects with the longest QTc experienced the greatest reduction in QTc (Patient 2: 684 to 496 ms; Patient 5: 638 to 441 ms; and Patient 7, 560 to 408 ms in QTc lead V2before and after therapy). There was no apparent correlation between the location of the mutation and the effect of QTc shortening (Table 1, Fig. 2). The mean QTc, as measured in leads II, V2, and V4, was significantly reduced after therapy with KCl and spironolactone (Fig. 3). For 81 ECG recordings and serum K+determinations, the QTc correlated inversely with serum K+(r = −0.52, p < 0.0001 by linear mixed model analysis) (Fig. 4). To assess QTc variability within the study population, we analyzed all available ECGs obtained before therapy. Although there was some variability in the measured QTc, the degree of variability was less than the decrease in QTc noted at the completion of therapy (Table 3).
QT dispersion also significantly improved in the study patients. The QT dispersion at baseline was 100 ± 54 ms and decreased to 41 ± 16 ms at the end of the study period (p = 0.03). Mutations in HERGare associated with a distinctive T-wave morphology (12). The ECGs of all eight study patients demonstrated the typical bifid or notched appearance of the T-wave. An elevation in serum K+resulted in normalization of the abnormal T-wave morphology in four of eight subjects (Fig. 5).
The application of molecular genetics to cardiovascular disease has allowed the identification of mutations in ion channel genes as the cause of LQTS. The specific genotype influences the characteristics of the clinical phenotype, including the arrhythmia trigger, frequency of life-threatening events, and T-wave morphology (12–14). The discovery of a distinct molecular basis for LQTS has fostered a hope for specific therapy directed at the gene defect.
The rationale for the current study is based on the observation that the IKrmagnitude increases paradoxically with increased extracellular K+, that is, despite a decrease in the chemical driving force. We hypothesized that increasing serum K+within the physiologic range would augment the repolarizing current and result in improvements in repolarization parameters in individuals with HERGmutations. We previously reported that an early increase in serum K+achieved by intravenous KCl reduced the QTc interval by 24% and improved repolarization parameters in LQT2 subjects (10). The current study demonstrates that a sustainable, mild increase in serum K+can be safely maintained by oral potassium supplementation and spironolactone. The increase in serum K+was associated with a significant reduction in QTc and QT dispersion in all subjects, as well as normalization of the T-wave morphology in one-half of the subjects. A dramatic decrease in QTc with elevated serum K+was observed in three individuals. The improvement in repolarization parameters achieved in this study suggests that oral KCl and spironolactone may be effective adjunctive therapy, together with beta-blockers, for the treatment of LQTS.
The precise mechanism whereby an increase in serum K+results in shortening of the QT interval in study patients is not known. The primary mechanism of HERGchannel sensitivity to extracellular K+is relief of the channel block by extracellular Na+(15,16). Additionally, increased extracellular K+induces a depolarizing shift in the voltage dependence of HERGchannel inactivation, resulting in an increase in channel availability (17,18). Either of these two mechanisms might increase the current magnitude through homomultimeric wild-type HERGchannels or heteromultimeric channels formed by wild-type and mutant subunits. The observation that HERG-specific T-wave dysmorphisms were normalized in some subjects suggests that IKrwas specifically increased. Alternatively, the increase in the repolarizing current may be due to an increased magnitude of the inward rectifier K+current, IK1, which is also paradoxically sensitive to increased extracellular K+(19). This hypothesis is more appealing given that the majority of the mutations cause a dominant-negative effect (Table 1) (20–24). It is unlikely that the improvement in repolarization parameters was due to a direct effect of spironolactone, given that spironolactone derivatives prolong the action potential duration in isolated cardiac preparations (25). However, we cannot exclude an indirect effect of aldosterone blockade on myocellular repolarization. Finally, increased serum potassium may exert secondary effects on other ion channels critical in modulating the cardiac action potential duration by altering the resting membrane potential of cardiomyocytes.
This is a small series with a relatively short-term duration of therapy and follow-up. Although the QTc was significantly shortened by treatment with oral potassium supplementation, it remains to be proven that changes in the QTc duration will translate into a decreased risk of symptoms or sudden cardiac death. It is also unclear whether the observed increase in serum K+is sustainable over the long run, without significant side effects. Although the side effects of therapy were minimal, the long-term safety and efficacy of oral KCl and spironolactone remain to be determined. Gynecomastia, a well-characterized side effect of high-dose spironolactone therapy, was not seen in our subjects, but may emerge as an important complication with prolonged therapy.
The results of the study must also be interpreted with caution, given the small sample size. Larger studies of greater duration are currently in progress to address the question of a long-term benefit of KCl therapy in LQTS.
Irrespective of the specific current that is modulated by extracellular K+, an increase in serum K+would be predicted to shorten repolarization in other forms of inherited LQTS. In fact, one could argue that the effect of increased serum K+may be greater in KCNQ1and SCN5Asubjects due to the presence of fully functional HERGchannels. In contrast, mexiletine is effective in shortening the QT interval only in individuals with mutations in SCN5A(LQT3), presumably by blocking the abnormally sustained plateau Na+current (26). Whether increasing serum K+proves to be effective in improving repolarization parameters in other forms of LQTS is currently under investigation.
We thank Patricia Whitaker for her assistance with the ECG testing. We also thank our patients with LQTS for their generous time and support.
☆ This work was supported by a grant from the Primary Children's Foundation and undertaken with the assistance of the Clinical Research Center at the University of Utah and with grant support (P-50 HL-52338) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
- human ether-a-go-gorelated gene
- rapidly activating delayed rectifier K+current
- long QT syndrome
- long QT syndrome type 2
- corrected QT interval
- Received December 12, 2002.
- Revision received July 6, 2003.
- Accepted July 7, 2003.
- American College of Cardiology Foundation
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