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(Circulation. 1996;94:1018-1022.)
© 1996 American Heart Association, Inc.

Articles

Genetically Defined Therapy of Inherited Long-QT Syndrome

Correction of Abnormal Repolarization by Potassium

Steve J. Compton, MD; Robert L. Lux, PhD; Matthew R. Ramsey, BS; Katie R. Strelich, MD; Michael C. Sanguinetti, PhD; Larry S. Green, MD; Mark T. Keating, MD; Jay W. Mason, MD

the Division of Cardiology (S.J.C., R.L.L., M.R.R., K.R.S., M.C.S., L.S.G., M.T.K., J.W.M.), Cardiovascular Research and Training Institute (R.L.L.), Howard Hughes Medical Institute and Department of Human Genetics (M.T.K.), and Eccles Program in Human Molecular Biology and Genetics (M.C.S.), University of Utah (Salt Lake City).

Correspondence to Dr Jay W. Mason, Division of Cardiology 4A-100, University of Utah Health Sciences Center, Salt Lake City, UT 84132-0001. E-mail jay.mason@hsc.utah.edu.

	Abstract

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Background Many members of families with inherited long-QT (LQT) syndrome have mutations in HERG, a gene encoding a cardiac potassium channel that is modulated by extracellular potassium. We hypothesized that an increase in serum potassium would normalize repolarization in these patients.

Methods and Results We studied seven subjects with chromosome 7–linked LQT syndrome and five normal control subjects. Repolarization was measured by ECG and body surface potential mapping during sinus rhythm, exercise, and atrial pacing, before and after serum potassium increase. Potassium administration improved repolarization in the LQT syndrome. At baseline, LQT subjects differed from control subjects: resting corrected QT interval (QT_c, 627±90 versus 425±25 ms, P=.0007), QT_c dispersion (133±62 versus 36±9 ms, P=.009), QT/RR slope (0.35±0.08 versus 0.24±0.07, P=.04), and global root-mean-square QT interval (RMS-QT_c; 525±68 versus 393±22, P=.002). All LQT subjects had biphasic or notched T waves. After administration of potassium, the LQT group had a 24% reduction in resting QT_c interval (from 617±92 to 469±23 ms, P=.004) compared with a 4% reduction among control subjects (from 425±25 to 410±45 ms, P>.05). The reduction was significantly greater in LQT subjects (P=.018). QT dispersion became normal in LQT subjects and did not change in control subjects. The slope of the relation between QT interval and cycle length (QT/RR slope) decreased toward normal. T-wave morphology improved in six of seven LQT subjects. The LQT group had a greater reduction in RMS-QT_c than control subjects (P=.04).

Conclusions An increase in serum potassium corrects abnormalities of repolarization duration, T-wave morphology, QT/RR slope, and QT dispersion in patients with chromosome 7–linked LQT.

Key Words: genes • long-QT syndrome • potassium

	Introduction

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Inherited long-QT (LQT) syndrome is characterized by prolongation of the QT interval on the ECG, syncope, and sudden death as a result of ventricular tachyarrhythmias.^{1 2 3 4} Other repolarization abnormalities identified in the syndrome include increased QT-interval dispersion on the 12-lead ECG,^{5 6 7} abnormal ST-T–wave morphology,^{8 9} T-wave alternans,¹⁰ an abnormal slope of the relation of QT interval to cycle length (QT/RR interval slope),^{11 12 13} and an abnormal QRST isoarea distribution.¹⁴

Current therapies include ß-adrenergic blockade,^{15 16} permanent pacing,^{17 18} and left cardiac sympathetic denervation,¹⁹ but these therapies have not been tested in prospective, randomized trials or proved to be effective in preventing sudden cardiac death. Furthermore, none of these therapies correct the repolarization abnormality.

Chromosome 7–linked LQT results from mutations in HERG,²⁰ a recently cloned gene²¹ that encodes subunits that form the human I_Kr potassium channel. Modulation by extracellular potassium is a hallmark of I_Kr in myocytes and HERG channels expressed in Xenopus oocytes.^{22 23} Outward current is paradoxically increased by increasing extracellular potassium within the physiological range, despite a decrease in the electrochemical gradient. Thus, we hypothesized that impaired I_Kr function could be improved by exogenously administered potassium, resulting in increased outward potassium current and shortening of repolarization. To investigate this hypothesis, we increased serum potassium in patients with chromosome 7–linked LQT syndrome and in normal control subjects and compared the resultant changes in repolarization.

	Methods

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Subjects
The research protocol was reviewed and approved by the University of Utah Institutional Review Board, and informed consent was obtained from participants. We studied seven adults from four families with chromosome 7–linked LQT syndrome and compared them with five normal control subjects without cardiovascular disease. No subjects had structural heart disease. Six of the subjects with LQT were taking ß-adrenergic antagonists; the seventh had an implanted dual-chamber pacemaker. None of the subjects were taking other medications known to affect cardiac repolarization.

Serum electrolyte levels were measured, and exercise stress testing was performed under standard Bruce protocol. Exercise data were excluded from analysis in one LQT subject whose heart rate did not increase >5 bpm. A 5F pacing catheter was placed in the coronary sinus via a right internal jugular venous sheath (except for one subject who underwent transesophageal pacing and another who refused pacing), and standard 12-lead ECG and a 32-lead body surface mapping system²⁴ were attached to the thorax. We chose to pace these patients to allow accurate determination of QT intervals after fixed pacing rates and to determine whether potassium therapy would be effective at faster cycle lengths. We used atrial pacing to allow accurate determination of QT intervals during identical heart rates and to determine whether potassium therapy would be effective at faster rates. The atrium was paced for 2 minutes at a rate slightly above the spontaneous rate before ECG, and body surface mapping recordings were obtained. ECG recordings were made at a paper speed of 25 mm/s. If the pacing artifact approached the T wave, the last paced beat was recorded to acquire an unperturbed TU. The cycle length of pacing was then reduced progressively by 50-ms decrements. Pacing and recording were repeated at each decrement until 1:1 atrioventricular conduction failed.

The subjects then received oral spironolactone (200 mg, followed by 100 mg every 2 hours) for the remainder of the protocol. Potassium chloride infusion was begun at 20 mEq/h. The subjects were given oral potassium chloride (60 mEq every 2 hours). The serum potassium level, an ECG, and body surface mapping during pacing at 100 bpm were obtained every 30 to 60 minutes until serum potassium had increased by 1.5 mEq/L above baseline. The complete pacing protocol was then repeated. The pacing catheter, venous sheath, and body surface mapping electrodes were then removed, and exercise stress testing was repeated while the serum potassium level was still elevated.

Data Analyses
The end of the QT interval was defined as the intersection of a tangent to the steepest downslope of the dominant repolarization wave with the isoelectric line.²⁵ The QT interval was defined as the longest interval of the 12 leads measured. When the P wave encroached on the T wave at shorter cycle lengths, measurements were taken on the QRST complex of the last paced beat after abrupt cessation of atrial pacing. Leads were excluded from analysis only when the end of the T wave was not clearly distinguishable. No more than 2 leads were excluded from any 12-lead ECG in the analyses of resting or paced rhythm, and no more than 5 leads were excluded in the treadmill exercise data.

T-wave morphology was defined as biphasic when two distinct components of opposite polarity were present and as notched when a second positive deflection interrupted the descending phase of the T wave.⁹

QT dispersion was defined as the difference between the longest and the shortest QT interval among the 12 leads in which it could be reliably measured. We also calculated the coefficient of variation for QT intervals in each ECG.⁷ Bazett's formula²⁶ was applied to QT intervals for calculation of the QT dispersion (QT_c dispersion) and the coefficient of variation of the QT interval.

Global repolarization was measured by body surface potential mapping. Global root-mean-square (RMS) signals were obtained by calculating the RMS voltage for all 32 body surface leads. The RMS-QT interval was measured digitally by an algorithm that defined the end of the interval as the intersection of a tangent to the steepest downslope of the global RMS T wave with the isoelectric line.

Statistical Analysis
Continuous variables are presented as geometric mean±SD. Student's two-tailed t test for paired data was used to compare values within subject groups; one-way ANOVA was used to compare values between subject groups. Repeated-measures ANOVA was used to evaluate group (LQT versus control) and treatment (baseline versus potassium) differences and to account for the measurements at multiple cycle lengths. Statistical significance was defined as P<.05. Statistical significance did not change when skewed variables were reanalyzed with the use of log-transformed data to normalize distribution. Analysis of QT/RR slopes during exercise was carried out using least squares analysis for each subject. RMS-QT_c was analyzed by multiple pairwise t tests instead of repeated-measures ANOVA because of the limited number of subjects with measurements at all cycle lengths.

	Results

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Baseline Clinical and ECG Characteristics
Repolarization was abnormal in the LQT group but not in control subjects. The LQT group had longer QT intervals, longer RMS-QT intervals, and greater QT dispersion⁷ at rest compared with control subjects (Table 1). The T waves were normal in control subjects but notched (n=6) or biphasic (n=1) in LQT subjects. During pacing, QT dispersion was significantly greater in LQT than normal subjects, except during pacing at a cycle length of 800 ms (P=.10). Dispersion did not correlate with paced cycle length in either group (r<.1). The age, sex distribution, resting heart rate, and potassium level were similar in the LQT and control groups. The clinical characteristics of the LQT group are outlined in Table 2.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of LQT Syndrome and Control Subjects

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of Long QT Syndrome Subjects

Effect of Potassium on QT Interval and Global Repolarization
The total potassium dose was 162±67 mEq in the LQT group and 104±5 mEq in the control group (P>.05). After administration of potassium, serum potassium in the LQT group rose by 1.4±0.7 mEq/L compared with 2.0±0.8 mEq/L in the control group (P>.05). The QT interval decreased significantly in the LQT group after potassium administration (P=.03 by repeated-measures ANOVA, Fig 1). QT-interval reduction was significant at all except the shortest paced cycle length. In the control group, QT-interval reduction with potassium was not statistically significant except at a pacing cycle length of 800 ms.

View larger version (14K): [in this window] [in a new window]   Figure 1. Mean±SEM QT interval at baseline and after administration of potassium. *P<.05 and **P<.01 indicate significant QT reduction after potassium administration.

In sinus rhythm, the QT_c interval decreased 24% (159±94 ms) in LQT subjects and 4% (15±22 ms) in control subjects (P<.012). QT_c variation within the LQT group (as measured by QT_c standard deviation) dropped with potassium at every cycle length (eg, 90 to 23 ms in sinus rhythm); this effect was not observed in the control group.

Total exercise times and maximum heart rates were similar in the LQT and control groups. During exercise at baseline, the QT/RR slope was steeper in the LQT group than for control subjects (0.34±0.08 versus 0.24±0.07, P=.038). After potassium administration, the mean QT/RR slope of the LQT group was no longer significantly different from that of control subjects (0.27±0.11 versus 0.20±0.09, P=.26).

LQT patients had significant reductions in RMS-QT and RMS-QT_c intervals at rest and at all paced cycle lengths (Table 3). Control patients had significant reductions in RMS-QT interval with potassium at all paced cycle lengths. This reduction was not significant in sinus rhythm. The reduction in the RMS-QT_c interval was greater in the LQT group than in control subjects at all cycle lengths and was statistically significant during sinus rhythm (P=.04).

View this table: [in this window] [in a new window]   Table 3. RMS-QTc Interval Changes

Effect of Potassium on QT Dispersion and T-Wave Morphology
The LQT group had significant reductions in resting QT dispersion (P<.006) and the coefficient of variation of the QT interval (P<.02, Table 4); these reductions were significant during pacing at all except the fastest rate (Fig 2). After administration of potassium, QT dispersion among LQT subjects was no longer significantly greater than that in control subjects. Control patients had no significant change in QT dispersion at any cycle length after administration of potassium.

View this table: [in this window] [in a new window]   Table 4. QTc Dispersion Changes

View larger version (12K): [in this window] [in a new window]   Figure 2. Effect of potassium on resting QT dispersion. Each pair of points represents resting QT dispersion in the same individual at baseline and after potassium administration. Open-ended lines represent LQT subjects; circle-ended lines represent control subjects.

Potassium administration led to resolution of notched T waves in five of six patients (see, for example, Fig 3), and the biphasic T waves in the seventh subject became monophasic. Control patients developed typical progressive T-wave peaking as the serum potassium concentration increased.

View larger version (14K): [in this window] [in a new window]   Figure 3. Effect of potassium on resting QT morphology. ECG tracings from LQT subject 3 during sinus rhythm at baseline and after potassium administration.

	Discussion

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In the present study, we show that potassium therapy improves repolarization in chromosome 7–linked LQT syndrome. The proposal to apply this therapy was dependent on the molecular genetic discovery that mutations in HERG cause chromosome 7–linked LQT syndrome.²¹ That discovery led to physiological studies establishing that HERG encodes the I_Kr channel protein.^{23 27} That knowledge led to our plan to take advantage of an unusual behavior of I_Kr: it is activated by an increase in potassium, thereby reducing the duration of repolarization. With the exception of a recent study by Schwartz et al²⁸ in the setting of chromosome 3–associated LQT, specific therapy in inherited cardiac diseases^{29 30 31} has not depended on molecular genetic information. Although our therapeutic strategy was defined by the specific genetic defect, the data presented do not prove that potassium therapy would be effective solely in chromosome 7–linked LQT syndrome.

The reduction in QT_c interval seen in the present study was greater than that achieved with other published therapies. ß-Adrenergic blockers have not been subjected to controlled trials in this syndrome but are thought to reduce symptoms and the risk of sudden death. However, these medications have not been shown to shorten the QT_c interval. Left cardiac sympathetic denervation reduced QT_c by only 6% to 8%.¹⁹ A maximum QT_c reduction of 11% has been reported during permanent pacing.^{17 18}

Abnormal T-wave morphology is a diagnostic criterion for inherited LQT syndrome³² and may change with ß-blockade.^{9 33} Biphasic and notched T waves have been associated with abnormal echocardiographic findings,³⁴ syncope, and cardiac arrest.⁹ Resolution of the bifid T wave was seen in two of eight patients treated with ß-blockers⁹ compared with six of seven subjects in the present study.

Several other investigators^{5 6 7} reported increased QT dispersion in LQT syndrome before the availability of genotyping. ß-Blockade did not change resting QT dispersion in two studies,^{5 35} although an exercise-induced increase in QT_c dispersion was prevented with the use of esmolol.³⁵ The only therapy reported to reduce resting QT dispersion is left cardiac sympathetic denervation.⁷ Dispersion remained greater with this long-term therapy than we observed after short-term potassium administration (78±45 versus 42±28 ms).

Our findings might be explained by increased modulation of I_Kr by potassium in the setting of ß-adrenergic blockade because ß-blocking medications were being used by most of the LQT subjects and none of the control subjects. However, we are unaware of published data that suggest this effect, and we demonstrated comparable QT shortening in the one LQT patient who was not taking ß-adrenergic–blocking medication.

The genetic abnormality in LQT has been mapped in separate pedigrees to three additional loci: chromosome 11p15.5,³⁶ chromosome 3p21-24,³⁷ and chromosome 4q25-27.³⁸ Linkage and mutational analyses have demonstrated that mutations in SCN5A, the cardiac sodium channel, cause chromosome 3–linked LQT syndrome.³⁸ Further understanding of the physiological abnormalities of these diseases will direct future therapies; for example, sodium channel blockade has been proposed for treatment of the chromosome 3–linked disorder.²⁸

The short-term nature of this study does not permit conclusions to be made about the possible benefits of long-term potassium therapy. A long-term trial of potassium therapy is necessary to determine its potential for reducing symptoms and prolonging survival in chromosome 7–linked LQT syndrome.²⁸ Potassium therapy may also be effective in the treatment of some acquired LQT syndromes.³⁹

	Acknowledgments

 
This work was supported by the Hewlett-Packard Fellowship Program; a grant (P50-HL-52338) from the National Heart, Lung, and Blood Institute; and a grant (M01-RR-00064) from the National Center for Research Resources. We are indebted to Kathryn W. Timothy and G. Michael Vincent, MD, for their thoughtful advice and their assistance in identifying LQT subjects. We thank Mary Jo Ausman, RN, for assistance with the stress tests. We especially thank the LQT and control subjects for their time and support.

Received December 28, 1995; revision received February 28, 1996; accepted May 19, 1996.

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				X. H.T. Wehrens, M. A. Vos, P. A. Doevendans, and H. J.J. Wellens Novel Insights in the Congenital Long QT Syndrome Ann Intern Med, December 17, 2002; 137(12): 981 - 992. [Abstract] [Full Text] [PDF]

				F. M. Mullins, S. Z. Stepanovic, R. R. Desai, A. L. George Jr., and J. R. Balser Extracellular Sodium Interacts with the HERG Channel at an Outer Pore Site J. Gen. Physiol., September 30, 2002; 120(4): 517 - 537. [Abstract] [Full Text] [PDF]

				I. Splawski, K. W. Timothy, M. Tateyama, C. E. Clancy, A. Malhotra, A. H. Beggs, F. P. Cappuccio, G. A. Sagnella, R. S. Kass, and M. T. Keating Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia Science, August 23, 2002; 297(5585): 1333 - 1336. [Abstract] [Full Text] [PDF]

				M. Chinushi, H. Kasai, M. Tagawa, T. Washizuka, Y. Hosaka, Y. Chinushi, and Y. Aizawa Triggers of ventricular tachyarrhythmias and therapeutic effects of nicorandil in canine models of LQT2 and LQT3 syndromes J. Am. Coll. Cardiol., August 7, 2002; 40(3): 555 - 562. [Abstract] [Full Text] [PDF]

				X. Xu, J. J. Salata, J. Wang, Y. Wu, G.-X. Yan, T. Liu, R. A. Marinchak, and P. R. Kowey Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H664 - H670. [Abstract] [Full Text] [PDF]

				F. J He and G. A MacGregor Fortnightly review: Beneficial effects of potassium BMJ, September 1, 2001; 323(7311): 497 - 501. [Full Text] [PDF]

				K J Paavonen, H Swan, K Piippo, L Hokkanen, P Laitinen, M Viitasalo, L Toivonen, and K Kontula Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome Heart, July 1, 2001; 86(1): 39 - 44. [Abstract] [Full Text] [PDF]

				S. G. Priori, R. Bloise, and L. Crotti The long QT syndrome Europace, January 1, 2001; 3(1): 16 - 27. [PDF]

				L. Zhang, K. W. Timothy, G. M. Vincent, M. H. Lehmann, J. Fox, L. C. Giuli, J. Shen, I. Splawski, S. G. Priori, S. J. Compton, et al. Spectrum of ST-T-Wave Patterns and Repolarization Parameters in Congenital Long-QT Syndrome : ECG Findings Identify Genotypes Circulation, December 5, 2000; 102(23): 2849 - 2855. [Abstract] [Full Text] [PDF]

				C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]

				I. Splawski, J. Shen, K. W. Timothy, M. H. Lehmann, S. Priori, J. L. Robinson, A. J. Moss, P. J. Schwartz, J. A. Towbin, G. M. Vincent, et al. Spectrum of Mutations in Long-QT Syndrome Genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 Circulation, September 5, 2000; 102(10): 1178 - 1185. [Abstract] [Full Text] [PDF]

				H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]

				W. Shimizu and C. Antzelevitch Effects of a K+ Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome Circulation, August 8, 2000; 102(6): 706 - 712. [Abstract] [Full Text] [PDF]

				C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]

				J C Hancox, K C R Patel, and J V Jones Antiarrhythmics---from cell to clinic: past, present, and future Heart, July 1, 2000; 84(1): 14 - 24. [Full Text] [PDF]

				P. C Viswanathan and Y. Rudy Pause induced early afterdepolarizations in the long QT syndrome: a simulation study Cardiovasc Res, May 1, 1999; 42(2): 530 - 542. [Abstract] [Full Text] [PDF]

				M. Berthet, I. Denjoy, C. Donger, L. Demay, H. Hammoude, D. Klug, E. Schulze-Bahr, P. Richard, H. Funke, K. Schwartz, et al. C-terminal HERG Mutations : The Role of Hypokalemia and a KCNQ1-Associated Mutation in Cardiac Event Occurrence Circulation, March 23, 1999; 99(11): 1464 - 1470. [Abstract] [Full Text] [PDF]