JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2003; 42:1777-1782, doi:10.1016/j.jacc.2003.07.006
© 2003 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Etheridge, S. P.
Right arrow Articles by Mason, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Etheridge, S. P.
Right arrow Articles by Mason, J. W.

CLINICAL RESEARCH: ELECTROPHYSIOLOGIC DISORDERS

A new oral therapy for long QT syndrome

Long-term oral potassium improves repolarization in patients with HERG mutations

Susan P. Etheridge, MD, FACC*,*, Steven J. Compton, MD, FACC{dagger}, Martin Tristani-Firouzi, MD* and Jay W. Mason, MD, FACC{ddagger}

* Primary Children's Medical Center and the Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA
{dagger} Alaska Heart Institute, Anchorage, Alaska, USA
{ddagger} Division of Cardiology, University of Kentucky, Lexington, Kentucky, USA

Manuscript received December 12, 2002; revised manuscript received July 6, 2003, accepted July 7, 2003.

* 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.
pcsether{at}ihc.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
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 IKr is 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 HERG mutations. 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.

Abbreviations and Acronyms
  HERG = human ether-a-go-go related gene
  IKr = rapidly activating delayed rectifier K+ current
  LQTS = long QT syndrome
  LQT2 = long QT syndrome type 2
  QTc = corrected QT interval

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). HERG encodes the channel that underlies the cardiac rapidly activating delayed rectifier K+ current, IKr (7,8). Modulation by extracellular potassium is a hallmark of IKr in myocytes and heterologously expressed HERG channels (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 IKr channel 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 HERG mutations (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.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
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 HERG mutations. 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 t test (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.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Table 1 describes the HERG nucleotide substitution, coding effect, and functional effect of the mutation in the eight subjects. Figure 1 depicts the location of the mutations within the HERG channel 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.


View this table:
[in this window]
[in a new window]
  		Table 1 Location and Functional Effects of HERG Mutations in Eight Study Patients

 


View larger version (30K):
[in this window]
[in a new window]
  		Figure 1 Topology of the HERG channel subunit and location of HERG mutations. Six membrane-spanning domains are depicted, with the pore helix located between the fifth and sixth transmembrane domains.

 

View this table:
[in this window]
[in a new window]
  		Table 2 Patient Demographic Data

 
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 V2 before 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).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2 The individual response of the corrected QT interval (QTc) to increased serum K+ in long QT syndrome type 2 (LQT2) subjects. Scatter plot of QTc intervals measured in lead V2 at baseline and after a four-week course of oral KCl and spironolactone. An increase in serum K+ from 4.0 ± 0.3 at baseline to 5.2 ± 0.3 mEq/l resulted in a decrease in QTc in all subjects.

 


View larger version (24K):
[in this window]
[in a new window]
  		Figure 3 The mean corrected QT interval (QTc) shortens in response to an elevation in serum K+. Graphic demonstration of the mean QTc intervals measured in ECG leads II, V2, and V4 at baseline and after increasing the serum K+ level with oral KCl and spironolactone. The treatment protocol was associated with a statistically significant decrease in QTc (p value = 0.002, 0.003, and 0.003 for leads II, V2, and V4, respectively, using the paired t test).

 


View larger version (23K):
[in this window]
[in a new window]
  		Figure 4 Relationship between individual serum K+ measurement and corrected QT interval (QTc). Scatter plot demonstrating a negative correlation between the QTc interval and serum K+ level from eight study patients (total of 81 determinations). Individual symbols represent a single study patient (Fig. 2). (r = –0.52, p < 0.0001 by linear mixed model analysis). The ECGs and serum electrolytes were obtained on the same day.

 

View this table:
[in this window]
[in a new window]
  		Table 3 Corrected QT Interval Variability (Lead V2) on Pre-Treatment Electrocardiograms

 
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 HERG are 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).



View larger version (86K):
[in this window]
[in a new window]
  		Figure 5 The effect of elevated serum K+ on T-wave morphology. Representative ECG tracings from study Patients 2, 4, 5, and 6, showing the improvements in repolarization and T-wave morphology after increasing serum K+. Values represent serum K+ levels at baseline and after four weeks of KCl and spironolactone therapy.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
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 IKr magnitude 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 HERG mutations. 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 HERG channel 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 HERG channel inactivation, resulting in an increase in channel availability (17,18). Either of these two mechanisms might increase the current magnitude through homomultimeric wild-type HERG channels 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 IKr was 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.

Study limitations.   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.

Clinical implications.   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 KCNQ1 and SCN5A subjects due to the presence of fully functional HERG channels. 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.


   Acknowledgments
 
We thank Patricia Whitaker for her assistance with the ECG testing. We also thank our patients with LQTS for their generous time and support.


   Footnotes
 
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.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol. 2000;36:1–12[Abstract/Free Full Text]
  2. Schwartz PJ, Locati E. The idiopathic long QT syndrome: pathogenetic mechanisms and therapy. Eur Heart J. 1985;6(Suppl D):103–114
  3. Moss AJ. Management of patients with the hereditary long QT syndrome. J Cardiovasc Electrophysiol. 1998;9:668–674[Medline]
  4. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101:616–623[Abstract/Free Full Text]
  5. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569–580[CrossRef][Medline]
  6. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102:1178–1185[Abstract/Free Full Text]
  7. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307[CrossRef][Medline]
  8. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92–95[Abstract/Free Full Text]
  9. Sanguinetti MC, Jurkiewicz NK. Role of external Ca++ and K+ in gating of cardiac delayed rectifier K+ currents. Pflugers Arch. 1992;420:180–186[CrossRef][Medline]
  10. Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium. Circulation. 1996;94:1018–1022[Abstract/Free Full Text]
  11. Linker NJ, Colonna P, Kekwick CA, Till J, Camm AJ, Ward DE. Assessment of QT dispersion in symptomatic patients with congenital long QT syndromes. Am J Cardiol. 1992;69:634–638[CrossRef][Medline]
  12. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000;102:2849–2855[Abstract/Free Full Text]
  13. International Long-QT Syndrome Registry Research GroupZareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. N Engl J Med. 1998;339:960–965[Abstract/Free Full Text]
  14. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103:89–95[Abstract/Free Full Text]
  15. Numaguchi H, Johnson JP Jr, Petersen CI, Balser JR. A sensitive mechanism for cation modulation of potassium current. Nat Neurosci. 2000;3:429–430[CrossRef][Medline]
  16. Mullins FM, Stepanovic SZ, Desai RR, George AL Jr, Balser JR. Extracellular sodium interacts with the HERG channel at an outer pore site. J Gen Physiol. 2002;120:517–537[Abstract/Free Full Text]
  17. Wang S, Morales MJ, Liu S, Strauss HC, Rasmusson RL. Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes. FEBS Lett. 1996;389:167–173[CrossRef][Medline]
  18. Yang T, Snyders DJ, Roden DM. Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells. Circ Res. 1997;80:782–789[Abstract/Free Full Text]
  19. Sakmann B, Trube G. Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol. 1984;347:641–657[Abstract/Free Full Text]
  20. Rajamani S, Anderson CL, Anson BD, January CT. Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block. Circulation 2002;150:2830–5.
  21. Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, Brown AM. Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome. J Mol Cell Cardiol 2000;32:2327–37.
  22. Kagan A, Yu Z, Fishman GI, McDonald TV. The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. J Biol Chem 2000;275:11241–8.
  23. Nakajima T, Furukawa T, Tanaka T, et al. Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ Res 1998;83:415–22.
  24. Kupershmidt S, Yang T, Chanthaphaychith S, Wang Z, Towbin JA, Roden DM. Defective human Ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus. J Biol Chem 2002;277:27442–8.
  25. Coraboeuf E, Deroubaix E. Effect of a spirolactone derivative, sodium canrenoate, on mechanical and electrical activities of isolated rat myocardium. J Pharmacol Exp Ther. 1974;191:128–138[Abstract/Free Full Text]
  26. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy. Circulation. 1995;92:3381–3386[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Circ Arrhythmia ElectrophysiolHome page
A. J. Moss and I. Goldenberg
Importance of Knowing the Genotype and the Specific Mutation When Managing Patients With Long-QT Syndrome
Circ Arrhythmia Electrophysiol, August 1, 2008; 1(3): 219 - 226.
[Full Text] [PDF]

Home page
 Circ Arrhythmia ElectrophysiolHome page
G. M. Vincent
Genotyping Has a Minor Role in Selecting Therapy for Congenital Long-QT Syndromes at Present
Circ Arrhythmia Electrophysiol, August 1, 2008; 1(3): 227 - 233.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. B. Thomsen, P. G.A. Volders, J. D.M. Beekman, J. Matz, and M. A. Vos
Beat-to-Beat Variability of Repolarization Determines Proarrhythmic Outcome in Dogs Susceptible to Drug-Induced Torsades de Pointes
J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1268 - 1276.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
S. L. Venance, S. C. Cannon, D. Fialho, B. Fontaine, M. G. Hanna, L. J. Ptacek, M. Tristani-Firouzi, R. Tawil, R. C. Griggs, and the CINCH investigators
The primary periodic paralyses: diagnosis, pathogenesis and treatment
Brain, January 1, 2006; 129(1): 8 - 17.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
W. Shimizu
The long QT syndrome: Therapeutic implications of a genetic diagnosis
Cardiovasc Res, August 15, 2005; 67(3): 347 - 356.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. Kang, X.-L. Chen, H. Wang, J. Ji, H. Cheng, J. Incardona, W. Reynolds, F. Viviani, M. Tabart, and D. Rampe
Discovery of a Small Molecule Activator of the Human Ether-a-go-go-Related Gene (HERG) Cardiac K+ Channel
Mol. Pharmacol., March 1, 2005; 67(3): 827 - 836.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Csanady
More on the history of arrhythmia in long QT syndrome
J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1339 - 1339.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon
Pharmacology of cardiac potassium channels
Cardiovasc Res, April 1, 2004; 62(1): 9 - 33.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Etheridge, S. P.
Right arrow Articles by Mason, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Etheridge, S. P.
Right arrow Articles by Mason, J. W.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK