Heart & Lung 43 (2014) 541e545
Contents lists available at ScienceDirect
Heart & Lung journal homepage: www.heartandlung.org
Congenital long QT syndrome: Severe Torsades de pointes provoked by epinephrine in a digenic mutation carrier Vern Hsen Tan, MBBS, MRCP a, b, Henry Duff, MD a, Vikas Kuriachan, MD, FHRS a, Brenda Gerull, MD a, * a b
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada Cardiology Department, Changi General Hospital, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 June 2014 Received in revised form 22 July 2014 Accepted 24 July 2014 Available online 16 September 2014
Congenital Long QT Syndrome (LQTS) is a potentially lethal cardiac channelopathy characterized by prolongation of the corrected QT (QTc) interval on the surface electrocardiogram. The hallmark phenotypic features are syncope, seizure or sudden death, however most of the mutation carriers are asymptomatic and their risk for arrhythmias such as Torsade de pointes (TdP) are low. We report a case of Long QT syndrome with a corrected QT of 520 ms. For symptom e arrhythmia correlation a loop recorder was implanted with no documented arrhythmias. Epinephrine testing was performed for clinical risk stratification leading to Torsades de pointes during recovery phase which required defibrillation. Genetic testing discovered two pathogenic heterozygous mutations in two different LQT genes (SCN5A and KCNQ1). We propose a calcium homeostasis mechanism for the interaction of both mutations that exaggerated the phenotype, while each mutation by itself is causing a relatively modest phenotype. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Long QT syndrome Digenic mutation Torsade de pointes Epinephrine test
Introduction
Case report
Congenital Long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphic ventricular tachycardia (Torsades de Pointes; TdP), and sudden arrhythmic death.1 Digenic mutations (two mutations in different genes) or more often compound heterozygosity (two different mutations in the same gene) in LQTSrelated genes occurred in 2.0%e8.5% in published reports2e5 and are associated with significantly longer QTc intervals2,4,5 and more severe phenotypes.2,4 In this report, we describe a case where severe TdP occurred and subsequently two pathogenic heterozygous mutations in two different LQT genes have been identified suggesting an interaction between both mutated gene products.
The proband is a 39 year-old female patient who was referred to us based on a resting QTc of 520 ms (Fig. 1) after a second episode of likely vasovagal syncope. The first episode occurred 6 years prior to the current presentation and was suggestive of vasovagal syncope. The second, more recent episode occurred during micturition and was preceded with nausea and dizziness. Apart from a corrected QT of 520 ms, no other abnormalities were seen on ECG. All other cardiac investigations including an echocardiogram and exercise stress test were unremarkable. In view of a lack of symptomerhythm correlation, she had a loop recorder implanted and was put on Nadolol which was gradually increased to 60 mg, twice daily. However, over a period of 12 months she did not have any syncope spells and no documented arrhythmias on the loop recorder. The family history revealed that her paternal uncle died of drowning at the age of 16 and her nephew (maternal brother’s child) died suddenly at age of 4 months old. For further risk stratification and to determine the type of LQTS we decided to perform an epinephrine drug challenge and started an incremental epinephrine infusion from 0.05 mcg per kg per minute up to 0.2 mcg per kg per minute after stopping Nadolol for a week. The QTc interval was calculated using the Bazett formula (QT divided by the square root of RR interval). The QTc prior to the epinephrine challenge was 567 ms and prolonged up to a maximum QTc of 596 ms at 0.2 mcg per kg per minute epinephrine
Abbreviations: LQTS, Long QT syndrome; QTc, Corrected QT interval; TdP, Torsade de pointes; VT, Ventricular tachycardia; ICD, Implantable cardioverter defibrillator; LQT1, Long QT type 1; LQT3, Long QT type 3; PVCs, Premature ventricular complexes; WT, Wild-type; KCNQ1, Potassium voltage-gated channel, type 1; SCN5A, Sodium channel, voltage-gated, type V, alpha subunit. * Corresponding author. Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Health Research Innovation Centre, Room GAA08, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4Z6. Tel.: þ1 403 210 6908; fax: þ1 403 210 9350. E-mail address: [email protected] (B. Gerull). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2014.07.004
542
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
Fig. 1. Resting 12-lead ECG of the proband.
infusion (Fig. 2). There was no occurrence of tachyarrhythmia during the infusion. However, during the washout period (5 min after stopping epinephrine infusion), a gradually prolong ReR interval developed followed by frequent premature ventricular bigeminies preceded by augmented T-U complexes (Fig. 3A). This was followed by non-sustained ventricular tachycardia (VT) (again, the first ventricular tachycardia (VT) beat was preceded by an augmented TeU complex) culminating to persistent polymorphic VT resembling of Torsades de pointes (TdP) (Fig. 3B) which required defibrillation. Given her significant arrhythmias induced by epinephrine, she eventually underwent dual chamber implantable cardioverter defibrillator (ICD) implantation and was placed at lower rate of 70 beats per minute. A year after ICD implantation, she developed polymorphic VT (Fig. 4) treated successfully with an ICD shock which awoken her from sleep. Subsequent genetic testing of 12 genes known to cause LQTS identified two pathogenic mutations in two different proteins,
KCNQ1 (p.R518X) and SCN5A (p.F1617del), causing LQTS type 1 (LQT1) and LQTS type 3 (LQT3), respectively. Further family screening identified that the proband inherited one mutation from each parent (Fig. 5). Her mother carrying the KCNQ1 mutation showed a baseline QTc of 467 ms and significantly prolonged up to a maximum of 516 ms at 0.2 mcg/kg/min epinephrine infusion indicating clinical manifestation of LQTS (Fig. 2). The probands father showed a normal baseline QTc (390 ms) with a maximum QTc of 476 ms at 5 min after stopping epinephrine (Fig. 2). Both children of the proband had borderline QTc intervals of 450 ms and inherited one mutation each as shown in Fig. 4. All first degree relatives of the proband were asymptomatic. Discussion This case interestingly illustrates an LQT phenotype with mutations involving both KCNQ1 and SCN5A genes. Accordingly, our
Fig. 2. Comparison of ECGs (lead II) between the proband and her parents before and at maximum epinephrine dosage.
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
543
Fig. 3. (A) During epinephrine washout phase, frequent PVCs preceded by gradually prolonged ReR interval. Each PVC was preceded by an augmented TeU complex (a). (B) At 10 min during epinephrine washout phase, frequent PVCs preceded by augmented T-U complexes (b) in the setting of a long QTc culminating to develop Torsades de pointes.
discussion will focus on the utility of genetic testing and epinephrine testing as well as potential mechanism or interaction of both mutations. According to the Heart Rhythm Society and European Heart Rhythm Association expert consensus statement on genetic testing for channelopathies,6 genetic testing is recommended for patients with strong clinical index suspicion for an LQTS phenotype as seen in our case (resting 12 lead ECG showed prolonged QTc in the absence of reversible cause). The advent of genetic testing in particular for LQTS subtypes has important implications in diagnosis, prognosis as well as therapeutic management.6 However, the dilemma faced in this case is which mutation (LQT1 or LQT3) is the dominant one or how do they interfere with each other? The escalating dose of epinephrine introduced by the Mayo group was found to be particularly useful in diagnosing LQT1.7 However, there is no test available for risk stratification in patient with LQTS. In our patient, the epinephrine test was performed because it was thought to be helpful to further clarify her diagnosis (type of LQTS) and risk for arrhythmias without the knowledge of the results of genetic testing. It is interesting to note that frequent ventricular bigeminies and the first beat of polymorphic VT or TdP were consistently preceded by an augmented TeU complex (Fig. 3A
and B). In ventricular bigeminies complexes, the amplitude of the augmented TeU complex is gradually increased in subsequent beats which possibly indicates an imminent risk of TdP. Kirchhof et al showed that abnormal giant T-U waves separate TdP initiation in LQTS patients from premature ventricular complexes (PVCs) in other diseases and from other PVCs in LQTS patients. They further suggest that this may help to identify an imminent risk of onset of TdP.8 The rationale for the ICD implantation was based on the induction of TdP during the epinephrine washout in the setting of a documented long QTc. Moreover, about a year later, the patient had an ICD treated episode of TDP during sleep, a trigger which is typically observed in LQTS type 3. Epinephrine challenges in her parents were leading to QT prolongation, but no significant arrhythmias and both as well as her children where consequently treated with beta-blocker. Previous studies have examined the electrophysiologic effects of the individual mutations observed in the patients presented herein.9,10 Huang et al examined the electrophysiologic manifestations of the p.R518X mutation in KCNQ1.9 In the clinical study of p.R518X mutation, the phenotype was syncope and LQTS in the proband but nuclear family members carrying the same mutation
544
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
Fig. 4. ICD dot plot tracing (left upper corner) and intracardiac electrogram. Dot plot tracing shows the onset of ventricular arrhythmias as evidenced by ventricular rate > atrial rate. Intracardiac electrogram shows polymorphic ventricular tachycardia which was terminated by an ICD shock.
had no phenotype. The electrophysiologic characterization of the resultant IKs current-density was critically dependent on the ratio of wild-type (WT) to mutation-carrying monomers that were co-expressed in Xenopus oocytes. When mutant monomers were co-expressed with WT monomers at a 1:1 ratio there was no dominant negative effect however when the ratio of WT: mutation carrying monomers was 1:3 a dominant-negative impairment of IKs expression was observed. Interesting a subsequent study indicated that in the setting of calmodulin binding to KCNQ1 can exaggerate the phenotype of p.R518X resulting in a dominant negative phenotype. These data suggest that generally the p.R518X mutation produces a relative minor phenotype but that intracellular environmental features can exaggerate the phenotype. The phenotype induced by the isolated SCN5A mutation p.F1617del also produces a relatively modest phenotype.10 This mutation produces a negative shift in the sodium channel availability, steady state inactivation, of cardiac INa. The mutation also produces an increase in the late component of INa but this increase was statistically significant only at þ40 mV. At the plateau
potentials (0 mV) there was no significant difference. Single channel analysis showed some increase in channel open times at voltages >20 mV. At 0 mV they channel open times were equal to that seen in the þ/þ channel. These data indicate that the electrophysiologic consequences of the F1617del mutation are subtle and voltage-dependent. Thus, genetic/electrophysiologic modeling to replicate digenic mutation to study the electrophysiology effect might be difficult due to the subtleties of individual mutations. The single mutations taken in isolation produce modest phenotypes. However our proband carried both of these mutations (digenic). Is there a plausible mechanism to indicate why synergistic QT prolongation and propensity to Torsades could be observed in individuals simultaneously carrying both mutations? It seems plausible that the sodium channel mutation could induce an increase in late sodium current influx. Acting via the sodium calcium exchanger increased intracellular sodium leads to an increased calcium influx and thereby to SR calcium overload. When epinephrine was applied, epinephrine will increase the transmembrane calcium current resulting in exaggerated SR load and
Fig. 5. Family tree of the proband (arrow) together with the ECG phenotype and genotype.
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
calcium release. Moreover, epinephrine induced increases in intracellular calcium could alter Caþ2 calmodulin interaction with the KCNQ potassium channels resulting in synergistic prolongation of the QT interval. Consistent with the literature,11 this could exaggerate the phenotype. The limitation of this case report is clearly that this is just an example of one case and the patient’s family, and although it is consistent with the literature, it does not conclusively prove the concept, and would need to be replicated in other cases or ideally, a case series. Conclusion A digenic proband carrying mutations in both SCN5A and KCNQ1 manifests Torsades after epinephrine. Nuclear family members carrying either of the isolated mutations had no phenotypes. A calcium homeostasis mechanism for the interaction is proposed. Conflict of interest: None for all authors. References 1. Roden DM, George Jr AL, Bennett PB. Recent advances in understanding the molecular mechanisms of the Long QT syndrome. J Cardiovasc Electrophysiol. 1995;6:1023e1031.
545
2. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe Long-QT syndrome. Circulation. 2004;109:1834e1841. 3. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long qt syndrome genetic testing. Heart Rhythm. 2005;2:507e517. 4. Itoh H, Shimizu W, Hayashi K, et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010;7:1411e1418. 5. Lieve KV, Williams L, Daly A, et al. Results of genetic testing in 855 consecutive unrelated patients referred for Long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013;7:553e561. 6. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace. 2011;13:1077e1109. 7. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital Long-QT syndrome: Diagnostic accuracy of the paradoxical QT response. Circulation. 2006;113:1385e1392. 8. Kirchhof P, Franz MR, Bardai A, Wilde AM. Giant T-U waves precede Torsades de pointes in Long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol. 2009;54:143e149. 9. Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res. 2001;51:670e680. 10. Chen T, Inoue M, Sheets MF. Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delf1617. Am J Physiol Heart Circ Physiol. 2005;288:H2666eH2676. 11. Ghosh S, Nunziato DA, Pitt GS. KCNQ1 assembly and function is blocked by Long-QT syndrome mutations that disrupt interaction with calmodulin. Circ Res. 2006;98:1048e1054.
Contents lists available at ScienceDirect
Heart & Lung journal homepage: www.heartandlung.org
Congenital long QT syndrome: Severe Torsades de pointes provoked by epinephrine in a digenic mutation carrier Vern Hsen Tan, MBBS, MRCP a, b, Henry Duff, MD a, Vikas Kuriachan, MD, FHRS a, Brenda Gerull, MD a, * a b
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada Cardiology Department, Changi General Hospital, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 June 2014 Received in revised form 22 July 2014 Accepted 24 July 2014 Available online 16 September 2014
Congenital Long QT Syndrome (LQTS) is a potentially lethal cardiac channelopathy characterized by prolongation of the corrected QT (QTc) interval on the surface electrocardiogram. The hallmark phenotypic features are syncope, seizure or sudden death, however most of the mutation carriers are asymptomatic and their risk for arrhythmias such as Torsade de pointes (TdP) are low. We report a case of Long QT syndrome with a corrected QT of 520 ms. For symptom e arrhythmia correlation a loop recorder was implanted with no documented arrhythmias. Epinephrine testing was performed for clinical risk stratification leading to Torsades de pointes during recovery phase which required defibrillation. Genetic testing discovered two pathogenic heterozygous mutations in two different LQT genes (SCN5A and KCNQ1). We propose a calcium homeostasis mechanism for the interaction of both mutations that exaggerated the phenotype, while each mutation by itself is causing a relatively modest phenotype. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Long QT syndrome Digenic mutation Torsade de pointes Epinephrine test
Introduction
Case report
Congenital Long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphic ventricular tachycardia (Torsades de Pointes; TdP), and sudden arrhythmic death.1 Digenic mutations (two mutations in different genes) or more often compound heterozygosity (two different mutations in the same gene) in LQTSrelated genes occurred in 2.0%e8.5% in published reports2e5 and are associated with significantly longer QTc intervals2,4,5 and more severe phenotypes.2,4 In this report, we describe a case where severe TdP occurred and subsequently two pathogenic heterozygous mutations in two different LQT genes have been identified suggesting an interaction between both mutated gene products.
The proband is a 39 year-old female patient who was referred to us based on a resting QTc of 520 ms (Fig. 1) after a second episode of likely vasovagal syncope. The first episode occurred 6 years prior to the current presentation and was suggestive of vasovagal syncope. The second, more recent episode occurred during micturition and was preceded with nausea and dizziness. Apart from a corrected QT of 520 ms, no other abnormalities were seen on ECG. All other cardiac investigations including an echocardiogram and exercise stress test were unremarkable. In view of a lack of symptomerhythm correlation, she had a loop recorder implanted and was put on Nadolol which was gradually increased to 60 mg, twice daily. However, over a period of 12 months she did not have any syncope spells and no documented arrhythmias on the loop recorder. The family history revealed that her paternal uncle died of drowning at the age of 16 and her nephew (maternal brother’s child) died suddenly at age of 4 months old. For further risk stratification and to determine the type of LQTS we decided to perform an epinephrine drug challenge and started an incremental epinephrine infusion from 0.05 mcg per kg per minute up to 0.2 mcg per kg per minute after stopping Nadolol for a week. The QTc interval was calculated using the Bazett formula (QT divided by the square root of RR interval). The QTc prior to the epinephrine challenge was 567 ms and prolonged up to a maximum QTc of 596 ms at 0.2 mcg per kg per minute epinephrine
Abbreviations: LQTS, Long QT syndrome; QTc, Corrected QT interval; TdP, Torsade de pointes; VT, Ventricular tachycardia; ICD, Implantable cardioverter defibrillator; LQT1, Long QT type 1; LQT3, Long QT type 3; PVCs, Premature ventricular complexes; WT, Wild-type; KCNQ1, Potassium voltage-gated channel, type 1; SCN5A, Sodium channel, voltage-gated, type V, alpha subunit. * Corresponding author. Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Health Research Innovation Centre, Room GAA08, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4Z6. Tel.: þ1 403 210 6908; fax: þ1 403 210 9350. E-mail address: [email protected] (B. Gerull). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2014.07.004
542
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
Fig. 1. Resting 12-lead ECG of the proband.
infusion (Fig. 2). There was no occurrence of tachyarrhythmia during the infusion. However, during the washout period (5 min after stopping epinephrine infusion), a gradually prolong ReR interval developed followed by frequent premature ventricular bigeminies preceded by augmented T-U complexes (Fig. 3A). This was followed by non-sustained ventricular tachycardia (VT) (again, the first ventricular tachycardia (VT) beat was preceded by an augmented TeU complex) culminating to persistent polymorphic VT resembling of Torsades de pointes (TdP) (Fig. 3B) which required defibrillation. Given her significant arrhythmias induced by epinephrine, she eventually underwent dual chamber implantable cardioverter defibrillator (ICD) implantation and was placed at lower rate of 70 beats per minute. A year after ICD implantation, she developed polymorphic VT (Fig. 4) treated successfully with an ICD shock which awoken her from sleep. Subsequent genetic testing of 12 genes known to cause LQTS identified two pathogenic mutations in two different proteins,
KCNQ1 (p.R518X) and SCN5A (p.F1617del), causing LQTS type 1 (LQT1) and LQTS type 3 (LQT3), respectively. Further family screening identified that the proband inherited one mutation from each parent (Fig. 5). Her mother carrying the KCNQ1 mutation showed a baseline QTc of 467 ms and significantly prolonged up to a maximum of 516 ms at 0.2 mcg/kg/min epinephrine infusion indicating clinical manifestation of LQTS (Fig. 2). The probands father showed a normal baseline QTc (390 ms) with a maximum QTc of 476 ms at 5 min after stopping epinephrine (Fig. 2). Both children of the proband had borderline QTc intervals of 450 ms and inherited one mutation each as shown in Fig. 4. All first degree relatives of the proband were asymptomatic. Discussion This case interestingly illustrates an LQT phenotype with mutations involving both KCNQ1 and SCN5A genes. Accordingly, our
Fig. 2. Comparison of ECGs (lead II) between the proband and her parents before and at maximum epinephrine dosage.
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
543
Fig. 3. (A) During epinephrine washout phase, frequent PVCs preceded by gradually prolonged ReR interval. Each PVC was preceded by an augmented TeU complex (a). (B) At 10 min during epinephrine washout phase, frequent PVCs preceded by augmented T-U complexes (b) in the setting of a long QTc culminating to develop Torsades de pointes.
discussion will focus on the utility of genetic testing and epinephrine testing as well as potential mechanism or interaction of both mutations. According to the Heart Rhythm Society and European Heart Rhythm Association expert consensus statement on genetic testing for channelopathies,6 genetic testing is recommended for patients with strong clinical index suspicion for an LQTS phenotype as seen in our case (resting 12 lead ECG showed prolonged QTc in the absence of reversible cause). The advent of genetic testing in particular for LQTS subtypes has important implications in diagnosis, prognosis as well as therapeutic management.6 However, the dilemma faced in this case is which mutation (LQT1 or LQT3) is the dominant one or how do they interfere with each other? The escalating dose of epinephrine introduced by the Mayo group was found to be particularly useful in diagnosing LQT1.7 However, there is no test available for risk stratification in patient with LQTS. In our patient, the epinephrine test was performed because it was thought to be helpful to further clarify her diagnosis (type of LQTS) and risk for arrhythmias without the knowledge of the results of genetic testing. It is interesting to note that frequent ventricular bigeminies and the first beat of polymorphic VT or TdP were consistently preceded by an augmented TeU complex (Fig. 3A
and B). In ventricular bigeminies complexes, the amplitude of the augmented TeU complex is gradually increased in subsequent beats which possibly indicates an imminent risk of TdP. Kirchhof et al showed that abnormal giant T-U waves separate TdP initiation in LQTS patients from premature ventricular complexes (PVCs) in other diseases and from other PVCs in LQTS patients. They further suggest that this may help to identify an imminent risk of onset of TdP.8 The rationale for the ICD implantation was based on the induction of TdP during the epinephrine washout in the setting of a documented long QTc. Moreover, about a year later, the patient had an ICD treated episode of TDP during sleep, a trigger which is typically observed in LQTS type 3. Epinephrine challenges in her parents were leading to QT prolongation, but no significant arrhythmias and both as well as her children where consequently treated with beta-blocker. Previous studies have examined the electrophysiologic effects of the individual mutations observed in the patients presented herein.9,10 Huang et al examined the electrophysiologic manifestations of the p.R518X mutation in KCNQ1.9 In the clinical study of p.R518X mutation, the phenotype was syncope and LQTS in the proband but nuclear family members carrying the same mutation
544
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
Fig. 4. ICD dot plot tracing (left upper corner) and intracardiac electrogram. Dot plot tracing shows the onset of ventricular arrhythmias as evidenced by ventricular rate > atrial rate. Intracardiac electrogram shows polymorphic ventricular tachycardia which was terminated by an ICD shock.
had no phenotype. The electrophysiologic characterization of the resultant IKs current-density was critically dependent on the ratio of wild-type (WT) to mutation-carrying monomers that were co-expressed in Xenopus oocytes. When mutant monomers were co-expressed with WT monomers at a 1:1 ratio there was no dominant negative effect however when the ratio of WT: mutation carrying monomers was 1:3 a dominant-negative impairment of IKs expression was observed. Interesting a subsequent study indicated that in the setting of calmodulin binding to KCNQ1 can exaggerate the phenotype of p.R518X resulting in a dominant negative phenotype. These data suggest that generally the p.R518X mutation produces a relative minor phenotype but that intracellular environmental features can exaggerate the phenotype. The phenotype induced by the isolated SCN5A mutation p.F1617del also produces a relatively modest phenotype.10 This mutation produces a negative shift in the sodium channel availability, steady state inactivation, of cardiac INa. The mutation also produces an increase in the late component of INa but this increase was statistically significant only at þ40 mV. At the plateau
potentials (0 mV) there was no significant difference. Single channel analysis showed some increase in channel open times at voltages >20 mV. At 0 mV they channel open times were equal to that seen in the þ/þ channel. These data indicate that the electrophysiologic consequences of the F1617del mutation are subtle and voltage-dependent. Thus, genetic/electrophysiologic modeling to replicate digenic mutation to study the electrophysiology effect might be difficult due to the subtleties of individual mutations. The single mutations taken in isolation produce modest phenotypes. However our proband carried both of these mutations (digenic). Is there a plausible mechanism to indicate why synergistic QT prolongation and propensity to Torsades could be observed in individuals simultaneously carrying both mutations? It seems plausible that the sodium channel mutation could induce an increase in late sodium current influx. Acting via the sodium calcium exchanger increased intracellular sodium leads to an increased calcium influx and thereby to SR calcium overload. When epinephrine was applied, epinephrine will increase the transmembrane calcium current resulting in exaggerated SR load and
Fig. 5. Family tree of the proband (arrow) together with the ECG phenotype and genotype.
V.H. Tan et al. / Heart & Lung 43 (2014) 541e545
calcium release. Moreover, epinephrine induced increases in intracellular calcium could alter Caþ2 calmodulin interaction with the KCNQ potassium channels resulting in synergistic prolongation of the QT interval. Consistent with the literature,11 this could exaggerate the phenotype. The limitation of this case report is clearly that this is just an example of one case and the patient’s family, and although it is consistent with the literature, it does not conclusively prove the concept, and would need to be replicated in other cases or ideally, a case series. Conclusion A digenic proband carrying mutations in both SCN5A and KCNQ1 manifests Torsades after epinephrine. Nuclear family members carrying either of the isolated mutations had no phenotypes. A calcium homeostasis mechanism for the interaction is proposed. Conflict of interest: None for all authors. References 1. Roden DM, George Jr AL, Bennett PB. Recent advances in understanding the molecular mechanisms of the Long QT syndrome. J Cardiovasc Electrophysiol. 1995;6:1023e1031.
545
2. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe Long-QT syndrome. Circulation. 2004;109:1834e1841. 3. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long qt syndrome genetic testing. Heart Rhythm. 2005;2:507e517. 4. Itoh H, Shimizu W, Hayashi K, et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010;7:1411e1418. 5. Lieve KV, Williams L, Daly A, et al. Results of genetic testing in 855 consecutive unrelated patients referred for Long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013;7:553e561. 6. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace. 2011;13:1077e1109. 7. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital Long-QT syndrome: Diagnostic accuracy of the paradoxical QT response. Circulation. 2006;113:1385e1392. 8. Kirchhof P, Franz MR, Bardai A, Wilde AM. Giant T-U waves precede Torsades de pointes in Long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol. 2009;54:143e149. 9. Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res. 2001;51:670e680. 10. Chen T, Inoue M, Sheets MF. Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delf1617. Am J Physiol Heart Circ Physiol. 2005;288:H2666eH2676. 11. Ghosh S, Nunziato DA, Pitt GS. KCNQ1 assembly and function is blocked by Long-QT syndrome mutations that disrupt interaction with calmodulin. Circ Res. 2006;98:1048e1054.
