EDITORIAL COMMENTARY
Congenital long QT syndrome: The race to refine risk Elizabeth Vickers Saarel, MD, Susan P. Etheridge, MD From the Department of Pediatric Cardiology, University of Utah, Salt Lake City, Utah.
Congenital long QT syndrome (LQTS) affects 1:2000 people and is a leading cause of sudden cardiac death (SCD) in the young. Since LQTS was first recognized in the mid-20th century, medical researchers have made large inroads toward understanding the cause of and predicting risk for sudden death in individual patients. Early investigators suspected the disease was heritable, and LQTS was the first arrhythmia syndrome for which specific genetic defects were identified.1,2 However, prior quixotic clinical predictions that genetic laboratory tests would make diagnosis and prognostication in LQTS straightforward and easy are incorrect to date. The fact remains there is no single historical question, physical finding, or laboratory or clinical test that defines risk. Clinical and genetic research continue to refine methods for diagnosis and prediction of sudden death in LQTS, and the publication by Earle et al3 in this issue of HeartRhythm adds valuable information to the body of knowledge. Although genetic testing is fast becoming important for patient management and family screening, traditional clinical tools remain of utmost importance in the diagnosis, risk stratification, and treatment of patients with LQTS.4 As with most conditions in medicine, patient history is key. Historically, patients presented with symptoms of syncope, seizures, or aborted sudden death. As family screening practices have become more widespread, patients increasingly are diagnosed in the presymptomatic phase of the disease. The clinical presentation of LQTS continues to expand as it is now recognized that sudden infant death syndrome is a manifestation of LQTS, and, most recently, that LQTS may contribute to the pathogenesis of some intrauterine deaths.5 Electrocardiographic (ECG) testing at rest and with exercise are still the cornerstone of diagnosis and risk stratification in LQTS. Further clinical testing with drug challenges can be useful for diagnosis but have not been implicated in prognosis. Finally, age, gender, and compliance with medication and lifestyle prescription are important in LQTS risk stratification.6
Address reprint requests and correspondence: Dr. Elizabeth Vickers Saarel, Department of Pediatric Cardiology, University of Utah, 100 N. Mario Capecchi Dr, PCMC Cardiology, Salt Lake City, UT 84113. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
Although understanding the molecular aspects of LQTS has inspired new therapies and done much to move us toward a more definitive risk assessment strategy, we have not yet achieved an ideal model. Since the early 1990s, genetic information has added both specificity and sensitivity to traditional clinical tools in the diagnosis of LQTS.7 Molecular testing has refined risk for sudden death by definitively assigning patients to one of 16 LQTS genes, each with its own typical phenotype.8 Further realization that molecular and structural location, as well as biophysical function, contribute to the disease phenotype has allowed a more detailed understanding of the genotypes. Patients with mutations located in the transmembrane region have a significantly higher rate of cardiac events than those with mutations located in the C terminus. In addition, mutations in the transmembrane domain were suggested to be associated with a greater prolongation of the QTc during exercise. More recently, it was found that that this can be even more specifically defined. Areas within the transmembrane region may have distinct functional domains, with the C loops (but not in the membrane-spanning domain) being associated with increased risk for life-threatening cardiac events compared with other mutations in the KCNQ1 channel.9 Thus, not all mutations in the same gene have the same clinical consequence or even response to therapy. Furthermore, family members with the same LQTS genetic mutation at the same location with the same molecular functional consequences can have vastly different clinical expression. Thus, the equation between genotype and phenotype in LQTS is even more complex. Why is there such incomplete penetrance and variable expressivity in LQTS? In an effort to explain this variable genetic clinical expression, bench researchers have started to investigate new potential genetic modifiers, such as single nucleotide polymorphisms (SNPs), in LQTS.10 The study by Earle et al3 addresses this relatively new area of investigation in LQTS research. Because clinicians and patients still hope for the day when genetic blueprint analysis not only will make or confirm the diagnosis but will define management and prognosis, researchers continue to untangle the genetic mysteries and dilemmas of LQTS. General population genome-wide association studies have reported correlations between SNPs and the QT interval on resting ECG, risk for SCD, and other cardiac risk factors. http://dx.doi.org/10.1016/j.hrthm.2013.10.041
84 These particular findings clearly beg the question regarding SNP correlations with phenotype in genotype-positive LQTS patients. One of the first SNPs to be investigated in LQTS was the nitric oxide synthase 1 adaptor protein (NOS1AP), previously proven to be associated with SCD in U.S. community-based populations. Indeed, several investigators recently reported a correlation between NOS1AP polymorphisms and clinical outcomes in LQTS.10,11 The primary aim of this study was the assessment of the clinical outcomes in a cohort of 273 New Zealanders (NZ) with gene-positive LQTS type 1, 2, or 3 and correlation with a wide spectrum of alleles at 34 SNPs. Laboratory determination of five SNPs failed, so findings for 29 SNPs in 16 genes were reported. Patients with compound mutations were excluded from analysis. The population studied, representing 93 families with a wide range of ages and mixed gender, was ethnically and racially diverse from itself, and the inclusion of this population is diverse from populations previously studied in this manner. For the purpose of data analysis, patients were divided into two racial groups, Caucasian or Pacific Islander/NZ Maori. Probands in this database had been referred to the NZ Cardiac Inherited Disease Registry due to worrisome symptoms. Family members identified by cascade genetic screening were also included in this Registry and study. Overall, the NZ Inherited Cardiac Disease Registry represents a highly symptomatic group of gene-positive LQTS patients with 67% exhibiting symptoms including 11% with SCD or resuscitated SCD. Clinical data analyzed in conjunction with genetic variants included demographic data, QTc interval, and the most severe clinical event expressed by each patient. A significant finding from these data confirms prior reports; NOS1AP polymorphisms modulate clinical phenotype in patients with LQT1.10 In the ground-breaking report by Crotti et al,10 they ask the question as to whether their findings that NOS1AP’s biologic influence in their founder population in South Africa will be applicable to other populations. This report confirms that NOS1AP modulates repolarization in other populations throughout the world, namely, Caucasian and Pacific Islander/Maori New Zealanders. An important finding of this study was the correlation between NOS1AP and risk of events that was independent of the QTc in this population. Clinicians and patients are indeed closer to the quixotic dream of accurate genetic diagnosis and prognostication in LQTS. Areas of potential future investigation based on clinical LQTS include SNPS or other genetic factors that regulate intracellular and extracellular serum salt levels or autonomic nervous system during exercise, sleep, and startle. Also, given the difference in presentation and outcomes between male and females, sexspecific modifiers of LQTS genetic expression will be of future interest. Finally, molecular investigators in LQTS have the fascinating question of ideal patient-specific drug therapies to unravel. Which drug at what dose for each patient? Finally, perhaps basic scientists will help clinicians untie the mystery of patient compliance and noncompliance with clinical therapeutic recommendations, including prescribed behavior modification
Heart Rhythm, Vol 11, No 1, January 2014 and drug therapy (we can dream, can’t we?). Have we yet a modifier that “improves” the disease? Although not yet perfect, molecular genetic assessment in LQTS is leading the way for similar disease discoveries in the other channelopathies and genetically mediated cardiac disease processes. Presumably other genetic modifiers of LQTS phenotype will be more easily identified in groups that are less racially and genetically diverse than the NZ Cardiac Inherited Disease Registry. Until bench research identifies the perfect array of molecular genetic tests to diagnosis and risk stratify patients with proven or possible LQTS, clinicians will still need to rely on traditional clinical methods. The bench to bedside parley continues.12 Not only do clinical questions steer molecular investigation, clinical research questions are also honed by molecular diagnostic gray zones, prompting recent studies such as the report by Obeyesekere et al13 that traditional exercise testing is useful for further characterization of genetic variants of unknown significance in patients with suspected LQTS. Indeed, we have put our dream of perfect laboratory tests in LQTS aside for today so that we will not, like the infamous Don Quixote, “from so little sleeping and so much reading … [cause our] brain [to dry] up and [go] completely out of [our] mind.” That said, our long-term money will still reside on “The Ingenious [Gentlemen and Gentlewomen]” at the LQTS molecular research bench, like Earle et al, if we have to bet on a future more perfect diagnostic and prognostic formula in LQTS.
References 1. Garza LA, Vick RL, Nora JJ, McNamara DG. Heritable q-t prolongation without deafness. Circulation 1970;41:39–48. 2. Keating M, Atkinson D, Dunn C, et al. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704–706. 3. Earle NHD, Pilbrow A, Crawford J, et al. Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome. Heart Rhythm 2014;11:76–82. 4. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation 1993;88:782–784. 5. Crotti L, Tester DJ, White WM, et al. Long qt syndrome-associated mutations in intrauterine fetal death. JAMA 2013;309:1473–1482. 6. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;5124: 2291–2300. 7. Hofman N, Wilde AA, Tan HL. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J 2007;28:1399. 8. Goldenberg I, Thottathil P, Lopes CM, et al. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm 2012;9:49–56. 9. Barsheshet A, Goldenberg I, O-Ochi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012;125:1988–1996. 10. Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the longQT syndrome. Circulation 2009;120:1657–1663. 11. Amin AS, Giudicessi JR, Tijsen AJ, et al. Variants in the 3' intranslated region of the KCNQ1-encoded kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J 2012;33: 714–723. 12. Mathias A, Moss AJ, Lopes CM, et al. Prognostic implications of mutationspecific QTc standard deviation in congenital long QT syndrome. Heart Rhythm 2013;10:720–725. 13. Obeyesekere MN, Sy RW, Klein GJ, et al. End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome. J Cardiovasc Electrophysiol 2012;23:637–642.
Congenital long QT syndrome: The race to refine risk Elizabeth Vickers Saarel, MD, Susan P. Etheridge, MD From the Department of Pediatric Cardiology, University of Utah, Salt Lake City, Utah.
Congenital long QT syndrome (LQTS) affects 1:2000 people and is a leading cause of sudden cardiac death (SCD) in the young. Since LQTS was first recognized in the mid-20th century, medical researchers have made large inroads toward understanding the cause of and predicting risk for sudden death in individual patients. Early investigators suspected the disease was heritable, and LQTS was the first arrhythmia syndrome for which specific genetic defects were identified.1,2 However, prior quixotic clinical predictions that genetic laboratory tests would make diagnosis and prognostication in LQTS straightforward and easy are incorrect to date. The fact remains there is no single historical question, physical finding, or laboratory or clinical test that defines risk. Clinical and genetic research continue to refine methods for diagnosis and prediction of sudden death in LQTS, and the publication by Earle et al3 in this issue of HeartRhythm adds valuable information to the body of knowledge. Although genetic testing is fast becoming important for patient management and family screening, traditional clinical tools remain of utmost importance in the diagnosis, risk stratification, and treatment of patients with LQTS.4 As with most conditions in medicine, patient history is key. Historically, patients presented with symptoms of syncope, seizures, or aborted sudden death. As family screening practices have become more widespread, patients increasingly are diagnosed in the presymptomatic phase of the disease. The clinical presentation of LQTS continues to expand as it is now recognized that sudden infant death syndrome is a manifestation of LQTS, and, most recently, that LQTS may contribute to the pathogenesis of some intrauterine deaths.5 Electrocardiographic (ECG) testing at rest and with exercise are still the cornerstone of diagnosis and risk stratification in LQTS. Further clinical testing with drug challenges can be useful for diagnosis but have not been implicated in prognosis. Finally, age, gender, and compliance with medication and lifestyle prescription are important in LQTS risk stratification.6
Address reprint requests and correspondence: Dr. Elizabeth Vickers Saarel, Department of Pediatric Cardiology, University of Utah, 100 N. Mario Capecchi Dr, PCMC Cardiology, Salt Lake City, UT 84113. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
Although understanding the molecular aspects of LQTS has inspired new therapies and done much to move us toward a more definitive risk assessment strategy, we have not yet achieved an ideal model. Since the early 1990s, genetic information has added both specificity and sensitivity to traditional clinical tools in the diagnosis of LQTS.7 Molecular testing has refined risk for sudden death by definitively assigning patients to one of 16 LQTS genes, each with its own typical phenotype.8 Further realization that molecular and structural location, as well as biophysical function, contribute to the disease phenotype has allowed a more detailed understanding of the genotypes. Patients with mutations located in the transmembrane region have a significantly higher rate of cardiac events than those with mutations located in the C terminus. In addition, mutations in the transmembrane domain were suggested to be associated with a greater prolongation of the QTc during exercise. More recently, it was found that that this can be even more specifically defined. Areas within the transmembrane region may have distinct functional domains, with the C loops (but not in the membrane-spanning domain) being associated with increased risk for life-threatening cardiac events compared with other mutations in the KCNQ1 channel.9 Thus, not all mutations in the same gene have the same clinical consequence or even response to therapy. Furthermore, family members with the same LQTS genetic mutation at the same location with the same molecular functional consequences can have vastly different clinical expression. Thus, the equation between genotype and phenotype in LQTS is even more complex. Why is there such incomplete penetrance and variable expressivity in LQTS? In an effort to explain this variable genetic clinical expression, bench researchers have started to investigate new potential genetic modifiers, such as single nucleotide polymorphisms (SNPs), in LQTS.10 The study by Earle et al3 addresses this relatively new area of investigation in LQTS research. Because clinicians and patients still hope for the day when genetic blueprint analysis not only will make or confirm the diagnosis but will define management and prognosis, researchers continue to untangle the genetic mysteries and dilemmas of LQTS. General population genome-wide association studies have reported correlations between SNPs and the QT interval on resting ECG, risk for SCD, and other cardiac risk factors. http://dx.doi.org/10.1016/j.hrthm.2013.10.041
84 These particular findings clearly beg the question regarding SNP correlations with phenotype in genotype-positive LQTS patients. One of the first SNPs to be investigated in LQTS was the nitric oxide synthase 1 adaptor protein (NOS1AP), previously proven to be associated with SCD in U.S. community-based populations. Indeed, several investigators recently reported a correlation between NOS1AP polymorphisms and clinical outcomes in LQTS.10,11 The primary aim of this study was the assessment of the clinical outcomes in a cohort of 273 New Zealanders (NZ) with gene-positive LQTS type 1, 2, or 3 and correlation with a wide spectrum of alleles at 34 SNPs. Laboratory determination of five SNPs failed, so findings for 29 SNPs in 16 genes were reported. Patients with compound mutations were excluded from analysis. The population studied, representing 93 families with a wide range of ages and mixed gender, was ethnically and racially diverse from itself, and the inclusion of this population is diverse from populations previously studied in this manner. For the purpose of data analysis, patients were divided into two racial groups, Caucasian or Pacific Islander/NZ Maori. Probands in this database had been referred to the NZ Cardiac Inherited Disease Registry due to worrisome symptoms. Family members identified by cascade genetic screening were also included in this Registry and study. Overall, the NZ Inherited Cardiac Disease Registry represents a highly symptomatic group of gene-positive LQTS patients with 67% exhibiting symptoms including 11% with SCD or resuscitated SCD. Clinical data analyzed in conjunction with genetic variants included demographic data, QTc interval, and the most severe clinical event expressed by each patient. A significant finding from these data confirms prior reports; NOS1AP polymorphisms modulate clinical phenotype in patients with LQT1.10 In the ground-breaking report by Crotti et al,10 they ask the question as to whether their findings that NOS1AP’s biologic influence in their founder population in South Africa will be applicable to other populations. This report confirms that NOS1AP modulates repolarization in other populations throughout the world, namely, Caucasian and Pacific Islander/Maori New Zealanders. An important finding of this study was the correlation between NOS1AP and risk of events that was independent of the QTc in this population. Clinicians and patients are indeed closer to the quixotic dream of accurate genetic diagnosis and prognostication in LQTS. Areas of potential future investigation based on clinical LQTS include SNPS or other genetic factors that regulate intracellular and extracellular serum salt levels or autonomic nervous system during exercise, sleep, and startle. Also, given the difference in presentation and outcomes between male and females, sexspecific modifiers of LQTS genetic expression will be of future interest. Finally, molecular investigators in LQTS have the fascinating question of ideal patient-specific drug therapies to unravel. Which drug at what dose for each patient? Finally, perhaps basic scientists will help clinicians untie the mystery of patient compliance and noncompliance with clinical therapeutic recommendations, including prescribed behavior modification
Heart Rhythm, Vol 11, No 1, January 2014 and drug therapy (we can dream, can’t we?). Have we yet a modifier that “improves” the disease? Although not yet perfect, molecular genetic assessment in LQTS is leading the way for similar disease discoveries in the other channelopathies and genetically mediated cardiac disease processes. Presumably other genetic modifiers of LQTS phenotype will be more easily identified in groups that are less racially and genetically diverse than the NZ Cardiac Inherited Disease Registry. Until bench research identifies the perfect array of molecular genetic tests to diagnosis and risk stratify patients with proven or possible LQTS, clinicians will still need to rely on traditional clinical methods. The bench to bedside parley continues.12 Not only do clinical questions steer molecular investigation, clinical research questions are also honed by molecular diagnostic gray zones, prompting recent studies such as the report by Obeyesekere et al13 that traditional exercise testing is useful for further characterization of genetic variants of unknown significance in patients with suspected LQTS. Indeed, we have put our dream of perfect laboratory tests in LQTS aside for today so that we will not, like the infamous Don Quixote, “from so little sleeping and so much reading … [cause our] brain [to dry] up and [go] completely out of [our] mind.” That said, our long-term money will still reside on “The Ingenious [Gentlemen and Gentlewomen]” at the LQTS molecular research bench, like Earle et al, if we have to bet on a future more perfect diagnostic and prognostic formula in LQTS.
References 1. Garza LA, Vick RL, Nora JJ, McNamara DG. Heritable q-t prolongation without deafness. Circulation 1970;41:39–48. 2. Keating M, Atkinson D, Dunn C, et al. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704–706. 3. Earle NHD, Pilbrow A, Crawford J, et al. Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome. Heart Rhythm 2014;11:76–82. 4. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation 1993;88:782–784. 5. Crotti L, Tester DJ, White WM, et al. Long qt syndrome-associated mutations in intrauterine fetal death. JAMA 2013;309:1473–1482. 6. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;5124: 2291–2300. 7. Hofman N, Wilde AA, Tan HL. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J 2007;28:1399. 8. Goldenberg I, Thottathil P, Lopes CM, et al. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm 2012;9:49–56. 9. Barsheshet A, Goldenberg I, O-Ochi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012;125:1988–1996. 10. Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the longQT syndrome. Circulation 2009;120:1657–1663. 11. Amin AS, Giudicessi JR, Tijsen AJ, et al. Variants in the 3' intranslated region of the KCNQ1-encoded kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J 2012;33: 714–723. 12. Mathias A, Moss AJ, Lopes CM, et al. Prognostic implications of mutationspecific QTc standard deviation in congenital long QT syndrome. Heart Rhythm 2013;10:720–725. 13. Obeyesekere MN, Sy RW, Klein GJ, et al. End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome. J Cardiovasc Electrophysiol 2012;23:637–642.
