Cardiogenetics 2017; volume 7:6304

Sudden in a young patient with atrial Case Report Correspondence: María Angeles Espinosa Castro, Inherited Cardiovascular A 22-year-old man suffered a sudden Program, Department, Gregorio María Tamargo, without previous symptoms Marañón Hospital, Dr. Esquerdo, 46, 28007, María Ángeles Espinosa, while he was at rest, waiting for a subway Madrid, Spain. Víctor Gómez-Carrillo, Miriam Juárez, train. Cardiopulmonary resuscitation was Tel.: +34.91.586.82.90. immediately started using an Automated E-mail: [email protected] Francisco Fernández-Avilés, External that identified the Raquel Yotti Key words: KCNQ1; ; channelopa- presence of and thy; sudden cardiac death; . Inherited delivered a . Return of spontaneous Program, Cardiology Department, circulation was achieved after three Contributions: MT, acquisition and interpreta- Gregorio Marañón Hospital, Madrid, attempts, being atrial fibrillation (AF) the tion of data for the work, ensuring that ques- Spain patient’s rhythm at this point (Figure 1). tions related to the accuracy or integrity of any He was admitted to our Cardiovascular part of the work is appropriately investigated and therapeutic and resolved; MAE, conception of the work, was performed over a period critical revision of the intellectual content, final approval of the version to be published, Abstract of 24 h. After completing hypothermia, ensuring that questions related to the accuracy rewarming, and another 24 h of controlled of any part of the work is appropriately inves- Sudden cardiac death (SCD) in young normothermia the patient awakened with no tigated and resolved; VG-C, acquisition and patients without structural disease is residual neurologic damage. During hospi- interpretation of data for the work; MJ, acqui- frequently due to inherited talization, structural heart disease was ruled sition of data for the work; FF-A, final such as long QT syndrome (LQTS), out with a transthoracic echocardiogram, approval of the version to be published; RY, or Catecholaminergic coronary angiography and a cardiac mag- critical revision of the intellectual content, final approval of the version to be published, polymorphic ventricular . netic resonance. Since AF persisted, an Accordingly, the addition of ensuring that questions related to the accuracy elective electrical was suc- of theonly work is appropriately investigated. to clinical data may be useful to identify the cessfully performed at day four after admis- cause of the sudden death in this population. sion. 12-lead electrocardiogram (ECG) Conflict of interest: the authors declare no in the KCNQ1 encoded Kv7.1 showed a normal QT interval with a correct- potential conflict of interest. channel are related to type 1 LQTS, familial ed QT (QTc) of 423 ms. Continuous useECG atrial fibrillation (AF), short QT syndrome, showed no electrical abnormali- Funding: Fondo Europeo de Desarrollo and SCD. We present a clinical case where Regional, Instituto de Salud Carlos III, ties after returning to (Figure Madrid, Spain. the presence of AF after resuscitation in a 2). An exercise test on treadmill showed no young man with cardiac arrest was the key ventricular ectopics or ventricular arrhyth- Conference presentation: this case was accept- clinical data to suspect an inherited disorder mias (VA). QTc interval shortened accord- ed for poster presentation at the and genetic testing was the main determi- ingly and at 4 min of recovery remained 2016 annual congress of the Heart Failure nant for identifying the cause of the cardiac <460 ms. Flecainide test was also normal. Association of the ESC in Florence, Italy. arrest. The KCNQ1 p.Arg231His mutation An implantable cardioverter defibrillator Received for publication: 24 September 2016. explained the combined phenotype of AF (ICD) was implanted as secondary preven- and susceptibility to ventricular arrhyth- Revision received: 26 July 2017. tion. Accepted for publication: 14 August 2017. mias. The case highlights the importance of The patient was an exchange student continued research in and molecu- withcommercial no previous relevant medical records This work is licensed under a Creative lar mechanisms of channelopathies. and all his family lived overseas. The fami- Commons Attribution NonCommercial 4.0 ly pedigree was recorded. There was no License (CC BY-NC 4.0). known history of SCD, unexplained syn- ©Copyright M. Tamargo et al., 2017 cope or AF in the family. His mother had Introduction Non Licensee PAGEPress, Italy died due to a non-cardiac disease and his Cardiogenetics 2017; 7:6304 Sudden cardiac death (SCD) is a major father and two sisters were alive and appar- doi:10.4081/cardiogenetics.2017.6304 contributor to cardiovascular mortality being ently healthy. A paternal cousin had also responsible for approximately 25% of total died but the patient was not aware of the cardiovascular in the world with a details (Figure 3). global estimated incidence of 4 million cases Next generation sequencing of a set of ed ( 40 mg twice a day) and genetic 1 per year. {Priori, 2015 #12@@author- 76 cardiac disease-related genes identified counselling given. Unfortunately, we could year}{Priori, 2015 #12@@hidden}{Priori, the heterozygous KCNQ1 missense variant not study any member of the family so the 2015 #1}{Priori, 2015 #3}{Priori, 2015 p.Arg231His (R231H) in exon 5. This vari- current status of the relatives is not avail- #1}Although ischaemic heart disease ant results in the replacement of the normal able. We strongly recommended him to accounts for the majority of cases, in patients arginine codon (CGC) with a histidine advise all his first-degree relatives for under 40 years old, inherited structural or codon (CAC) at the amino acid position 231 purely arrhythmogenic cardiac disorders in the S4 domain of the . It has genetic screening and clinical cardiac eval- such as long QT syndrome (LQTS), Brugada been previously described in patients with uation with at least a basal ECG, treadmill syndrome (BS) or Catecholaminergic poly- type 1 LQTS (LQT1) and interfamilial exercise test and Holter monitoring in order morphic (CPVT) are early-onset AF.3-7 to assess arrhythmic risk in the family and the main cause of SCD.2 Treatment with beta blockers was start- provide preventive care.

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QT was unmasked during infusion of epi- and AF.4,7 Moreover, in a family with early Discussion nephrine7 and information about the QT onset AF, a male gene carrier experienced interval or the exact phenotype is lacking in SCD at rest (while sleeping) having normal SCD in young patients is a dramatic 5 7 event and identifying the final cause might the other case. The last patient was a 1 QT, just as the case of our patient. be challenging. Once ischaemic heart dis- year-old female with LQTS (QTc 479 ms) Even if initially the R231H mutation ease and structural have been ruled out, the aetiology still remains unknown in up to 50% of the cases.2 In this scenario, an inherited arrhythmogenic dis- order should always be considered. In our case, the patient presented nor- mal ECG intervals and provocative tests were negative for LQTS, BS and CPVT. However, he had lone persistent AF which is a rare finding in a young patient with a structural normal heart. The presence of the KCNQ1 R231H variant was the key point to reach a final diagnosis. KCNQ1 gene codes for the pore-form- ing a-subunit Kv7.1 which is a main com- ponent of the macromolecular voltage- gated channel protein that carries the slowly activated delayed rectifier potas- sium current (IKs). IKs plays an important role in human cardiac , partic- only ularly at fast rates and when sympathetic tone increases. IKs has a small amplitude under basal conditions so it is not a major contributing factor to normal repolarization use but it is highly recruited when the action Figure 1. First ECG after resuscitation showing atrial fibrillation as the baseline rhythm. potential duration (APD) prolongs and dur- ing β-adrenergic stimulation.8,9 Therefore, IKs protects against excessive lengthening of APD and is the main responsible for the adaptation of the APD to .10 LQT1 is caused by loss-of-function mutations in KCNQ1 gene. The subsequent IKs current decrease leads to a delayed repo- larization, QT interval prolongation and enhanced susceptibility to ventricular , notably torsade de Pointes that commercial occur mainly at exercise and during sympa- thetic stress.11 Contrarily, gain of function mutations of the KCNQ1 gene have also been described, resulting in shortening of the APD and the refractory period.Non Gain of function mutations have been associated with sinus , SQTS and familial AF.7,12 The KCNQ1 R231H variant is consid- ered a pathogenic mutation. It was first described by Napolitano in a patient with LQTS, though there is no information avail- able regarding the QT interval or the exact phenotype.3 Posteriorly, other 7 non-related families and 19 carriers have been reported.4-7 Interestingly, early-onset AF was the main phenotype in the families whereas most carriers (14) had a normal QT interval. 2 gene carriers presented upper limit QTc: a newborn male with fetal brady- cardia6 and a patient with AF.7 The 3 Figure 2. ECG after electrical cardioversion. The patient returned to sinus rhythm. QTc remaining patients reviewed are described interval 423 ms (Bazett’s formula). as having long QT, though in one case long

[Cardiogenetics 2017; 7:6304] [page 19] Clinical and Experimental Cases/Hypothesis

ventricular arrhythmias and the preven- tion of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J Figure 3. Pedigree of the family. The black arrow indicates the proband. Deceased family 2015;36:2793-867. members are represented with single slanted line figures. 2. Semsarian C, Ingles J, Wilde AA. Sudden cardiac death in the young: the molecular autopsy and a practical was associated with LQT1 and it was AF who carries the R231H variant. As the approach to surviving relatives. Eur believed to produce a loss of function of the case previously reported by Bartos,7 QT Heart J 2015;36:1290-6. channel,6 functional analyses have shown interval was not abnormally prolonged. An 3. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT that it indeed accelerates IKs activation lead- interesting observation in our opinion is that ing to an increased K+ efflux (gain-of-func- in both cases the SCD episode was at rest, a syndrome: development and validation tion) during the repolarization. At atrial rare finding in KCNQ1 mutations since β- of an efficient approach to genotyping level, the subsequent shortening of the APD adrenergic stimulation is the main trigger in clinical practice. JAMA and refractoriness may promote reentrant for VA in LQT1 patients. The regulation of 2005;294:2975-80. 4. Johnson JN, Tester DJ, Perry J, et al. arrhythmias and explain the AF phenotype the IKs channel is very complex and other of the carriers.7 molecules apart from PKA are implicated. Prevalence of early-onset atrial fibrilla- The question is, however, how a gain of Even if a misregulation in the PKA activa- tion in congenital long QT syndrome. function mutation in KCNQ1 can lead in tion has been proposed as an explanation Heartonly Rhythm 2008;5:704-9. certain cases to LQTS or may produce a for ventricular abnormal repolarization in 5. Kapplinger JD, Tester DJ, Salisbury lethal VA even if the QT is not clearly pro- KCNQ1 R231H carriers, we think that fur- BA, et al. Spectrum and prevalence of longed. Tetrameric phosphorylation of ther investigations are required to fully mutations from the first 2,500 consecu- tive unrelated patients referred for the Kv7.1 is required in order to enhance IKs understand the underlying molecular mech-use current in response to β-adrenergic stimula- anisms of such particular phenotype. FAMILION long QT syndrome genetic tion, a mechanism that is regulated by pro- This case illustrates the importance of test. Heart Rhythm 2009;6:1297-303. tein kinase A (PKA).13 Recent investigations genetic testing as a tool in the diagnostic 6. Guerrier K, Czosek RJ, Spar DS, have shown that some LQT1 mutations that approach of unexplained SCD since genetic Anderson J. Long QT genetics mani- are resistant to PKA activation are related to technologies can diagnose up to 27% of festing as atrial fibrillation. Heart severe phenotypes with high risk of syn- these unexplained cases.15 The identifica- Rhythm 2013;10:1351-3. cope and SCD.14 Computational modeling tion of a pathogenic mutation and a deeper 7. Bartos DC, Anderson JB, Bastiaenen R, suggests that the R231H mutation minimal- study of the effects of its expression besides et al. A KCNQ1 mutation causes a high ly affect the ventricular APD. Hence, a sig- the genotype itself might provide new penetrance for familial atrial fibrilla- nificant QT prolongation should not be insights into the understanding of inherited tion. J Cardiovasc Electrophysiol expected in most of the carriers. However, cardiac disorders. 2013;24:562-9. functional analyses show that the mutation commercial 8. Terrenoire C, Clancy CE, Cormier JW, impairs the PKA-dependent phosphoryla- et al. Autonomic control of cardiac tion of the Kv7.1channel. Therefore, in action potentials: role of potassium R231H carriers, exercise and sympathetic- Conclusions channel kinetics in response to sympa- induced IKs increase is prevented at ventric- thetic stimulation. Circ Res 2005;96: A significant number of SCD especially ular level. The resistance to PKA phospho- e25-34. Nonin the young remain unexplained after a rylation might explain how a gain-of-func- 9. Volders PG, Stengl M, van Opstal JM, careful medical investigation. An inherited tion mutation might also cause abnormal et al. Probing the contribution of IKs to arrhythmogenic disorder should then be ventricular repolarization under certain cir- canine ventricular repolarization: key suspected. Genetic testing should be consid- cumstances even when it does not produce a role for beta-adrenergic receptor stimu- ered in the diagnostic workup in these lengthening of the ventricular APD.7 lation. Circulation 2003;107:2753-60. cases. The identification of a pathogenic We believe that our case is in accor- 10. Jost N, Virag L, Bitay M, et al. mutation and subsequent investigation of dance to previous literature review. It seems Restricting excessive cardiac action the molecular mechanisms underlying the that R231H mutation unique properties lead potential and QT prolongation: a vital phenotype might provide a personalized to a very particular phenotype of early onset role for IKs in human ventricular mus- diagnosis, care and treatment to patients and AF due to the increase IKs current at atrial cle. Circulation 2005;112:1392-9. their families. level. Though the QT interval can be upper 11. Sanguinetti MC. Long QT syndrome: limit or slightly prolonged, most patients do ionic basis and mechanism not present a typical LQTS but they still in long QT syndrome type 1. J may have a significant risk of lethal Cardiovasc Electrophysiol 2000;11: arrhythmias because the ventricular References 710-2. excitability seems to be very abnormal. To 1. Priori SG, Blomstrom-Lundqvist C, 12. Chen YH, Xu SJ, Bendahhou S, et al. the best of our knowledge, this is the second Mazzanti A, et al. 2015 ESC Guidelines KCNQ1 gain-of-function mutation in patient reported suffering cardiac arrest and for the management of patients with familial atrial fibrillation. Science

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2003;299:251-4. 2002;295:496-9. 15. Bagnall RD, Weintraub RG, Ingles J, et 13. Marx SO, Kurokawa J, Reiken S, et al. 14. Heijman J, Spatjens RL, Seyen SR, et al. A prospective study of sudden car- Requirement of a macromolecular sig- al. Dominant-negative control of diac death among children and young naling complex for beta adrenergic cAMP-dependent IKs upregulation in adults. N Engl J Med 2016;374:2441- receptor modulation of the KCNQ1- human long-QT syndrome type 1. Circ 52. KCNE1 . Science Res 2012;110:211-9.

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