Cardiogenetics 2017; volume 7:6304 Sudden death in a young patient with atrial fibrillation Case Report Correspondence: María Angeles Espinosa Castro, Inherited Cardiovascular Disease A 22-year-old man suffered a sudden Program, Cardiology Department, Gregorio María Tamargo, cardiac arrest 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 Defibrillation that identified the Raquel Yotti Key words: KCNQ1; mutation; channelopa- presence of ventricular fibrillation and thy; sudden cardiac death; atrial fibrillation. Inherited Cardiovascular Disease delivered a shock. 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 Intensive Care Unit and therapeutic and resolved; MAE, conception of the work, hypothermia 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 heart disease is residual neurologic damage. During hospi- interpretation of data for the work; MJ, acqui- frequently due to inherited channelopathies 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, Brugada syndrome or Catecholaminergic coronary angiography and a cardiac mag- critical revision of the intellectual content, final approval of the version to be published, polymorphic ventricular tachycardia. netic resonance. Since AF persisted, an Accordingly, the addition of genetic testing ensuring that questions related to the accuracy elective electrical cardioversion 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 Mutations 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, monitoring 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 sinus rhythm (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 Heart Failure 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 genetics 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 deaths in the world with a details (Figure 3). global estimated incidence of 4 million cases Next generation sequencing of a set of ed (Nadolol 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 ion channel. 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 ventricular tachycardia (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. [page 18] [Cardiogenetics 2017; 7:6304] Clinical and Experimental Cases/Hypothesis 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 cardiomyopathy 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 potassium channel protein that carries the slowly activated delayed rectifier potas- sium current (IKs). IKs plays an important role in human cardiac repolarization, 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 heart rate.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 arrhythmias, 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 bradycardia, 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).