The congenital long QT syndrome and implications for young athletes

The congenital long QT syndrome (LQTS) is caused by cardiac ion channel mutations, which predispose young individuals to sudden cardiac death often related to exercise. The issue of LQTS and sports participation has received significant publicity due to reports of sudden death in young competitive athletes. This article reviews the pathophysiology, clinical characteristics, and management of LQTS in the physically active and athletic population.     

Impaired cardiac sympathetic innervation in symptomatic patients with long QT syndrome

Purpose  

Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using ¹²³I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype.     

Whole-exome sequencing and electrophysiological study reveal a novel loss-of-function mutation of KCNA10 in epinephrine provoked long QT syndrome with familial history of sudden cardiac death

Congenital long QT syndrome (LQTS) is one type of inherited fatal cardiac arrhythmia that may lead to sudden cardiac death (SCD). Mutations in more than 16 genes have been reported to be associated with LQTS, whereas the genetic causes of about 20% of cases remain unknown. In the present study, we investigated a four-generation pedigree with familial history of syncope and SCD. The proband was a 33-year-old young woman who experienced 3 episodes of syncope when walking at night. The electrocardiogram revealed a markedly epinephrine-provoked prolonged QT interval (QT = 468 ms, QTc = 651 ms) but no obvious arrhythmia in the resting state. Three family members have died of suspected SCD. Whole-exome sequencing and bioinformatic analysis based on pedigree revealed that a novel missense mutation KCNA10 (c.1397G＞A/Arg466Gln) was the potential genetic lesion. Sanger sequencing was performed to confirm the whole-exome sequencing results. This mutation resulted in the K_V1.8 channel amino acid residue 466 changing from arginine to glutamine, and the electrophysiological experiments verified it as a loss-of-function mutation of K_V1.8, which reduced the K⁺ currents of K_V1.8 and might result in the prolonged QT interval. These findings suggested that KCNA10 (c.1397G＞A) mutation was possibly pathogenic in this enrolled LQTS family, and may provide a new potential genetic target for diagnosis and counseling of stress-related LQTS families as well as the postmortem diagnosis of SCD.     

Evaluation of regional cardiac sympathetic innervation in congenital long QT syndrome using 123I-MIBG scintigraphy

The aim of this study was to determine whether sympathetic imbalance in congenital long QT syndrome (LQTS) can be identified by cardiac sympathetic neuronal dysinnervation. 123I-metaiodobenzylguanidine (MIBG) is a tracer of the norepinephrine analogue which reflects the regional innervation and norepinephrine kinetics in cardiac sympathetic nerves. Sixteen patients with LQTS, who were members of 12 families, and 7 normal controls underwent MIBG scintigraphy. Myocardial SPET and planar images were obtained 15 min and 4 h after the injection of MIBG in each patient. The relative regional uptake (RRU) and regional washout rate (rWR) of MIBG at 4 h in each of nine regions were compared with those in the control group. The heat-to-mediastinum ratio (H/M) and global washout rate (GWR) were also calculated. The RRU, rWR, H/M and GWR showed no significant difference between LQTS patients and normal controls. Furthermore, the RRU in 96% of all regions in LQTS was within the mean +/- 2 standard deviations of that in the control group. Patients with LQTS have normal cardiac sympathetic innervation, as assessed by MIBG. The sympathetic imbalance hypothesis is unlikely to be attributed to an abnormal distribution and different regional norepinephrine kinetics of cardiac sympathetic nerves.     

Overview of sudden cardiac death in young athletes

Sudden cardiac death is the leading cause of nontraumatic mortality in young athletes. The estimated incidence varies; however, recent studies have provided more accurate data. Most cases are attributed to silent hereditary or congenital cardiac disorders, many of which may be detected through preparticipation screening programs. This article provides a comprehensive review of the incidence and etiology of sudden cardiac death in young athletes, with practical advice regarding evaluation and management in light of a large number of recent advances. A brief outline of current perspectives on preparticipation screening programs and prevention is included.     

The importance of a teleradiographic evaluation of cardiac volume in subjects with the long QT syndrome

The increase in electrocardiographic QT interval, denominated "long QT" syndrome, is related to syncopes and sudden death during anger, fear, physical effort, or sleep. Its diagnosis is important because mortality rate is high among untreated patients. In this study the author tried to single out, with the help of conventional radiology, some radiological elements belonging to this syndrome. Heart diameters and volume could be determined by means of teleroentgenography in 24 patients affected with "long QT" syndrome. The method employed considerably reduced the factors preventing a correct determination of heart size. In most of the cases examined, heart diameters and volume were increased, the heart had a globose shape with a lifted tip, the second right arch was accentuated, and the space behind the sternum reduced: these elements suggest a volumetric increase in the right sections of the heart. No relationship was found between QT value and increase in heart size. The results suggest the existence of a non-casual relationship between electrocardiographical anomaly and increase in the volume of the right sections of the heart.     

Molecular screening of selected long QT syndrome (LQTS) mutations in 165 consecutive bodies found in water

The association of the long QT-syndrome (LQTS) with single accidental drowning or near-drowning cases has been recently emphasised, but no data on the prevalence of LQTS among drowning victims are currently available. In this study, we have retrospectively screened specific founder mutations in KCNQ1 (KVLQT1) and KCNH2 (HERG) genes in 165 consecutive bodies found in water in Finland. We found a KCNH2-Fin mutation in a 44-year-old woman whose death was classified as suicidal drowning, whereas no other carriers of the two LQTS founder mutations were identified among the remaining 164 victims. This study provides the first estimate of the minimum prevalence of LQTS (0.61%, CI(95): 0.02-3.33) in such a setting and demonstrates the value of genetic analysis of LQTS in putative drownings. The detection of a LQTS founder mutation in a body found in water is a relatively rare event based on our study sample. This finding is, however, of utmost medico-legal importance, since it broadens the spectrum of potential causes and manners of death.     

Mutations in the SCN5A gene: Evidence for a link between long QT syndrome and sudden death?

Mutations in cardiac ion channel genes leading to channel dysfunctions or changes in the gene expression may cause inherited arrhythmogenic diseases. These genetic diseases are important causes of sudden unexplained death (SUD). Ten cases of SUD, including six cases of sudden infant death syndrome (SIDS) and four cases of SUD from people in the age of 14–40 years were examined by postmortem molecular analysis. Genomic DNA was extracted from blood cells and two long QT syndrome relevant genes, SCN5A encoding the α-subunit of the voltage-gated sodium channel Na_v1.5 and KCNH2 encoding the α-subunit of the voltage-gated potassium channel HERG were selected for mutation analysis by complete gene sequencing. Various silent mutations in the KCNH2 and SCN5A genes as well as the known H558R polymorphism in SCN5A were detected. Moreover, sequence variations in the 3′ untranslated region (3′UTR) and 5′ untranslated region (5′UTR) of the SCN5A gene were observed. This study suggests that these areas are important regions to investigate the impact of changes in cardiac ion channel function on the risk of sudden unexpected death.     

Medico-legal perspectives on sudden cardiac death in young athletes

Sudden cardiac death (SCD) in a young athlete represents a dramatic event, and an increasing number of medico-legal cases have addressed this topic. In addition to representing an ethical and medico-legal responsibility, prevention of SCD is directly correlated with accurate eligibility/disqualification decisions, with an inappropriate pronouncement in either direction potentially leading to legal controversy. This review summarizes the common causes of SCD in young athletes, divided into structural (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, congenital coronary artery anomalies, etc.), electrical (Brugada, congenital LQT, Wolf-Parkinson-White syndrome, etc.), and acquired cardiac abnormalities (myocarditis, etc.). In addition, the roles of hereditary cardiac anomalies in SCD in athletes and the effects of a positive result on them and their families are discussed. The medico-legal relevance of pre-participation screening is analyzed, and recommendations from the American Heart Association and European Society of Cardiology are compared. Finally, the main issues concerning the differentiation between physiologic cardiac adaptation in athletes and pathologic findings and, thereby, definition of the so-called gray zone, which is based on exact knowledge of the mechanism of cardiac remodeling including structural or functional adaptions, will be addressed.

     

The long QT syndrome: considerations in the athletic population

In athletes, ventricular arrhythmias and sudden cardiac death are rare and unpredictable events. Often, an underlying heart disease is present, but pre-existing clinical signs or symptoms may not be recognized. Primary electrical disorders (such as the long QT syndrome) are rarely present in athletes but, so far, are a considerable reason for disqualification from sport activity. These disorders are mostly inherited, and patients should be referred to a cardiologist with special experience. Through the efforts of molecular genetics and cellular electrophysiology, an increasing understanding of the underlying mechanisms of arrhythmogenesis is being gathered. During the past decade, evidence has grown that establishing accurate genetic diagnoses and dissection of molecular disease mechanisms can have an impact on prognosis, and help direct therapy in a range of cardiovascular diseases. Further achievements in the areas of clinical and molecular research, improvement of medical education, and expansion of genotyping facilities will facilitate the correct and immediate identification of affected patients.     

Post-mortem toxicology analysis in a young sudden cardiac death cohort

Risk of sudden cardiac death (SCD) increases with age, and several studies have examined the impact of different drugs on cardiovascular function. However, few studies have integrated epidemiological drug consumption data and genetic background in the context of cardiac death. We performed a retrospective population-based study in forensic sudden death cases from a 9-year period in Catalonia. The young cohort included 924 cases 18–50 years old, 566 of which had a cardiac cause of death. Complete autopsy, toxicological, and histopathological studies were performed. Molecular autopsy using next-generation sequencing was performed in nearly 400 cardiac cases. Cases related with fatal acute intoxication were excluded. Drug consumption prevalence was similar between forensic cases of cardiac and non-cardiac origin (62.5% versus 69.5%), with the exception of alcohol, which was more prevalent in the cardiac group than in the non-cardiac group (23.3% versus 17.1%). Individuals in the toxicology-positive group were carriers of more rare genetic variants and were significantly younger than the toxicology-negative group. Psychopharmacological drugs were identified in 22.3% of cardiac cases, and molecular autopsy identified an association between antiepileptic drugs or caffeine and pathogenic or likely pathogenic variants in arrhythmogenic genes. Specific substances could therefore play an essential role as triggers of SCD in genetically predisposed young people.     

Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study

Sudden infant death syndrome (SIDS) is a frequent cause of death among infants. The etiology of SIDS is unknown and several theories, including fatal ventricular arrhythmias, have been suggested. We performed an epidemiological and genetic investigation of SIDS victims to estimate the presence of inherited long QT syndrome (LQTS) as a contributor for SIDS. Forty-one consecutively collected and unrelated SIDS cases were characterized by clinical and epidemiological criteria. We performed a comprehensive gene mutation screening with single-strand conformation polymorphism analysis and sequencing techniques of the most relevant LQTS genes to assess mutation frequencies. In vitro characterization of identified mutants was subsequently performed by heterologous expression experiments in Chinese hamster ovary cells and in Xenopus laevis oocytes. A positive family history for LQTS was suspected by mild prolonged Q-T interval in family members in 2 of the 41 SIDS cases (5%). In neither case, a family history of sudden cardiac death was present nor a mutation could be identified after thorough investigation. In another SIDS case, a heterozygous missense mutation (H105L) was identified in the N-terminal region of the KCNQ1 (LQTS 1) gene. Despite absence of this mutation in the general population and a high conservational degree of the residue H105 during evolution, electrophysiological investigations failed to show a significant difference between wild-type and KCNQ1_H105L/minK-mediated I_Ks currents. Our data suggest that a molecular diagnosis of SIDS related to LQTS genes is rare and that, even when an ion channel mutation is identified, this should be regarded with caution unless a pathophysiological relationship between SIDS and the electrophysiological characterization of the mutated ion channel has been demonstrated.H. Wedekind, T. Bajanowski and P. Friederich contributed equally to this study.     

Long QT syndrome KCNH2 mutation with sequential fetal and maternal sudden death

We report a case of a woman who experienced intrauterine fetal death at full term pregnancy, and then died suddenly soon after learning about the death of her fetus. At autopsy, previously undiagnosed neurofibromatosis and an adrenal gland pheochromocytoma were discovered in the mother. Genetic screening also revealed a novel KCNH2mutation in both fetus and mother indicating type 2 congenital long-QT syndrome (LQTS). A catecholamine surge was suspected as the precipitating event of fetal cardiac arrhythmia and sudden fetal death, while the addition of emotional stress provoked a lethal cardiac event in the mother. This case illustrates the potential for lethal interactions between two occult diseases (pheochromocytoma, LQTS).     

Second opinion system for sudden cardiac death cases in forensic practice

International Journal of Legal Medicine - Sudden cardiac death (SCD) represents a considerable percentage of cardiovascular deaths worldwide. The most frequent pathological substrate of SCD is...     

Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark

International Journal of Legal Medicine - Sudden unexpected death in the young continues to be an important unsolved challenge. A significant proportion of the deaths are suspected to be caused by...     

Massive parallel sequencing applied to the molecular autopsy in sudden cardiac death in the young

Sudden cardiac death in the young is a very traumatic event that occurs often in apparently healthy individuals without an explainable cause of death after a comprehensive medico-legal investigation. Knowledge about the pathologies with a risk of sudden death is increasingly showing a greater underlying genetic heterogeneity, which provides one of the main handicaps for molecular autopsy. On the other hand the enormous technological advances in sequencing technologies, allow us to analyse as many genes as we want at a cost increasingly reduced. The sum of these two factors (increased knowledge of genetics and available technologies) allow us to make an individualized study of the causes of sudden cardiac death in young adults, through massive sequencing of all potential genes involved in the process. We define this approach as massive genomic autopsy, and with this review we will try to explain the possible scenarios and methods available for its implementation.     

Screening young athletes for prevention of sudden cardiac death: Practical recommendations for sports physicians

Regular intensive exercise in athletes increases the relative risk of sudden cardiac death (SCD) compared with the relatively sedentary population. Most cases of SCD are due to silent cardiovascular diseases, and pre‐participation screening of athletes at risk of SCD is thus of major importance. However, medical guidelines and recommendations differ widely between countries. In Italy, the National Health System recommends pre‐participation screening for all competitive athletes including personal and family history, a physical examination, and a resting 12‐lead electrocardiogram (ECG). In the United States, the American College of Cardiology and the American Heart Association recommend a pre‐participation screening program limited to the use of specific questionnaires and a clinical examination. The value of a 12‐lead ECG is debated based on issues surrounding cost‐efficiency and feasibility. The aim of this review was to focus on (i) the incidence rate of cardiac diseases in relation to SCD; (ii) the value of conducting a questionnaire and a physical examination; (iii) the value of a 12‐lead resting ECG; (iv) the importance of other cardiac evaluations in the prevention of SCD; and (v) the best practice for pre‐participation screening.