Genetics and genomics of long QT syndrome

In the past decade, molecular genetics has revealed that some life-threatening arrhythmogenic disorders, such as long QT syndrome, are due to mutated genes encoding ion channels that generate the cardiac action potential. Great efforts made in various fields have partly solved problems caused by unforeseen genetic diversity of these congenital arrhythmogenic disorders, while the genetics of these disorders has recently proved to be applicable to very wide-ranging conditions associated with sudden cardiac death, and increased knowledge about the human genome will revolutionize researches into arrhythmic diseases in future. The purpose of this review is to outline the recent advances and problems in the molecular genetics in long QT syndrome.     

The Abuse of Rest as a Therapeutic Agent

Abstract

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.     

Recent developments in the management of patients at risk for sudden cardiac death

Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is an important cause of mortality in the United States, 4% of which occurs in patients with structurally normal hearts. At least some arrhythmias are caused by ≥ 1 mutation in 1 of the genes that control electrical conduction through the heart by altering calcium homeostasis or depolarization or repolarization gradients in the ventricle. Although SCD may be the first presentation, patients may often present with symptoms of palpitations or hemodynamic compromise, such as dizziness, seizure, or syncope, particularly following exertion. They may also be made aware of possibly having the condition due to symptoms in other family members. The primary care physician is ideally placed to investigate these symptoms, including detailed clinical and family histories and examining the baseline electrocardiogram. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist, and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other treatments being developed. β-Blockers are often very effective in preventing arrhythmic episodes associated with catecholaminergic polymorphic ventricular tachycardia and some subtypes of long QT syndrome. In certain situations, calcium channel blockers may also be used. Quinidine and isoproterenol can be useful in treating Brugada syndrome. Left cervicothoracic stellectomy may occasionally be used in the treatment of long QT syndrome. As the genetic basis of these diseases becomes known, genetic testing is forming an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation.     

Genetic defects, ionic currents and electrocardiographic alterations

Most experimental data on the kinetic properties of cardiac ion channels and their modification by genetic defects have been obtained in expression systems (e.g., Xenopus oocyte), away from the cellular environment where these channels function to generate the cardiac action potential. In this article, we describe the use of computational biology (computer simulations) in integrating such information on single ion channels into models of the functioning cardiac cell. We use this approach to mechanistically relate molecular processes to whole-cell electrophysiological function and its manifestation in electrocardiographic waveforms. Examples are provided from the congenital long QT syndrome and the Brugada syndrome.     

Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome

BACKGROUND: Long QT syndrome (LQTS) is a hereditary cardiac arrhythmogenic disorder characterized by prolongation of the QT interval in the electrocardiogram, torsades de pointes arrhythmia, and syncopes and sudden death. LQTS is caused by mutations in ion channel genes. However, only in half of the families is it possible to identify mutations in one of the seven known LQTS genes, why further genetic heterogeneity is expected. The genes KCND2 and KCND3, encoding the alpha-subunits of the voltage-gated potassium channels Kv4.2 and Kv4.3 conducting the fast transient outward current (I(TO,f)) of the cardiac action potential (AP) in the myocardium, have been associated with prolongation of AP duration and QT prolongation in murine models. METHODS: KCND2 and KCND3 were examined for mutations using single-strand conformation polymorphism (SSCP) analysis in 43 unrelated LQTS patients, where mutations in the coding regions of known LQTS genes had been excluded. RESULTS: Seven single nucleotide polymorphismsm (SNPs) were found, two exonic SNPs in KCND2 and three exonic and two intronic in KCND3. None of the five exonic SNPs had coding effect. All seven SNPs are considered normal variants. CONCLUSION: The data suggest that mutations in KCND2 and KCND3 are not a frequent cause of long QT syndrome.     

The genetic basis for cardiac dysrhythmias and the long QT syndrome.

Cardiac muscle excitation is the result of ion fluxes through cellular membrane channels. Any alterations in channel proteins that produce abnormal ionic fluxes will change the cardiac action potential and the pattern of electrical firing within the heart. The idiopathic long QT syndrome (LQTS) is an inherited cardiac pathology localized to mutated genes encoding for myocardial, voltage-activated sodium and potassium ion channels. The expression of abnormal sodium and potassium channels results in aberrant ionic fluxes that produce a prolonged ventricular repolarization. This prolonged time to repolarization is the electrophysiologic basis for prolongation of the QT interval. Individuals with LQTS are at significant risk for developing lethal ventricular dysrhythmias due to an abnormal pattern of cardiac excitation. Identification of a genetic basis for LQTS has had significant implications for genetic counseling, the development of effective antidysrhythmic drug therapies, and nursing interventions.     

Sudden arrhythmia death syndrome: importance of the long QT syndrome

In approximately 5 percent of sudden cardiac deaths, no demonstrable anatomic abnormality is found. Some cases are caused by sudden arrhythmia death syndrome. A prolonged QT interval is a common thread among the various entities associated with sudden arrhythmia death syndrome. A number of drugs are known to cause QT prolongation (e.g., terfenadine), as are hypokalemia, hypomagnesemia, myocarditis, and endocrine and nutritional disorders. Recently, attention has focused on a group of inherited gene mutations in cardiac ion channels that cause long QT syndrome and carry an increased risk for sudden death. Some of the highest rates of inherited long QT syndrome occur in Southeast Asian and Pacific Rim countries. The median age of persons who die of long QT syndrome is 32 years; men are predominately affected. In addition to a prolonged QT interval, which occurs in some but not all persons with long QT syndrome, another characteristic electrocardiographic abnormality is the so-called Brugada sign (an upward deflection of the terminal portion of the QRS complex). Most cardiac events are precipitated by vigorous exercise or emotional stress, but they also can occur during sleep. Torsades de pointes and ventricular fibrillation are the usual fatal arrhythmias. Long QT syndrome should be suspected in patients with recurrent syncope during exertion and those with family histories of sudden, unexpected death. Unfortunately, not all persons with long QT syndrome have premonitory symptoms or identifiable electrocardiographic abnormalities, and they may first present with sudden death. Beta blockers, potassium supplements, and implantable defibrillators have been used for treatment of long QT syndrome. Identifying the specific gene mutation in a given patient with long QT syndrome can help guide prophylactic therapy.     

Congenital long QT syndromes: clinical features, molecular genetics and genetic testing

Congenital long QT syndrome (LQTS) is a primary electrical disease characterized by a prolonged QT interval in the surface electrocardiogram and increased predisposition to a typical polymorphic ventricular tachycardia, termed Torsade de Pointes. Most patients with LQTS are asymptomatic and are diagnosed incidentally based on an electrocardiogram. Symptomatic patients may suffer from severe cardiac events, such as syncope and/or sudden cardiac death. Autosomal dominant forms are caused by heterozygous mutations in genes encoding the components of the ion channels. The autosomal recessive form with congenital deafness is also known as Jervell and Lang-Nielsen syndrome. It is caused by homozygous mutations or certain compound heterozygous mutations. Depending on the genetic defects, there are differences in the age of onset, severity of symptoms, and number of cardiac events and event triggers. With advances in gene technology, it is now feasible to perform genetic testing for LQTS, especially for those with family history. Identification of the mutation will lead to better management of symptoms and more targeted treatment, depending on the underlying genetic defect, resulting in a reduction of mortality and cardiac events.     

Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG

Patients with LQTS (long QT syndrome) with a mutation in a cardiac ion channel gene, leading to mild-to-moderate channel dysfunction, may manifest marked QT prolongation or torsade de pointes only upon an additional stressor. A 59-year-old woman had marked QT prolongation and repeated torsade de pointes 3 months after initiation of probucol, a cholesterol-lowering drug. We identified a single base substitution in the HERG gene by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of Met(124)-->Thr (M124T) in the N-terminus. Three other relatives with this mutation also had QT prolongation and one of them had a prolonged QT interval and torsade de pointes accompanied by syncope after taking probucol. We expressed wild-type HERG and HERG with M124T in Xenopus oocytes and characterized the electrophysiological properties of these HERG channels and the action of probucol on the channels. Injection of the M124T mutant cRNA into Xenopus oocytes resulted in expression of functional channels with markedly smaller amplitude. In both HERG channels, probucol decreased the amplitude of the HERG tail current, decelerated the rate of channel activation, accelerated the rate of channel deactivation and shifted the reversal potential to a more positive value. The electrophysiological study indicated that QT lengthening and cardiac arrhythmia in the two present patients were due to inhibition of I(Kr) (rapidly activating delayed rectifier K(+) current) by probucol, in addition to the significant suppression of HERG current in HERG channels with the M124T mutation.     

A 2015 focus on preventing drug-induced arrhythmias

Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed human ether-a-go-go-related gene channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this assessment strategy led to a great amount of false positive outcomes. Therefore, this review will discuss new pharmaceutical strategies: the cardiac safety proposal that recently emerged, the Comprehensive in vitro Proarrhythmia Assay, combining in vitro assays that integrate effects on main cardiac ion channels, with computational models of human ventricular action potential as well as assays using human stem cell-derived cardiomyocytes for an improved prediction of drug’s proarrhythmic liability, alternative pharmacological perspectives as well as the current treatment of drug-induced long QT syndrome.     

The evolving role of genetics in the diagnosis and management of heart disease

The role of genetics in heart disease diagnosis and management is expanding daily. Clear genetic components have been found for diseases such as hypertrophic cardiomyopathy, heart failure, and coronary artery disease. Rhythm disturbances with genetic components are atrial fibrillation and long QT syndrome. Gene therapies to treat cardiac diseases include those designed to prevent vein graft stenosis and those that promote coronary angiogenesis.     

Fatal QT interval

A 21-year-old woman, without medical history, was admitted after cardiac arrest. Cardiopulmonary resuscitation and use of semiautomatic defibrillator quickly restored sinus rhythm. Clinical examination was normal with no cardiac murmur or abnormal heart sound. Electrocardiogram revealed sinus rhythm with short QT interval. Serum electrolytes and arterial blood gazes were normal. One hour after admission, lethal ventricular fibrillation occurred. Factors that shorten QT interval including increase in heart rate, hyperthermia, increased calcium, or potassium plasma levels and acidosis were excluded. Short-QT syndrome has been recently recognized as a genetic ion channel dysfunction leading to an abbreviation of action potential and a potential substrate for arrhythmias. This syndrome is characterized by a short QT interval (typically <320 milliseconds), associated with a high incidence of sudden death, syncope, or atrial fibrillation in individuals with an apparently normal heart. Implementation of an internal cardiac defibrillator remains the only effective preventive treatment.     

Congenital long QT syndrome: considerations for primary care physicians

Congenital long QT syndrome is an inherited disorder of cardiac repolarization that predisposes to syncope and to sudden death from polymorphic ventricular tachycardia. The disorder should be suspected when the electrocardiogram shows characteristic QT abnormalities, or when there is a family history of long QT syndrome or of an event that raises suspicion of long QT syndrome, such as sudden death, syncope, or ill-defined "seizure" disorder. We can now classify some types of congenital long QT syndrome according to their genetic mutations and their triggers, such as exercise, rest, or startle.     

Short QT syndrome: a case report and review of literature

The short QT syndrome has been recently recognised as a genetic ion channel dysfunction. This new clinical entity is associated with an incidence of sudden cardiac death, syncope, and atrial fibrillation in otherwise healthy individuals. The distinctive ECG pattern consists of an abnormally short QT interval, a short or even absent ST segment and narrow T waves. A 30-year-old resuscitated woman with short QT syndrome is described together with an example of the classic ECG characteristics. A short-coupled variant of torsade de pointes was reveal on Holter recordings. The implantable cardioveter defibrillator seems to be the therapy of choice to prevent from sudden cardiac death. Quinidine proved to be efficient in prolonging the QT interval and rendering ventricular tachyarrhythmias non-inducible in patients with a mutation in KCNH2 (HERG). Our preliminary data suggest amiodarone combined with beta-blocker may be helpful in treating episodes of polymorphic ventricular tachycardia for patients with an unknown genotype. Because the short QT syndrome often involves young patients with an apparently normal heart, it is imperative for physicians to recognize the clinical features of the short QT syndrome in making a timely correct diagnosis.     

The genetics of cardiac disease associated with sudden cardiac death: a paper from the 2011 william beaumont hospital symposium on molecular pathology

Sudden cardiac death due to ventricular arrhythmia most commonly occurs in the setting of coronary artery disease. However, a number of inherited syndromes have now been identified that carry a significant risk of sudden cardiac death and that are disproportionately represented in the young. Arrhythmia in such conditions may result from genetically mediated structural heart disease (eg, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy) or from altered function of cardiac ion channels in the absence of overt structural disease (eg, Brugada syndrome and long QT syndrome). The past 15 years have seen considerable progress in our understanding of the genetic underpinnings of these disorders. With the advent of clinical genetic testing as a routine part of clinical care, a new knowledge base is required of practicing cardiologists and genetic testing facilities, particularly related to the rational ordering of genetic testing and the interpretation of results. This review addresses the latest findings in regard to the genetic causes of inherited syndromes associated with sudden cardiac death and summarizes recently published guidelines for the genetic testing of affected individuals and their families.     

Clinical characteristics and treatment of short QT syndrome

Short QT syndrome is a new inherited disorder associated with familial atrial fibrillation and/or sudden death or syncope. To date, three different mutations in genes encoding cardiac ion channels (KCNH2, KCNQ1 and KCNJ2) have been identified as causing short QT syndrome. All mutations lead to a gain in function of the affected current (IK(r), IK(s )and IK(1)). The syndrome is characterized in the few patients identified so far by a shortened QT interval of less than 300-325 ms after correction for heart rate at rates below 80 beats per minute. However, no boundary or limit for the QT interval can yet be determined, as more knowledge about this disease is still restricted to a small patient population. Furthermore, the QT interval lacks adaptation to heart rate. The majority of patients exhibit shortened atrial and ventricular effective refractory periods and inducibility of ventricular fibrillation. Death already occurs in newborns, so the short QT syndrome may also account for deaths classified as sudden infant death syndrome. The therapy of choice in families with a history of sudden death or syncope seems to be the implantable cardioverter-defibrillator. Whether patients without a family history of sudden death or symptoms need a defibrillator cannot yet be answered, and requires further investigation. Pharmacologic treatment has only been investigated in patients with a mutation in KCNH2 (HERG), and it could be demonstrated that the mutant currents may be insufficiently suppressed by drugs that are targeted to block the specific current (e.g., sotalol or ibutilide) in patients with a mutation in the IK(r-)coding gene KCNH2 (HERG). Interestingly, in this specific patient population, quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods. Implantable cardioverter-defibrillator therapy is associated with an increased risk of inappropriate therapies for T-wave oversensing, although this risk can be resolved by reprogramming implantable cardioverter-defibrillator detection algorithms.     

Renal cell carcinoma: staging and surveillance

Renal cell carcinoma is a common malignancy with many histologic subtypes. Appropriate treatment depends not only upon the specific subtype but also the size of the tumor and extent of spread at time of presentation. Approximately 5% of RCCs are part of a hereditary syndrome which must also be considered in the therapeutic decisions. Although some RCCs are detected with ultrasound, CT or MR is required for staging. CT is used most commonly as it is most readily available and relatively less expensive than MR imaging. The TNM classification of the American Joint Committee on Cancer has largely replaced the Robson classification. Early detection, accurate staging, and improved treatment options have resulted in improved 5-year survival of patients with renal carcinoma.     

Long QT syndrome: from channels to cardiac arrhythmias

Long QT syndrome, a rare genetic disorder associated with life-threatening arrhythmias, has provided a wealth of information about fundamental mechanisms underlying human cardiac electrophysiology that has come about because of truly collaborative interactions between clinical and basic scientists. Our understanding of the mechanisms that control the critical plateau and repolarization phases of the human ventricular action potential has been raised to new levels through these studies, which have clarified the manner in which both potassium and sodium channels regulate this critical period of electrical activity.     

低钾血症中遗传性肾小管疾病的临床特点分析

目的 探讨不同病因所致低钾血症的临床特点及治疗预后,提高遗传性肾小管疾病的诊治水平。方法 回顾性分析山东第一医科大学附属省立医院小儿内分泌综合科病房收治低钾血症患者,排除胃肠道失钾和营养不良的易辨识因素,收集临床病例资料。部分患者进行基因检测,对遗传性肾小管疾病的临床特点进行分析。结果 低钾血症患者65例,男29例,女36例。共有47例属于遗传性肾小管疾病,包括Bartter综合征(23例)、肾小管酸中毒(14例)、Gitelman综合征(8例)、范可尼综合征(2例)。10例患者行基因检测,明确致病变异9例,包括新发变异1例。Bartter综合征为低血钾、低血钠、低氯代谢性碱中毒;Gitelman综合征生化表现为低血钾低氯;肾小管酸中毒表现为低钾高氯酸中毒。Bartter综合征发病年龄最小,其次是肾小管酸中毒,Gitelman综合征多为年长儿。Bartter综合征最常见的就诊症状为胃肠道不适、多饮多尿、生长迟缓,Gitelman综合征以胃肠道症状、生长迟缓为主要就诊原因,肾小管酸中毒患者多以四肢乏力、生长迟缓为主要就诊症状。经治疗,遗传性肾小管疾病患儿预后较好,多数实现生化正常和生长追赶。结论 遗传性肾小管疾病是低钾血症的常见病因,具有不同临床和生化特点,基因检测有助于确诊,长期治疗随访有助于改善预后。