Recognition and Management Considerations of Cardiac Channelopathies in the Intensive Care Unit.

The understanding and prevalence of cardiac channelopathies has grown over time. Many patients are asymptomatic but are at risk for malignant arrhythmias during high-acuity medical admissions. Long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are discussed with specific consideration given for the role these medical conditions play during an intensive care unit admission-for either cardiac or noncardiac reasons.

Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency.

Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient's lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.

[Why do we need genetics in cardiac rhythmology?] / Welche Bedeutung hat die Genetik in der Rhythmologie?

A variety of arrhythmogenic cardiac diseases such as channelopathies and cardiomyopathies are caused by genetic alterations. In patients with these diseases, malignant arrhythmias or sudden cardiac death frequently manifest already during young adulthood. Early recognition, risk stratification and adequate therapy is therefore essential to avoid sudden cardiac death. This review summarizes the implications of genetic testing for diagnosis, risk stratification and therapy of patients with cardiac channelopathies (long-QT syndrome, short-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia) and inherited cardiomyopathies (hypertrophic, dilatative or arrhythmogenic right ventricular cardiomyopathy).

Subcutaneous implantable cardioverter defibrillator in cardiomyopathies and channelopathies.

: Cardiomyopathies and channelopathies are heterogeneous disorders that increase the risk of sudden cardiac death (SCD). Implantable cardioverter-defibrillator (ICD) therapy is safe and effective for preventing SCD in patients at risk for malignant ventricular arrhythmias. Because of the poor positive predictive value of current risk stratification tools, the majority of patients implanted with an ICD will never receive a life-saving therapy but will be exposed to the risk of complications such as device infection, lead failure and inappropriate therapy. Subcutaneous ICD (S-ICD) now constitutes a valuable alternative to conventional transvenous ICD in patients with cardiomyopathies and channelopathies as it provides protection from SCD while avoiding the risks of intravascular lead infection or failure. This may be particularly advantageous for young patients with a very long life expectancy. On the other hand, S-ICD cannot deliver antitachycardia pacing or antibradycardia pacing. The purpose of this article is to review the available evidence and the future perspectives of S-ICD therapy in patients with cardiomyopathies or channelopathies.

Cardiac Channelopathies: Recognition, Treatment, Management.

The discovery of the human genome has ushered in a new era of molecular testing, advancing our knowledge and ability to identify cardiac channelopathies. Genetic variations can affect the opening and closing of the potassium, sodium, and calcium channels, resulting in arrhythmias and sudden death. Cardiac arrhythmias caused by disorders of ion channels are known as cardiac channelopathies. Nurses are important members of many interdisciplinary teams and must have a general understanding of the pathophysiology of the most commonly encountered cardiac channelopathies, electrocardiogram characteristics, approaches to treatment, and care for patients and their families. This article provides an overview of cardiac channelopathies that nurses might encounter in an array of clinical and research settings, focusing on the clinically relevant features of long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Genetic basis of channelopathies and cardiomyopathies in Hong Kong Chinese patients: a 10-year regional laboratory experience.

INTRODUCTION: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. METHODS: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1,KCNH2,KCNE1,KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy. RESULTS: There were 17 males and 11 females; their mean age at diagnosis was 39 years (range, 1-80 years). The major clinical presentations included syncope, palpitations, and abnormal electrocardiography findings. A family history was present in 13 (46%) patients. There were 26 different heterozygous mutations detected, of which six were novel-two in SCN5A (NM_198056.2:c.429del and c.2024-11T>A), two in MYBPC3 (NM_000256.3:c.906-22G>A and c.2105_2106del), and two in LMNA (NM_170707.3:c.73C>A and c.1209_1213dup). CONCLUSIONS: We have characterised the genetic heterogeneity in channelopathies and cardiomyopathies among Hong Kong Chinese patients in a 10-year case series. Correct interpretation of genetic findings is difficult and requires expertise and experience. Caution regarding issues of non-penetrance, variable expressivity, phenotype-genotype correlation, susceptibility risk, and digenic inheritance is necessary for genetic counselling and cascade screening.

Clinical and Genetic Diagnosis of Nonischemic Sudden Cardiac Death.

INTRODUCTION AND OBJECTIVES: Nonischemic sudden cardiac death (SCD) is predominantly caused by cardiomyopathies and channelopathies. There are many diagnostic tests, including some complex techniques. Our aim was to analyze the diagnostic yield of a systematic diagnostic protocol in a specialized unit. METHODS: The study included 56 families with at least 1 index case of SCD (resuscitated or not). Survivors were studied with electrocardiogram, advanced cardiac imaging, exercise testing, familial study, genetic testing and, in some cases, pharmacological testing. Families with deceased probands were studied using the postmortem findings, familial evaluation, and molecular autopsy with next-generation sequencing (NGS). RESULTS: A positive diagnosis was obtained in 80.4% of the cases, with no differences between survivors and nonsurvivors (P=.53). Cardiac channelopathies were more prevalent among survivors than nonsurvivors (66.6% vs 40%, P=.03). Among the 30 deceased probands, the definitive diagnosis was given by autopsy in 7. A diagnosis of cardiomyopathy tended to be associated with a higher event rate in the family. Genetic testing with NGS was performed in 42 index cases, with a positive result in 28 (66.6%), with no differences between survivors and nonsurvivors (P=.21). CONCLUSIONS: There is a strong likelihood of reaching a diagnosis in SCD after a rigorous protocol, with a more prevalent diagnosis of channelopathy among survivors and a worse familial prognosis in cardiomyopathies. Genetic testing with NGS is useful and its value is increasing with respect to the Sanger method.

Phenotype-driven molecular autopsy for sudden cardiac death.

A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.

Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench.

BACKGROUND: Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. METHODS AND RESULTS: Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na(+) currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function. CONCLUSION: Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.

[Clinical and molecular genetic analysis of a family with normokalemic periodic paralysis].

OBJECTIVE: Periodic paralysis (PP) is one type of skeletal muscle channelopathies characterized by episodic attacks of weakness. It is usually classified into hyperkalemic periodic paralysis (HyperPP), hypokalemic periodic paralysis (HypoPP) and normokalemic periodic paralysis (NormoPP) based on the blood potassium levels. HypoPP is the most common type of these three and NormoPP is the rarest one. The aim of this study was to explore the clinical and genetic features of a Chinese family with normokalemic periodic paralysis (NormoKPP). METHOD: Clinical features of all patients in the family with NormoKPP were analyzed. Genomic DNA was extracted from peripheral blood leukocytes and amplified with PCR. We screened all 24 exons of SCN4A gene and then sequence analysis was performed in those who showed heteroduplex as compared with unaffected controls. RESULT: (1) Fifteen members of the family were clinically diagnosed NormoKPP, and their common features are: onset within infacy, episodic attacks of weakness, the blood potassium levels were within normal ranges, high sodium diet or large dosage of normal saline could attenuate the symptom. One muscle biopsy was performed and examination of light and electronic microscopy showed occasionally degenerating myofibers. (2) Gene of 12 patients were screened and confirmed mutations of SCN4A genes--c. 2111 T > C/p. Thr704Met. CONCLUSION: The study further defined the clinical features of patients with NormoKPP, and molecular genetic analysis found SCN4A gene c. 2111 T > C/p. Thr704Met point mutation contributed to the disease. In line with the autosomal dominant inheritance laws, this family can be diagnosed with periodic paralysis, and be provided with genetic counseling. And the study may also help the clinical diagnosis, guide treatment and genetic counseling of this rare disease in China.

Síndrome de QT corto / Short QT syndrome

El síndrome de QT corto es una canalopatía hereditaria caracterizada por un anormal acortamiento del intervalo QT (IQT), por un riesgo incrementado para el desarrollo de fibrilación auricular y/o arritmias ventriculares malignas y por la ausencia de cardiopatía estructural. Es una enfermedad heterogénea y se han identificado mutaciones en los genes codificadores de los canales de potasio y de calcio. Un incremento en las corrientes neta de salida de potasio o una disminución en al entrada de calcio favorecen el acortamiento heterogéneo de la repolarización ventricular. La marcada abreviación de la longitud de onda del circuito es un factor arritmogénico adicional. El curso clínico oscila desde formas asintomáticas hasta fibrilación auricular paroxística o permanente, síncope, arritmias ventriculares y muerte súbita. El electrocardiograma muestra IQT 220-360 ms, ondas T altas y puntiagudas, prolongación del intervalo pico-final de la onda T e IQT rígido. Es poco frecuente, pero importante por el riesgo elevado de muerte súbita, que en ocasiones puede ser el debut. Puede presentarse solapado al síndrome de Brugada y a la repolarización precoz. El diagnóstico precisa excluir las causas secundarias que acortan el IQT y la no identificación de una mutación no lo excluye. La estimulación eléctrica programada tiene pobre valor diagnóstico y pronóstico. En los sujetos con muerte súbita abortada o con arritmias ventriculares con compromiso hemodinámica, el desfibrilador es la terapéutica de elección. La quinidina es una opción terapéutica alternativa

The short QT syndrome is an inherited channelopathy characterized by an abnormal shortening of the QT interval (QTI), an increased risk of developing atrial fibrillation and/or malignant ventricular arrhythmias, and the absence of structural heart disease. It is a heterogeneous disease and mutations have been identified in the genes encoding potassium and calcium channels. An increase in potassium net efflux or a decrease in calcium influx facilitate the heterogeneous shortening of ventricular repolarization. A marked shortening of the wavelength of the circuit is an additional arrhythmogenic factor. The clinical course ranges from asymptomatic forms to paroxysmal or permanent atrial fibrillation, syncope, ventricular arrhythmias and sudden death. The ECG shows QTI 220-360 ms, high and sharp T waves, prolongation of the final peak interval of the T wave, and QTI drive. It is a rare disease whose importance lies in the high risk of sudden death, which may sometimes be its debut. It may overlap Brugada syndrome and early repolarization. Diagnosis requires excluding secondary causes of QTI shortening. Failure to identify a mutation does not exclude it. Programmed electrical stimulation has a low diagnostic and prognostic value. Defibrillation is the therapy of choice for patients with aborted sudden death or ventricular arrhythmias with hemodynamic compromise. Quinidine is an alternative therapeutic option

Screening for, and management of, possible arrhythmogenic syndromes (channelopathies/ion channel diseases).

This survey assesses the current management strategies for individuals with electrocardiographic features, suggesting an arrhythmogenic syndrome [including long QT syndrome (LQTS), Brugada syndrome (BS), catecholaminergic polymorphic ventricular tachycardia (CPVT) or short QT syndrome] or family members of patients with a known arrhythmogenic syndrome, in 44 large European centres. The principal findings of this survey were: (i) the number of new patients with arrhythmogenic syndromes (symptomatic and asymptomatic) is relatively small; (ii) the clinical work-up of these patients consists mainly of non-invasive tests; (iii) a relatively high use of genetic testing is noted, especially in LQTS and CPVT; (iv) EP testing is commonly performed in asymptomatic BS patients and in family members of symptomatic BS patients; and (v) the majority of European electrophysiologists focus on first-degree relatives when dealing with family members of an index patient.

Congenital long QT syndrome presenting with a history of epilepsy: misdiagnosis or relationship between channelopathies of the heart and brain?

A 60-year-old man with a long history of epilepsy was referred for cardiologic evaluation. An earlier diagnosis of epilepsy was made on the basis of his clinical manifestation of tonic-clonic seizure. Electroencephalography (EEG) demonstrated paroxysmal slow waves in response to intermittent photic stimulation. However, electrocardiography (ECG) revealed bradycardia (heart rate, 48 bpm) and marked QT prolongation (QTc 477 ms). ECG monitoring confirmed remarkable QT prolongation; ventricular ectopy triggering torsades de pointes was recorded during seizure. The patient underwent temporary antitachycardia pacing, and an implantable cardioverter defibrillator (ICD) was finally implanted. Long QT syndrome (LQTS) genetic testing was conducted and a diagnosis of LQT2 was confirmed by the identification of mutation in KCNH2 (HERG). LQTS is associated with abnormal channel function due to mutations in ion channel genes. Epilepsy, a disorder of neural function, is also associated with abnormal channel function. The possibility that some channelopathies can manifest as both LQTS and epilepsy is discussed.

Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias.

PURPOSE OF REVIEW: To summarize advances in our understanding of the clinical phenotypes, genetics, and molecular pathophysiology of the periodic paralyses, the nondystrophic myotonias, and other muscle channelopathies. RECENT FINDINGS: The number of pathogenic mutations causing periodic paralysis, nondystrophic myotonias, and ryanodinopathies continues to grow with the advent of exon hierarchy analysis strategies for genetic screening and better understanding and recognition of disease phenotypes. Recent studies have expanded and clarified the role of gating pore current in channelopathy pathogenesis. It has been shown that the gating pore current can account for the molecular and phenotypic diseases observed in the muscle sodium channelopathies, and, given that homologous residues are affected in mutations of calcium channels, it is possible that pore leak represents a pathomechanism applicable to many channel diseases. Improvements in treatment of the muscle channelopathies are on the horizon. A randomized controlled trial has been initiated for the study of mexiletine in nondystrophic myotonias. The class IC antiarrhythmia drug flecainide has been shown to depress ventricular ectopy and improve exercise capacity in patients with Andersen-Tawil syndrome. SUMMARY: Recent studies have expanded our understanding of gating pore current as a disease-causing mechanism in the muscle channelopathies and have allowed new correlations to be drawn between disease genotype and phenotype.

Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease.

BACKGROUND: Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy. OBJECTIVE: To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. DESIGN: Observational, prospective case series. SETTING: Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. MAIN OUTCOME MEASURES: Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. RESULTS: All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy. CONCLUSIONS: Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody-associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.

Diagnosis and management of hyperinsulinaemic hypoglycaemia of infancy.

Hyperinsulinaemic hypoglycaemia is a cause of persistent hypoglycaemia in the neonatal and infancy periods. Prompt recognition and management of patients with hyperinsulinaemic hypoglycaemia are essential, if brain damage and long-term neurological sequelae are to be avoided. Hyperinsulinaemic hypoglycaemia can be transient, prolonged, or persistent (congenital). Advances in the fields of molecular biology, genetics, and pancreatic beta-cell physiology are beginning to provide novel insights into the mechanisms causing congenital forms of hyperinsulinism. So far mutations in six different genes have been described that lead to unregulated insulin secretion. The histological differentiation of focal and diffuse congenital hyperinsulinism has radically changed the surgical approach to this disease. Until recently, highly invasive investigations were performed to localize the focal lesion, but recent experience with (18)F-L-dopa positron emission tomography scanning suggests that this technique is highly sensitive for differentiating diffuse from focal disease as well as for accurately locating the focal lesion. Despite recent advances, the genetic basis of congenital hyperinsulinism is still unknown in about 50% of the patients, and the management of medically unresponsive diffuse disease remains a real challenge.

[Short QT syndrome]. / Kurzes QT-Syndrom.

Short QT syndrome is a new genetic disorder associated with familial atrial fibrillation and/or sudden death or syncope. To date, different mutations in genes encoding for cardiac ion channels (KCNH2, KCNQ1, and KCNJ2) have been identified to cause the short QT syndrome. The mutations lead to a gain of function of the affected current (IKr, IKs, and IK1). The phenotype is characterized by a shortened QT interval<335 ms after correction for heart rate at rates<80 beats/min. Furthermore, the QT interval poorly adapts to heart rate. Patients exhibit shortened atrial and ventricular effective refractory periods and, in the majority, inducibility of ventricular fibrillation. Death occurs already in newborns. Therapy of choice seems to be the implantable cardioverter defibrillator because of the high incidence of sudden death. Pharmacological treatment has been studied and it could be demonstrated, that some mutant currents may be insufficiently suppressed by drugs targeted to block the specific current such as, e.g., sotalol or ibutilide in patients with a mutation in the IKr-coding gene KCNH2 (HERG). Quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods in some patients.