Mutations In Cardiac Ion Channels Research Articles

Genetics of atrial fibrillation-practical applications for clinical management: if not now, when and how?

The prevalence and economic burden of atrial fibrillation (AF) are predicted to more than double over the next few decades. In addition to anticoagulation and treatment of concomitant cardiovascular conditions, early and standardized rhythm control therapy reduces cardiovascular outcomes as compared with a rate control approach, favouring the restoration, and maintenance of sinus rhythm safely. Current therapies for rhythm control of AF include antiarrhythmic drugs (AADs) and catheter ablation (CA). However, response in an individual patient is highly variable with some remaining free of AF for long periods on antiarrhythmic therapy, while others require repeat AF ablation within weeks. The limited success of rhythm control therapy for AF is in part related to incomplete understanding of the pathophysiological mechanisms and our inability to predict responses in individual patients. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to rhythm control approach. Over the last decade, tremendous progress has been made in defining the genetic architecture of AF with the identification of rare mutations in cardiac ion channels, signalling molecules, and myocardial structural proteins associated with familial (early-onset) AF. Conversely, genome-wide association studies have identified common variants at over 100 genetic loci and the development of polygenic risk scores has identified high-risk individuals. Although retrospective studies suggest that response to AADs and CA is modulated in part by common genetic variation, the development of a comprehensive clinical and genetic risk score may enable the translation of genetic data to the bedside care of AF patients. Given the economic impact of the AF epidemic, even small changes in therapeutic efficacy may lead to substantial improvements for patients and health care systems.

Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.

Several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.

TO IMPLANT OR NOT TO IMPLANT: A CASE OF CLINICALLY-DIAGNOSED BUT GENETICALLY INDETERMINATE LONG-QT SYNDROME

Long QT syndrome (LQTS) encompasses one or more gene mutations of cardiac ion channels predisposing patients to ventricular dysrhythmias and sudden cardiac death. Due to seizures from dysrhythmia-induced cerebral anoxia, LQTS is often misdiagnosed as epilepsy. We discuss the decision to place an ICD

Understanding AF Mechanisms Through Computational Modelling and Simulations

AF is a progressive disease of the atria, involving complex mechanisms related to its initiation, maintenance and progression. Computational modelling provides a framework for integration of experimental and clinical findings, and has emerged as an essential part of mechanistic research in AF. The authors summarise recent advancements in development of multi-scale AF models and focus on the mechanistic links between alternations in atrial structure and electrophysiology with AF. Key AF mechanisms that have been explored using atrial modelling are pulmonary vein ectopy; atrial fibrosis and fibrosis distribution; atrial wall thickness heterogeneity; atrial adipose tissue infiltration; development of repolarisation alternans; cardiac ion channel mutations; and atrial stretch with mechano-electrical feedback. They review modelling approaches that capture variability at the cohort level and provide cohort-specific mechanistic insights. The authors conclude with a summary of future perspectives, as envisioned for the contributions of atrial modelling in the mechanistic understanding of AF.

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost, time, and labor intensive. We implemented a strategy for performing high-throughput functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery. We demonstrated the success of this approach by evaluating 78 variants in KCNQ1, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying >65% of the studied KCNQ1 variants. Our results illustrate an efficient and high-throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.

A multiplex PCR strategy to screen for known mutations in families with sudden cardiac death burden.

Ventricular tachyarrythmia occurring in ischemic heart disease, dilated/hypertrophic cardiomyopathies or rare monogenic mutations of cardiac ion channels or associated proteins belong to the most frequent causes of sudden cardiac death (SCD). In further decades, next generation sequencing and bioinformatic analysis will become the gold standard of SCD risk stratification. At the moment, Sanger-sequencing is still obligatory in genetic diagnosis. A multiplex polymerase chain reaction (PCR) assay detecting eight SCD mutations in one reaction-tube was developed. To test the general validity of the assay, it was used with 12 patients, who had one or two of the eight mutations (LMNA, p.V256V; SCN5A, p.R1583C; RYR2, p.G1885E; MYH7, V606M; DSG2, p.T335A; KCNJ8, p.S422L; MYBPC, p.E441K; TNNT2, A38V). Thereafter, we tested the multiplex assay in a real diagnostic environment within a high risk family of several past SCD cases. This method allows efficient discrimination of multiple mutations by allele-specific PCR with standard PCR conditions. It relies on obtaining a PCR product specific to the mutation or wildtype—using primers that have the 3′end base complementary to the DNA template site, i.e. a specific primer only permits amplification to take place when its 3′terminal nucleotide matches with its target sequence. The PCR products are further analyzed by length, with Tape Station®(Agilent Technologies, Germany), a high-fidelity capillary chromatography test. The novel multiplex PCR assay strategy could be a good additional test used for SCD risk stratification. Advantages of the test are high velocity and ease of implementation, low price and flexibility of application within cardiomyopathy families for screening purposes.

Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs)

Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine. This would be facilitated by deriving hPSC-CMs from patients or susceptible individuals as hiPSCs. For all applications, however, precise measurement and analysis of hPSC-CM electrical properties are essential for identifying changes due to cardiac ion channel mutations and/or drugs that target ion channels and can cause sudden cardiac death. Compared with manual patch-clamp, multi-electrode array (MEA) devices offer the advantage of allowing medium- to high-throughput recordings. This protocol describes how to dissociate 2D cell cultures of hPSC-CMs to small aggregates and single cells and plate them on MEAs to record their spontaneous electrical activity as field potential. Methods for analyzing the recorded data to extract specific parameters, such as the QT and the RR intervals, are also described here. Changes in these parameters would be expected in hPSC-CMs carrying mutations responsible for cardiac arrhythmias and following addition of specific drugs, allowing detection of those that carry a cardiotoxic risk.

Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs).

Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine. This would be facilitated by deriving hPSC-CMs from patients or susceptible individuals as hiPSCs. For all applications, however, precise measurement and analysis of hPSC-CM electrical properties are essential for identifying changes due to cardiac ion channel mutations and/or drugs that target ion channels and can cause sudden cardiac death. Compared with manual patch-clamp, multi-electrode array (MEA) devices offer the advantage of allowing medium- to high-throughput recordings. This protocol describes how to dissociate 2D cell cultures of hPSC-CMs to small aggregates and single cells and plate them on MEAs to record their spontaneous electrical activity as field potential. Methods for analyzing the recorded data to extract specific parameters, such as the QT and the RR intervals, are also described here. Changes in these parameters would be expected in hPSC-CMs carrying mutations responsible for cardiac arrhythmias and following addition of specific drugs, allowing detection of those that carry a cardiotoxic risk.

Sudden Infant Death and Modulation of Late Sodium Current by Hypoxia, Investigated in Induced Pluripotent Stem Cells

Sudden infant death (SIDS) occurs in about 0.4 per 1000 life births in the United States and other western countries. Recognized risk factors for SIDS are prone sleeping position, maternal smoking, and bed sharing. These factors point to the potential involvement of respiratory stress in the syndrome.Furthermore, in about 20% of SIDS cases, mutations in cardiac ion channels have been found. Of those, about 50% affect the cardiac sodium channel, which is also affected in individuals suffering from long-QT syndrome type 3 (LQT3). In these mutated ion channels, the late component of the sodium current during the plateau phase of the cardiac action potential is markedly increased, due to incomplete inactivation of the channels.We hypothesise that a combination of hypoxia, induced by respiratory stress, and cardiac sodium channel mutations that increase the late sodium current, cause an synergistic increase in late sodium current, which predisposes vulnerable infants to sudden arrhythmic death.Preliminary data using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) supports this hypothesis. Using microelectrode arrays, we were able to show that in a pharmacological model of LQT3, hypoxic conditions dramatically increase the field potential upstroke velocity, which is an indirect marker of the sodium channel availability.Cells were treated with Anthopleurin-A, which destabilises the inactive state of cardiac sodium channels. Under hypoxic conditions, the field potential upstroke velocity was increased by about 4-fold, compared to normoxic conditions. This effect was not present in untreated control cells. The late sodium current blocker Ranolazine was able to reduce this effect in a dose dependent manner, suggesting that indeed the late sodium current was responsible for this effect.

Dan Roden: learn, apply, evolve.

As a scientist, Dan Roden grew up as clinical electrophysiology did. Widely recognized for his research into mechanisms behind abnormal heart rhythms and drug responses, Roden was on the front lines in the 1980s and 1990s as new antiarrhythmic drugs were tested, the ability to use catheters to study drug actions evolved, and the specialty of clinical electrophysiology arose. From his first publication, appearing in the New England Journal of Medicine in 1980,1 Roden set a tone for a career focused on variable action of antiarrhythmic therapies and genetic determinants of that variation. Much of his current work focuses on individual cardiac ion channel mutations and their role in variable responses to drug therapy, and applications of genomics to healthcare. Among his achievements, Roden is credited with developing the idea of reduced repolarization reserve leading to acquired long QT intervals and arrhythmias2–4 and was one of the first to suggest that early afterdepolarizations cause long QT-related arrhythmias.5,6 As leader of Vanderbilt University’s pharmacogenomics project PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care & Treatment)—which pre-emptively enhances individuals’ electronic medical records with personalized information about genetic variants that could guide drug therapy—Roden and colleagues7 have demonstrated multiple advantages of preemptive genotyping. Meanwhile Vanderbilt’s massive BioVU DNA bank, which includes ≈175 000 human DNA samples and which Roden pioneered and directs, is similarly showing the power of incorporating genomic data into electronic medical records, for research purposes.7–11 Roden, who initially flirted with a future in journalism, described to Circulation Research some of his interests beginning as a child of immigrants in Montreal and leading to not just 1 career as an investigator, but a series of interlinked careers—in clinical pharmacology, cellular electrophysiology, molecular genetics, and population science. The paradigm for his progress, …

8.2 Cardiac Ion Channelopathies in Unexplained Stillbirths

BackgroundAlthough cardiac ion channelopathies are reported in up to 15% of sudden infant deaths, the prevalence in unexplained stillbirths is not known.ObjectiveTo determine the prevalence of genetic mutations in cardiac...

Cardiac Channelopathies Associated with Infantile Fatal Ventricular Arrhythmias: From the Cradle to the Bench

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. 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. 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.

Atrial standstill in a patient with progressive severe heart failure

Atrial standstill (AS) is a very rare condition characterized by complete loss of electrical and mechanical activity and excitability of the atria. Absence of P waves, bradycardia and junctional escape rhythm may suggest AS on surface ECG. In nearly half of the reported cases, the condition manifested with syncope [1, 2]. AS must be differentiated from common sinus node disease with sinus arrest or highgrade sinoatrial block that may have similar symptoms and surface ECG presentation [3]. AS has been rarely described to be primary with familial clustering and/or associated cardiac ion channel mutations [2, 4]. More commonly, it has been linked to heart disorders such as myocarditis, ischemic heart disease, or dilated cardiomyopathy [5–7]. AS occurring in the context of structural myocardial disease may indicate a poor prognosis [1, 8]. A 48-year-old female patient was referred to our emergency department due to fatigue, progressive dyspnoea on exertion and recurring syncope since a few months. Three years earlier she had presented to our outpatient clinic for recurrent pulmonary infections, where a normal ECG had been registered (Fig. 1a). Four months before she had been hospitalized at an external institution for ascites and pleural effusion of unknown origin and atrial fibrillation was diagnosed on surface ECG. A diuretic as well as oral anticoagulation were initiated. At presentation, the patient reported no family history of syncope or sudden death, and physical examination revealed cachexia (BMI 18.6 kg/m), but no obvious cardiopulmonary pathologies. Shortly after admission, the patient exhibited rapid polymorphic ventricular tachycardia (VT), requiring CPR and defibrillation. Twelve-lead surface ECG, recorded prior the arrhythmic event, showed absence of P waves with an escape rhythm of 48/min, a QRS duration of 70 ms, constant R–R intervals, and a prolonged QT interval of 600 ms (QTc 536 ms) (Fig. 1b). Laboratory findings revealed mild hypokalemia (3.2 mmol/ L), slightly elevated liver enzymes, an INR value of 2.1, N-terminal pro-BNP of 1,465 pg/mL (7.39 of normal value) and an ANP of 2.89 nmol/L (1.59 of normal value), whereas normal values were found for calcium, blood cell count, CRP, renal and thyroid functional parameters and CK. Chest X-ray revealed marked cardiomegaly, and the echocardiogram showed a dilated left ventricle with a severely reduced left ventricular ejection fraction (LVEF) of 20 %. Of note, LVEF had been reported to be 45 and 60 %, 2 and 3 months earlier, respectively. Furthermore, echocardiography showed dilated right and left atria along with moderate to severe tricuspid and moderate mitral regurgitation. A transesophageal echocardiogram revealed a thrombus in the left atrial appendage, where no significant flow was identifiable with Doppler imaging (Fig. 1c, d). Few hours after admission, the patient again developed recurrent polymorphic VT with syncope and need for defibrillation despite normalization of potassium levels (Fig. 1e). Coronary artery disease was ruled out angiographically and a temporary transvenous pacemaker was inserted. Myocardial biopsies were taken from the right ventricle, but provided no evidence for acute myocarditis [9], arrhythmogenic right ventricular dysplasia [10], amyloidosis or hemosiderosis. This was in line with findings from cardiac MRI, so that idiopathic dilated cardiomyopathy was diagnosed. With ventricular overdrive pacing at 80 bpm and initiation of beta-blocker medication VT did M. R. Schroeter (&) G. Hasenfus M. Zabel D. Vollmann Abt. Kardiologie und Pneumologie, Universitatsmedizin Gottingen, Herzzentrum, Robert-Koch-Str. 40, 37099 Gottingen, Germany e-mail: mschroeter@med.uni-goettingen.de

Ion channel complex disease in long QT syndrome

Sixty years have passed since the first report of congenital long syndrome (LQTS). The pathogenesis of LQTS was speculated to be ion channel dysfunction in the early 1990s, 1 and mutations in cardiac ion channels were found one after another at the end of the 20th century. 2‐4 Since mutations in cardiac ion channels induced various diseases, including LQTS, Brugada syndrome, and progressive cardiac conduction disease, these inherited arrhythmic diseases were named “ion channel diseases” or “channelopathies.” 5 At first, mutations found in inherited arrhythmia diseases were all mutations in a-subunits of the channels, which are the main components of the ion channels, the mutations in the b-subunit, an auxiliary subunit of the channel, were later reported in Jervell and Lange-Nielsen syndrome, a phenotype of LQTS. 6 It was then shown that the regulation of channels depends not only on its a- and b-subunits but also on multiple cytoskeletal and membrane proteins and that mutations in these protein genes can also cause inherited arrhythmia syndromes. For example, the a-subunit of the cardiac sodium channel (NaV1.5) encoded by the SCN5A gene composes a main channel protein and conducts cardiac sodium current. Some auxiliary proteins interact with NaV1.5 and control its transport to the sarcolemma, cellular location, and gating properties by phosphorylation or dephosphorylation, and anchor NaV1.5 to the cytoskeleton. Mutations in some of these auxiliary proteins showed clinical phenotypes similar to type 3 LQTS (gain of function) or Brugada syndrome (loss of function). Thus, the recent concept of “channelopathy” should not be limited to mutations in the channel protein itself but should be expanded to mutations in the adaptor proteins. Cardiac potassium currents that contribute to ventricular repolarization consist of a rapid activation component (IKr) and a slow activation component (IKs). IKs is activated at phases 2 and 3 of action potential, and it terminates the

In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling

Introduction: Genetic forms of the Short QT Syndrome (SQTS) arise due to cardiac ion channel mutations leading to accelerated ventricular repolarization, arrhythmias and sudden cardiac death. Results from experimental and simulation studies suggest that changes to refractoriness and tissue vulnerability produce a substrate favorable to re-entry. Potential electromechanical consequences of the SQTS are less well-understood. The aim of this study was to utilize electromechanically coupled human ventricle models to explore electromechanical consequences of the SQTS.Methods and Results: The Rice et al. mechanical model was coupled to the ten Tusscher et al. ventricular cell model. Previously validated K+ channel formulations for SQT variants 1 and 3 were incorporated. Functional effects of the SQTS mutations on [Ca2+]i transients, sarcomere length shortening and contractile force at the single cell level were evaluated with and without the consideration of stretch-activated channel current (Isac). Without Isac, at a stimulation frequency of 1Hz, the SQTS mutations produced dramatic reductions in the amplitude of [Ca2+]i transients, sarcomere length shortening and contractile force. When Isac was incorporated, there was a considerable attenuation of the effects of SQTS-associated action potential shortening on Ca2+ transients, sarcomere shortening and contractile force. Single cell models were then incorporated into 3D human ventricular tissue models. The timing of maximum deformation was delayed in the SQTS setting compared to control.Conclusion: The incorporation of Isac appears to be an important consideration in modeling functional effects of SQT 1 and 3 mutations on cardiac electro-mechanical coupling. Whilst there is little evidence of profoundly impaired cardiac contractile function in SQTS patients, our 3D simulations correlate qualitatively with reported evidence for dissociation between ventricular repolarization and the end of mechanical systole.

Sudden Infant Death Syndrome and Cardiac Channelopathies: From Mechanisms to Prevention of Avoidable Tragedies

The sudden infant death syndrome (SIDS), with the load of mystery surrounding its causes and with the devastating impact on the affected families, remains the greatest contributor to post-neonatal mortality during the first year of life. Following a succinct review of the non-cardiac genetic factors, which have been associated with SIDS, we focus on the cardiac hypothesis for SIDS and specifically on those diseases produced by cardiac ion channel mutations, the so-called channelopathies. Special attention is devoted to the fact that these causes of SIDS, and especially the long QT syndrome, are preventable if diagnosed in time. This highlights the importance of neonatal ECG screening and carries a number of practical implications, including medico-legal considerations.

Development of a Long QT-Syndrome mutation detection method

Sudden cardiac death (SCD) especially in younger adults with no previous symptoms is a challenging problem in forensic diagnostics, occurring with an incidence of about 80,000 per year in Germany. Long QT-Syndrome (LQTS) and other cardiac disorders associated with abnormality of cardiac rhythm triggered by mutations of cardiac ion channels have to consider if no cause of death is detectable during autopsy. A molecular genetic screening can help to ensure. Meanwhile twelve genes are known in which more than 700 different mutations are associated with LQTS. The three major LQTS-susceptibility genes are KCNQ1, KCNH2 and SCN5A. They are responsible for 75% of all congenital LQTS cases. We developed a rapid, sensitive and reasonable method for the simultaneously screening of the most common LQTS mutations, focused on these three genes. Using the SNaPshot ® minisequencing primer extension assay a total of 91 Single-Nucleotide Polymorphisms (SNPs) were examined in six multiplex assays. The data suggest that this technique is applicable, solid, flexible and a good alternative to complete sequencing.

Defining a New Paradigm for Human Arrhythmia Syndromes

Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. More recently, a new paradigm for human arrhythmia has emerged based on gene mutations that affect the activity of cardiac ion channel- and transporter- associated proteins. As part of the Circulation Research thematic series on inherited arrhythmias, this review focuses on the emerging field of human arrhythmias caused by dysfunction in cytosolic gene products (including ankyrins, yotiao, syntrophin, and caveolin-3) that regulate the activities of key membrane ion channels and transporters.

Long QT syndrome provoked by induction of general anesthesia -A case report-

Long QT syndrome (LQTS) is an arrhythmogenic cardiovascular disorder resulting from mutations in cardiac ion channels. LQTS is characterized by prolonged ventricular repolarization and frequently manifests itself as QT interval prolongation on the electrocardiogram (ECG). A variety of commonly prescribed anesthetic drugs possess the adverse property of prolonging cardiac repolarization and may provoke serious ventricular tachyarrhythmia called 'torsades de pointes', ventricular fibrillation, and sudden death. We experienced a case of ventricular tachycardia and ventricular fibrillation after anesthetic induction and it came out into the open that anesthetic induction provoked long QT syndrome.

Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome

The congenital form of the long QT syndrome (LQTS) results from mutations in cardiac ion channels with a high degree of genetic heterogeneity. Ten different genes and >400 mutations with varying penetrance have been identified to date. Drug-induced acquired LQTS with torsade de pointes tachycardia as its most relevant clinical manifestation has been described as a result of previously unsuspected congenital LQTS. Only rarely, macroscopic T-wave alternans (TWA) is documented before the onset of torsade de pointes. A 62-year-old male patient without previously documented QT prolongation …