Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients

Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On ß blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2–37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with ß blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of ß blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.     

Genetic Mutation in Korean Patients of Sudden Cardiac Arrest as a Surrogating Marker of Idiopathic Ventricular Arrhythmia

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.     

Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia

Background  

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.     

EMBASE search strategies for identifying methodologically sound diagnostic studies for use by clinicians and researchers

Background

The recurrence of cardiac events in patients with idiopathic ventricular fibrillation (VF) excluding patients with the Brugada syndrome is unclear since this entity remains present in previous studies.

Methods

Since 1992, 18 patients (72% male) with idiopathic VF out of 455 ICD implants were treated with an implantable cardioverter defibrillator (ICD). The mean age at first ICD implantation was 42 ± 14 years. Brugada syndrome, as well as other primary electrical diseases (e.g. long QT), were systematically excluded in all patients by the absence of the typical electrocardiogram (ST elevation in the right precordial leads) at rest and/or after pharmacological tests (ajmaline, flecainide, or procainamide). Recurrence of cardiac events was prospectively assessed.

Results

During a mean follow-up period of 41 ± 27 months, VF recurrence with appropriate shock occurred in 7 patients (39%) covering a total of 27 shocks. The median time to first appropriate shock was 12 ± 9 months. There were no deaths. In the electrophysiological study, 39% of patients were inducible, but inducibility failed to predict subsequent arrhythmic events. Forty-four percent of patients suffered 21 inappropriate shocks, which were caused by sinus tachycardia, atrial arrhythmias or lead malfunction.

Conclusion

Idiopathic ventricular fibrillation patients have a high recurrence rate of potentially fatal ventricular arrhythmias, excluding patients with the Brugada syndrome or other known causes. ICD prevents sudden cardiac death but inappropriate shocks remained a major issue in this young and active population.     

Wolf-parkinson-white syndrome presented with broad QRS complex tachycardia

Broad QRS complex tachycardia is tachycardia with widened QRS complex more than 12 s and caused by various mechanisms, either supraventricular or ventricular. It is important to differentiate between ventricular and supraventricular because it will determine treatment and prognosis of patients. We report a case which was referred to us and first diagnosed as ventricular tachycardia but happened to be atrial fibrillation with RBBB. On ECG examination we found irregular broad complex of tachycardia, RBBB, extreme right axis and heart rate 170-180 beat/minute. Intravenous bolus of 300 mg amiodarone was administered within 30 minutes and continued with 900 mg/24 hours. During administration of amiodarone, heart rhythm was converted to sinus rhythm with short PR interval (0.09 s), left axis deviation, and positive delta wave at lead V1. The final diagnosis of wolf-parkinson-white (WPW) syndrome was then confirmed.     

A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most common causes of sudden cardiac death (SCD) during childhood and in adolescence. Trans-2, 3-enoyl-CoA reductase-like (Tecrl) gene mutations (Arg196Gln and c.331+1G > A splice site mutation) were first reported in CPVT. Tecrl homozygous c.331+1G > A splice site mutation in iPSCs revealed a definite correlation between Tecrl and Ca²⁺ transport in cardiomyocytes. However, no other researchers have confirmed Tecrl mutations in CPVT with literature review. In this study, a case of compound heterozygosity in the Tecrl gene (Arg196Gln and c.918+3T > G splice site mutation) was first identified in a 13-year-old boy with CPVT by whole-exome sequencing (WES) and confirmed by Sanger sequence. Support vector machine and neural network analysis predicted that Arg196Gln mutation could decrease the stability of Tecrl structure, the confidence scores were ?0.8929 and ?0.9930. A STRUM server also confirmed that Arg196Gln mutation may decrease the binding capacity of the substrate and cause an amino acid substitution immediately upstream of the 3-oxo-5-alpha steroid 4-dehydrogenase domain. According to the “human splicing finder” indication and Alamut Visual Splicing Prediction, the c.918 + 3T > G mutation could influence Tecrl variable splicing. Thus, we confirmed that Tecrl as a new gene which is associated with CPVT.     

Severe arrhythmia after lithium intoxication in a patient with bipolar disorder admitted to the intensive care unit

Despite its narrow therapeutic index, lithium remains widely used as a mood stabilizer for the treatment of bipolar disease. The cardiac side-effects of lithium have been well documented, and may induce non-specific T-wave flattening, prolonged QT interval, sinus node dysfunction and also ventricular tachycardia and ventricular fibrillation. We report the case of a 61-year-old male patient diagnosed with bipolar disorder who developed life-threatening cardiac manifestations secondary to severe lithium poisoning. Although hemodialysis was performed and the arrhythmias were adequately treated, the patient died on the sixth day after hospital admission due hemorrhagic complications after tracheostomy.     

Modeling the His-Purkinje Effect in Non-invasive Estimation of Endocardial and Epicardial Ventricular Activation

Inverse electrocardiography (iECG) estimates epi- and endocardial electrical activity from body surface potentials maps (BSPM). In individuals at risk for cardiomyopathy, non-invasive estimation of normal ventricular activation may provide valuable information to aid risk stratification to prevent sudden cardiac death. However, multiple simultaneous activation wavefronts initiated by the His-Purkinje system, severely complicate iECG. To improve the estimation of normal ventricular activation, the iECG method should accurately mimic the effect of the His-Purkinje system, which is not taken into account in the previously published multi-focal iECG. Therefore, we introduce the novel multi-wave iECG method and report on its performance. Multi-wave iECG and multi-focal iECG were tested in four patients undergoing invasive electro-anatomical mapping during normal ventricular activation. In each subject, 67-electrode BSPM were recorded and used as input for both iECG methods. The iECG and invasive local activation timing (LAT) maps were compared. Median epicardial inter-map correlation coefficient (CC) between invasive LAT maps and estimated multi-wave iECG versus multi-focal iECG was 0.61 versus 0.31. Endocardial inter-map CC was 0.54 respectively 0.22. Modeling the His-Purkinje system resulted in a physiologically realistic and robust non-invasive estimation of normal ventricular activation, which might enable the early detection of cardiac disease during normal sinus rhythm.

     

Cardiac arrhythmias in aluminium phosphide poisoning studied by on continuous holter and cardioscopic monitoring

Variable incidences of cardiac arrhythmias (based on isolated 12 lead ECG records) have been reported in patients of aluminium phosphide (ALP) poisoning. We did continuous holter and cardioscopic monitoring in ICU in 30 patients of acute ALP poisoning. Supraventricular and ventricular ectopics were recorded in each and every patient. Life threatening ventricular tachycardia was recorded in 40% cases and ventricular fibrillation in 23.3% cases. Supraventricular tachycardia and atrial flutter/fibrillation occurred in 46.7% and 20% patients, respectively. ST-T changes simulating myocardial ischaemia were also present in all patients (S-T depression in 90%, S-T elevation in 10%). One-third of the patients developed variable degrees of heart block, IV amiodarone/xylocard could revert dangerous ventricular arrhythmias to sinus rhythm in 4 cases. Toxic myocarditis produced by phosphine seems to be responsible for the development of these arrhythmias.     

Cardiac rhythm in healthy elderly subjects

Summary To study the normal cardiac rhythm in elderly subjects we performed 24-h Holter monitoring on 94 subjects aged over 70 years. We had previously discarded those with cardiac disease by using history, physical examination, electrocardiography (ECG), chest X-radiography and Doppler echocardiography. The maximum, average and minimum heart rates were 113, 79 and 62, respectively, during the day, and 90, 64 and 53 during the night. Supraventricular and ventricular arrhythmias were frequent (91% and 89.4% respectively). Some 50% of the subjects had complex ventricular arrhythmias. Two subjects presented with sinus pauses of more than 2 s, and 4 had Wenckebach second-degree atrioventricular (AV) block. During a follow-up averaging 20.8 months, there were no deaths or symptoms of an arrhythmic origin.Abbreviations ECG electrocardiogram - AV atrioventricular - HBP hypertension - AT atrial tachycardia - FC functional class - VT ventricular tachycardia - bpm beats per minute - SVE supraventricular extrasystoles - AF atrial fibrillation - VE ventricular extrasystole - W-AVB Wenckebach atrioventricular block     

Juvenile sudden death in a family with polymorphic ventricular arrhythmias caused by a novel RyR2 gene mutation: evidence of specific morphological substrates

We report on a family with a history of sudden death and effort-induced polymorphic ventricular arrhythmias. The index case was a 17-year-old boy who died suddenly and at postmortem had evidence of fibrofatty replacement in the right ventricular free wall, consistent with arrhythmogenic right ventricular cardiomyopathy, as well as calcium phosphate deposits within the myocytes. A molecular genetics investigation carried out in the paraffin-embedded myocardium of the subject and in blood samples of family members disclosed a missense mutation in exon 3 (230C-->T; A77V) of the cardiac ryanodine receptor type 2 gene. The carriers showed effort-induced polymorphic ventricular tachycardia in the setting of normal resting electrocardiogram and trivial echocardiographic abnormalities, consistent with catecholaminergic polymorphic ventricular tachycardia. The observation of both arrhythmogenic right ventricular cardiomyopathy type 2 and catecholaminergic polymorphic ventricular tachycardia in the same family suggests that the two entities might correspond to different degrees of phenotypic expression of the same disease. This experience underscores the importance of a precise autopsy diagnosis in the case of sudden cardiac death, including molecular genetics, and the mission of pathologists to guide further clinical investigation of family members.     

CARDIAC RHABDOMYOMA ASSOCIATED WITH TUBEROUS SCLEROSIS

An autopsy case of cardiac rhabdomyoma associated with tuberous sclerosis in a 27-day-old infant is presented. He was born with severe cyanosis. Echocardiogram revealed the presence of multiple mass lesions, some of which protruded into the left ventricle at the level of subaortic valve. From the age of 4 days, cardiac arrhythmia developed and lasted until his death. The arrythmia started as WPW syndrome and atrial extrasystoles and then additional paroxysmal supraventricular tachycardia, ventricular fibrillation, sinus arrest, and S-A block occurred. Computed tomographic scanning of the brain revealed the presence of symmetric high-density spots around the central part of lateral ventricle. Before his death paroxysmal supraventricular tachycardia occurred frequently which changed to ventricular fibrillation and he collapsed without urination and then died. Autopsy examination revealed the presence of generalized congestion, multiple nodules of cardiac rhabdomyoma, some of which causing subaortic stenosis, and tuberous sclerosis in the brain. From the clinical and autopsy findings, the direct cause of death was attributable to the cardiac rhabdomyoma.     

Cardiac rhabdomyoma associated with tuberous sclerosis. An autopsy case of newborn infant died of cardiac failure

An autopsy case of cardiac rhabdomyoma associated with tuberous sclerosis in a 27-day-old infant is presented. He was born with severe cyanosis. Echocardiogram revealed the presence of multiple mass lesions, some of which protruded into the left ventricle at the level of subaortic valve. From the age of 4 days, cardiac arrhythmia developed and lasted until his death. The arrhythmia started as WPW syndrome and atrial extrasystoles and then additional paroxysmal supraventricular tachycardia, ventricular fibrillation, sinus arrest, and S-A block occurred. Computed tomographic scanning of the brain revealed the presence of symmetric high-density spots around the central part of lateral ventricle. Before his death paroxysmal supraventricular tachycardia occurred frequently which changed to ventricular fibrillation and he collapsed without urination and then died. Autopsy examination revealed the presence of generalized congestion, multiple nodules of cardiac rhabdomyoma, some of which causing subaortic stenosis, and tuberous sclerosis in the brain. From the clinical and autopsy findings, the direct cause of death was attributable to the cardiac rhabdomyoma.     

Intravenous magnesium for cardiac arrhythmias: jack of all trades.

Intravenous magnesium has been used to prevent and treat many different types of cardiac arrhythmia. It has diverse electrophysiological actions on the conduction system of the heart; including prolonging sinus node recovery time, and reducing automaticity, atrioventricular nodal conduction, antegrade and retrograde conduction over an accessory pathway, and His-ventricular conduction. Intravenous magnesium can also homogenise transmural ventricular repolarisation. Because of its unique and diverse electrophysiological actions, intravenous magnesium has been reported to be useful in preventing atrial fibrillation and ventricular arrhythmias after cardiac and thoracic surgery; in reducing the ventricular response in acute onset atrial fibrillation, including for patients with Wolff-Parkinson-White syndrome; in the treatment of digoxin induced supraventricular and ventricular arrhythmias, multifocal atrial tachycardia, and polymorphic ventricular tachycardia or ventricular fibrillation from drug overdoses. Intravenous magnesium is, however, not useful in monomorphic ventricular tachycardia and shock-resistant ventricular fibrillation. Large randomised controlled studies are needed to confirm whether intravenous magnesium can improve patient centre outcomes in different cardiac arrhythmias.     

Long QT Syndrome: a Korean Single Center Study

The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.     

Reducing false alarm rates for critical arrhythmias using the arterial blood pressure waveform

BackgroundOver the past two decades, high false alarm (FA) rates have remained an important yet unresolved concern in the Intensive Care Unit (ICU). High FA rates lead to desensitization of the attending staff to such warnings, with associated slowing in response times and detrimental decreases in the quality of care for the patient. False arrhythmia alarms are commonly due to single channel ECG artifacts and low voltage signals, and therefore it is likely that the FA rates may be reduced if information from other independent signals is used to form a more robust hypothesis of the alarm’s etiology.MethodsA large multi-parameter ICU database (PhysioNet’s MIMIC II database) was used to investigate the frequency of five categories of false critical (“red” or “life-threatening”) ECG arrhythmia alarms produced by a commercial ICU monitoring system, namely: asystole, extreme bradycardia, extreme tachycardia, ventricular tachycardia and ventricular fibrillation/tachycardia. Non-critical (“yellow”) arrhythmia alarms were not considered in this study. Multiple expert reviews of 5386 critical ECG arrhythmia alarms from a total of 447 adult patient records in the MIMIC II database were made using the associated 41,301 h of simultaneous ECG and arterial blood pressure (ABP) waveforms. An algorithm to suppress false critical ECG arrhythmia alarms using morphological and timing information derived from the ABP signal was then tested.ResultsAn average of 42.7% of the critical ECG arrhythmia alarms were found to be false, with each of the five alarm categories having FA rates between 23.1% and 90.7%. The FA suppression algorithm was able to suppress 59.7% of the false alarms, with FA reduction rates as high as 93.5% for asystole and 81.0% for extreme bradycardia. FA reduction rates were lowest for extreme tachycardia (63.7%) and ventricular-related alarms (58.2% for ventricular fibrillation/tachycardia and 33.0% for ventricular tachycardia). True alarm (TA) reduction rates were all 0%, except for ventricular tachycardia alarms (9.4%).ConclusionsThe FA suppression algorithm reduced the incidence of false critical ECG arrhythmia alarms from 42.7% to 17.2%, where simultaneous ECG and ABP data were available. The present algorithm demonstrated the potential of data fusion to reduce false ECG arrhythmia alarms in a clinical setting, but the non-zero TA reduction rate for ventricular tachycardia indicates the need for further refinement of the suppression strategy. To avoid suppressing any true alarms, the algorithm could be implemented for all alarms except ventricular tachycardia. Under these conditions the FA rate would be reduced from 42.7% to 22.7%. This implementation of the algorithm should be considered for prospective clinical evaluation. The public availability of a real-world ICU database of multi-parameter physiologic waveforms, together with their associated annotated alarms is a new and valuable research resource for algorithm developers.     

Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe arrhythmogenic disorder. Although usually transmitted in a recessive form, few cases of dominant mutations have been reported. Thirteen mutations in the CASQ2 gene have been reported so far in association with CPVT. We performed molecular analysis of the CASQ2 gene in 43 probands with CPVT and identified eight mutations in five patients. Six mutations were novel: one was a single nucleotide deletion, three affected consensus splice sites, and two had unknown consequences: the c.939 + 5G>C and the synonymous c.381C>T variations. We demonstrated that these two variations affected CASQ2 splicing using a splicing minigene assay. These data increased significantly the number of CASQ2 mutations described in association with CPVT, revealed the high prevalence of splicing and truncating mutations in this gene and brought new insight regarding the dominant inheritance of the disease. Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.Hum Mutat 32:1–5, 2011. © 2011 Wiley‐Liss, Inc.     

Detection of life-threatening cardiac arrhythmias using the wavelet transformation

Time-frequency wavelet theory is used for the detection of life threatening electrocardiography (ECG) arrhythmias. This is achieved through the use of the raised cosine wavelet transform (RCWT). The RCWT is found to be useful in differentiating between ventricular fibrillation, ventricular tachycardia and atrial fibrillation. Ventricular fibrillation is characterised by continuous bands in the range of 2–10 Hz; ventricular tachycardia is characterised by two distinct bands: the first band in the range of 2–5 Hz and the second in the range of 6–8 Hz; and atrial fibrillation is determined by a low frequency band in the range of 0–5 Hz. A classification algorithm is developed to classify ECG records on the basis of the computation of three parameters defined in the time-frequency plane of the wavelet transform. Furthermore, the advantage of localising and separating ECG signals from high as well as intermediate frequencies is demonstrated. The above capabilities of the wavelet technique are supported by results obtained from ECG signals obtained from normal and abnormal subjects.     

152例青年学生晕厥患者动态心电图分析

目的:评价动态心电图在青年晕厥患者中的诊断价值。方法:在152例青年晕厥患者中,进行了动态心电图和心电图检查。结果:对窦性心动过速,各种传导阻滞,Q-T间期延长的检出率与普通心电图差异不大,而对窦性静止,快-慢综合征,阵发性室上性心动过速,阵发性室性心动过速动态心电图明显优于普通心电图(P<0.01)。结论:动态心电图为诊断心源性晕厥可提供依据。     

Fever-induced QTc prolongation and ventricular fibrillation in a healthy young man

Long QT syndrome is associated with lethal tachyarrhythmia that can lead to syncope, seizure, and sudden death. Congenital long QT syndrome is a genetic disorder, characterized by delayed cardiac repolarization and prolongation of the QT interval on the electrocardiogram (ECG). Type 2 congenital long QT is linked to mutations in the human ether a go-go-related gene (HERG). There are environmental triggers of adverse cardiac events such as emotional and acoustic stimuli, but fever can also be a potential trigger of life-threatening arrhythmias in long QT syndrome type 2 patients. Herein, we report a healthy young man who experienced fever-induced polymorphic ventricular tachycardia and QT interval prolongation.