Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome

OBJECTIVES: This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation carriers. BACKGROUND: The LQT1 form of congenital long QT syndrome is associated with high vulnerability to sympathetic stimulation and appears with incomplete penetrance. METHODS: The 12-lead electrocardiographic parameters before and after epinephrine infusion were compared among 19 mutation carriers with a baseline corrected QT interval (QTc) of > or =460 ms (Group I), 15 mutation carriers with a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls (Group IV). RESULTS: The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak-end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger in Group I than in the other three groups. Epinephrine (0.1 microg/kg/min) increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in Groups I and II, but not in Groups III and IV. The sensitivity and specificity of QTce measurements to identify mutation carriers were 59% (20/34) and 100% (27/27), respectively, before epinephrine, and the sensitivity was substantially improved to 91% (31/34) without the expense of specificity (100%, 27/27) after epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers in Groups I and II, and the prolongation of the mean QTce with epinephrine was significantly larger in symptomatic patients. CONCLUSIONS: Epinephrine challenge is a powerful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death.     

S4153R Is a Gain-of-Function Mutation in the Cardiac Ca Release Channel Ryanodine Receptor Associated With Catecholaminergic Polymorphic Ventricular Tachycardia and Paroxysmal Atrial Fibrillation

Mutations in ryanodine receptor 2 (RYR2) gene can cause catecholaminergic polymorphic ventricular tachycardia (CPVT). The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. The mutation has been functionally characterized via store-overload-induced Ca²⁺ release (SOICR) and tritium-labelled ryanodine ([³H]ryanodine) binding assays. The S4153R mutation enhanced propensity for spontaneous Ca²⁺ release and reduced SOICR threshold but did not alter Ca²⁺ activation of [³H]ryanodine binding, a common feature of other CPVT gain-of-function RYR2 mutations. We conclude that the S4153R mutation is a gain-of-function RYR2 mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation.     

Mechanism underlying catecholaminergic polymorphic ventricular tachycardia and approaches to therapy

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by VT induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. The diagnosis is made based on reproducible ventricular tachyarrhythmias including bidirectional VT and polymorphic VT during exercise testings. Two causative genes of CPVT have been identified: RYR2, encoding the cardiac ryanodine receptor (RyR2) Ca²⁺ release channel, and CASQ2, encoding cardiac calsequestrin. A mutation in RYR2 or CASQ2 is identified in approximately 60% of patients with CPVT. Mutations in these two genes destabilize the RyR2 Ca²⁺ release channel complex in sarcoplasmic reticulum and result in spontaneous Ca²⁺ release through RyR2 channels leading to delayed after depolarization, triggered activity, and bidirectional/polymorphic VT. Implantable cardioverter defibrillators (ICDs) are recommended for prevention of sudden death in patients with CPVT.1. A.E. Epstein, J.P. DiMarco, K.A. Ellenbogen, et al., ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008;117:e350 However, painful shocks can trigger further adrenergic stress and arrhythmias, and deaths have occurred despite appropriate ICD shocks. Treatment with β-adrenergic blockers reduces arrhythmia burden and mortality, but is not completely effective. The beneficial effects of Ca²⁺ channel blocker verapamil in combination with β-blocker have been reported, but the role of verapamil has not been well assessed. Because Ca²⁺ leakage through ryanodine channel is a common mechanism of CPVT, ryanodine channel block may have a therapeutic effect. We discovered that flecainide directly inhibits RyR2 channels and prevent CPVT. Left cardiac sympathetic denervation may be an effective alternative treatment in combination with ICD, especially for patients whose arrhythmias are not controlled by drug therapies.     

A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia

Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy usually caused by gain-of-function mutations ryanodine receptor type-2 (RyR2). Left ventricular non-compaction (LVNC) is an often genetic cardiomyopathy. A rare LVNC-CPVT overlap syndrome may be caused by exon 3 deletion in RyR2. We sought to characterize the phenotypic spectrum and molecular basis of a novel RyR2 mutation identified in a family with both conditions.

Cardiac Calsequestrin: The New Kid on the Block in Arrhythmias

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disease characterized by physical or emotional stress-induced ventricular arrhythmias in the absence of any structural heart disease or QT prolongation. Thus far, mutations in genes encoding the sarcoplasmic reticulum Ca²⁺ release channel (RYR2) and the sarcoplasmic reticulum Ca²⁺ binding protein cardiac calsequestrin (CASQ2) have been identified in CPVT patients. Here, we review the role of cardiac calsequestrin in health and disease, with a particular focus on how calsequestrin deficiency can cause arrhythmia susceptibility. Clinical implications and a promising new drug therapy for CPVT are discussed.     

Adrenergic Nervous System Influences on the Induction of Ventricular Tachycardia

Background: Sudden cardiac death is a major cause of mortality in western countries and the ventricular tachyarrhythmias are mainly involved in this regard. The adrenergic autonomic nervous system has influences in provoking life‐threatening arrhythmias, and the prevention of such arrhythmias with beta‐blockers supports this viewpoint. To evaluate the effect of the adrenergic nervous system and some catecholamine‐releasing stimuli on the induction of ventricular tachycardia, we decided to explore the occurrence of ventricular tachycardia in patients subjected to three consecutive tests, exercise testing, isoproterenol infusion, and mental stress. Methods: Nineteen subjects who experienced exercise test‐induced ventricular tachycardia were subjected to an isoproterenol infusion and mental stress. All but one patient had cardiac disease, with 70% due to Chagas’disease. Seventeen of the 19 study subjects had normal ventricular function. Results: Exercise test‐induced ventricular tachycardia was nonsustained in 17 patients and sustained in 2 cases. Isoproterenol infusion induced nonsustained ventricular tachycardia in 9 of 19 patients. Mental stress, on its own, was able to induce nonsustained ventricular tachycardia in 2 of 19 patients. Conclusions: Among patients preselected for exercise‐induced ventricular tachycardia, almost half could be induced into ventricular tachycardia by isoproterenol infusion. Mental stress was a less powerful inducer of ventricular arrhythmias in this study group. A.N.E. 2002;7(4):281–288     

儿茶酚胺介导的多形性室速研究进展

儿茶酚胺介导的多形性室速是一种少见却严重的遗传性心律失常,表现为无器质性心脏病的个体在运动或激动时发生双向性、多形性室速导致发作性晕厥及进展为心室颤动导致猝死。心肌细胞肌浆网异常释放钙离子使细胞内钙离子超载引起的延迟后除极可能是儿茶酚胺介导的多形性室速发生的机制。目前已知的和儿茶酚胺介导的多形性室速相关的基因为常染色体显性遗传的RyR2（位于1q42.1-q43）和常染色体隐性遗传的CASQ2（位于1p13.3-p11）。治疗：β-阻断剂适用于所有临床症状的个体和可能有RyR2突变而没有心脏事件（晕厥）或运动试验诱发的室性心律失常等病史的个体。反复心脏骤停患者需植入式心律转复除颤器。每6至12个月随访以监测疗效。患者所有的一级亲属,都应予心脏评估。     

Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves.

AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.     

Ion Channel Mechanisms Related to Sudden Cardiac Death in Phenotype‐Negative Long‐QT Syndrome Genotype–Phenotype Correlations of the KCNQ1(S349W) Mutation

Phenotype‐Negative LQTS. Background: Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype‐negative long‐QT syndrome (LQTS) are limited. Methods and Results: We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc‐matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild‐type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc‐matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations. Conclusions: The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal‐range QTc. (J Cardiovasc Electrophysiol, Vol. 22, pp. 193‐200, February 2011)     

Accelerated Junctional Rhythm and Nonalternans Repolarization Lability Precede Ventricular Tachycardia in Casq2−/− Mice

Repolarization Lability in Casq2?/? Mice . Background: Calsequestrin‐2 (CASQ2) is a Ca²⁺ buffering protein of myocardial sarcoplasmic reticulum. CASQ2 mutations underlie a form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The CPVT phenotype is recapitulated in Casq2 ?/? mice. Repolarization lability (RL)—beat‐to‐beat variability in the T wave morphology—has been reported in long‐QT syndrome, but has not been evaluated in CPVT. Methods and Results: ECG from Casq2 ?/? mice was evaluated with respect to heart rate (HR) and RL changes prior to onset of ventricular tachycardia (VT) to gain insight into arrhythmogenesis in CPVT. Telemetry from unrestrained mice (3‐month‐old males, 5 animals of each genotype) and ECG before and after isoproterenol administration in anesthetized mice was analyzed. Average HR in sinus rhythm (SR), occurrence of nonsinus rhythm and RL were quantified. HR was slower in Casq2 ?/? animals. Accelerated junctional rhythm (JR) occurred more frequently in Casq2 ?/? mice and often preceded VT. In Casq2 ?/? mice, HR increased prior to VT onset, prior to onset of JR and on transition from JR to VT. RL increased during progression from SR to VT and after isoproterenol administration in Casq2 ?/?, but not in Casq2+/+ animals. Isoproterenol did not increase repolarization alternans in either genotype. Conclusions: Accelerated JR, likely caused by triggered activity in His/Purkinje system, occurs frequently in Casq2 ?/? mice. The absence of CASQ2 results in increased RL. The increase in HR and in RL precede onset of arrhythmias in this CPVT model. Nonalternans RL precedes ventricular arrhythmia in wider range of conditions than previously appreciated. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1355‐1363, December 2012)     

Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing

BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). OBJECTIVES: The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. METHODS: Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. RESULTS: Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. CONCLUSION: Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.     

Distinct U wave changes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT)

Although catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with fatal ventricular arrhythmias and sudden death, the ECG findings are not fully understood. In this paper, we report on alterations in the U-wave. Seven patients from 6 families with CPVT in which bidirectional tachycardia and polymorphic VT were induced by exercise or isoproterenol infusion visited our hospitals. VT was not inducible by programmed electrical stimulation. A novel gene mutation of the ryanodine receptor 2 (RyR2) was confirmed in 2 families. In one of these patients, U-wave alternans was observed following ventricular pacing at 160 beats/min. In the other patient, U-wave alternans was observed during the recovery phase after the exercise stress test, which was terminated because of polymorphic VT. In both cases, leads V3-V5 were the leads showing alternans most clearly. In the third patient, a negative U-wave became positive following a pause from sinus arrest and a change in T-wave was also noted. Since such findings were not found in the other subjects who underwent electrophysiologic study, isoproterenol infusion or exercise stress testing, the phenomenon seems to be relevant to the underlying pathogenesis of CPVT. The genesis and significance of U-wave alteration need to be determined.     

Unusual clinical presentation in a family with catecholaminergic polymorphic ventricular tachycardia due to a G14876A ryanodine receptor gene mutation

A family was identified, of whom which 11 members were carriers of the G14876A ryanodine 2 receptor mutation. All but 1 were symptomatic at the time of the study. Exercise testing showed bidirectional or polymorphic arrhythmias in 4 patients, whereas in 5 patients, it showed monomorphic or rare minor polymorphic ventricular arrhythmias. Two young patients died suddenly at rest while asleep. This study demonstrates that arrhythmias occurring during exercise stress testing in patients affected by catecholaminergic polymorphic ventricular tachycardia (CPVT) could be minor even in very symptomatic patients. The diagnosis of CPVT must be considered in these patients with a familial history of typical CPVT.     

Effects of Myocardial Perfusion on QT Dispersion in Patients with Hypertrophic Cardiomyopathy

Background: In patients with hypertrophic cardiomyopathy (HCM), myocardial ischemia and myocardial fibrosis as well as ventricular tachyarrhythmia are frequently observed. An increase of heterogeneity of repolarization provided the development of ventricular tachyarrhythmia. The aims of the present study are to evaluate the influence of exercise‐induced myocardial perfusion abnormalities on QT dispersion and to assess whether QT dispersion was involved in ventricular tachycardia (VT) in patients with HCM. Methods: Thirty‐eight patients with HCM and 20 control subjects underwent an exercise stress test, and QT intervals were measured pre‐exercise and at 3 minutes after peak exercise. All subjects underwent thallium (TI)‐201 stress myocardial imaging, and their TI‐201 defect score and exerciseinduced myocardial ischemia were evaluated. Results: Twelve patients (31%) revealed sustained or nonsustained VT. The pre‐exercise QTc dispersion (QTcD) was significantly correlated with the Tl‐201 defect score (r = 0.61, P < 0.0001). The QTcD at 3 minutes after peak exercise was significantly greater in patients with exerciseinduced myocardial ischemia than without exercise‐induced myocardial ischemia (96 ± 36, 72 ± 24 ms^1/2, P < 0.03). The QTcD at 3 minutes after peak exercise was significantly greater in patients with VT than without VT (111 ± 23, 64 ± 17 ms^1/2, P < 0.0001). Conclusion: It is suggested that the degree of myocardial fibrosis influences the pre‐exercise QTcD, and exercise‐induced myocardial ischemia precipitates the increase in the QTcD at 3 minutes after peak exercise in patients with HCM. The increased QTcD at 3 minutes after peak exercise may play a role in identifying patients at a potentially higher risk. A.N.E. 2000;5(1):60–67     

Epinephrine Bolus Test in Detecting Long QT Syndrome Mutation Carriers with Indeterminable Electrocardiographic Phenotype

Background: In long QT syndrome (LQTS), prolonged and heterogeneous ventricular repolarization predisposes to serious arrhythmias. We examined how QT intervals are modified by epinephrine bolus in mutation carriers of three major LQTS subtypes with indefinite QT interval. Methods: Genotyped, asymptomatic subjects with LQTS type 1 (LQT1; n = 10; four different KCNQ1 mutations), type 2 (LQT2; n = 10; three different HERG mutations), and type 3 (LQT3; n = 10; four different SCN5A mutations), and healthy volunteers (n = 15) were examined. Electrocardiogram was recorded with body surface potential mapping system. After an epinephrine 0.04 μg/kg bolus QT end, QT apex, and T‐wave peak‐to‐end (Tpe) intervals were determined automatically as average of 12 precordial leads. Standard deviation (SD) of the 12 channels was calculated. Results: Heart rate increased 26 ± 10 bpm with epinephrine bolus, and similarly in all groups. QT end interval lengthened, and QT apex interval shortened in LQTS and normals, leading to lengthening of Tpe interval. However, the lengthening in Tpe was larger in LQTS than in normals (mean 32 vs 18 ms; P < 0.05) and SD of QT apex increased more in LQTS than in normals (mean 23 vs 7 ms; P < 0.01). The increase in Tpe was most pronounced in LQT2, and in SD of QT apex in LQT1 and LQT2. Conclusions: Abrupt adrenergic stimulation with a moderate dose of exogenous epinephrine affects ventricular repolarization in genotype‐specific fashion facilitating distinction from normals. This delicate modification may help in diagnosing electrocardiographically silent mutation carriers when screening LQTS family members. Ann Noninvasive Electrocardiol 2011;16(2):172–179     

Sudden death in a young man with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial condition that presents with exercise-induced syncope or sudden death in children or young adults. In most cases the disease is caused by a mutation in the cardiac ryanodine receptor (RyR2) gene. Current evidence suggests that primary therapy for CPVT is beta blockade and implantable cardioverter defibrillator (ICD) placement. There is a recent report of a patient with CPVT who died despite appropriate ICD therapies, and we report a similar case. Our patient died after probably initially receiving inappropriate ICD shocks for atrial fibrillation. We recommend that utmost efforts should be made to prevent shocks including repeated exercise testing to confirm suppression of PVT.     

Adrenergic modulation of gastric inhibitory polypeptide secretion in man

In order to examine the effect of adrenergic influences on gastric inhibitory polypeptide (GIP) secretion, a series of glucose tolerance tests was carried out in seven healthy volunteers during intravenous infusion of epinephrine (6 g/min), epinephrine plus phentolamine (5 mg stat+0.5 mg/min), epinephrine plus propranolol (5 mg stat+0.08 mg/min), and saline. No drug infusion modified fasting GIP levels. Alpha-adrenergic stimulation (epinephrine+propranolol) significantly reduced the GIP response (P<0.02) and completely inhibited the insulin response (P<0.005) to oral glucose, compared with control experiments. Epinephrine alone and epinephrine+phentolamine did not influence glucose-stimulated GIP. These results suggest the possibility that the adrenergic nervous system may have a role in the regulation of GIP secretion in man.     

Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice (P=0.02). Twenty-one mice (8 WT, 8 RyR(R4496C), and 5 RyR(R4496C) pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) mice but none of the WT developed VT (P=0.02); 4/5 RyR(R4496C) mice pretreated with propranolol developed VT (P=0.56 nonsignificant versus RyR(R4496C) mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias.     

Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death

Objective

This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope.

Long‐Term Outcome After Catheter Ablation for Left Posterior Fascicular Ventricular Tachycardia Without Development of Left Posterior Fascicular Block

Long‐Term Outcome After Substrate‐Based Ablation of LPF VT During SR . Background: Catheter ablation of left posterior fascicular (LPF) ventricular tachycardia (VT) is commonly performed during tachycardia. This study reports on the long‐term outcome of patients undergoing ablation of LPF VT targeting the earliest retrograde activation within the posterior Purkinje fiber network during sinus rhythm (SR). Methods: This study retrospectively analyzed 24 consecutive patients (8 female; mean age 26 ± 11 years) referred for catheter ablation of electrocardiographically documented LPF VT. Programmed stimulation was performed to induce tachycardia, while mapping and ablation was aided by use of a 3D electroanatomical mapping system. Catheter ablation targeted the earliest potential suggestive of retrograde activation within the posterior Purkinje fiber network (retro‐PP) recorded along the posterior mid‐septal left ventricle during SR if LPF VT was noninducible. Results: Overall, 21/24 (87.5%) patients underwent successful catheter ablation in SR targeting the earliest retro‐PP, while 3/24 (12.5%) patients were successfully ablated during tachycardia. In none of the patients, ablation resulted in LPF block. No procedure‐related complications occurred. After a median follow‐up period of 8.9 (4.8–10.9) years, 22/24 (92%) patients were free from recurrent VT. Conclusion: In patients presenting with LPF VT, ablation of the earliest retro‐PP along the posterior mid‐septal LV during SR results in excellent long‐term outcome during a median follow‐up period of almost 9 years. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1179–1184, November 2012)