Inducible Polymorphic Ventricular Tachycardia Research Articles

Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

Management of ventricular arrhythmias in suspected channelopathies.

Although structural heart disease remains the predominant substrate for ventricular arrhythmia, channelopathies including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndrome (ERS) are less common but important contributing entities. These etiologies require specific therapies potentially contrary to empirical management of arrhythmias associated with structural heart disease. Conventional therapy including antiarrhythmic drug therapy may not only fail to resolve unstable arrhythmias but worsen them. Additionally, channelopathy patients with implantable cardioverter defibrillators (ICD) and arrhythmic storms represent a major challenge, and the acute care team needs to be cognizant of unique circumstances that require specific acute therapies beyond empirical advanced life support algorithm recommendations.1 Successful and considered acute management of ventricular arrhythmias is contingent on a number of variables, including knowledge of the cardiac substrate or potential substrate; form, mechanism, and precipitants of ventricular arrhythmias; and acute effect of potential therapies. In the longer term, an understanding of the natural history of the channelopathy along with the efficacy of long-term therapy will lead to superior outcomes. This review will present the risk of ventricular arrhythmias associated with these uncommon entities, the evolving understanding of the mechanism of arrhythmia, and the mechanistic basis of therapies along with a clinical approach to summarize the evidence pertaining to acute and long-term management. Patients with a prolonged QT interval are at risk of sudden cardiac death (SCD) due to Torsade de Pointes (TdP; Figure 1). Most patients with congenital LQTS are asymptomatic and diagnosed incidentally on electrocardiogram screening or following family screening. However, syncope, aborted SCD, or SCD may be the first presentation. Most arrhythmic events in congenital LQT1 occur during physical or emotional stress, at rest or in association with sudden auditory stimulation in LQT2, and during sleep or rest in LQT3 …

Cardiac effects of muscarinic receptor antagonists used for voiding dysfunction

Antimuscarinic agents are the main drugs used to treat patients with the overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Since the treatment is not curative and since OAB is a chronic disease, treatment may be life-long. Antimuscarinics are generally considered to be ‘safe’ drugs, but among the more serious concerns related to their use is the risk of cardiac adverse effects, particularly increases in heart rate (HR) and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes). An elevated resting HR has been linked to overall increased morbidity and mortality, particularly in patients with cardiovascular diseases. QT prolongation and its consequences are not related to blockade of muscarinic receptors, but rather linked to inhibition of the hERG potassium channel in the heart. However, experience with terodiline, an antimuscarinic drug causing torsade de pointes in patients, has placed the whole drug class under scrutiny. The potential of the different antimuscarinic agents to increase HR and/or prolong the QT time has not been extensively explored for all agents in clinical use. Differences between drugs cannot be excluded, but risk assessments based on available evidence are not possible.

Implantable cardioverter defibrillator therapy for non-ischaemic cardiomyopathy. What is the role of programmed electrical stimulation?

Sudden cardiac death (SCD) is an important public health problem, and is the cause of death of between 0.1% and 0.2% of our population annually. We have a technology that can significantly reduce that risk, but implantable cardioverter defibrillator (ICD) therapy brings with it unavoidable morbidity, small risks, and large costs to our healthcare systems. We have a clear responsibility to target this treatment accurately. While we have excellent trial evidence that ICD implantation reduces SCD in selected patients, our risk stratification has low positive and negative predictive accuracy and we continue to search for better tools. Intuitively, programmed electrical stimulation (PES) should contribute to risk stratification for ventricular arrhythmias: it may demonstrate the presence of a substrate capable of sustained ventricular arrhythmia and also provide a measure of the trigger required to induce it. Programmed electrical stimulation was widely used in serial anti-arrhythmic drug testing, but with new trial data and improved understanding of the dynamic electrophysiological properties of ischaemic and non-ischaemic myocardium, its role has become controversial. The study by Rolf et al. 1 reports on a non-ischaemic secondary prevention population in which the induction of polymorphic ventricular tachycardia (pVT) or ventricular fibrillation (VF) was associated with increased total, cardiac, and sudden deaths and ICD therapy for ventricular rhythms >240 b.p.m. compared with patients in whom no sustained arrhythmia was induced. They recommend a prospective study of the value of PES in non-ischaemic cardiomyopathy. The role of ICD therapy in dilated non-ischaemic cardiomyopathy (DCM) has been addressed in five studies: the event rate in the cardiomyopathy trial (CAT)2 was low and no significant mortality difference was seen with ICD therapy and the inducibility of VT or VF did not correlate with survival. The amiodarone vs. implantable cardioverter defibrillator trial (AMIOVIRT) showed no reduction in overall or arrhythmic … *Corresponding author. Tel: +44 191 233 6161, Fax: +44 191 213 0498, Email: chris.plummer{at}nuth.nhs.uk

Electrocardiographic Transmural Dispersion of Repolarization in Patients with Inherited Short QT Syndrome

Short QT syndrome (SQTS) carries an increased risk for sudden cardiac death. However, only a short QT interval does not express the risk of ventricular arrhythmias. Thus, additional evaluation of the repolarization abnormality in SQTS patients is essential. In experimental models of SQTS, increased transmural dispersion of repolarization (TDR) and its electrocardiographic counterpart T-wave peak to T-wave end interval (TPE) appeared critical for induction of polymorphic ventricular tachycardia (PMVT). In a clinical study with acquired long QT syndrome patients, TPE/QT ratio > 0.28 indicated arrhythmia risk. We hypothesized that the TPE/QT ratio would be greater in SQTS patients than in control subjects. We compared the behavior of the electrocardiographic TDR in three seriously symptomatic SQTS patients of unknown genotype presenting baseline QTc values < 320 ms and in nine healthy age-matched control subjects. We determined QT and TPE intervals as well as TPE/QT ratio from 24-hour ECG recordings using a computer-assisted program. Diurnal average of TPE/QT ratio was 0.28 +/- 0.03 in SQTS patients and 0.21 +/- 0.02 in control subjects (P = 0.01). SQTS patients had also lesser capacity to change TPE intervals from steady-state conditions to abrupt maximal values than control subjects. SQTS patients have increased and autonomically uncontrolled electrocardiographic TDR. According to experimental SQTS models, the present results may in part explain increased vulnerability of SQTS patients to ventricular arrhythmias.

Brugada Syndrome with Marked Conduction Disease: Dual Implications of a SCN5A Mutation

A 51-year-old woman presented with an episode of syncope. Upon further review she was found to have a typical Brugada type pattern on her electrocardiogram. She did not have evidence for structural heart disease. At electrophysiological testing she was found to have marked infrahisian conduction disease and had easily inducible polymorphic ventricular tachycardia. She underwent implantation of a dual-chamber implantable cardioverter defibrillator (ICD) and family screening was recommended. Genetic analysis revealed a novel nonsense mutation in the gene encoding for the sodium channel (SCN5A). Five months after ICD implantation the patient had an episode of ventricular fibrillation documented on ICD interrogation. This case is unique as it is consistent with an overlap syndrome, namely both Brugada Syndrome and distal atrioventricular (AV) conduction disease secondary to a novel SCN5A mutation in a young female. This finding highlights the phenotypic heterogeneity of novel SCN5A mutations.

Electrocardiographic transmural dispersion of repolarization in patients with inherited short QT syndrome

Short QT syndrome carries an increased risk for sudden cardiac death. However, not all patients are susceptible for ventricular arrhythmias, necessitating preferably noninvasive methods for risk stratification. In experimental models it has been shown that increased left ventricle wall transmural dispersion of repolarization (TDR) facilitates induction of polymorphic ventricular tachycardia. Therefore, TDR or T-wave peak to T-wave end interval (TPE) and TPE/QT ratio might serve as an index for the risk of pmVT in the SQTS.

Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2(R4496C+/-)). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2(R4496C+/-) myocytes (P=0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2(R4496C+/-) myocytes (P=0.001). DADs and triggered activity were abolished by ryanodine (10 micromol/L) but not by K201 (1 micromol/L or 10 micromol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2(R4496C+/-) mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2-FKBP12.6 interaction both in WT and RyR2(R4496C+/-) either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2(R4496C+/-) myocytes and ventricular arrhythmias in RyR2(R4496C+/-) mice; and (3) RyR2-FKBP12.6 interaction in RyR2(R4496C+/-) is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex.

Predictive Value of Ventricular Arrhythmia Inducibility for Subsequent Ventricular Tachycardia or Ventricular Fibrillation in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II Patients

In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable cardioverter-defibrillator (ICD)-randomized patients underwent electrophysiologic testing. Both inducible and noninducible patients received an ICD. We correlated inducibility with the occurrence of subsequent ventricular tachycardia (VT) or ventricular fibrillation (VF). Intracardiac ICD electrograms for subsequent events were analyzed to categorize the spontaneous arrhythmia as VT or VF. The two-year Kaplan-Meier event rate for VT in inducible patients was 29.0% versus 19.3% in noninducible patients. However, ICD therapy for spontaneous VF was less common at two years in inducible patients (3.2%) than in noninducible patients (8.6%). In the MADIT II study, inducibility predicted an increased likelihood of VT but decreased VF. We correlated electrophysiologic inducibility with spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. In the MADIT II study, 593 (82%) of 720 implantable cardioverter-defibrillator (ICD) randomized patients underwent electrophysiologic testing. Patients received an ICD whether they were inducible or not. A "standard" inducibility definition included sustained monomorphic or polymorphic VT induced with three or fewer extrastimuli or VF induced with two or fewer extrastimuli. We compared a narrow inducibility definition (only monomorphic VT) and a broad definition (standard definition plus VF with three extrastimuli). We used ICD-stored electrograms to categorize spontaneous VT or VF. Inducible patients (standard definition) had a greater likelihood of experiencing ICD therapy for VT than noninducible patients (p = 0.023). Unexpectedly, ICD therapy for spontaneous VF was less common (p = 0.021) in inducible patients than in noninducible patients. The two-year Kaplan-Meier event rate for VT or VF was 29.4% for inducible patients and 25.5% for noninducible patients. Standard inducibility did not predict the combined end point of VT or VF (p = 0.280, by log-rank analysis). The narrow inducibility definition outperformed the standard definition, whereas the broad definition appeared inferior to the standard definition. In the MADIT II study patients, inducibility was associated with an increased likelihood of VT. Noninducible MADIT II study subjects using this electrophysiologic protocol had a considerable VT event rate and a higher VF event rate than inducible patients. Induction of polymorphic VT or VF, even with double extrastimuli, appears less relevant than induction of monomorphic VT.

Female Gender is a Risk Factor for Drug-Induced Long QT and Early Afterdepolarizations (EADS) in Anesthetized Dogs

Clinical observations and experimental data in isolated rabbit and dog Purkinje fibers and in vivo in rabbits indicate that female gender is more sensitive to drug-induced long QT and cardiac arrhythmia. However, to-date there has been no demonstration of a gender difference in vivo in dogs and therefore male dogs tend to be the chosen sex for cardiovascular safety pharmacology tests. As such, this may potentially lead to wrong conclusions on the QT-related arrhythmogenic risk of a new chemical entity. Methods and Results We evaluated potential gender differences in the following variables, in neuromuscular blocked, mechanically ventilated anesthetized dogs: ventricular repolarization (ECG lead II, QT and QTcV; right ventricular endocardial monophasic action potential (MAP), duration at 90% repolarization, APD90 and APD90cV), spatial dispersion of the T wave (Tp-Te), instability of QTend (QT TI: total instability) and occurrence of EADs on the MAP signal. These parameters were derived from continuous recording of ECG and MAP signals. 20 female and 18 male dogs were treated with dofetilide (0.05 mg/kg i.v. infusion over 10 min). At baseline, there was no statistically significant gender difference observed in the values of the various parameters, while dofetilide infusion produced marked prolongation. Median maximum percentage changes of baseline in females versus males were respectively: heart rate (+3% / +6%, ns ), QT (+23% / +14%, p = 0.003 ), QTcV (+20% / +15%, p = 0.03 ), APD90 (+26% / +17%, p = 0.006 ), and APD90cV (+24% / +18%, p = 0.009 ). In addition, dofetilide tended to differently increase Tp-Te (+40% / +23%, ns ) and QT TI (+150% / +104%, ns ), more in female than in male animals. Furthermore, dofetilide infusion elicited more incidences of EADs on the MAP signal in female than in male dogs (73% versus 48%). Conclusion The present study confirms that female gender may be a risk factor for drug-induced long QT in the dog. Indeed, since significant alterations in additional markers beyond QT interval itself are more pronounced in female dogs and EADs occur more frequently in this sex, female dogs could be more sensitive to induction of polymorphic ventricular tachycardia (TdP). As such, consideration should be given to incorporation of female dogs into standard cardiovascular safety evaluations, or at least be the chosen single sex for drug safety evaluation for the identification of QT/TdP related adverse effects.

Female Gender is a Risk Factor for Drug-Induced Long QT and Torsade de Point (TdP) in Anesthetized, Beagle Dogs

The female gender is known to be more sensitive to drug-induced long QT and cardiac arrhythmia, based on clinical observations, experimental in vitro data, in isolated rabbit and dog Purkinje fibers, and also in vivo data in rabbits. However, to-date there has been no demonstration of a gender difference in vivo in dogs. As such, the aim of this study was to try and elucidate whether a gender difference is present in this species in vivo. This knowledge is important to drug safety evaluation since conventionally the male dog is the chosen sex for safety pharmacology studies. We evaluated potential gender differences in the following variables in neuromuscular blocked, mechanically ventilated anesthetized dogs: ventricular repolarization (ECG lead II, QT and qtcv; right ventricular endocardial monophasic action potential (MAP), duration at 90% repolarization, (APD90), spatial dispersion of the T wave (Tp-Te), instability of qtend (QT TI: total instability), occurrence of eads and/or tdps. These parameters were derived from continuous beat-to-beat recordings of ECG and MAP signals. 20 female and 18 male dogs were treated with dofetilide (0.05 mg/kg i.v. Infusion over 10 min). At baseline, no statistically significant gender difference was observed on the various parameters, whilst dofetilide infusion produced greater electrophysiological alterations in females than in males. The respective median maximum percentage changes from baseline in females versus males were: heart rate (+3% / +6%, ns), QT (+23% / +14%, p = 0.003), qtcv (+20% / +15%, p = 0.03) and APD90 (+26% / +17%, p = 0.006). Dofetilide tended to differently increase Tp-Te (+40% vs +23%, ns) and QT TI (+150% vs +104%), more in female than in male animals. Additionally, dofetilide infusion elicited more incidences of eads on the MAP signal in female than in male dogs (73% versus 48%). Furthermore, the ikr blocker dofetilide (0.05 mg/kg iv) combined with Iks blocker HMR1556 (0.5 mg/kg iv) elicited tdps in 3 out of 4 female dogs in our preliminary investigations. Similar to man, the present study suggests that the female gender may be a risk factor for drug-induced long QT. Indeed, since significant alterations in additional markers beyond QT interval itself appear to be more pronounced in female dogs and eads occur more frequently in this sex, female dogs could be more sensitive to induction of polymorphic ventricular tachycardia (tdp). As such, consideration should be given to incorporation of female dogs into standard cardiovascular safety evaluations, or at least be the chosen single sex for drug safety evaluation, since the use of males may potentially lead to an underestimate of the QT-related pro-arrhythmogenic risk of a new chemical entity.

Infarct morphology identifies patients with substrate for sustained ventricular tachycardia

We sought to evaluate whether infarct size characterization by cardiac magnetic resonance imaging (MRI) is a better predictor of inducible ventricular tachycardia (VT) than left ventricular ejection fraction (LVEF). Inducibility of VT at electrophysiologic study (EPS) and low LVEF can identify patients with a substrate for VT. Magnetic resonance imaging has been shown to identify, with high precision, areas of myocardial infarction and may therefore be a better tool to evaluate for a substrate for VT. We studied 48 patients with known coronary artery disease who were referred for EPS using cine and gadolinium-enhanced MRI. Wall motion and infarct characteristics were determined blindly and compared among patients with no inducible ventricular arrhythmias (n = 21), those with inducible monomorphic VT (MVT, n = 18), and those with either inducible polymorphic VT or ventricular fibrillation (n = 9). Patients with MVT had larger infarcts than patients who did not have inducible arrhythmias (mass: 49 +/- 5 g [SE] vs. 28 +/- 5 g, p < 0.005; surface area: 172 +/- 15 cm(2) vs. 93 +/- 14 cm(2), p < 0.0005). Patients with polymorphic VT/fibrillation had intermediate values (mass: 36 +/- 7 g; surface area: 115 +/- 22 cm(2)). Ejection fraction was inversely related to infarct mass and surface area, with R(2) values ranging from 0.21 to 0.27. Logistic regression and receiver-operating characteristic analysis demonstrated that infarct mass and surface area were better predictors of inducibility of MVT than LVEF. Infarct surface area and mass, as measured by cardiac MRI, are better identifiers of patients who have a substrate for MVT than LVEF. Further evaluation of infarct size characterization by cardiac MRI as a predictor of sudden cardiac death is warranted.

Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice.

Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor gamma coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.

Surgical treatment of tachyarrhythmias due to postinfarction left ventricular aneurysm with endoaneurysmorrhaphy and cryoablation

In this study, the efficacy of left ventricular (LV) endoaneurysmorrhaphy and cryoablation without intraoperative electrophysiologic mapping was evaluated in patients with postinfarction LV aneurysm and sustained ventricular tachycardia (VT). A prospective study was performed on all patients operated with malignant VT in the presence of a resectable LV aneurysm between July 1990 and February 2001. The study included 31 patients, 20 men and 11 women, with a mean age of 65.5 years (47-84). Monomorphic, polymorphic VT or ventricular fibrillation was present in all patients prospectively, and VT was incessant in 11. Twenty-six patients had an anterior, four patients had an inferior and one patient a posterolateral myocardial wall infarction. All patients had a well-limited ventricular aneurysm. Ten patients had three, eight patients two and 13 patients had single vessel coronary artery disease. Mean preoperative ejection fraction was 34.8 +/- 14.5% (8-62) and mean end-diastolic volume index was 141.5 +/- 51.8 ml/m(2) (57-288). Six patients had mitral regurgitation grade III or IV. All patients underwent extensive cryoablation at the transition zone of scar and viable tissue and LV remodelling with prosthetic patch in 26 patients. Associated procedures were CABG in 19 patients (61%) and mitral valve reconstruction in six patients (19%). Postoperative electrophysiologic study (EPS) revealed freedom from VT induction in 25 patients and inducible VT in five patients. One patient had inducible polymorphic VT. Five patients received an implantable cardioverter defibrillator (ICD) and three patients had a permanent pacemaker implanted. After a mean follow-up of 30 +/- 27 months (6-132) there was one arrhythmia-related death. There was one early hospital readmission for clinical VT and no need for late ICD implantation. In patients suffering from ventricular arrhythmias in the presence of a complicated postinfarction LV aneurysm, combined 'blind' cryoablation and endoaneurysmorrhaphy offers excellent arrhythmia control and clinical and haemodynamic outcome.

What is the sudden death syndrome in Southeast Asian males?

Sudden unexplained death syndrome describes the death of apparently healthy individuals--usually young men--in whom postmortem examination does not reveal the cause of death. The victims are in apparently good health and usually die at night while sleeping. They die within minutes after the onset of agonal respiration. Patients who have been resuscitated were found to have ventricular fibrillation and inducible polymorphic ventricular tachycardia in the electrophysiologic laboratory. This syndrome has been most frequently described in young Southeast Asian men. In this review, the epidemiology, clinical and electrophysiologic manifestations, pathology and risk factors, prognosis, and treatments for sudden unexplained death syndrome are described.

Vagal modulation of ventricular tachyarrhythmias induced by left ansae subclaviae stimulation in rabbits.

Previous evidence has shown that vagal nerve activity modulates ventricular arrhythmias in patients and in animal models. However, the effects of direct vagus nerve stimulation on ventricular tachyarrhythmias brought by direct sympathetic nerve stimulation have not been elucidated. In the present study, the effects of electrical stimulation of the left cervical vagus nerve on ventricular tachycardia (VT) which was induced by electrical stimulation of the left ansae subclaviae (LAS) in rabbits were assessed. Monophasic action potentials (MAPs) of the left ventricular endocardium were recorded simultaneously with surface ECG. In 27 rabbits tested, the stimulation of LAS induced VT in 19 rabbits. Polymorphic VT (PVT) was induced in 14 rabbits (PVT group), whereas monomorphic VT (MVT) was induced in 5 rabbits (MVT group). Vagus nerve stimulation during the sympathetically-induced PVT led to a restoration of sinus rhythm in 10 of 14 rabbits, while that during the sympathetically-induced MVT did not restore sinus rhythm in any of the 5 rabbits. Vagus nerve stimulation during the stimulation of LAS, which was of subthreshold intensity for the induction in VT, did not result in an induction of PVT in any of the 14 rabbits in the PVT group, while it induced slow MVT in 3 of 5 rabbits in the MVT group. These results indicate that vagus nerve stimulation preferentially exerts protective antiarrhythmic effects against PVT induced by sympathetic neural stimulation in this model, while it occasionally induces slow MVT under conditions in which sympathetic nerve activity in potentially elevated.

Induction of polymorphic ventricular tachycardia by programmed ventricular stimulation in vasospastic angina pectoris

This study was designed to examine the ventricular vulnerability of patients with vasospastic angina. Fourteen patients (mean age 57 ± 9 years) with vasospastic angina underwent electrophysiologic testing during the asymptomatic phase (baseline) and after the relief of acetylcholine-induced spasm with isosorbide dinitrates. Twenty patients without structural heart disease served as a control group. By programmed ventricular stimulation, polymorphic ventricular tachycardia (VT) was induced at baseline in 6 of 14 patients, with 1 patient developing ventricular fibrillation and 7 of 14 patients developing repetitive ventricular responses. After isosorbide dinitrate, polymorphic VT was induced in only 1 patient who had ventricular fibrillation at baseline. Repetitive ventricular responses were induced in 3 of 5 patients who had VT at baseline and in 4 of the 7 patients with repetitive ventricular responses at baseline. There was a significant difference in the incidences and severity of induced ventricular arrhythmias between the 2 phases (p <0.01). Among 20 control subjects, repetitive ventricular responses were induced only in 6 patients, but no VT was induced. There was a significant difference in the incidence of induced ventricular arrhythmias and VT at baseline between the vasospastic angina and control groups (p <0.001 and <0.01, respectively). Thus, patients with vasospastic angina had increased ventricular vulnerability, even during the symptom-free period without ischemic events, which could predispose to the development of life-threatening arrhythmias aggravated by vasospastic attacks.

Effect of Left Ventricular Hypertrophy and Its Regression on Ventricular Electrophysiology and Vulnerability to Inducible Arrhythmia in the Feline Heart

Left ventricular hypertrophy (LVH) is associated with an increased risk of death, susceptibility to ventricular arrhythmia, and multiple electrophysiological abnormalities. The purpose of the present study was to determine whether the susceptibility to arrhythmia and electrical abnormalities persists after regression of hypertrophy in an animal model of LVH. We placed constricting bands on the ascending aorta of cats (n = 9) or performed sham operations (n = 9). Serial cardiac echocardiography was performed to measure left ventricular wall thickness. After LVH had developed in the banded animals, the constricting bands were removed and serial echocardiograms were used to monitor for regression of hypertrophy. Electrophysiological studies were performed in cats that showed regression of LVH (Regress, n = 5), those that showed no change in LV wall thickness (No Regress, n = 4), and in the sham-operated animals (Sham). Cats with persistent LVH had a higher incidence of inducible polymorphic ventricular tachycardia (4 of 4) compared with Regress (1 of 5) or Sham (1 of 9) cats (P < .05) and had lower ventricular fibrillation thresholds (9 +/- 2 mA) than Regress (17 +/- 4 mA) or Sham (16 +/- 3 mA) cats (P < .05). Persistent LVH in the No Regress group was associated with prolongation of epicardial monophasic action potential duration (MAPD) in the left but not the right ventricle. Dispersion of refractoriness was greater in the No Regress group (P < .05 versus Regress or Sham). Regress cats were identical to Sham cats in having a low incidence of inducible polymorphic ventricular arrhythmia, high fibrillation threshold, and MAPD measurements (P = NS versus Sham). LVH produces multiple electrophysiological abnormalities and increased vulnerability to inducible polymorphic ventricular arrhythmia in this model of LVH. Cats that show regression of hyperthrophy have normal ventricular electrophysiology and have the same low vulnerability to inducible ventricular arrhythmia as Sham animals.

Polymorphic ventricular tachycardia induced by programmed stimulation: Response to procainamide

Objectives. This study was designed to evaluate the effects of procainamide on polymorphic ventricular tachycardia induced by programmed stimulation and to correlate the responses with heart disease, left ventricular endocardial activation abnormalities and the signal-averaged electrocardiogram (ECG).Background. Polymorphic ventricular tachycardia is induced frequently during electrophysiologic studies. In many patients this response is an artifact of programmed stimulation; in others, it appears to be clinically relevant. Previous observations have suggested that in some patients type IA antiarrhythmic agents can change the response to programmed stimulation from polymorphic to uniform ventricular tachycardia.Methods. Programmed right ventricular stimulation was performed in the absence of antiarrhythmic drugs and after procainamide. Signal-averaged ECGs and left ventricular maps were performed during sinus rhythm in the absence of antiarrhythmic drugs.Results. We evaluated 79 consecutive patients undergoing clinical electrophysiologic studies, in whom polymorphic ventricular tachycardia was the only arrhythmia induced in the absence of antiarrhythmic drugs. After procainamide administration, uniform monomorphic ventricular tachycardia was induced in 24 patients (Group 1), inducible polymorphic ventricular tachycardia persisted in 30 patients (Group 2) and no ventricular tachycardia could be induced in the remaining 25 patients (Group 3). Twenty-three (96%) of 24 patients developing uniform ventricular tachycardia after procainamide administration had coronary artery disease compared with 63% of Group 2 and 48% of Group 3 patients (p = 0.003). Left ventricular aneurysms were also found more frequently (46%) in the patients developing uniform ventricular tachycardia after procainamide than in either Group 2 or Group 3 (13% and 0%, respectively, p < 0.008).Abnormalities of the signal-averaged ECG typically seen in patients with spontaneous reentrant sustained ventricular tachycardia were significantly more frequent in patients who developed inducible uniform ventricular tachycardia after procainamide than in those who did not. Similarly, patients developing uniform ventricular tachycardia after procainamide had more extensive abnormalities of left ventricular endocardial activation revealed by catheter maps during sinus rhythm.Conclusions. The conversion of inducible polymorphic ventricular tachycardia to uniform ventricular tachycardia after procainamide administration occurs almost exclusively in patients with coronary disease, previous myocardial infarction and abnormal left ventricular function. This response may permit activation mapping of tachycardias, allowing the appllcation of surgical or catheter ablation techniques that would otherwise not be possible in such patients.

Differences in electrophysiological substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Insights from endocardial mapping and signal-averaged electrocardiography.

Many studies have combined patients with hemodynamically well-tolerated ventricular tachycardia (VT) and those with cardiac arrest (CA) as a single, homogenous group. Recent studies suggest that these two groups have different electrophysiological substrates and responses to therapy. Most of these studies, however, enrolled patients with a variety of cardiac diagnoses. We used signal-averaged electrocardiography (SAECG) and endocardial catheter mapping to define the electrophysiological substrate in patients with coronary artery disease and VT or CA and correlate the results of the two methods. We also examined the usefulness of SAECG in CA patients to differentiate those with inducible arrhythmias from those who are noninducible. VT patients were more likely to have had a prior myocardial infarction (p = 0.0005) and to have inducible arrhythmias (p = 0.0001) than were CA patients. The induced arrhythmias in patients who presented with VT was VT in more than 90% of cases, whereas in CA patients, polymorphic ventricular tachycardia (PMVT) accounted for one third of induced arrhythmias. Mean filtered QRS duration was longer (135 versus 120 msec) and the terminal QRS voltage was smaller (20 versus 34 microV) in VT than in CA patients (p less than 0.01). Sixty-three percent of CA patients and 87% of VT patients had abnormal SAECG (p = 0.001). VT patients had more extensive endocardial abnormalities and more abnormal (53% versus 40%, p = 0.002), fractionated (8% versus 3%, p = 0.02), late (17% versus 8%, p = 0.0003), and late abnormal or fractionated (14% versus 4%, p = 0.0001) sites than CA patients. VT patients had a greater duration of the longest electrogram (129 versus 109 msec, p = 0.0006) and total endocardial activation time (68 versus 54 msec, p = 0.009). Among CA patients, those with induced VT had more extensive substrate than did those with induced PMVT and were similar to VT patients with induced VT. Among CA patients, the trend for more patients with inducible VT (77%) or PMVT (55%) than noninducible patients (47%) to have an abnormal SAECG did not reach statistical significance (p = 0.14). The positive and negative predictive values of an abnormal SAECG were 77% and 44%, respectively. VT patients have more extensive endocardial substrate than CA patients, which translates into greater and more frequent SAECG abnormalities. Among CA patients, there are significant differences in substrate between patients with induced VT and those with induced PMVT. SAECG is not useful in differentiating CA patients who have inducible VT or PMVT from those who do not.