Use of Oxprenolol in Cardiac Arrhythmias Associated with Acute Myocardial Ischaemia

Oxprenolol, a new beta-receptor blocking drug with intrinsic sympathomimetic activity, was used to treat 63 episodes of cardiac arrhythmia occurring in 43 patients with acute myocardial infarction or myocardial ischaemia. The drug was most effective in abolishing ventricular ectopic beats and supraventricular tachycardia. The best method of administration was by continuous intravenous infusion and the most satisfactory bolus does was 6 mg. The main side effect was hypotension, which occurred in 59% of episodes of arrhythmia that had responded previously to intravenous administration. Oxprenolol was often effective in lignocaine-resistant arrhythmia. The two main advantages of oxprenolol over propranolol are the reduced likelihood of adversely affecting myocardial function and the diminished tendency to produce bronchospasm.     

Evaluation of biological availability and anti-arrhythmic effect of a new drug Phenytoinum "Polfa"]

Studies were performed in 15 patients with ventricular arrhythmia. During the first day, the patients received 1000 mg of a new micronised form of Phenytoinum "Polfa" or adequate dose of a foreign drug in 3 doses every 3 hours and subsequently during 10 days alternatively native or foreign drug in a daily dose 300 mg. Twenty-four EKG Holter monitoring and determination of serum drug level were carried out after a 10-day treatment; area under the curve (AUC) in one 8 h dose interval was determined. Studies have shown usefulness of a new form of Phenytoinum (Polfa). Blood serum drug levels near to the therapeutic ones were observed. Steady-state Phenytoinum concentration was 11.1 +/- 5.9 micrograms/ml and after foreign drug it was 11.7 +/- 6.1 micrograms/ml, AUC0-8 was 90.4 and 105.3 micrograms/ml/h respectively. In 9/15 patients (60%) Phenytoinum (Polfa) produced substantial improvement in the cardiac arrhythmia.     

Isolation of residual sinus node during catheter ablation for the treatment of inappropriate sinus tachycardia

Inappropriate sinus tachycardia is an unusual arrhythmia that is difficult to treat. To date, catheter ablation has concentrated on modifying the sinus node to attain rate control. We describe a patient where sinoatrial block was created by radiofrequency ablation for the treatment of inappropriate sinus tachycardia.     

Chlorpromazine: cardiac arrhythmogenicity in the cat

To determine the effect of chlorpromazine on ouabain-induced arrhythmia and death, dial-urethane anesthetized cats were pretreated with chlorpromazine (5, 10, 20, 30, 40, or 60 mg/kg, i.v.) and then administered ouabain (2 microgram/kg/min, i.v.). Blood pressure, heart rate and lead II electrocardiogram (ECG) were monitored. The dosages of ouabain necessary to induce premature ventricular contractions, ventricular tachycardia and death were determined. No significant correlation between the dose of chlorpromazine given and the dose of ouabain required to produce arrhythmia or death was found. These doses of chlorpromazine could, therefore, be considered neither arrhythmogenic nor antiarrhythmic in the ouabain model. To determine whether chlorpromazine produced arrhythmia in the dial-urethane anesthetized cat model, the drug was infused at a rate of 1 mg/kg/min, i.v. Chlorpromazine produced arrhythmia at 185 +/- 4.3 minutes and death via cardiovascular collapse at 128 +/- 4.7 minutes. Bilateral adrenal vein ligation, employed to eliminate the influence of adrenal catecholamines, decreased the dosage of chlorpromazine necessary to produce arrhythmia and death to 67.8 +/- 17.7 and 84.7 +/- 15.7 mg/kg, respectively. Thus, adrenal catecholamines did not appear to contribute to chlorpromazine-induced arrhythmia, although the procedure of bilateral adrenal vein ligation appeared to be deleterious in combination with chlorpromazine. In all experiments, chlorpromazine depressed blood pressure without producing the reflex tachycardia normally seen with hypotension. This suggests that the drug may be interfering with the baroreceptor reflex arc. As chlorpromazine modifies the autonomic parameters of blood pressure, heart rate, and cardiac electrophysiology, sudden unexplained death in patients managed with this agent may be due to drug-induced arrhythmia.     

Normal Heart Ventricular Tachycardia Associated with Pregnancy: Successful Treatment with Catheter Ablation

Background

Normal heart ventricular arrhythmia occurring during pregnancy has been previously described. Whilst there are established reports of catheter ablation to treat supraventricular arrhythmia during pregnancy, there are no reports of ablation to treat ventricular tachycardia.

Case

We present the case of a 36 year old women, 31 weeks into an otherwise uncomplicated pregnancy, experiencing significant, troublesome and drug refractory tachycardia emanating from the right ventricular outflow tract.

Conclusion

We describe a successful radio frequency ablation in the third trimester of pregnancy.     

基于心脏电生理模型的心律失常机制研究进展

揭示发病机制是心律失常诊断、治疗、药物研发和设备设计的关键.整合当前在心脏分子生物学、生物化学、生理学及解剖学方面的最新成果,构建从离子通道、心肌细胞、心肌纤维、心肌组织、心脏器官到躯体各个层次的多尺度多模态心脏电生理模型,用于系统研究微观局部变化发生、发展、转化为宏观心律失常表现的过程,将彻底改变传统从基因突变、蛋白质表达、细胞电生理、临床表现单独研究心律失常的方式,实现微观与宏观研究的统一,使心脏电生理模型成为系统研究心律失常发病机制的有力手段.本文综述了心脏电生理模型的构建方法和研究进展,讨论了多尺度心脏电生理模型在揭示心律失常机制研究中的作用和地位,给出了基于心脏电生理模型心律失常研究的挑战和重要发展方向.     

Short-coupled variant of torsade de pointes

A 36-year-old man with a history of primary sclerosing cholangitis and epilepsy was admitted to our hospital for cholangitis. During admission he was resuscitated because of ventricular fibrillation. ECGs showed multiple ventricular premature beats (VPBs) with a short coupling interval (240 ms), resulting in frequent torsade de pointes (TdP). In total, the patient had to be defibrillated 12 times. Short-coupled TdP is a rare variant of polymorphic ventricular tachycardia, with unknown aetiology. Verapamil seems to be the only drug able to suppress the arrhythmia. Verapamil, however, does not lower the risk of sudden death; therefore, an ICD implantation is advised. (Neth Heart J 2008;16:246-9.)     

Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation

Pharmacological management of cardiac arrhythmias has been a long and widely sought goal. One of the difficulties in treating arrhythmia stems, in part, from incomplete understanding of the mechanisms of drug block and how intrinsic properties of channel gating affect drug access, binding affinity, and unblock. In the last decade, a plethora of genetic information has revealed that genetics may play a critical role in determining arrhythmia susceptibility and in efficacy of pharmacological therapy. In this context, we present a theoretical approach for investigating effects of drug-channel interaction. We use as an example open-channel or inactivated-channel block by the local anesthetics mexiletine and lidocaine, respectively, of normal and DeltaKPQ mutant Na(+) channels associated with the long-QT syndrome type 3. Results show how kinetic properties of channel gating, which are affected by mutations, are important determinants of drug efficacy. Investigations of Na(+) channel blockade are conducted at multiple scales (single channel and macroscopic current) and, importantly, during the cardiac action potential (AP). Our findings suggest that channel mean open time is a primary determinant of open state blocker efficacy. Channels that remain in the open state longer, such as the DeltaKPQ mutant channels in the abnormal burst mode, are blocked preferentially by low mexiletine concentrations. AP simulations confirm that a low dose of mexiletine can remove early afterdepolarizations and restore normal repolarization without affecting the AP upstroke. The simulations also suggest that inactivation state block by lidocaine is less effective in restoring normal repolarization and adversely suppresses peak Na(+) current.     

Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data

High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.     

Atrial flutter catheter ablation in adult congenital heart diseases

The important increase in life expectancy of adult patients with congenital heart disease (ACHD) has generated new challenges, including arrhythmias that represent one of the main late complications. Reentrant atrial arrhythmias are by far the main mechanism encountered, and catheter ablation has been now presented as a first-line therapy in this patient population. The number of procedures is expected to continuously increase year after year. The heterogeneity and complexity of phenotypes encountered require these cases to be performed by highly experienced operators, in specialized centers with multidisciplinary competencies. A thorough knowledge and understanding of anatomic specificities, vascular access issues, and main circuits encountered according to underlying phenotype is essential. Acute success rates have significantly improved and are now excellent, but recurrences remain a common issue, with different mechanisms or circuits frequently encountered. Observational data have suggested the interest of systematically targeting all inducible atrial arrhythmias, whether previously documented or not, and a lot of hope and research is based on the prediction of arrhythmia substrate before arrhythmia development by imaging or electroanatomic mapping to deliver a prophylactic patient tailored ablation approach. In this review, we summarize those different points in the most common or distinctive defects to offer a didactic overview of atrial flutter catheter ablation in ACHD patients.     

68例服胺碘酮的75岁以上老年心律失常患者甲功变化分析

目的：探讨口服小剂量胺碘酮对老年心律失常患者甲状腺功能的作用和影响。方法：回顾性分析老年器质性心脏病心律失常患者68例,记录胺碘酮治疗方案与疗效、甲状腺变化及随访干预措施情况。结果：老年人服用胺碘酮引起甲状腺疾病发生率为31．8％（22／68）,以甲状腺功能减退25．7％（18／68）为主,大致为甲状腺功能亢进（6．1％,4／68）的4倍。采用小剂量胺碘酮方案出现的甲状腺功能紊乱多数经过减量或停药逆转或恢复。结论：老年人服用胺碘酮甲状腺功能紊乱发生率高,但临床表现不典型,应更密切地监测甲状腺功能;甲状腺功能紊乱经胺碘酮及时减量或停药等措施多能逆转或恢复。     

Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients

Mutations in one of the ion channels shaping the cardiac action potential can lead to action potential prolongation. However, only in a minority of cardiac arrest cases mutations in the known arrhythmia-related genes can be identified. In two patients with arrhythmia and cardiac arrest, we identified the point mutations P91L and E33V in the KCNA5 gene encoding the Kv1.5 potassium channel that has not previously been associated with arrhythmia. We functionally characterized the mutations in HEK293 cells. The mutated channels behaved similarly to the wild-type with respect to biophysical characteristics and drug sensitivity. Both patients also carried a D85N polymorphism in KCNE1, which was neither found to influence the Kv1.5 nor the Kv7.1 channel activity. We conclude that although the two N-terminal Kv1.5 mutations did not show any apparent electrophysiological phenotype, it is possible that they may influence other cellular mechanisms responsible for proper electrical behaviour of native cardiomyocytes.     

Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contac C capsule.

Phenothiazines are known to produce electrocardiographic repolarization abnormalities. Thioridazine and mesoridazine appear to induce such changes more frequently than other neuroleptics and are also known to induce fatal ventricular arrhythmia. The woman described in this article died after taking her usual dose of thioridazine, 100 mg/d, in combination with a single capsule of Contac. C, a decongestant-antihistamine containing phenylpropanolamine and chlorpheniramine. Phenylpropanolamine, an ephedrine-like drug, was thought to have favoured the initiation by thioridazine of the ventricular arrhythmia that led to the woman''s death. It is therefore suggested that ephedrine-like medications not be given to patients receiving thioridazine.     

菊米提取液抗实验性心律失常作用的研究

目的：观察菊米提取液对氯仿、乌头碱和缺血诱发的心律失常的作用：方法：采用氯仿诱导小鼠心律失常,静脉注射乌头碱和冠脉结扎法诱导大鼠心律失常,术前5d给予菊米提取液,记录心电图曲线、结果：菊米提取液能剂量依赖性地明显降低氯仿诱导的小鼠室颤发生率与对照组相比,奎尼丁可明显减少乌头碱（30μg／kg）诱导的大鼠室性早搏和室性心动过速的发生次数,缩短心律失常的持续时间=但菊米提取液组对乌头碱诱导的大鼠心律失常无明显作用：高浓度菊米提取液（2．0g／kg）可明显降低缺血复灌性心律失常评分。但低、中浓度菊米提取液（0．5g／kg和1．0g／kg）对缺血心脏心律失常评分无明显作用.结论：菊米提取液可对抗氯仿和缺血诱导的实验性心律失常,但对乌头碱引发的心律失常无影响.     

Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism

BACKGROUND: The antiepileptic drug phenytoin (PHT) is a human and animal teratogen. The teratogenicity has been linked to PHT-induced embryonic cardiac arrhythmia and hypoxic damage during a period when regulation of embryonic heart rhythm is highly dependent on a specific K(+) ion current (I(Kr)). PHT has been shown to inhibit I(Kr). The aims of this study were to investigate whether teratogenic doses cause embryonic hypoxia during and after the I(Kr) susceptible period and to further characterize PHT effects on embryonic heart rhythm. METHODS: Pregnant C57BL mice were administered the hypoxia marker pimonidazole followed by PHT or saline (controls) on GD 10 or GD 15. The embryos were fixed and sectioned, and the immunostained sections were analyzed with a computer assisted image analysis. Effects of PHT (0-250 microM) on heart rhythm in GD 10 embryos cultured in vitro were videotaped and then analyzed by using a digitalization technique. RESULTS: PHT dose-dependently increased the hypoxia staining (6- and 11-fold after maternal dosing of 100 and 150 mg/kg, respectively) during the period I(Kr) is expressed and functional (GD 10). In contrast, there were no differences between the PHT doses in hypoxia staining, and much less pronounced hypoxia after this period (GD 15). With increasing PHT concentrations, increased length of the interval (bradycardia) and large variations in length between individual heartbeats (arrhythmia) were recorded. CONCLUSIONS: PHT induced bradycardia/arrhythmia and severe embryonic hypoxia during the I(Kr) susceptible period, supporting the idea of an I(Kr)-arrhythmia-hypoxia-related teratogenic mechanism.     

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC₅₀ values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.     

80例急性心肌梗死患者心电监护及护理

目的总结急性心肌梗死患者心电监护及护理经验。方法对本院性心肌梗死患者及时进行心电监护,对出现的心律失常者进行对症处理。结果本组80例患者中出现心律失常55例,其中室性心律失常48例,临床治愈45例;出现心室颤动7例,4例及时电复律转为窦性心律,3例抢救无效死亡。本组心律失常均发生在心肌梗死后1周内,尤其是发病24小时内,出现最多。结论心律失常是心肌梗死患者常见的并发症,也是患者死亡的主要原因,持续心电监护对患者心律失常的及时发现、明确诊断、指导抢救有重要意义。     

The role of dynamic instability and wavelength in arrhythmia maintenance as revealed by panoramic imaging with blebbistatin vs. 2,3-butanedione monoxime

Unlike other excitation-contraction uncouplers, blebbistatin has few electrophysiological side effects and has gained increasing acceptance as an excitation-contraction uncoupler in optical mapping experiments. However, the possible role of blebbistatin in ventricular arrhythmia has hitherto been unknown. Furthermore, experiments with blebbistatin and 2,3-butanedione monoxime (BDM) offer an opportunity to assess the contribution of dynamic instability and wavelength of impulse propagation to the induction and maintenance of ventricular arrhythmia. Recordings of monophasic action potentials were used to assess effects of blebbistatin in Langendorff-perfused rabbit hearts (n = 5). Additionally, panoramic optical mapping experiments were conducted in rabbit hearts (n = 7) that were sequentially perfused with BDM, then washed out, and subsequently perfused with blebbistatin. The susceptibility to arrhythmia was investigated using a shock-on-T protocol. We found that 1) application of blebbistatin did not change action potential duration (APD) restitution; 2) in contrast to blebbistatin, BDM flattened APD restitution curve and reduced the wavelength; and 3) incidence of sustained arrhythmia was much lower under blebbistatin than under BDM (2/123 vs. 23/99). While arrhythmias under BDM were able to stabilize, the arrhythmias under blebbistatin were unstable and terminated spontaneously. In conclusion, the lower susceptibility to arrhythmia under blebbistatin than under BDM indicates that blebbistatin has less effects on arrhythmia dynamics. A steep restitution slope under blebbistatin is associated with higher dynamic instability, manifested by the higher incidence of not only wave breaks but also wave extinctions. This relatively high dynamic instability leads to the self-termination of arrhythmia because of the sufficiently long wavelength under blebbistatin.     

Unusual signals in a halo catheter: what is the mechanism?

In this "featured arrhythmia" article we present a set of unusual intracardiac electrode tracings that were recorded in a patient with typical clockwise flutter but a very dilated right atrium. The potential mechanism underlying this phenomenon is discussed with reference to the current literature.