Kegg Pathway: Antiarrhythmic drugs

Curr Pharm Des. 2009; 15(32): 3734-3741
Roden DM, Kannankeri PJ, Darbar D

Abnormalities of cardiac rhythm are common clinical problems, resulting in symptoms such as palpitations, breathlessness, stroke, and sudden death. drugs used to treat arrhythmias have variable actions ranging from completely effective to serious adverse effects, including (paradoxically) sudden death due to drug-induced arrhythmias. Experiments to define the genetic basis for arrhythmia susceptibility and variable responses to Antiarrhythmic therapies rely on precise clinical phenotyping. Initial studies used candidate gene approaches, but are now turning to contemporary methods such as genome-wide association. Identification of loci for arrhythmia susceptibility in turn provide a starting point for both understanding underlying biologic pathways as well as improved selection appropriate therapies.

Planta Med. 2009 Nov 16;
Ritter M, Melichar K, Strahler S, Kuchta K, Schulte J, Sartiani L, Cerbai E, Mugelli A, Mohr FW, Rauwald HW, Dhein S

Although several Antiarrhythmic drugs of chemical origin are in clinical use since decades, their application is often limited by their adverse effects and especially by their inherited proarrhythmic risk, which can lead to a significantly increased mortality in patients receiving these compounds. On the other hand, aqueous extracts from the aerial parts of the European Lamiaceae LEONURUS CARDIACA (Ph.Eur.) have been used for centuries as a remedy against tachyarrhythmia and other cardiac disorders. Nevertheless, a scientific basis for the claim of direct cardiac electrophysiological, Antiarrhythmic, or functional effects of LEONURUS CARDIACAE herba (LCH) preparations has not been established until now. In order to enrich the active constituents from the primary extract which was tested as the most cardioactive, namely the aqueous Soxhlet extract, and to eliminate undesired substances such as the dichloromethanic fraction or potassium, a bioassay guided fractionation procedure was applied, resulting in the development of a LEONURUS CARDIACA refined extract (LCRE) which was characterised together with LEONURUS crude extracts by a newly developed gradient elution HPLC fingerprint analysis for separation and quantification of six major phenolics as well as by qNMR for determining the stachydrine content. This refined extract was applied intracoronarily in isolated rabbit hearts perfused according to the Langendorff technique. Mapping experiments with 256 electrodes on the heart surface showed a reduction of left ventricular pressure and an increase of relative coronary flow at concentrations of 1.0 and 2.0 mg/mL LCRE. Furthermore, the PQ-interval was prolonged and both the basic cycle length and the activation recovery interval increased. In addition, voltage-clamp measurements were performed on the following cell models in order to characterise the electrophysiological profile of LCRE: neonatal rat ventricular cardiomyocytes to investigate the effect on I (Na) and I (Ca.L), sinoatrial node cells and ventricular myocytes isolated from adult guinea pigs to test effects on I (f) and action potential (AP) duration, as well as HERG-transfected HEK 293 cells to analyse the influence on the I (K.r). In these voltage clamp experiments LCRE exerted a calcium-antagonistic activity by I (Ca.L) blockade, reduced the repolarising current I (K.r), and prolonged the AP-duration, while I (Na) was not affected. Although LCRE displayed only weak effects on the I (f) amplitude and voltage dependence, it significantly prolonged the activation time constant of I (f). Thus, LCRE acts on multiple electrophysiological targets, specifically I (Ca.L), I (K.r), and I (f), observed both at whole organ and single cell level.

J Cardiovasc Electrophysiol. 2009 Nov 12;
DE Greef Y, Tavernier R, Vandekerckhove Y, Duytschaever M

Triggering Pulmonary Veins and Recurrence After Ablation. Purpose: To identify procedural parameters predicting recurrence of atrial fibrillation (AF) after a first circumferential pulmonary vein isolation (CPVI). Methods: One hundred seventy-one patients undergoing CARTO-guided CPVI for recurrent AF with a left atrial (LA) diameter <45 mm were studied. Follow-up (symptoms and 7-day Holter) was performed at 1 and 3 months and every 3 months thereafter. Clinical and procedural characteristics between successful patients and patients undergoing repeat ablation were compared. In addition, procedural parameters of the first procedure were compared with parameters during repeat ablation. Results: After first CPVI, 80% of patients were free of AF without Antiarrhythmic drugs after a follow-up (FU) of 28 +/- 11 months (N = 136). Thirty-five patients (20%) had recurrence of AF of which 25 underwent repeat ablation (N = 25). Clinical characteristics did not differ between the successful and repeat group. A triggering vein during the index procedure was significantly more observed in the repeat group (56% vs 11%, P < 0.001). At repeat ablation, 2.6 +/- 1.2 veins per patient were reconnected. Whereas there was no preferential reconnecting PV, all PVs triggering at index were reconnected (100%). Conclusions: (1) In patients with symptomatic recurrent AF, the presence of a triggering pulmonary vein during ablation is a paradoxical predictor for AF recurrence after PV isolation. (2) The consistent finding of reconnection of the triggering PV at repeat ablation, suggests that, in these patients, the triggering PV is the culprit vein and that reconnection invariably results in clinical AF recurrence. (3) The present study advocates a strategy of even more stringent PV isolation in case of a triggering PV. (J Cardiovasc Electrophysiol, Vol. pp. 1-8).

Europace. 2009 Nov 11;
Miyazaki S, Kuwahara T, Kobori A, Takahashi Y, Takei A, Sato A, Isobe M, Takahashi A

Aims Bepridil is highly effective in terminating persistent atrial fibrillation (AF). Despite continued treatment, a high rate of AF recurrence after pharmacological cardioversion (PC) with bepridil has been reported. Bepridil therapy is also associated with significant adverse effects. Methods and results This retrospective case-control study included 82 patients with persistent AF (PEF). Group 1 (22 patients) comprised cases undergoing AF ablation following attempted PC with bepridil. Group 2 (60 patients) comprised control that underwent AF ablation without bepridil pre-treatment. In Group 1, 15 patients (68%) restored sinus rhythm (SR) with bepridil (SR group) and 7 continued to have AF (AF group). SR group underwent extensive pulmonary vein isolation (EPVI) alone. AF group and Group 2 underwent linear ablation after EPVI, if AF was inducible. At the end of 18 +/- 5 months off Antiarrhythmic drugs, the AF-free rate was 87% in SR group, 29% in AF group, and 72% in Group 2 (72 vs. 29%, P = 0.02). Conclusion Following AF ablation in patients who successfully restored SR with bepridil pre-treatment, AF-free rate was significantly higher than in those who failed to do so. Conversion to SR with bepridil might help select the optimal patients with PEF for catheter ablation.

Heart. 2009 Nov 11;
Schilling R

Atrial fibrillation (AF) is the commonest atrial arrhythmia and represents a large burden on modern health services. Large multicentre randomised trials have demonstrated that a rhythm control strategy (using Antiarrhythmics and DC cardioversion) has no morbidity or mortality advantage over rate control. Therefore, for most patients, attempts to cardiovert AF to sinus rhythm (SR) should be reserved for those patients that are symptomatic despite adequate rate control. For recent onset AF (<24 hours) the use of agents like flecainide can be highly successful to pharmacologically cardiovert AF, although caution should be exercised in patients who have the potential for structural or coronary artery disease because of the risk of proarrhythmia. If there any is doubt as to the suitability of a patient for pharmacological cardioversion then DC cardioversion is the safer option. The high recurrence rate of AF after cardioversion (71 to 84% at 1 year) means that the use of Antiarrhythmic drugs to maintain SR is recommended. The irreversible side effects of amiodarone mean that it should be avoided whenever possible for long term maintenance therapy, although it is useful in short courses (8 weeks to 6 months), particularly for patients who had a successfully treated secondary cause for AF. Other agents like flecainide and sotalol are also useful but should not be used for patients with structural heart disease. Data supporting the use of newer agents like dronedarone at present are limited.

J Cardiovasc Electrophysiol. 2009 Nov 10;
Wieczorek M, Hoeltgen R, Akin E, Salili AR, Oral H, Morady F

PV Isolation Using Bipolar/Unipolar RF Energy. Background: Electrical disconnection of the pulmonary veins (PV) plays an important role in the ablation of paroxysmal atrial fibrillation (AF). Antral ablation using a conventional steerable ablation catheter often is technically challenging and time consuming. Methods: Eighty-eight patients (mean age 58 +/- 11 years) with symptomatic paroxysmal AF underwent ablation with a circular mapping/ablation decapolar catheter (PVAC). Ablation was performed in the antral region of the PVs with a power-modulated bipolar/unipolar radiofrequency (RF) generator using 8-10 W delivered simultaneously through 2-10 electrodes, as selected by the operator. Seven-day Holter monitor recordings were performed off Antiarrhythmic drugs at 3-, 6-, and 12-month follow-up, and patients were requested to visit the hospital in the event of ongoing palpitations. All follow-up patients were divided into 2 groups: Group 1 with a follow-up of less than 1 year and group 2 patients completing a 1-year follow-up. Results: Overall, 338 of 339 targeted PVs (99%) were isolated with the PVAC with a mean of 24 +/- 9 RF applications per patient, a mean total procedure time of 125 +/- 28 minutes, and a mean fluoroscopy time of 21 +/- 13 minutes. Freedom from AF off Antiarrhythmic drugs was found in 82 and 79% of group 1 and group 2 patients, respectively. No procedure-related complications were observed. Conclusion: PV isolation by duty-cycled unipolar/bipolar RF ablation can be effectively and safely performed with a circular, decapolar catheter. Twelve-month follow-up data compare favorably with early postablation results, indicating stable effects over time. (J Cardiovasc Electrophysiol, Vol. pp. 1-7).

Indian Pacing Electrophysiol J. 2009; 9(6): 351-4
Vanga SR, Vacek J, Berenbom L, Lakkireddy DR

Management of ventricular tachycardia (VT) storm in a patient with an implantable cardioverter-defibrillator (ICD) is a challenging medical emergency. We describe a patient with cardiac sarcoidosis (CS) and an ICD who is admitted with VT storm. Management of VT was difficult due to resistance to multiple Antiarrhythmic drugs. He responded to immunosuppressive therapy supporting active CS as the cause of his VT. This case suggests that CS may underlie some cases of refractory VT and that immunosuppressive therapy may be effective in controlling this arrhythmia.

G Ital Cardiol (Rome). 2009 Sep; 10(9): 580-95
Oreto G, Luzza F, Satullo G, Donato A, Carbone V, Calabrò MP

The correct diagnosis of wide QRS complex tachycardia is an old problem, but it is still a new problem since no simple approach aimed at solving it is up to now available, despite the amount of research devoted to this topic. A wide QRS tachycardia can be: 1) ventricular tachycardia; 2) supraventricular tachycardia with bundle branch block that may be either preexisting or due to aberrant conduction, namely tachycardia-dependent; a further possibility is the effect of Antiarrhythmic drugs, which slow down intraventricular conduction, resulting in marked QRS complex widening; 3) supraventricular tachycardia with conduction of impulses to the ventricles over an accessory pathway (preexcited tachycardia). The origin of a wide QRS complex tachycardia can be reliably identified using a "holistic" approach, namely taking into account all of the available items: no single criterion, thus, is able to provide a simple and quick solution to the problem in all cases. The electrocardiographic signs are, without any exception, suggestive of ectopy, namely ventricular origin of the impulses; supraventricular tachycardia with aberrant conduction may be diagnosed only by excluding all of the items favoring ectopy. The classic diagnostic criteria include: 1) atrio-ventricular dissociation, characterized by absence of any relationship between QRS complexes and P waves; this phenomenon is at times immediately recognizable but more often can be discovered only by means of a detailed analysis of the tracing; 2) second degree ventriculo-atrial block, characterized by a relationship between QRS complexes and P waves, but with more ventricular complexes than P waves; 3) fusion and/or capture beats; 4) concordant precordial pattern, a sign that can be also expressed as absence of RS (or even rs, Rs, rS) complexes in the precordial leads; 5) an interval > 100 ms from the beginning of the QRS complex to the nadir of S wave in any precordial lead. Vagal maneuvers and analysis of previous ECGs recorded during sinus rhythm, if available, can provide further keys to the diagnosis. Some criteria proposed in the past, such as QRS axis or ventricular complex duration, are nowadays no longer considered; in addition, it has been demonstrated that items such as age, hemodynamic status, heart rate and regularity of R-R intervals may be misleading and should not be taken into account. Analysis of QRS configuration in leads V1 and V6 is a keystone in distinguishing the origin of wide QRS tachycardia: diagnostic criteria rely upon the assumption that aberration is due to a functional bundle branch block, whereas ectopy derives from a totally abnormal activation of the ventricles. Aberration, thus, results in a "typical" bundle branch block morphology, whereas ectopy is expressed by an "atypical" bundle branch block. Specific criteria, based on analysis of leads V1 and V6, have been developed to distinguish the two conditions from each other. The criteria based on QRS configuration, however, suffer from limitations since unexpected complicating factors, such as a previous myocardial infarction, can result in an "atypical" form of bundle branch block even in the presence of supraventricular tachycardia. A new algorithm has recently been introduced, based on analysis of lead aVR only. Any of the following features, observed in this lead, pinpoints a diagnosis of ventricular tachycardia: 1) a dominant R wave (R or Rs complexes); 2) an initial q or r wave with duration > 40 ms (qR or rS complexes); 3) a notch in the descending Q wave limb in a negative (Qr or QS) complex. In the absence of these signs, the ratio between the voltages recorded during the first and the last 40 ms of the QRS complex helps distinction between ectopy and aberration: a ratio < or = 1 suggests ventricular tachycardia whereas a ratio > 1 indicates supraventricular tachycardia. A hard diagnostic problem is associated with preexcited tachycardia, the condition resulting whenever supraventricular tachycardia impulses are conducted to the ventricles over an accessory pathway. This situation is far more rare than ectopy and aberration, and can be ruled out in the presence of negative precordial concordance (QS complexes in all the chest leads) or deep q waves in a precordial lead other than V1. A QRS morphology not consistent with any of the typical patterns observed in the various locations of the accessory pathways rules out a preexcited tachycardia, too.

Europace. 2009 Nov 3;
Bertaglia E, Tondo C, De Simone A, Zoppo F, Mantica M, Turco P, Iuliano A, Forleo G, La Rocca V, Stabile G

Aims In the last decade, several approaches to ablating triggers and substrates of atrial fibrillation (AF) have been developed. However, most studies have reported data only on short- or medium-term follow-up. The aim of this study was to investigate whether the 1-year efficacy of catheter ablation for AF is predictive of long-term clinical success. Methods and results Between February 2001 and October 2003, 229 consecutive patients affected by drug-refractory paroxysmal or persistent AF underwent a single radiofrequency catheter ablation procedure (anatomical approach in 146 patients and electrophysiologically guided approach in 83 patients). Of these patients, 177 (mean age 59.1 +/- 10.5 years, 57.6% with paroxysmal AF) were free from any atrial arrhythmia recurrence after 12 months. These 177 patients were subsequently followed up for at least another 24 months, by means of electrocardiogram and 24 h Holter monitoring. After a mean follow-up of 49.7 +/- 13.3 months (range 36-83 months), 58.2% of the patients were free from any atrial arrhythmia recurrence (39.5% without Antiarrhythmic drugs). The actuarial atrial arrhythmia recurrence rate was 13.0% at 2 years, 21.8% at 3 years, 35.0% at 4 years, 46.8% at 5 years, and 54.6% at 6 years. Atrial arrhythmia-free survival was similar in patients with paroxysmal or persistent AF, with and without Antiarrhythmic drugs during the follow-up, who underwent electrophysiologically guided pulmonary vein (PV) isolation or anatomical PV ablation. Conclusion Even patients in whom catheter ablation prevents AF recurrence for 1 year should not be considered 'cured', since >40% of them will suffer AF recurrence over a long-term clinical follow-up.

J Am Coll Cardiol. 2009 Nov 3; 54(19): 1747-62
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta(1)-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta(2)-ARs and alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.

Polim Med. 2009; 39(3): 37-45
Musial W, Kokol V, Voncina B

In this study we assessed the influence of lidocaine hydrochloride on the pH of diluted aqueous dispersions of modified poly(N-isopropylacrylamide), at temperature assigned as normalized skin surface temperature, and below and over the lower critical solution temperature value. Three different N-isopropylacrylamide polymer derivatives were synthesized by surfactant free emulsion polymerization, and assessed in the terms of pH in the aqueous dispersions in the presence and absence oflidocaine hydrochloride. The tendency in observed system was similar at three different temperatures, when lidocaine was applied. The pH value increased from the range between 5,39 - 5,90 up to the range 6,22 - 6,55. However, the step of pH between the temperature of 25 degrees C and 32 degrees C was more radical, comparing to 32 degrees C and 45 degrees C. The lidocaine hydrochloride influences the pH patterns observed at various temperature in polymeric systems: measurements of preparations applied on the skin or mucosa should be evaluated in respective temperature range.

Tumori. 2009 Jul-Aug; 95(4): 547-9
Tayer-Shifman OE, Rottenberg Y, Shuvy M

The superior toxicity profile is one of the major reasons for the widespread use of gemcitabine in cancer treatment. Bone marrow suppression is the most common side effect, while non-hematological events are relatively infrequent. Cardiac toxicity is a rare complication and cardiac arrhythmia is even rarer. We report the case of a 67-year-old woman with metastatic breast cancer without a history of cardiac arrhythmia or ischemic heart disease who developed supraventricular tachycardia. The symptoms had started immediately after gemcitabine treatment. The arrhythmia responded poorly to common treatment and was eventually controlled by oral propranolol five days after admission. The present case suggests that supraventricular tachycardia may be triggered by gemcitabine even without underlying significant heart disease and may be resistant to conventional therapy.

J drugs Dermatol. 2009 Oct; 8(10): 948-51
Patel R, Halem M, Zaiac M

BACKGROUND: Palmar hyperhidrosis is an uncomfortable condition that can severely affect a patient's quality of life. Injections of botulinum toxin have proven to be an efficient treatment modality, however the pain associated with palmar injections has limited the use of this therapy. OBJECTIVE: The authors describe a novel method of analgesia combining topical analgesic cream and forced cold air during botulinum injection treatment of palmar hyperhidrosis. CASE REPORT: This is a case report of a patient with a 10-year history of palmar hyperhidrosis. Both hands were pretreated with topical anesthetic cream and the right hand was additionally treated with forced cold air at a distance of 1 cm for up to 30 seconds before injection administration. After the botulinum injection was administered to both hands, the patient was subjectively asked about pain during injection. RESULTS: The patient subjectively reported a 75% decrease in the intensity of pain with the combination use of topical anesthetic cream and forced cold air, which she said made the injections more tolerable. No epidermal changes were noted at the time of treatment or at follow-up. CONCLUSION: The use of botulinum toxin for the treatment of palmar hyperhidrosis is limited due to the pain associated with injections of the palm. In this case report, we describe the successful use of forced cold air with topical anesthetic cream to lessen the pain of botulinum toxin injections during the treatment of hyperhidrosis.

Gend Med. 2009 Sep; 6(3): 419-32
Volgman AS, Manankil MF, Mookherjee D, Trohman RG

BACKGROUND: In 1995, atrial fibrillation (AF) was estimated to affect 2.2 million people in the United States. After the age of 75 years (the median age for onset of AF), approximately 60% of people with AF are women. Women have a significantly higher risk of AF-related stroke than do men and are more likely to live with stroke-related disability and a significantly lower quality of life. OBJECTIVE: This article provides an overview of the contributing factors and clinical presentation of AF in women and offers a rational, safe, effective, and gender-specific approach to therapy for women with AF. METHODS: Search engines, including PubMed and Google Scholar, were used to review the English-language literature addressing AF gender differences for the years 1989-2009. The search term atrial fibrillation was combined with multiple other terms, as well as with female, gender, sex, or women. Full-length manuscripts were reviewed. Original studies obtained were searched for additional relevant manuscripts using the cited references. RESULTS: Studies have shown that women are more likely than men to experience symptomatic attacks, a higher frequency of recurrences, and significantly higher heart rates during AF. Hormonal fluctuations during the menstrual cycle that affect QT intervals are an important consideration when selecting Antiarrhythmic drugs for premenopausal women. Women are treated with statins less frequently than are men, possibly contributing to an increased incidence of AF in women. Women may have a higher incidence of AF because of the association with obesity. Some evidence suggests that women have a significantly higher risk of bleeding from anticoagulation. Reluctance among physicians and patients to use warfarin may be especially problematic in elderly women, who benefit most from it. Outcomes after catheter ablation for AF are similar between the sexes, yet women are referred later and less frequently. CONCLUSIONS: We favor emphasizing therapies to prevent AF and ensure safe arrhythmia management (ie, rate control and appropriate anticoagulation) once AF has been diagnosed. Gender differences should be kept in mind for women with AF to reduce risks and improve quality of life.

Curr Treat Options Cardiovasc Med. 2009 Oct; 11(5): 373-80
Kumar K, Zimetbaum PJ

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and a major cause of morbidity. In the past decade, there have been significant advances in the nonpharmacologic management of AF. However, despite these advances there continues to be a great need for Antiarrhythmic drugs to suppress AF. Existing medications have moderate efficacy for AF termination and suppression and have significant associated side effects, limiting their use. The need for new therapies has spawned the growth of several exciting drugs at various stages of development for the medical management of AF. Some agents are derivatives of currently available compounds, whereas others have been newly developed to focus on novel ion current targets. Dronedarone is the first Antiarrhythmic agent in a decade to be recommended for approval by the US Food and Drug Administration for the management of AF. It is expected to a have a dramatically improved side effect profile, which likely will be the key factor in its prominence in our armamentarium in the future; however, dronedarone appears to have only moderate efficacy. Other novel agents are in various stages of development. Vernakalant, an "atrial selective" compound, will be useful in the acute chemical cardioversion of AF but not atrial flutter. Although vernakalant is similar in efficacy to ibutilide, it carries a significantly reduced risk of torsades de pointes. Ranolazine, initially developed for treating chronic angina, has important effects on ion currents potentially useful in arrhythmia management. Clinical trials specifically studying AF suppression will need to be performed before the utility of ranolazine can be extended. It is hoped that as our understanding of the pathophysiology of AF improves, innovative targets for pharmacologic therapy will emerge. However, the challenge of proving efficacy and safety in large randomized controlled trials will remain for any promising new agent.

Circ Arrhythm Electrophysiol. 2009 Oct; 2(5): 511-23
Itoh H, Sakaguchi T, Ding WG, Watanabe E, Watanabe I, Nishio Y, Makiyama T, Ohno S, Akao M, Higashi Y, Zenda N, Kubota T, Mori C, Okajima K, Haruna T, Miyamoto A, Kawamura M, Ishida K, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Sugimoto Y, Ashihara T, Hayashi H, Ito M, Imoto K, Matsuura H, Horie M

BACKGROUND: drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonAntiarrhythmic drugs than by Antiarrhythmic drugs (Antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Circ Arrhythm Electrophysiol. 2009 Oct; 2(5): 481-7
Khaykin Y, Skanes A, Champagne J, Themistoclakis S, Gula L, Rossillo A, Bonso A, Raviele A, Morillo CA, Verma A, Wulffhart Z, Martin DO, Natale A

BACKGROUND: The study was conducted to compare relative safety and efficacy of pulmonary vein antrum isolation (PVAI) using intracardiac echocardiographic guidance and circumferential pulmonary vein ablation (CPVA) for atrial fibrillation (AF) using radiofrequency energy. METHODS AND RESULTS: Sixty patients (81% men; 81% paroxysmal; age, 56+/-8 years) failing 2+/-1 Antiarrhythmic drugs were randomly assigned to undergo CPVA (n=30) or PVAI (n=30) at 5 centers between December 2004 and October 2007. CPVA patients had circular lesions placed at least 1 cm outside of the veins. Ipsilateral veins were ablated en block with the end point of disappearance of potentials within the circular lesion. Left atrial roof line and mitral isthmus line were ablated without verification of block. For patients in AF postablation or with AF induced with programmed stimulation, complex fractionated electrograms were mapped and ablated to the end point of AF termination or disappearance of complex fractionated electrograms. PVAI did not include complex fractionated electrogram ablation. Esophageal temperature was monitored and kept within 2 degrees C of baseline or under 39 degrees C. Success was defined as absence of atrial tachyarrhythmias (AF/AT) off Antiarrhythmic drugs. There was no difference between CPVA and PVAI regarding to baseline variables, catheter used, duration of the procedure, or RF delivery. Fluoroscopy time was longer with PVAI (54+/-17 minutes versus 77+/-18 minutes, P=0.0001). No significant complications occurred in either arm. PVAI was more likely to achieve control of AF/AT off Antiarrhythmic drugs (57% versus 27%, P=0.02) at 2+/-1 years of follow-up. CONCLUSIONS: A single PVAI procedure is more likely to result in freedom from AF/AT off Antiarrhythmic drugs than CPVA supplemented by complex fractionated electrogram ablation in select patients.

Anesth Analg. 2009 Nov; 109(5): 1691-4
Ben-Ari A, Moreno M, Chelly JE, Bigeleisen PE

We describe an ultrasound-guided technique of continuous bilateral paravertebral block using an intercostal approach in 12 patients undergoing elective abdominal surgery. Postoperatively, each of the patient's paravertebral catheters was bolused with 10 mL lidocaine (15 mg/mL), and each of the patient's catheters was infused with 0.2% ropivacaine at 10 mL/h. Using a pinprick test, the median number of dermatomes blocked after the initial bolus was 5 (interquartile range, 4-6), and 23 of 24 catheters produced a local anesthetic block. The median verbal pain score on postoperative day 1 was 5.5 (interquartile range, 3.5-6), and median dose of IV hydromorphone consumed during the first 24 h after surgery was 1.9 mg (interquartile range, 0.7-5.05). All catheters were removed within 72 h after surgery.

Anesth Analg. 2009 Nov; 109(5): 1679-83
Movafegh A, Nouralishahi B, Sadeghi M, Nabavian O

INTRODUCTION: In this prospective, randomized, double-blind study, we evaluated the effect of an ultra-low dose of naloxone added to lidocaine and fentanyl mixture on the onset and duration of axillary brachial plexus block. METHODS: One hundred twelve patients scheduled for elective forearm surgery under axillary brachial plexus block were randomly allocated to receive 34 mL lidocaine 1.5% with 3 mL of isotonic saline chloride (control group, n = 28), 34 mL lidocaine 1.5% with 2 mL (100 microg) of fentanyl and 1 mL of isotonic saline chloride (fentanyl group, n = 28), 34 mL lidocaine 1.5% with 2 mL saline chloride and 100 ng (1 mL) naloxone (naloxone group, n = 28), or 34 mL lidocaine 1.5% with 2 mL (100 microg) of fentanyl and 100 ng (1 mL) naloxone (naloxone + fentanyl group, n = 28). A multiple stimulation technique was used in all patients. After performing the block, sensory and motor blockades of radial, median, musculocutaneous, and ulnar nerves were recorded at 5, 15, and 30 min. The onset time of the sensory and motor blockades was defined as the time between the last injection and the total abolition of the pinprick response and complete paralysis, respectively. The duration of sensory and motor blocks was considered as the time interval between the complete block and the first postoperative pain and complete recovery of motor functions. RESULTS: Sensory and motor onset times were longer in the naloxone (sensory onset time: 15 +/- 3, and motor onset time: 21 +/- 4) and naloxone + fentanyl group than control or fentanyl groups (sensory onset time: 10 +/- 3 min in control group, 10 +/- 4 min in fentanyl group, and 17 +/- 3 min in naloxone + fentanyl group, motor onset time: 15 +/- 5 min in control group, 14 +/- 7 min in fentanyl group, and 17.3 +/- 3.4 min in naloxone + fentanyl group) (P < 0.001). The duration of time to first postoperative pain and motor blockade was significantly longer in the naloxone (92 +/- 10 and 115 +/- 10 min) and naloxone + fentanyl groups (98 +/- 12 and 122 +/- 16 min) than control (68 +/- 7 and 89 +/- 11 min) and fentanyl groups (68 +/- 11 and 90 +/- 12 min) (P < 0.001). The time to first postoperative pain was significantly longer in the naloxone and naloxone + fentanyl groups than in the control or fentanyl groups (P < 0.001). CONCLUSIONS: The addition of an ultra-low dose of naloxone to lidocaine 1.5% solution with or without fentanyl solution in axillary brachial plexus block prolongs the time to first postoperative pain and motor blockade but also lengthens the onset time.

Anesth Analg. 2009 Nov; 109(5): 1486-92
Assad AR, Delou JM, Fonseca LM, Villela NR, Nascimento JH, Verçosa N, Lopes AG, Capella MA

BACKGROUND: Propofol (2,6-diisopropylphenol) has been shown to protect several organs, including the kidneys, from ischemia-reperfusion (I-R)-induced injury. Although propofol affects adenosine triphosphate-sensitive potassium (K(ATP)) channels in nonrenal tissues, it is still not clear by which mechanisms propofol protects renal cells from such damage. In this study, we investigated whether propofol induces renal preconditioning through renal K(ATP) channels. METHODS: A reversible ATP depletion (antimycin A) followed by restoration of substrate supply in LLC-PK1 cells was used as an in vitro model of renal I-R. Cell viability was assessed by dimethylthiazol-diphenyltetrazol bromide and trypan blue dye exclusion test assays. Apoptosis was evaluated by annexin V-fluorescein isothiocyanate staining by flow cytometry and immunofluorescence. Propofol treatments were initiated at various time intervals: 1 or 24 h before ischemia, only during ischemia, or only during reperfusion. To evaluate the mechanisms of propofol protection, specific K(ATP) channel inhibitors or activators were used in some experiments during propofol pretreatment. RESULTS: Propofol attenuated I-R injury on LLC-PK1 cells when present either 1 or 24 h before initiated I-R, and also during the recovery period, but not when added only during ischemia. Propofol pretreatment significantly protected LLC-PK1 from I-R-induced apoptosis. The protective effect of propofol was prevented by glibenclamide (a sarcolemmal ATP-dependent K(+) channel blocker) and decreased by 5-hydroxidecanoic acid (a mitochondrial ATP-dependent K(+) channel blocker), but it was not modified by diazoxide (a selective opener of ATP-sensitive K(+) channel). CONCLUSION: Propofol protected cells against apoptosis induced by I-R. This protection was probably due to a preconditioning effect of propofol and was, at least in part, mediated by K(ATP) channels.