Tadalafil entfaltet seine Wirkung über eine selektive Hemmung der PDE5, wodurch die Konzentration von cGMP im glatten Muskelgewebe stabil bleibt. Diese biochemische Modulation resultiert in einer langanhaltenden Relaxation der Gefäßwände. Der Wirkstoff wird nach oraler Einnahme effizient resorbiert, mit einer Bioverfügbarkeit von rund 80 %. Seine Halbwertszeit von bis zu 36 Stunden ist innerhalb dieser Substanzklasse außergewöhnlich. Abgebaut wird er in der Leber, hauptsächlich durch CYP3A4, mit anschließender biliärer Exkretion. Typische unerwünschte Wirkungen entstehen durch eine verstärkte Vasodilatation, etwa Kopfschmerzen oder Flush. Pharmakologisch wird cialis generika vor allem durch die verlängerte Wirkungsdauer charakterisiert.
Pii: s0003-4975(99)01267-9
CURRENT REVIEW Atrial Fibrillation After Cardiac Operation: Risks, Mechanisms, and Treatment Charles W. Hogue, Jr, MD, and Mary L. Hyder, MD Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri Atrial fibrillation (AF) is a common complication of who may tolerate these drugs. Preliminary investigations cardiac operations that leads to increased risk for throm- showing sotalol and amiodarone to be effective in pre- boembolism and excessive health care resource utiliza- venting postoperative AF are encouraging, but early data tion. Advanced age, previous AF, and valvular heart have been limited to selective patient populations and operations are the most consistently identified risk fac- have not adequately evaluated safety. Newer class III tors for this arrhythmia. Dispersion of repolarization antiarrhythmic drugs under development may have a leading to reentry is believed to be the mechanism of role in the treatment of postoperative AF, but the risk of postoperative AF, but many questions regarding the drug-induced polymorphic ventricular tachycardia must pathophysiology of AF remain unanswered. Treatment is be considered. Nonpharmacologic interventions under aimed at controlling heart rate, preventing thromboem- consideration for the treatment of AF in the nonsurgical bolic events, and conversion to sinus rhythm. Multiple setting, such as automatic atrial cardioversion devices investigations have examined methods of preventing and multisite atrial pacing, may eventually have a role postoperative AF, but the only firm conclusions that can for selected cardiac surgical patients. be drawn is to avoid -blocker withdrawal after opera- (Ann Thorac Surg 2000;69:300 – 6) tion and to consider -blocker therapy for other patients 2000 by The Society of Thoracic Surgeons Atrial fibrillation (and/or flutter; AF) is a common patients with postoperative AF especially for those with complication of cardiac operations and an impor- low cardiac output [1, 2, 10]. Patients developing postop- tant source of patient morbidity and increased resource erative AF are hospitalized 3 to 4 days longer than utilization [1–9]. The incidence of this arrhythmia is patients remaining in sinus rhythm leading to increased dependent on definitions (eg, duration, presence of hospital cost [1–3]. Recent analysis involving 2,417 pa- symptoms), patient characteristics, type of operation, and tients having CABG at 24 U.S. medical centers estimated method of arrhythmia monitoring [1–9]. In a series of that postoperative AF increased the cost of operation 3,983 patients undergoing cardiac operations at our insti- by $1,616 per patient [2]. In a single center study, post- tution, Creswell and colleagues [1] found the incidence of operative AF was associated with $10,055 to $11,500 AF detected by continuous electrocardiographic teleme- of additional hospital charges for CABG [3]. Thus, the try monitoring to be 32% after coronary artery bypass health economic implications of postoperative AF are grafting (CABG), 42% after mitral valve replacement, substantial. 49% after aortic valve replacement, and 62% after com- bined CABG and valve procedures. Other researchers Risk Factors have reported atrial arrhythmias in 27% to 33% of pa- tients after CABG [2, 3]. Of more concern is the finding Patient age has consistently been demonstrated to be the that the frequency of AF may be increasing. In their most important risk factor for postoperative AF with series where surgeons and methods of arrhythmia mon- incidence rates of more than 50% for patients older than itoring were constant, Creswell and associates [1] found 80 years undergoing CABG compared with 5% for pa- that the incidence of AF after CABG increased from 26% tients less than 50 years [1–3]. This association has been in 1986 to 36% in 1991. The latter finding was attributable explained to be attributable to age-related structural to an increase in the mean age of the surgical patients. changes in the atrium such as dilation, muscle atrophy, Postoperative AF is usually well tolerated but tachy- decreased conduction tissue, and fibrosis [11, 12]. Other cardia and loss of organized atrial contraction may result investigators have shown prolonged atrial conduction in hypotension and congestive heart failure in some detected by routine and signal-averaged electrocardio- patients. Even when hemodynamically tolerated, postop- grams and lowered arrhythmia threshold at the time of erative AF has consequences. The risk for perioperative operation to be associated with risk for postoperative AF stroke has been shown to be nearly threefold higher for [6, 8, 9]. Recently, we have reported that patients devel- oping AF after CABG have reduced complexity of heart rate variability compared with patients remaining in Address reprint requests to Dr Hogue, Department of Anesthesiology, sinus rhythm and that this finding along with tachycardia Washington University School of Medicine, 660 S Euclid Ave, Box 8054, St. Louis, MO 63110; e-mail: hoguec@notes.wustl.edu. identified risk for AF with high predictive accuracy [13]. 2000 by The Society of Thoracic Surgeons 0003-4975/00/$20.00 Published by Elsevier Science Inc PII S0003-4975(99)01267-9 Ann Thorac Surg HOGUE AND HYDER 2000;69:300 – 6 POSTOPERATIVE ATRIAL FIBRILLATION Whether these methods or other electrophysiologic mea- only reducing cardiac sympathetic tone will be ineffective surements can be feasibly applied to routine clinical for preventing postoperative AF in all patients. settings for identifying AF risk remains to be established. The reason for the delay in the onset of AF more than 2 to Many other risk factors for postoperative AF have been 3 days after operation is not clear. One possibility is that the identified but the results have been inconsistent between onset of AF is related to an exaggerated inflammatory studies [1–3, 14, 15]. The latter risks include history of response especially involving the pericardium [30, 31]. Me- rheumatic heart disease, left ventricular hypertrophy, hy- chanical stretching of the atrium can alter cellular electro- pertension, preoperative digoxin use, obstructive lung dis- physiologic properties suggesting that increased intravas- ease, peripheral vascular disease, and increasing aortic cular volume due to postoperative mobilization of cross-clamp duration [1–3, 14, 15]. The atria are inade- interstitial fluid could contribute to the development of AF quately cooled during hypothermic cardioplegic arrest [16, [32]. Tachycardia or brief episodes of AF lead to shortening 17]. Early return of atrial electrical activity during aortic of the atrial effective refractory period (electrophysiologic cross-clamping is related to atrial conduction abnormalities remodeling) promoting the maintenance of AF [33–36]. and AF risk after operation in experimental and clinical Alterations in calcium-handling proteins have been sug- investigations [16, 17]. Type of cardioplegia, however, does gested to be an important mechanism for this electrophysi- not seem to alter the risk for postoperative AF [18, 19]. ologic remodeling [34–37]. Downregulation of mRNA for L-type calcium channels and for sarcoplasmic reticular calcium–ATPase have been demonstrated in atrial tissue Mechanisms obtained before cardiac operations in patients with preex- The electrophysiologic mechanism of postoperative AF is isting AF and perhaps these mechanisms contribute to believed to be reentry that results from dispersion of susceptibility to postoperative AF [38]. The hypothesis that atrial refractoriness [5, 20, 21]. When adjacent atrial areas postoperative AF is related to altered gene expression is an have dissimilar or nonuniform refractoriness, a depolar- attractive explanation for varying individual susceptibility izing wavefront becomes fragmented as it encounters and for the time lag between operation and the onset of the both refractory and excitable myocardium [5, 20, 21]. This arrhythmia. allows the wavefront to return and stimulate previously refractory but now repolarized myocardium leading to Treatment incessant propagation of the wavefront or reentry [5, 20, Ventricular rate control, anticoagulation, and conversion 21]. Currently, there is not an adequate explanation for to sinus rhythm are the primary goals of the treatment of why some patients develop postoperative AF whereas AF. Rate control can be achieved with -adrenergic others having the same surgical interventions remain in receptor or calcium channel blocking drugs. Diltiazem sinus rhythm. Individuals vulnerable to AF are specu- and verapamil are effective for heart rate control, but the lated to have the electrophysiologic substrate (nonuni- former is usually better tolerated especially for patients form dispersion of atrial refractoriness) before operation with impaired left ventricular function, whereas use of that is then aggravated by surgical perturbations [5]. the latter drug can result in hypotension [39, 40]. Digoxin It is widely believed that enhanced sympathetic ner- may be a useful drug for slowing heart rate for situations vous system activity increases susceptibility to postoper- where -blockers and calcium channel blocking drugs ative AF [4, 7, 22–25]. Sympathetic activation, however, is are contraindicated. Digoxin slows atrioventricular con- highest the first 24 hours after operation, whereas the duction to a large degree by enhancement of vagal tone. onset of AF usually occurs between the second and third In the setting of high sympathetic nervous system drive postoperative days [1–3, 26]. Furthermore, the atrial elec- as occurs perioperatively, its efficacy may be limited [26]. trophysiologic effects of autonomic nervous system stim- Mural thrombus formation is the most serious compli- ulation are complex. In contrast to the ventricle where cation of AF. In an autopsy series involving nonsurgical sympathetic activation decreases and vagal stimulation patients, 21% of 642 patients with a history of AF had increases the threshold for tachycardia and fibrillation, atrial thrombi compared with 2% of control patients [41]. both sympathetic and parasympathetic activation alter Atrial thrombi were found in 30% of patients with valvu- atrial refractoriness, possibly contributing to the arrhyth- lar heart disease-related AF compared with 14% of pa- mia substrate [27, 28]. Heightened vagal tone has been tients with nonvalvular-related AF. In this series, thrombi demonstrated before AF in nonsurgical patients [29]. were twice as likely to occur in the left compared with the Recently, we evaluated cardiac sympathovagal balance right atrium. Left atrial thrombus is reported in 13% to before the onset of AF in patients recovering from CABG 29% of patients undergoing transesophageal echocardi- [13]. Either higher or lower measures of heart rate vari- ography and the potential for thrombus formation occurs ability were observed before AF, a finding consistent with early after the onset of AF [42– 45]. Multiple clinical trials divergent autonomic conditions before arrhythmia onset have shown that anticoagulation reduces the risk of [13]. The latter findings support the possibility that in thromboembolic stroke in nonsurgical patients with some patients heightened sympathetic tone is present chronic AF, but the use of anticoagulation for these before AF but in others, either higher vagal tone or purposes in cardiac surgical patients has not be evalu- dysfunctional autonomic heart rate control is present ated with clinical trials [46 – 48]. The use of anticoagula- before arrhythmia onset [13]. Thus, measures aimed at tion therapy in the surgical patient is balanced against HOGUE AND HYDER Ann Thorac Surg POSTOPERATIVE ATRIAL FIBRILLATION 2000;69:300 – 6 Table 1. Summary of Trials Evaluating -Adrenergic Receptor Blocking Drugs, Calcium Channel Blocking Drugs, and Type I Anti-Arrhythmic Drugs for the Prevention of Postoperative Atrial Fibrillation/Flutter (AF) Frequency AF Frequency AF Study Design Subjects Treatment Group Control Group Andrews et al [22] Meta-analysis Digoxin vs placebo Verapamil vs placebo
-Blockers vs placebo Kowey et al [23] Meta-analysis Digoxin vs placebo
-Blockers vs placebo
-Blockers & Digoxin vs placebo Laub et al [63] Procainamide vs placebo Gold et al [64] Procainamide vs placebo Hannes [59] Diltiazem vs nitroglycerin Seitelberger et al [60] Diltiazem vs nitroglycerin Merrick et al [62] Propafenone vs atenolol a p ϭ NS vs control group. b p Յ 0.05 vs control group. DB ϭ double-blind; R ϭ prospectively randomized. the individual risk of pericardial hemorrhage. Anticoag- 20% to 34% for placebo-treated patients (p Ͻ 0.01) (Table ulation has been recommended for patients with AF after 1) [22, 23]. These studies have limitations: the data is 10 to cardiac procedures when the arrhythmia is persistent or 15 years old, the patients were mostly men, had normal when there is associated valvular heart disease or im- or mildly impaired left ventricular function, and few paired left ventricular function [14, 15]. patients had diabetes [22, 23]. There are also limitations Electrical cardioversion is indicated whenever AF is as- inherent with meta-analysis such as publication bias sociated with hemodynamic deterioration. Some forms of where small negative studies are less likely to be pub- atrial flutter (atrial flutter rate, ϷϽ 340/min) can be con- lished than similar sized positive studies (ie, the studies verted to sinus rhythm with overdrive atrial pacing. There is used for this type of retrospective analysis) [57]. Interpre- no consensus regarding when antiarrhythmic drug therapy tation of these investigations must also consider the should be started for postoperative AF. Procainamide, ami- inconsistent methods of arrhythmia monitoring and the odarone, and propafenone are effective for these purposes, inconsistent management of patients whom were receiv- but only the former two drugs are available in parental ing -blockers before operation in these trials. That is, formulations in the United States [49–54]. There are little some patients receiving placebo postoperatively were data that have compared the safety and efficacy of each of subjected to -blocker withdrawal [22, 23]. Failure to these antiarrhythmic drugs in cardiac surgical patients. In a restart -blockers after CABG has been shown to be small prospectively randomized trial, amiodarone and associated with a greater than twofold higher rate of propafenone were equally effective in converting AF devel- postoperative AF [58]. oping after CABG to sinus rhythm [54]. Conversion was Other pharmacologic approaches evaluated for the more delayed with amiodarone (19% at 1 hour versus 83% prevention of postoperative AF are listed in Table 1. at 24 hours), but control of ventricular rate was observed Digoxin and verapamil are no more effective than pla- within 10 minutes. The use of sotalol for treatment of cebo (Table 1) [22]. A nonblinded, single center study postoperative AF has also been reported, but a parental showed that diltiazem when given for 24 hours after form of this drug is not available in the U.S. and its use was operation reduced the frequency of AF [59, 60]. In light of associated with a high frequency of hypotension [55]. Ibuti- experimental data suggesting that calcium channel lide is a pure class III antiarrhythmic agent (prolongation of blockers promote the development of AF, further inves- repolarization) that received Food and Drug Administra- tigations of the efficacy of diltiazem seem warranted [61]. tion approval in 1996. The efficacy of ibutilide for converting Small trials have produced inconsistent results on the AF has been demonstrated, but these data were derived efficacy of procainamide in preventing postoperative AF from clinical trials that did not include cardiac surgical and propafenone was found to be no more effective than patients [56]. Although intravenous ibutilide has a rapid atenolol for AF prophylaxis [62– 64]. onset of action and is hemodynamically well tolerated, a Stalol and amiodarone possess both membrane- concern with its use was the high rate of polymorphic stabilizing properties (class III effects) and -blocking ventricular tachycardia (8% of patients receiving ibutilide). properties that make them appealing for AF prophylaxis. Sotalol has been shown to be effective for this use (Table Arrhythmia Prophylaxis 2) [9, 25, 65– 67]. Many of these trials, however, had
-Blockers have been the most widely studied drugs for open-labeled, nonblinded study design and the methods the prevention of postoperative AF [4, 22–25]. Separate of monitoring the electrocardiogram were inconsistent. meta-analyses have shown that the frequency of AF after Furthermore, the management after operation for pa- cardiac operations in patients receiving -blockers was tients receiving preoperative -blocker therapy was not collectively 9% to 10% compared with incidence rates of always clearly defined [9, 25, 65– 67]. Finally, in some of Ann Thorac Surg HOGUE AND HYDER 2000;69:300 – 6 POSTOPERATIVE ATRIAL FIBRILLATION Table 2. Clinical Investigations of Sotalol for the Prevention of Atrial Fibrillation After Cardiac Surgery Incidence of Atrial Drug/Dose ECG Monitoring Fibrillation Jansen et al [65] Metoprolol: 0.1 mg/kg IV Telemetry ECG for 48 h Metoprolol: 15.3%a then 50 mg TID, PO then 12 lead ECG TID. Sotalol: 2.4%a,b Sotalol: 0.3 mg/kg IV; 80 mg TID, PO Controls: 36% Controls: routine care Suttorp et al [25] Sotalol: 40 mg TID, PO Telemetry ECG for 60 h Sotalol 40 mg: 13.9% Sotalol: 80 mg TID, PO then 12 lead ECG with Sotalol 80 mg: 10.9% Propranolol: 10 mg QID, PO symptoms Propanolol 10 mg: 18.8% Propranolol: 20 mg QID, PO Propranolol 20 mg: 13.7% Nystrom et al [66] Sotalol: 160 mg BID, PO Telemetry for 48 h; daily Sotalol: 10%a Controls: half-dose of preoperative 12 lead ECG’s Controls: 29%
-blocker Suttorp et al [67] Sotalol: 40 mg QID, PO Telemetry for 60 h; 12 Sotalol: 16%a Controls: Placebo lead ECG with symptoms Controls: 33% Weber et al [9] Sotalol: 80 mg BID, PO Telemetry 24 h; 12 lead Sotalol: 26%a Controls: Placebo ECG with symptoms Controls: 44% a p Ͻ 0.05 vs controls. b p Ͻ 0.05 vs -adrenergic blocking drug. BID ϭ 2 times a day; PO ϭ orally; QID ϭ 4 times a day; TID ϭ 3 times a day. the trials the frequency of postoperative AF was no because most patients either do not develop the arrhyth- different between patients receiving sotalol versus a mia or it is transient and of little consequence. -Blockers
-blocker, questioning whether any prophylactic effect of are usually well tolerated but clinically important side sotalol was as a result of the membrane-stabilizing effects effects requiring discontinuation of sotalol were reported or -blocking properties of the drug [25]. in 13% of patients after cardiac operation [9, 25]. Toxicity Early data on the efficacy of amiodarone for the pre- (pulmonary fibrosis, worsening of heart failure, hypothy- vention of postoperative AF have been inconsistent (Ta- roidism, and hepatic toxicity) occurs in 5% to 10% of ble 3) [68, 69]. Daoud and colleagues [70], however, found patients receiving chronic amiodarone therapy, but the that amiodarone therapy beginning 1 week before car- lower doses and shorter duration of treatment for peri- diac operation and continued until hospital discharge operative arrhythmia control is better tolerated [71–74]. reduced the incidence of AF compared with placebo (25% In a small series, preoperative low-dose amiodarone versus 53%, p ϭ 0.003). The management of postoperative (mean dose, 205 Ϯ 70 mg/day) treatment did not increase
-blockers for the 30% of placebo patients receiving these the risk of pulmonary toxicity but it was associated with drugs preoperatively is not clear. In the placebo group, a higher need for inotropic support after cardiac opera- postoperative AF was more frequent for patients receiv- tion [73]. Proarrhythmic side effects of antiarrhythmic ing preoperative -blockers compared with patients not drugs is a bigger concern. In nonsurgical patients, there receiving these drugs before operation (61% versus 33%, is a threefold increased risk for life-threatening ventric- p ϭ 0.09). In the amiodarone group, the frequency of ular arrhythmias with class I antiarrhythmics [75]. The postoperative AF for patients receiving preoperative proarrhythmic risk associated with sotalol and amioda-
-blockers was 27%. rone is believed to be less but these life-threatening side effects have been reported in 4.3% to 5.9% of patients receiving sotalol after myocardial infarction and from Potential Antiarrhythmic Toxicity less than 1% to 2% for patients receiving amiodarone [76, The risk/benefit ratio for administering drugs for AF 77]. Data regarding the safety of sotalol and amiodarone prophylaxis is different than for arrhythmia treatment for the prevention of postoperative AF from adequately Table 3. Clinical Investigations of Amiodarone for the Prevention of Atrial Fibrillation After Cardiac Surgery Incidence of Atrial ECG Monitoring Fibrillation Hohnloser et al [68] 77 300 mg over 2 h after surgery; 1.2 gm/24 Holter for 48 h then Amidarone: 5%a h ϫ 2 days; 900 mg/24 h ϫ 2 days 12 lead ECG with symptoms Control: 21% Butler et al [69] 12 15 mg/kg after cross-clamp is removed; 200 Holter ϫ 6 days Amiodarone: 10%b mg TID ϫ 5 days, PO Controls: 20% Daoud et al [70] 12 200 mg TID, PO for 7 days before Telemetry ϫ 7 days Amiodaronec: 23% & 25%a surgery; 200 mg PO daily after surgery Controls: 42% & 53% until discharge a p Ͻ 0.05 vs control. b p ϭ no significance vs control. c Frequency of atrial fibrillation during hospitalization and combined for hospitalization and after discharge, respectively. PO ϭ orally; TID ϭ 3 times a day. HOGUE AND HYDER Ann Thorac Surg POSTOPERATIVE ATRIAL FIBRILLATION 2000;69:300 – 6 powered studies are not available, especially for patients ments for AF. Overdrive atrial pacing can reduce the at high risk for proarrhythmia (eg, impaired ventricular frequency of AF in patients with sick sinus syndrome but its function or myocardial ischemia) [76, 77]. efficacy after CABG has not been confirmed [88]. Pacing the right and left atrium simultaneously (dual site pacing) Atrial Fibrillation Prophylaxis and Patient reduces the recurrence of AF in nonsurgical patients with Outcomes intraatrial conduction abnormalities possibly by reducing dispersion of refractoriness [89]. A randomized study in Patients most susceptible to postoperative AF often have patients undergoing CABG found a trend for a lower other characteristics associated with surgical complica- frequency of AF in patient having biatrial pacing, especially tions and longer hospitalization (ie, the elderly, patients for patients receiving -blockers [90]. with chronic lung disease, peripheral vascular disease, Implantable automatic atrial defibrillator systems sim- prolonged aortic cross-clamp time). A possibility exist ilar to those used to terminate ventricular arrhythmias that in some situations AF is merely a marker and not are under investigation for nonsurgical patients with necessarily the cause for other morbidity and higher recurring AF but energy levels needed for successful hospital cost. Few investigators have examined whether atrial cardioversion (Ϸ1 to 5 J) are associated with dis- drug prophylaxis for AF improves outcomes. Kowey and comfort [91]. Innovations in electrode configurations and colleagues [4] found that acebutolol and digitalis led to a energy delivery characteristics result in lowered atrial lower frequency of AF compared with digitalis alone, but defibrillation thresholds to levels that are tolerable [92, this treatment did not lead to shorter duration of hospi- 93]. The feasibility of low-energy cardioversion of AF talization or reduced cost of cardiac operation. The data with temporary epicardial wire electrodes after cardiac of Daoud and associates [70] reiterates that patients with operations has been demonstrated [94]. This latter report AF have longer hospitalization and higher hospital cost, and other data from earlier trials in nonsurgical patients but whether prophylactic amiodarone therapy positively with AF suggest that, with further advances, temporary improved patient outcomes was not clearly demonstrated. automatic atrial defibrillator/pacing systems using tem- porary epicardial leads could conceivably be developed Other and Developing Treatments for the treatment of postoperative AF. This approach Total and ionized serum magnesium concentrations are could lead to early termination of postoperative AF, reduced by cardiopulmonary bypass [78]. Although hy- lowering the risk of thromboembolism, as well as allow- pomagnesemia may be related to supraventricular ar- ing for early pharmacologic therapy. rhythmias after cardiac operation, it is not clear whether magnesium replacement reduces this risk [71– 81]. Car- Conclusions diopulmonary bypass also results in an euthyroid sick state [82]. Preliminary trials in patients with reduced left Postoperative AF is a frequent complication of cardiac ventricular function undergoing CABG and receiving operations that increases health care resource utilization thyroid hormone to improve cardiac performance found and is associated with other serious adverse events. a lower incidence of AF in patients receiving triiodothy- Treatment AF is aimed at ventricular rate control, anti- ronine compared with controls [83]. coagulation, and restoration of sinus rhythm. At present Pharmacologic prolongation of atrial repolarization there is a lack of consensus regarding routine prophy- (class III effect) is an effective antifibrillatory strategy. laxis for this arrhythmia other than resuming -blocker Several new class III antiarrhythmic agents lacking auto- therapy early after operation and, possibly starting nomic blocking properties and other toxicity of sotalol
-blockers in other patients who may tolerate these and amiodarone are under development and these com- drugs [14, 15]. Perhaps, in the future, nonpharmacologic pounds may have eventual usefulness for patients un- methods of either AF prevention or early, automatic dergoing cardiac operations. As a class, these drugs cardioversion will contribute to improved treatment or prolong repolarization, refractoriness, increase ventricu- prevention of this arrhythmia. lar fibrillation threshold, and slow the rate of ventricular tachycardia [84]. For the most part, pure class III com- References pounds do not have negative inotropic effects but they do have proarrhythmic potential [84]. These agents have 1. Creswell LL, Schuessler RB, Rosenbloom M, et al. Hazards actions on different membrane currents such as specific of postoperative atrial arrhythmias. Ann Thorac Surg 1993; blockade of the delayed rectifier potassium current (eg, 56:539– 49. 2. Mathew JP, Parks R, Savino JS, et al. 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Termine Abo 1 (Mittwoch) Termine Abo 2 (Donnerstag) Termine Abo 3 (Freitag) Termine Abo 4 (Samstag) Wolfgang „Fifi“ Pissecker SUPERNACKT Wodka, Weiber, Wahnsinn. Damit kannte sich der Stripper Mike aus, bevor er Mitte 40 in die Midlife- Krise stürzt. Inzwischen dominieren Voltaren, ein bisschen Wehmut und viel Verdrängung! Ein Mann mit üppiger Vergangenheit, mickrig
_________________________________________________________________________ Shaykh Mashhoor Hasan Aal Salmaan (hafidhahullaah) THE RULING ON USING VIAGRA1 _________________ Many questions have arrived and in reality I feel ashamed to read them, some of these questions are from men and some from women. However, during these times wherein desires are agitated a person is not really sur