Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations

Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation.
Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF).
Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks).
Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD₉₀) and a significant use-dependent reduction in V_max leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 μM), high calcium ([Ca²⁺]_o= 5.4 mM), isoproterenol (Iso, 1 μM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. V_max, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals.
Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.     

Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol

OBJECTIVE: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. METHODS: Three groups of dogs were studied. Group I (n = 8) received no treatment. Group II (n = 7) and group III (n = 8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. RESULTS: Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9 +/- 0.4 pM in control dogs, 3.1 +/- 0.2 pM in group III, P < 0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P < 0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P < 0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69 +/- 12 ms in untreated dogs, 41 +/- 8 ms in group II (P < 0.05) and 34 +/- 8 ms (P < 0.05) in group III at PCL = 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208 +/- 5 ms versus 188 +/- 9 ms at PCL = 1000 ms, P < 0.05). The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. CONCLUSION: Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias.     

G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10?μg/kg G-CSF s.c. over 17?±?4?days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33?±?12?ms; p?相似文献   

Chronic Amiodarone Reduces Transmural Dispersion of Repolarization in the Canine Heart

Amiodarone Reduces Transmural Dispersion. Introduction: Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its β-blocking properties, amiodarone is known lo block the sodium, potassium, and calcium channels in the heart. Its complex electropharmacology notwithstanding, the reasons for the high efficacy of the drug remain unclear. Also not well understood is the basis for the low incidence of proarrhythmia seen with amiodarone relative to other agents with Class III actions. The present study was designed to examine the effects of chronic amiodarone in epicardial, endocardial, and M cells of the canine left ventricle. Methods and Results: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally (30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic amiodarone produced a greater prolongation of action potential duration in epicardium and endwardium, but less of an increase, or even a decrease at slow rates, in the M region, thereby reducing transmural dispersion of repolarization. In addition, chronic amiodarone therapy suppressed the ability of the I_kr, blocker, d-sotalol, to induce a marked dispersion of repolarization or early afterdepolarization activity. Conclusion: Our data demonstrate for the first time a direct effect of chronic amiodarone treatment to differentially alter the cellular electrophysiology of ventricular myocardium so as to produce an important decrease in transmural dispersion of repolarization, especially under conditions in which dispersion is exaggerated. These results may contribute to our understanding of the effectiveness of amiodarone in the treatment of life-threatening arrhythmias as well as to our understanding of the low incidence of proarrhythmia attending therapy with chronic amiodarone in comparison with other Class III agents.     

兔心肌心室间复极离散的电生理学机制研究

目的观察生理和缺血状态下兔心室间复极离散,探讨临床缺血心肌发生室性心律失常的电生理机制。方法酶解法急性分离兔心室肌细胞,采用细胞膜片钳技术,分别观察对照组(正常心室内膜动作电位时程)和缺血组(缺血心室内膜动作电位时程)在不同刺激频率下[即基础循环周长(basic cycle length,BCL)=2000、1000、500及250 ms]左右心室肌心内膜细胞的动作电位时程变化。结果对照组生理心肌的室间离散分别为(47.70±7.89)ms,(45.50±7.00)ms,(40.30±7.33)ms,(37.90±6.45)ms;缺血后心室间离散则分别为(91.90±7.67)ms,(91.40±7.62)ms,(88.60±7.78)ms,(89.20±6.91)ms。结论生理状态的心肌左右心室间存在复极离散,缺血状态下心室间复极离散增大。这种心室间的复极异质性可能是缺血心肌发生室性心律失常的电生理机制之一。     

The influence of ischaemia on the electrophysiological properties of amiodarone in chronically treated rabbit hearts

The effects of 30 min zero-flow ischaemia and reperfusion onthe electrophysiological properties of amiodarone were studiedin 11 rabbits treated with oral amiodarone (mean 117 mg kg ^-1day ^-1) for 2–3 months, and 11 controls. Experiments wereperformed in vitro in the isolated perfused interventricularseptum, and preischaemic values were compared with those obtainedin right ventricular papillary muscles from the same hearts.Prior to ischaemia, mean values of action potential duration(APD₉₀ and effective refractory period (ERP) were prolongedby 13% in the amiodarone-treated septa. Action potential upstrokevelocity (V_max) was reduced by 14% in the septa, but by 42%in papillary muscles. Ischaemia resulted in shortening of APD₉₀in both control and amiodarone-treated septa, with a loss ofthe ability of amiodarone to prolong APD₉₀. In contrast, ischaemiaresulted in a greater fall in V_max, gross lengthening in conductiontime and increase in stimulation threshold in the amiodarone-treatedsepta compared with controls. Reperfusion resulted in a restorationof the action of amiodarone on repolarization, and resolutionof the marked effects on excitability and conduction. The electrophysiological properties of amiodarone are considerablyaltered in ischaemic myocardium, with a reversible loss of itsability to prolong repolarization, but evidence suggestive ofa marked enhancement of its effect on the inward sodium current.     

The influence of ischaemia on the electrophysiological properties of amiodarone in chronically treated rabbit hearts

The effects of 30 min zero-flow ischaemia and reperfusion onthe electrophysiological properties of amiodarone were studiedin 11 rabbits treated with oral amiodarone (mean 117 mg kg ^-1day ^-1) for 2–3 months, and 11 controls. Experiments wereperformed in vitro in the isolated perfused interventricularseptum, and preischaemic values were compared with those obtainedin right ventricular papillary muscles from the same hearts.Prior to ischaemia, mean values of action potential duration(APD₉₀ and effective refractory period (ERP) were prolongedby 13% in the amiodarone-treated septa. Action potential upstrokevelocity (V_max) was reduced by 14% in the septa, but by 42%in papillary muscles. Ischaemia resulted in shortening of APD₉₀in both control and amiodarone-treated septa, with a loss ofthe ability of amiodarone to prolong APD₉₀. In contrast, ischaemiaresulted in a greater fall in V_max, gross lengthening in conductiontime and increase in stimulation threshold in the amiodarone-treatedsepta compared with controls. Reperfusion resulted in a restorationof the action of amiodarone on repolarization, and resolutionof the marked effects on excitability and conduction. The electrophysiological properties of amiodarone are considerablyaltered in ischaemic myocardium, with a reversible loss of itsability to prolong repolarization, but evidence suggestive ofa marked enhancement of its effect on the inward sodium current.     

Clofilium in the isolated perfused rabbit heart: A new model to study proarrhythmia induced by class III antiarrhythmic drugs

Objective: The clinical usefulness of class III antiarrhythmic drugs for the treatment of tachyarrhythmias is limited by their potential proarrhythmic effects, mainly torsades-depointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhibiting typical characteristics of class III drug-induced ventricular arrhythmias. Methods: Isolated rabbit hearts were perfused with a Krebs-Henseleit buffer containing 10 μM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K² and 0.5 mM Mg²⁺. Hearts subjected to either clofilium alone or modified buffer alone were used as controls. Results: Under clofilium the QT interval increased from 187±16 to 282±33 ms. Within 8 to 25 s after the change of the perfusate, ventricular arrhythmias developed in all hearts associated with a further QT prolongation to 380±73 ms when the first ventricular extrasystole occurred. Simultaneously, the monophasic action potential durations increased relatively more during late repolarization; from 99±21 to 110±25 ms (+11%) at 50% repolarization, from 143±24 to 178±40 ms (+24%) at 70%, and from 200±30 to 275±53 ms (+38%) at 90%. The predominant rhythm was polymorphic with either two alternating or multiple QRS morphologies exhibiting the characteristic features of torsades-depointes. All control hearts stayed in normal sinus rhythm. Conclusion: Under the conditions selected, the isolated perfused rabbit heart represents a useful experimental approach to study the proarrhythmic effects of class III agents. This model provides a convenient way to manipulate the ionic and pharmacologic millieu in a preparation conserving the functional anatomy of the whole organ without interference by cardiovascular reflexes. It might be useful for analyzing the conditions favoring and preventing drug-induced torsades-depointes. Received: 13 August 1997, Returned for revision: 10 September 1997, Revision received: 29 September 1997, Accepted: 22 October 1997     

Differential Effects of D-Sotalol, Quinidine, and Amiodarone on Dispersion of Ventricular Repolarization in the Isolated Rabbit Heart

Drug Effects on Dispersion of Repolarization. Introduction: increased dispersion of ventricular repolarization has been suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic drugs, such as d-sotalol, quinidine, and amiodarone. Methods and Results: The influence of d-sotalol, quinidine, and amiodarone on the dispersion of monophasic action potential (MAP) durations was studied in 55 isolated Langendorff-perfused rabbit hearts at different pacing cycle lengths (CLs). MAP dnration measured at 90% repolarization (APD₉₀) was determined from 6 to 8 endocardial and epicardial MAP recordings with dispersion of ventricular repolarization defined as the range of APD₉₀. The protocol was repeated 60 minutes after initiation of a perfusate containing increasing concentrations of d-sotalol (n = 12, 10^?6 M, 10^?5 M, and 5 × 10^?5 M) and quinidine (n = 8, 10^?6 M and 10^?5 M). Seventeen rabbits were fed with an aqueous solution of amiodarone (50 mg/kg per day over 4 weeks). The data of these experiments (n = 17) were compared with a series of 18 untreated control rabbits. Dispersion of ventricular repolarization was unchanged with the low concentration of d-sotalol (10^?6 M) but was increased—particularly at long CLs—with higher d-sotalol concentrations. With both concentrations of quinidine, dispersion of ventricular repolarization was increased in a rate-independent manner. Amiodarone did not affect dispersion of ventricular repolarization. Conclusions: Rate-dependent and concentration-dependent increases in dispersion of ventricular repolarization by d-sotalol and quinidine in this isolated rabbit heart model may help explain their proarrhythmic effects while the absence of an increase in dispersion of ventricular repolarization with amiodarone correlates with its clinically observed lower incidence of proarrhythmia.     

Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by I<Subscript>Kr</Subscript> blockers

Background Cytostatic agents such as anthracyclines may cause changes in the electrophysiologic properties of the heart. We hypothesized that anthracyclines facilitate life-threatening proarrhythmic side effects of cardiovascular and non-cardiovascular repolarization prolonging drugs. Methods and results The electrophysiologic effects of chronic administration of doxorubicin (Dox) were studied in ten rabbits, which were treated with Dox twice a week (1.5 mg/kg i. v.). A control group (11 rabbits) was given NaCl solution. Two of ten Dox rabbits died suddenly, the remaining animals showed mild clinical signs of heart failure after a period of six weeks. Echocardiography demonstrated a decrease in ejection fraction (pre treatment: 74 ± 23% to post treatment: 63 ± 16% (p <0.05)). In isolated hearts, action potential duration measured by eight simultaneously recorded monophasic action potentials (MAP) was similar in Dox and control hearts. However, in Dox rabbits, administration of the I_Kr–blocker erythromycin (150–300 μM) led to a significant greater prolongation of the mean MAP duration (63 ± 21ms vs 29 ± 12 ms, p <0.05) and the QT interval (100 ± 32ms vs 58 ± 17 ms, p <0.05) as compared to control. Moreover, I_Kr–block led to a more marked increase of dispersion of MAP₉₀ in the Dox group as compared to control hearts (23 ± 7ms vs. 9 ± 4 ms). In the presence of hypokalemia more episodes of early afterdepolarizations and torsade de pointes occurred (p <0.05). Conclusion Even during the early phase of chemotherapeutic treatment,before significant QT-prolongation is present,anthracyclines lead to an increased sensitivity to the proarrhythmic potency of I_Kr-blocking drugs. Thus, anthracycline therapy reduces repolarization reserve and thereby represents a novel contributing factor for the development of lifethreatening proarrhythmia.     

Effect of amiodarone on qt dispersion in the 12-lead standard electrocardiogram and its significance for subsequent arrhythmic events

Background and hypothesis: QT dispersion, measured as interlead variability of QT intervals in the surface electrocardiogram, has been demonstrated to provide an indirect measurement of the inhomogeneity of myocardial repolarization. The purpose of the present study was twofold: (1) to analyze the effect of amiodarone on QT dispersion measured in the 12-lead standard ECG, and (2) to examine the association between QT dispersion on amiodarone and subsequent arrhythmic events. Methods: To determine the effect of amiodarone on QT dispersion and its clinical significance for subsequent arrhythmic events, QT dispersion was measured in the 12-lead standard electrocardiogram (ECG) in 52 patients before and after administration of empiric amiodarone for ventricular tachyarrhythmias. Results: QT intervals increased from 401 ± 44 ms before amiodarone to 442 ± 53 ms after amiodarone therapy, and rate corrected QT intervals (QTc) increased from 452 ± 43 ms to 477 ± 37 ms, respectively (p<0.01). QT dispersion, QTc dispersion, and adjusted QTc dispersion, which take account of the number of leads measured, were not significantly different before and after initiation of amiodarone therapy (58 ± 24 ms vs. 61 ± 26 ms, 68 ± 29 vs. 66 ± 26 ms, and 22 ± 8 vs. 22 ± 8 ms, respectively, p = NS). During 31 ± 25 months follow-up after initiation of amiodarone therapy, arrhythmic events defined as sustained ventricular tachycardia, ventricular fibrillation, or sudden death occurred in 11 of 52 study patients (21%). QT dispersion, QTc dispersion, and adjusted QTc dispersion on amiodarone were not different between patients with and without arrhythmic events during follow-up (65 ± 14 vs. 59 ± 29 ms, 73 ± 15 vs. 64 ± 28 ms, and 25 ± 6 vs. 21 ± 8 ms, respectively, p=NS). Conclusions: We conclude that (1) amiodarone increases QT intervals and QTc intervals during sinus rhythm but does not significantly change measures of QT dispersion; and (2) QT dispersion measured in the 12-lead standard ECG after initiation of amiodarone therapy does not appear to be a useful marker for subsequent arrhythmic events.     

Ventricular transmural repolarization sequence: its relationship with ventricular relaxation and role in ventricular diastolic function

Aims: We investigated the role of ventricular repolarization sequencein ventricular diastolic function. Methods and results: Arterially perfused canine left ventricular wedge preparationwith simultaneous recording of action potentials and isometriccontractile force was used to establish the relationship betweenventricular repolarization and relaxation sequences. An isolatedrabbit working heart model was used to investigate role of ventricularrepolarization sequence in ventricular diastolic function. Undercontrolled conditions, similar to transmural dispersion of repolarization(TDR), there existed a time difference between initiation ofepicardial and endocardial relaxation (TR_Epi–Endo, 47.4± 13.9 ms) with epicardium relaxing earlier. There wasa strong correlation between TDR and TR_Epi–Endo (r² =0.99, n = 5) and the interventions that changed transmural repolarizationsequence led to parallel changes in transmural relaxation sequence.In isolated rabbit working hearts, reversal of the transmuralrepolarization sequence that manifested as negative T wave wasassociated with a significant increase in isovolumic relaxationtime (from 49.2 ± 19.1 to 76.4 ± 12.1 ms, n =5, P = 0.001). Conclusion: There is a strong correlation between transmural repolarizationand relaxation sequences. A positive T wave that denotes transmuralrepolarization sequence from epicardium to endocardium is essentialfor normal diastolic function of ventricle and the reversalof such sequence is associated with ventricular diastolic dysfunction.     

Torsade de pointes with a normal QT interval associated with hypokalemia: a case report

The patient was a 46-year-old man with a history of syncope attack after diarrhea. Nonsustained polymorphic ventricular tachycardia (PVT) initiated by short-coupled premature ventricular complex was detected by Holter monitoring. No organic heart disease was found, and the QT interval during sinus rhythm was normal. It was thought that the PVT might be related to hypokalemia, so electrophysiological studies were performed under the condition of hypokalemia (K=3.4mmol/L), after potassium loading (K=4.2mmol/L) and after oral amiodarone therapy. Under the condition of hypokalemia, nonsustained PVT occurred spontaneously, and the monophasic action potential duration at 90% repolarization (MAPD90) at the right ventricular apex was very short (175 ms). The MAPD90 returned to normal after loading potassium (230ms) and after oral amiodarone therapy (240ms), and PVT no longer occurred. With continued oral amiodarone and spironolactone therapy, the patient has been free of syncope attack over a follow-up period of 5 years.     

程序电刺激时心室复极离散度的研究

了解程序电刺激 (PES)时心室复极离散度的变化 ,探讨PES诱发室性快速心律失常 (VTA)的可能机制。采用单相动作电位 (MAP)标测技术测定 10例无器质性心脏病的阵发性室上性心动过速患者接受PES时的心室复极离散度。结果 :S1 S1 刺激 ( 5 0 0ms)时的动作电位时程 (APD)的离散度 (APDd)与窦性心律时无明显差异 ( 34± 10msvs38± 9ms ,P >0 .0 5 )。随S1 S2 间期缩短 ,各标测点S2 的APD逐渐缩短 ,且与S1 S2 间期呈正相关 ,但激动时间 (AT)及其离散度 (ATd)、APDd、复极时间离散度 (RTd)逐渐延长 ;S1 S2 间期缩短至有效不应期 (ERP) +30ms后 ,S2 的APDd、RTd大于窦性心律及S1 S1 刺激时 (APDd :5 1± 8msvs 38± 9ms或 34± 10ms,P <0 .0 5 ;RTd :39± 10msvs2 4± 7ms,P<0 .0 5 ) ,但ATd无明显增大。心室内各点有效不应期离散度为 31± 14ms,ERP APD平均为 0 .89± 0 .0 8。认为在无器质性心脏病者PES可使心室复极离散度增大 ,但不增加传导差异 ,不易诱发VTA     

Loss of Cardiac Magnesium in Experimental Heart Failure Prolongs and Destabilizes Repolarization in Dogs

Objectives. We sought to determine whether heart failure results in loss of cardiac magnesium sufficient to alter cellular electrophysiology.Background. Free magnesium has numerous intracellular roles affecting metabolism, excitability and RNA synthesis. Total cardiac magnesium content is reduced in heart failure, but it is unclear whether magnesium loss is primary or iatrogenic. Furthermore, it is unknown whether free magnesium levels are affected or whether a change in free magnesium would alter cellular electrophysiology.Methods. Eight mongrel dogs underwent demand ventricular pacing (VVI) at 250 beats/min for 3 weeks to induce heart failure. Sublingual epithelial magnesium was measured before pacing and at death. Left ventricular myocytes were isolated and loaded with Mag-Indo-1 to measure free magnesium ([Mg²⁺]_i); myocytes from eight normal dogs served as controls. To test whether changes in [Mg²⁺]_iin this range could alter cellular repolarization, current-clamped myocytes were dialyzed with 0.5 or 1.0 mmol/liter MgCl₂.Results. Mean sublingual epithelial magnesium fell significantly in the paced animals, from 36.9 ± 0.5 to 33.9 ± 0.7 mEq/liter (p < 0.01). Mean cardiac [Mg²⁺]_iwas significantly lower in the dogs with heart failure—0.49 ± 0.06 versus 1.06 ± 0.15 mmol/liter (p < 0.003). Time to 90% repolarization was significantly shorter in cells dialyzed with 1.0 mmol/liter compared with 0.5 mmol/liter MgCl₂in myocytes from normal dogs or dogs with heart failure (596 ± 34 vs. 760 ± 58 ms in normal dogs and 586 ± 29 vs. 838 ± 98 ms in dogs with heart failure; p < 0.05 for each).Conclusions. Experimental heart failure results in both tissue and cardiac magnesium loss in the absence of drug therapy. Free cardiac magnesium is significantly reduced, possibly contributing to abnormal repolarization in heart failure.     

Antiadrenergic effect of chronic amiodarone therapy in human heart failure.

OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.     

Beneficial effects of low dose amiodarone in patients with congestive cardiac failure: a placebo-controlled trial

The effects of amiodarone in a low dosage (200 mg every 8 h for 2 weeks, then 200 mg/day) was assessed in a double-blind placebo-controlled trial in 34 patients with a history of severe congestive heart failure but no sustained ventricular arrhythmia. Left ventricular ejection fraction, treadmill exercise tolerance and 48 h electrocardiographic monitoring were assessed before and repeatedly after beginning amiodarone or placebo therapy over 6 months, and side effects were monitored. In patients receiving amiodarone, the ejection fraction increased significantly from 19 +/- 7 to 29 +/- 15% at 6 months (p less than 0.01 from baseline), but not significantly in 14 placebo-treated patients (18 +/- 5 to 22 +/- 9%). Exercise tolerance increased significantly in amiodarone-treated patients (median 433 s to 907 s, p less than 0.05), but not significantly in placebo-treated patients (757 to 918 s). Nonsustained ventricular tachycardia was present in 88% of amiodarone-treated patients before, but in only 21% of patients after 6 months of treatment (p = 0.06); it was seen in 43% of placebo-treated patients at baseline and in 50% after 6 months. Fifty percent of amiodarone-treated patients had side effects (principally nausea) and the drug was withdrawn in 28% of cases; no life-threatening effects were seen. Low dose amiodarone appears to have a multifaceted potential to produce benefits in arrhythmia control, exercise tolerance and ventricular function in patients with a history of severe congestive heart failure, but better control of side effects (principally nausea) appears essential. Effects on mortality could not be determined from this study; such assessment requires a larger cohort of patients.     

Prolonged action potential durations,increased dispersion of repolarization,and polymorphic ventricular tachycardia in a mouse model of proarrhythmia

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I_Kr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10^-5M and 2 × 10^-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K⁺ =3.0 mM and in 10 of 12 hearts at K⁺ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.     

胺碘酮对心室慢性起搏阈值的影响

为探讨胺碘酮对心室慢性起搏阈值的影响 ,对 12例安置心脏起搏器 3个月后伴发症状性心律失常患者 ,予胺碘酮治疗 ,用相应的程控仪测试用药前后的起搏阈值。药前 ,药后 1h、4h、1周和 2周的起搏阈值 (输出固定为2 .5V)分别为 0 .0 8± 0 .0 2 ,0 .0 8± 0 .0 1,0 .0 7± 0 .0 2 ,0 .0 8± 0 .0 1和 0 .0 8± 0 .0 2ms(P >0 .0 5 )。结论 :胺碘酮对心室慢性起搏阈值无影响。     

右房左室起搏治疗慢性心力衰竭伴室内传导阻滞患者的初步临床观察

观察右房 左室起搏治疗慢性心力衰竭 (简称心衰 )的临床效果。选择 1 6例充血性心衰患者 (NYHA分级Ⅲ Ⅳ级 ) ,男 1 0例、女 6例 ,年龄 6 8.4± 6岁 ;均为窦性心律 ,合并有Ⅰ度房室阻滞 ,完全性左束支阻滞。按安置起搏器的模式分为右房 左室起搏治疗组 (LV组 ,n =6 ) ,右房双室起搏治疗组 (BiV组 ,n =1 0 )。左室起搏电极分别放置于心大静脉左室侧后分支 9例 ,心大静脉左室后分支 7例。观察起搏治疗前后左室心功能参数、6min步行距离、左室壁运动的同步性及体表心电图的变化。结果 :BiV组左室射血分数 (LVEF)由术前的 0 .2 3提高至 0 .31 (P <0 .0 0 1 ) ;在LV组LVEF由术前的 0 .2 4提高至 0 .33(P <0 .0 0 1 ) ;左室舒张末期容积指数在二组分别由术前的 1 4 9± 5 1ml/m2 和 1 5 3±5 3ml/m2 下降至 1 1 6± 38ml/m2 和 1 2 1± 4 1ml/m2 (P均 <0 .0 0 1 ) ;室间隔与左室后壁运动的延迟时间在二组分别由术前的 1 95± 94ms和 1 97± 89ms下降至 1 7± 6 0ms及 1 6± 5 6ms(P均 <0 .0 0 1 )。 6min步行距离则分别由术前的4 0 3± 5 3m和 4 0 1± 5 9m提高至 4 4 1± 6 2m和 4 4 2± 6 7m(P均 <0 .0 5 )。结论 :初步临床观察提示右房 左室起搏治疗与右房双室起搏治疗相比 ,同样可有效地改善慢性心衰?