Non-clinical factors influencing the selection of patients with acute coronary syndromes for angiography.

OBJECTIVE: To analyse clinical and non-clinical factors determining the selection for coronary angiography in patients with acute coronary syndromes (ACS). DESIGN: Single centre, prospective cohort study. PARTICIPANTS: Eighty consecutive patients admitted with a diagnosis of ACS during the period 21 May 2001 to 4 July 2001. SETTING: Coronary care unit of a tertiary referral centre, the Manchester Royal Infirmary. DATA COLLECTION: Information concerning baseline patient characteristics, clinical presentation, and the selection for angiography was collected from the patient notes. DATA COLLECTION: Windows SPSS version 9.0 using cross tabulations with chi(2) estimation and binomial logistic regression analysis. MAIN OUTCOME MEASURE: Selection for angiography in ACS. RESULTS: Cross tabulations with chi(2) analysis and logistic regression analysis identified significant non-clinical factors predicting the use of angiography. Although clinical factors such as recurrent ischaemia (odds ratio 5.11) influenced the decision to undergo coronary angiography, non-clinical factors such as young age (odds ratio 6.88 for <65 years old), gender (odds ratio 3.81 for males), admission on a weekday (odds ratio 0.2488 for admission on the weekend), and consultant in charge (odds ratio 0.111 for consultant "2") independently predicted the use of angiography in ACS. CONCLUSION: The selection of patients for angiography in ACS is not based purely on clinical criteria. Awareness of the apparent sources of bias among clinical decision makers may improve management of these patients.

The Midlands Trial of Empirical Amiodarone versus Electrophysiology-guided Interventions and Implantable Cardioverter-defibrillators (MAVERIC): a multi-centre prospective randomised clinical trial on the secondary prevention of sudden cardiac death.

AIMS: MAVERIC was a randomised clinical trial designed to test the possibility of prospectively identifying patients who would benefit most from the implantable cardioverter-defibrillator (ICD) by electrophysiology (EP) study in the context of secondary prevention of sudden cardiac death (SCD) through comparing EP-guided interventions (anti-arrhythmic drugs, coronary revascularization, and ICD) against empirical amiodarone therapy. METHODS: Two hundred and fourteen survivors of sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or SCD were randomized to either treatment strategy, pre-stratified for haemodynamic status at index event, and followed up for a median of 5 years. RESULTS: Of the 106 amiodarone arm patients, 89 (84%) received the drug and 5 (5%) received an ICD after crossing over. Of the 108 EP arm patients, 31 (29%) received an ICD, 46 (43%) received anti-arrhythmic drugs only (mainly amiodarone or sotalol) and 18 (17%) received coronary revascularization but no ICD. No significant differences in survival or arrhythmia recurrence existed between the two treatment arms after 6 years. However, ICD recipients had a lower mortality than non-ICD recipients, regardless of allocated treatment (hazard ratio=0.54, p=0.0391). CONCLUSIONS: Prospective selection of patients to receive the ICD by EP study did not improve survival compared with empirical amiodarone therapy among survivors of VT, VF or SCD, whereas ICD implantation improved survival regardless of allocated treatment. On this basis, routine EP study has no role in the management of such patients, who should be offered empirical ICD therapy according to the results of other secondary prevention ICD trials.

Comprehensive cardiac rehabilitation programme for implantable cardioverter-defibrillator patients: a randomised controlled trial.

OBJECTIVE: To investigate the effects of a 12 week comprehensive cardiac rehabilitation (CCR) programme on patients who have undergone implantation of an implantable cardioverter-defibrillator (ICD). DESIGN: Sixteen patients with ICDs (14 (88%) male, mean (SD) age 58 (10) years, range 34-74 years) were randomised to either attend an individually tailored CCR programme or receive usual care. They then changed to the alternative regimen for a further 12 weeks. Exercise capacity was assessed using a treadmill exercise test at baseline, after usual care, after CCR and 12 weeks after CCR to assess maintenance effects. Hospital anxiety and depression (HAD) scores were recorded at each stage. RESULTS: Exercise times (min:s; mean (SD)) increased by 16% from a baseline mean of 9:55 (2:33) to 11:11 (2:17) following attendance at CCR (95% confidence interval (CI) 0:34 to 1:58; p = 0.001). This improvement was maintained 12 weeks after attendance at CCR, at 11:20 (2:17) (p = 1.00). HAD scores for anxiety and depression decreased during CCR from a baseline of 13.4 (3.6) to 8.1 (3.6), 95% CI 3.5 to 7.0 (p < 0.001) and 9.9 (3.4) to 6.7 (2.9), 95% CI 1.9 to 4.4 (p = 0.002), respectively. These improvements were maintained at 12 weeks after CCR. No ventricular arrhythmias or ICD discharges occurred during the exercise components of the CCR. The total number of ventricular arrhythmias and ICD discharges was similar 12 weeks before, during, and 12 weeks after CCR. CONCLUSIONS: CCR appears to be safe for patients with ICDs. It can improve exercising ability and lower the levels of psychological distress. A larger multicentre study is recommended to confirm these findings.

Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation; a manifestation of atrial electrical remodelling in humans?

AIMS: The mechanism of atrial fibrillation recurrence following cardioversion is unknown, although experimental studies have indicated that changes in dispersion of atrial refractoriness may play a role. The aims of this study were to assess (1) if dispersion of atrial refractoriness is relevant to atrial fibrillation recurrence and (2) if dispersion of refractoriness is part of the atrial electrical remodelling process in humans. METHODS AND RESULTS: Thirty-seven consecutive patients underwent internal cardioversion (CV1) of persistent atrial fibrillation. Patients were monitored by daily transtelephonic recordings following discharge and if there was spontaneous atrial fibrillation recurrence they were rapidly admitted for repeat cardioversion (CV2). We used the 5th percentile of 100 consecutive atrial fibrillation cycle lengths (AFCL(P5)) and the atrial effective refractory period (AERP) as measures of atrial refractoriness at four different atrial sites. Dispersion of AFCL(P5)at CV1 was significantly higher in those who had subsequent recurrence of atrial fibrillation than in those who remained in sinus rhythm for at least 1 month after cardioversion (35+/-17 ms vs 9+/-13 ms;P<0.02). Dispersion of AFCL(P5)measured at CV2 was significantly lower than that measured in the same patients at CV1 (19+/-8 ms vs 35+/-11 ms;P=0.02). i.e. dispersion of AFCL(P5)had reduced following a period of sinus rhythm. In contrast, there was no difference in dispersion of AERP between the recurrers and non-recurrers. Dispersion of AERP between CV1 and CV2 did not change following a period of sinus rhythm. CONCLUSION: Dispersion of AFCL is relevant to atrial fibrillation recurrence and may represent a manifestation of atrial electrical remodelling in humans. Treatment directed at AFCL dispersion may be useful in the suppression of atrial fibrillation recurrence following cardioversion.

Flecainide widens the excitable gap at pivot points of premature turning wavefronts in rabbit ventricular myocardium.

INTRODUCTION: The mechanisms by which Class IC drugs slow the rate of functional reentrant arrhythmias are not completely understood. We hypothesized that flecainide widens the excitable gap beyond the pivot point of premature turning wavefronts. METHODS AND RESULTS: In eight perfused subepicardial layers of rabbit left ventricle, a linear lesion was made by radiofrequency (RF) ablation parallel to the fiber orientation. One end of the RF lesion was extended by a short incision. Pacing next to the lesion induced a wavefront propagating with a sharp U-turn around the end of the lesion in either the clockwise or counterclockwise direction. A high-density mapping electrode (240 electrodes, 350-microm resolution) was used to record unipolar electrograms at the pivot point. During control, the shortest V1-V2 interval proximal to the pivot point was 162 +/- 12 msec compared with 173 +/- 13 msec distal to the pivot point (difference 11 +/- 8 msec; P < 0.01). After infusion of flecainide 2 mg/L, the shortest V1-V2 interval proximal and distal to the pivot point were 217 +/- 29 msec and 244 +/- 36 msec (difference 27 +/- 16 msec; P < 0.01). Due to the increase in V1-V2 interval at the pivot point, flecainide widened the temporal excitable gap in the returning limb of the turning wavefront from 30 +/- 11 msec to 55 +/- 22 msec (P < 0.01). High-density mapping at the pivot point revealed that this widening of the excitable gap was due to both macroscopic discontinuous conduction and functional conduction block at the pivot point. CONCLUSION: Flecainide widens the excitable gap in the returning limb of premature U-turning wavefronts by causing macroscopic discontinuous conduction and functional conduction block at the pivot point.

Prevalence and significance of focal sources of atrial arrhythmia in patients undergoing cardioversion of persistent atrial fibrillation.

INTRODUCTION: Recent reports have high-lighted the importance of focal atrial arrhythmias as a curable cause for a group of patients with frequently recurrent paroxysmal atrial fibrillation (AF). The importance of this arrhythmia mechanism in the general population of patients with persistent AF is unknown. METHODS AND RESULTS: After successful internal cardioversion of 50 consecutive patients with persistent AF (mean age 60 years, mean duration of AF 26 months), endocardial activity in the immediate postcardioversion period was analyzed for the presence of focal atrial activity. Postcardioversion atrial arrhythmias were considered to be focal if there was evidence of a localized source of repetitive early atrial activation, either in the form of (1) self-terminating monomorphic atrial tachycardia (at least five beats) or (2) recurrences of AF with an initial atrial activation sequence (first five beats) that was both monomorphic and reproducible with repeated recurrences. Evidence for a focal atrial arrhythmia was present in 20 of the total group of 50 patients (40%). Multivariate analysis of clinical characteristics revealed the diagnosis of lone AF as the only independent predictor of a focal source of AF (P = 0.028). Thirty-nine patients were discharged from hospital in sinus rhythm. At 1-month follow-up, 25 (64%) of these 39 patients had suffered AF recurrence. The only significant predictor of AF recurrence was evidence of a focal source of atrial arrhythmia immediately after cardioversion, with a relative risk of 1.73 (range 1.1 to 2.7; P = 0.015). CONCLUSION: Focal atrial arrhythmias are common in patients presenting with "idiopathic" persistent AF, suggesting a possible causative role in the generation of this common arrhythmia.

Preferential depression of conduction around a pivot point in rabbit ventricular myocardium by potassium and flecainide.

INTRODUCTION: During reentrant arrhythmias, the circulating wavefront often makes a sharp turn around a functional or anatomic barrier. We tested the hypothesis that lowering the safety factor for conduction by high K+ or flecainide preferentially depresses conduction of sharply turning wavefronts. METHODS AND RESULTS: In 16 Langendorff-perfused rabbit hearts, a thin layer of anisotropic ventricular myocardium was made using a cryoprocedure. In this layer, a linear radiofrequency lesion was made parallel to the fiber orientation. The tip of the lesion was extended by a short incision. U-turning wavefronts were initiated by pacing at one side of the lesion. A mapping electrode (240 electrodes, resolution 350 to 700 microm) was used to measure conduction times and velocity of planar waves (longitudinal and transverse) and U-turning wavefronts. The safety factor for conduction was lowered by high potassium (8, 10, and 12 mmol/L) and flecainide (1 and 2 mg/L). On average, high potassium and flecainide increased the conduction times of U-turning wavefronts 1.6 times more than longitudinal or transverse planar wavefronts (P < 0.01). At a critical lowering of the excitatory current, functional conduction block occurred at the pivot point, which forced the wavefront to make a longer U-turn. In these cases, the total U-turn conduction time increased from 27+/-9 msec to 75+/-37 msec. About 40% of this delay was caused by a shift of the pivot point and consequent lengthening of the returning pathway. CONCLUSION: Lowering the amount of excitatory current by potassium or flecainide preferentially impairs U-turn conduction. The occurrence of long delays and conduction block at pivot points may explain the mode of action of Class I drugs.

Reversal of atrial electrical remodeling after cardioversion of persistent atrial fibrillation in humans.

BACKGROUND: Although atrial electrical remodeling has been studied extensively in animal models, the reversibility of this phenomenon after termination of clinical atrial fibrillation (AF) has not been demonstrated. We aimed to examine this important question of reversibility by using AF cycle length (AFCL) and coupling intervals of atrial premature beats after cardioversion as measures of atrial refractoriness. METHODS AND RESULTS: We measured AFCL at the right atrial appendage and distal coronary sinus before attempting internal cardioversion in 39 patients with persistent AF. Patients were monitored by daily transtelephonic recordings after discharge and admitted rapidly for repeat internal cardioversion if there was spontaneous AF recurrence. Measurements of AFCL were repeated immediately before repeat cardioversions in the 17 patients who had recurrence of AF. There was an increase in AFCL from the initial cardioversion to that measured at the time of first AF recurrence at both the right atrial appendage (161+/-22 vs 167+/-26 ms, P=0.05) and distal coronary sinus (162+/-20 vs 168+/-22 ms, P=0.01) sites. The magnitude of increase in AFCL was positively correlated with duration of sinus rhythm before AF recurrence (r=0.524, P=0.001). Other measures of refractoriness (shortest coupling interval of atrial premature beats and directly measured refractory periods after cardioversion) also increased from initial to subsequent cardioversions. CONCLUSIONS: These findings demonstrate that changes in atrial electrophysiology associated with chronic AF in humans are reversible after cardioversion and that the extent of this reversal is dependent on the duration of sinus rhythm after cardioversion.

Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers.

AIMS: To investigate the effects of sibutramine in combination with alcohol in a double-blind, randomised, placebo-controlled, four-way crossover study in 20 healthy volunteers. METHODS: On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg-1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg-1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. RESULTS: Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl-1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. CONCLUSIONS: There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol-induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.

Profibrillatory effects of verapamil but not of digoxin in the goat model of atrial fibrillation.

INTRODUCTION: Verapamil and digoxin have been shown to modulate tachycardia-induced atrial electrical remodeling. The goal of the present study was to determine the direct effects of verapamil and digoxin on atrial fibrillation (AF), before and after electrical remodeling. METHODS AND RESULTS: In six goats we measured the AF cycle length (AFCL) and duration of AF (DurAF) of 50 consecutive induced paroxysms, before (t = 0) and after 24 hours (t = 24) of electrical remodeling. During AF, conduction velocity (CV(AF)), refractory period (RP(AF)), and type of AF (I, II, III) were determined. Verapamil was administered at a loading dose of 0.1 mg/kg, followed by a continuous (2-hour) infusion of 5 microg/kg/min. Digoxin was given intravenously as a single 0.02 mg/kg bolus. At t = 0 and t = 24, digoxin and verapamil caused a significant slowing of the ventricular rate of >40%. Digoxin had no effect on DurAF, AFCL, CV(AF), or RP(AF). Infusion of verapamil had a direct proarrhythmic effect. Both at t = 0 and t = 24, AFCL and RP(AF) were shortened by about 15%. During acute AF, verapamil prolonged the average duration of AF paroxysms from 7 to 16 seconds. After 24 hours of AF, the proarrhythmic effect was much stronger. Shortly after starting infusion (6 +/- 2 min), verapamil converted paroxysmal AF into sustained AF. As long as verapamil infusion was maintained, AF no longer terminated in any of the goats. This effect was associated with an increase in AF fragmentation from type I to type II-III. CONCLUSION: Verapamil shortens AFCL and RP(AF) in the presence and absence of electrical remodeling. After 24 hours, it exerted a marked proarrhythmic effect and converted paroxysmal (type I) into sustained (type III) AF. In contrast, digoxin had no effect on the rate or stability of AF.

Repetitive electrical remodeling by paroxysms of atrial fibrillation in the goat: no cumulative effect on inducibility or stability of atrial fibrillation.

INTRODUCTION: Episodes of atrial fibrillation (AF) are known to cause both a rapid reduction in atrial refractoriness (atrial electrical remodeling) and a more delayed increase in AF stability in the chronic goat model. The aims of this study were to examine (1) the hypothesis that an AF-induced increase in AF stability might be due to a mechanism with a longer onset and offset than that of changes in refractoriness and (2) the possibility that repeated paroxysms of maintained AF might cause a cumulative increase in AF stability independent of changes in atrial refractoriness. METHODS AND RESULTS: AF was maintained by rapid atrial pacing in seven goats for three consecutive 5-day periods, each separated from each other by 48 hours of sinus rhythm. Assessments of atrial refractory periods, conduction velocity, AF inducibility, and duration of individual episodes of AF were attempted at intervals throughout the protocol. Forty-eight hours of sinus rhythm was just sufficient for refractoriness changes to fully reverse in all goats, with no evidence of any "residual" increase in AF inducibility. There was no significant difference among any of the three periods of pacing-maintained AF with regard to time to develop episodes of AF of 60-second duration (22.1+/-13, 23.8+/-16, and 30.3+/-29 hours), 1-hour duration (56.6+/-28, 61.3+/-31, and 60.1+/-32 hours), or 24-hour duration (84.0+/-31, 87.0+/-33, and 83.5+/-32 hours). CONCLUSION: There is no evidence for a cumulative effect of AF paroxysms on AF inducibility or stability independent of changes in refractoriness. These findings highlight the importance of atrial refractoriness as a potential target for antiarrhythmic strategies aimed at inhibiting the self-perpetuation of AF.

The role of atrial electrical remodeling in the progression of focal atrial ectopy to persistent atrial fibrillation.

Although atrial fibrillation- (AF) induced changes in atrial refractoriness (atrial electrical remodeling) have been demonstrated in a number of different animal models, the clinical significance of this process is unknown. We describe a patient in whom there has been documented progression of atrial ectopy to persistent AF accompanied by evidence of atrial electrical remodeling, with reversal of remodeling following successful ablation of the focal source of AF. A second patient with focal AF, but with a "nonfocal" appearance on the ECG, is also described. These cases illustrate: (1) the possibility that a significant proportion of younger patients with idiopathic persistent AF may well have a focal source as the underlying abnormality; and (2) atrial electrical remodeling reverses following ablation of the underlying source.

Sibutramine pharmacokinetics in young and elderly healthy subjects.

OBJECTIVE: To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. METHODS: This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. RESULTS: The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k(el). CONCLUSIONS: The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.

Potential impact of antiarrhythmic drugs versus implantable defibrillators on the management of ventricular arrhythmias: the Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant registry data.

BACKGROUND: Survival was prolonged in selected patients with sustained ventricular arrhythmias who received implantable cardioverter defibrillators (ICDs) in the antiarrhythmics versus implantable defibrillators (AVID) study. The Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant in ventricular arrhythmias (MAVERIC) registry is a population based trial. OBJECTIVE: To determine the number of patients who satisfy the AVID criteria because of the high cost of ICDs. DESIGN: Observational study, based on a continuing trial. SETTING: All coronary care units in the Midlands region in the United Kingdom (population 9.1 million). PATIENTS: Patients presenting to a coronary care unit with sustained ventricular arrhythmias not related to an acute myocardial infarction are entered onto the registry. Those who consent to the MAVERIC study are randomised to receive either empirical amiodarone or electrophysiologically guided treatment. Demographic data, details of clinical presentation, and echocardiographic findings are collected. These data have been used to calculate the number of patients who satisfy the AVID criteria and would benefit from ICD implantation. The financial implications have been calculated for the region and nationally. RESULTS: 132 patients were entered onto the registry during the first five months of the MAVERIC study; 69 patients fulfilled the AVID criteria. Extrapolation of these data over a 12 month period suggests implantation of at least 166 new ICDs (compared with 23 implants in 1996). This would increase the UK ICD implant rate from five to at least 18 per million of the population, costing the National Health Service 24.1 Pounds million per annum. CONCLUSION: Application of the AVID criteria in the UK will cause a great increase in the ICD implant rate, with serious financial implications.