The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Potentiation rather than distraction in a trace fear conditioning procedure.

Trace conditioning procedures are defined by the introduction of a trace interval between conditioned stimulus (CS, e.g. noise or light) offset and unconditioned stimulus (US, e.g. footshock). The introduction of an additional stimulus as a distractor has been suggested to increase the attentional demands of the task and to extend the usefulness of the behavioural model. In Experiment 1, the CS was noise and the distractor was provided by an intermittent light. In Experiment 2, the CS was light and the distractor was provided by an intermittent noise. In both experiments, the introduction of a 10s trace interval weakened associative learning compared with that seen in a 0s delay conditioned group. However, there was no consistent evidence of distraction. On the contrary, in Experiment 1, associative learning was stronger (in both trace and delay conditioned groups) for rats conditioned also in the presence of the intermittent light. In Experiment 2, there was no such effect when the roles of the stimuli were reversed. The results of Experiment 2 did however confirm the particular salience of the noise stimulus. The finding of increased associative learning dependent on salience is consistent with arousal-mediated effects on associative learning.

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure.

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05µg/side) or D1 antagonist SCH23390 (0.5µg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning.

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex.

RATIONALE: Trace conditioning may provide a behavioural model suitable to examine the maintenance of 'on line' information and its underlying neural substrates. OBJECTIVES: Experiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions. RESULTS: Whilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 µg in 1.0 µl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval. CONCLUSIONS: Impaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function.

Supraventricular tachycardia promotes release of troponin I in patients with normal coronary arteries.

BACKGROUND: Troponin I and T are sensitive markers of myocardial injury. The presence of elevated troponin often prompts further investigation with coronary angiography. METHODS: We present a series of patients presenting to our unit with raised troponin I and supraventricular tachycardia (SVT) that prompted coronary angiography. RESULTS: All patients had normal epicardial vessels at angiogram, no evidence of muscle bridging or pulmonary embolism. CONCLUSION: The presence of tachycardia sufficient to warrant hospital admission can raise troponin, and this should be viewed in context when a decision on angiography is to be taken.

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.

Ablate and pace revisited: long term survival and predictors of permanent atrial fibrillation.

OBJECTIVE: To assess long term mortality and identify factors associated with the development of permanent atrial fibrillation after atrioventricular (AV) node ablation for drug refractory paroxysmal atrial fibrillation. DESIGN: Retrospective cohort study. SETTING: UK tertiary centre teaching hospital. PATIENTS: Patients admitted to the University Hospital Birmingham between January 1995 and December 2000. INTERVENTIONS: AV node ablation and dual chamber mode switching pacing. MAIN OUTCOME MEASURES: Long term mortality and predictors of permanent atrial fibrillation, assessed through Kaplan-Meier curves and logistic regression. RESULTS: 114 patients (1995-2000) were included: age (mean (SD)), 65 (9) years; 55 (48%) male; left atrial diameter 4 (1) cm; left ventricular end diastolic diameter 5 (1) cm; ejection fraction 54 (17)%. Indications for AV node ablation were paroxysmal atrial fibrillation in 95 (83%) and paroxysmal atrial fibrillation/flutter in 19 (17%). The survival curve showed a low overall mortality after 72 months (10.5%). Fifty two per cent of patients progressed to permanent atrial fibrillation within 72 months. There was no difference in progression to permanency between paroxysmal atrial fibrillation and paroxysmal atrial fibrillation/flutter (log rank 0.06, p = 0.8). Logistic regression did not show any association between the variables collected and the development of permanent atrial fibrillation, although age over 80 years showed a trend (p = 0.07). CONCLUSIONS: Ablate and pace is associated with a low overall mortality. No predictors of permanent atrial fibrillation were identified, but 48% of patients were still in sinus rhythm at 72 months. These results support the use of dual chamber pacing for paroxysmal atrial fibrillation patients after ablate and pace.

Prospective randomized study of ablation and pacing versus medical therapy for paroxysmal atrial fibrillation: effects of pacing mode and mode-switch algorithm.

BACKGROUND: Atrioventricular (AV) node ablation and pacing has become accepted therapy for drug-refractory paroxysmal atrial fibrillation (PAF). However, few data demonstrate its superiority over continued medical therapy. The influence of pacing mode and mode-switch algorithm has not been investigated. METHODS AND RESULTS: Symptomatic patients who had tried >/=2 drugs for PAF were randomized to continue medical therapy (n=19) or AV junction ablation and implantation of dual-chamber mode-switching (DDDR/MS) pacemakers (slow algorithm [n=19] or fast algorithm [n=18]). Follow-up over 18 weeks was at 6-week intervals and used quality-of-life questionnaires (Psychological General Well Being [PGWB], McMaster Health Index [MHI], cardiac symptom score), exercise testing, echocardiography, and Holter monitoring. Paced patients were randomized to DDDR/MS or VVIR and subsequently crossed over. Ablation and DDDR/MS pacing produced better scores than drug therapy for overall symptoms (-41%, P<0.01), palpitations (-58%, P=0. 0001), and dyspnea (-37%, P<0.05). Changes in score from baseline were better with ablation and DDDR/MS pacing for overall symptoms (-48% versus -4%, P<0.005), palpitation (-62% versus -5%, P<0.001), dyspnea (-44% versus -3%, P<0.005), and PGWB (+12% versus +0.5%, P<0. 05). DDDR/MS was better than VVIR pacing for overall symptoms (-21%, P<0.05), dyspnea (-30%, P<0.005), and MHI (+5%, P<0.03). There were no differences between algorithms. More patients developed persistent AF with ablation and pacing than with drugs at 6 weeks (12 of 37 versus 0 of 19, P<0.01). CONCLUSIONS: Ablation and DDDR/MS pacing produces more symptomatic benefit than medical therapy or ablation and VVIR pacing but may result in early development of persistent AF.

Ablation of the atrioventricular junction: technique, acute and long-term results in 115 consecutive patients.

Atrioventricular junctional ablation is an attempt to interrupt conduction from the atrium to the ventricle using radiofrequency energy. The objective is to ablate the compact atrioventricular node as high as possible, leaving a stable ventricular escape rhythm. The compact node is identified in part by its relation to His recordings and partly through the known anatomy. In our series of 115 consecutive patients, atrioventricular block was achieved from the right side in 96% of patients and the remainder had the atrioventricular node ablated from the left side. Long-term success, i.e. complete heart block, was achieved in all patients. Complications in this and other series are rare, but there remains concern about sudden death in these patients.

Mode switching in dual chamber pacemakers: effect of onset criteria on arrhythmia-related symptoms.

AIMS: Various mode-switching algorithms are available with different tachyarrhythmia detection criteria to be satisfied to initiate mode-switching. This study evaluated three different mode-switching algorithms in patients with paroxysmal atrial fibrillation. METHODS AND RESULTS: Seventeen patients completed the study. Three mode-switching algorithms were downloaded as software into the pacemaker, each for 1 month in a single-blind, randomized sequence. The criteria to initiate mode-switching were: mean atrial rate ('standard'), '4-of-7' or '1-of-1' atrial intervals to exceed the atrial detection rate. Symptoms for each were measured using the Symptom Checklist Frequency and Severity index. The median number of mode-switch episodes increased from 20 for 'standard' to 39 for '4-of-7' (P=0.029 vs 'standard') and 103 for '1-of-1' (P=0.0012 vs 'standard') onset criteria. Median duration of episodes decreased from 2.5 min with 'standard' to 1.4 min with '4-of-7' and 0.4 min with '1-of-1' onset criteria. Frequency of symptoms was lower using '4-of-7' (18.2 +/- 12.0 vs 23 +/- 12.0, P=0.08) or '1-of-1' (20.4 +/- 12.4 vs 23 +/- 12.0, P=0.07) than 'standard' onset criteria. Severity of arrhythmia tended to be less with either '4-of-7' (16 +/- 10.4 vs 19.1 +/- 19.4, P=0.12) or '1-of-1' (17.5 +/- 10.3 vs 19.1 +/- 9.4, P=0.18) than with 'standard' onset criteria. CONCLUSIONS: The more sensitive onset criteria for detection of atrial tachyarrhythmias were associated with lower frequency and severity of symptoms.

Placement of atrial pacing leads during atrial fibrillation. Feasibility and subsequent lead performance.

AIMS: To assess the feasibility of placing permanent atrial pacing leads during atrial fibrillation (AF) and whether such leads function satisfactorily. METHODS AND RESULTS: Prospective study of 17 consecutive patients in whom permanent atrial leads were positioned during an episode of paroxysmal AF. Fluoroscopic position ('figure of 8' or side-to-side movement and anterior position in RAO projection), lead impedance (> 300 but < 1000 ohms) and intracardiac electrogram (average peak to peak amplitude > 1 mV) were used to define an acceptable lead position. At 8 weeks post implant we measured: pulse duration pacing threshold at 5 V; lead impedance at 5 V and 0.5 ms; intracardiac electrogram (EGM) signal amplitude. At the end of the study we reviewed patients to establish whether AF had become permanent. In all patients, follow-up demonstrated satisfactory lead function. All leads had impedances between 300 and 1000 ohms. Pacing thresholds were all < 0.1 ms at 5 V. Mean atrial EGM amplitude seen in sinus rhythm was 3.3 mV (range 1.2-8.4); in patients where all follow-up was in AF in was 2.1 mV (range 1.5-2.5). Nine patients (53%) developed permanent AF. CONCLUSION: Placing atrial leads during AF is feasible using the technique described. However, some patients progress to chronic AF, eliminating the benefits of atrial pacing.

Diabetic peripheral neuropathy. Effectiveness of electrotherapy and amitriptyline for symptomatic relief.

OBJECTIVE: To evaluate the efficacy of combining electrotherapy with amitriptyline for the management of chronic painful peripheral neuropathy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients (n = 26) with peripheral neuropathy were treated with amitriptyline. After 4 weeks, those patients (n = 23) who failed to respond to amitriptyline or who only had partial relief were randomized between a sham treatment group (control) or an electrotherapy group. Transcutaneous electrotherapy was given for 12 weeks by a portable unit (H-wave machine) that generated a biphasic exponentially decaying waveform (pulse width 4 ms, 25-35 V, > or = 2 Hz). The degree of pain and discomfort was graded on a scale of 0-5. An analog scale was used to record the overall change in symptoms. RESULTS: Amitriptyline produced some degree of symptomatic relief in 15 (60%) of the 26 patients by the 4th week; pain scores decreased from 3.8 +/- 0.1 to 2.9 +/- 0.2 (P < 0.1) and the overall reduction in pain was 26 +/- 5% on an analog scale. In the amitriptyline plus sham treatment group (n = 9), pain scores declined from 2.8 +/- 0.3 to 1.9 +/- 0.5 (P < 0.03) and the overall reduction in pain was 55 +/- 12%, suggesting a procedure-related placebo effect. In the group receiving combined electrotherapy and amitriptyline (n = 14), symptomatic improvement occurred in 12 (85%) patients. Five (36%) of the patients in this group became asymptomatic. Pain scores declined from 3.2 +/- 0.2 to 1.4 +/- 0.4 (P < 0.01) and the overall reduction in pain was 66 +/- 10%. The degree of reduction in pain scores and the incremental relief (above the amitriptyline effect) were significantly greater (P < 0.03) with electrotherapy as compared with sham treatment. The outcomes indicate a substantial beneficial effect of electrotherapy over and above any placebo influence. CONCLUSIONS: Our clinical observations suggest that transcutaneous electrotherapy is effective in reducing the pain associated with peripheral neuropathy. This form of therapy may be a useful adjunctive modality when it is combined with a pharmacological agent, such as amitriptyline, to augment symptomatic relief.

Atrioventricular nodal ablation and implantation of mode switching dual chamber pacemakers: effective treatment for drug refractory paroxysmal atrial fibrillation.

OBJECTIVE: To assess the effect of atrioventricular node ablation and implantation of a dual chamber, mode switching pacemaker on quality of life, exercise capacity, and left ventricular systolic function in patients with drug refractory paroxysmal atrial fibrillation. PATIENTS: 18 consecutive patients with drug refractory paroxysmal atrial fibrillation. METHODS: Quality of life was assessed before and after the procedure using the psychological general wellbeing index (PGWB), the McMaster health index (MHI), and a visual analogue scale for cardiac symptoms. Nine of the patients also underwent symptom limited exercise tests and echocardiography to assess left ventricular systolic function. RESULTS: The procedure allowed a reduction in antiarrhythmic drug treatment (p < 0.01). PGWB and symptom scores improved (p < 0.01) but the MHI score did not change. Left ventricular systolic function and exercise capacity were unchanged. CONCLUSIONS: Atrioventricular node ablation and implantation of a DDDR/MS pacemaker is effective treatment for refractory paroxysmal atrial fibrillation, producing improved quality of life while allowing a reduction in drug burden. The popularity of the treatment is justified, but further studies are needed to determine optimum timing of intervention.

Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation.

OBJECTIVE: To evaluate the efficacy of transcutaneous electrotherapy for chronic painful peripheral neuropathy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty-one patients with symptoms and signs of peripheral neuropathy were randomized to the electrotherapy or sham treatment (control) group. The electrostimulation was given by a portable unit (H-Wave machine) than generated a biphasic, exponentially decaying waveform (pulse width 4 ms, 25-35 V, > or = 2 Hz). Patients treated each of their lower extremities for 30 min daily for 4 weeks at home. Nine patients from the sham-treatment group participated for a second period, during which all of them received the active electrotherapy. Patient's degree of pain and discomfort was graded on a scale of 0 to 5. RESULTS: In the sham-treated group (n = 13), the neuropathic symptoms improved in five (38%) patients, and the pain score declined from 2.92 +/- 0.13 to 2.38 +/- 0.26 (P < 0.04), suggesting a procedure-related placebo effect. In the electrotherapy group (n = 18), symptomatic improvement was seen in 15 (83%) cases, 3 of which were completely asymptomatic; the pain score declined from 3.17 +/- 0.12 to 1.44 +/- 0.25 (P < 0.01) and the posttreatment pain scores were considerably lower (P < 0.03), indicating a substantial treatment effect over and above any placebo influence. Patients in the electrotherapy group reported greater reduction in symptoms (52 +/- 7% vs. 27 +/- 10% in control subjects, P < 0.05) on an analog scale. Moreover, the electrotherapy decreased pain scores (from 3.0 +/- 0.62 to 1.56 +/- 0.32, P < 0.02) in nine patients who had received sham treatment earlier. CONCLUSIONS: A form of transcutaneous electrotherapy ameliorated the pain and discomfort associated with peripheral neuropathy. This novel modality offers a potential non-pharmacological treatment option.