A novel interpretation of immune redundancy and duality in reperfusion injury with important implications for intervention in ischaemic disease.

The majority of ischaemia related injury occurs upon tissue reperfusion. Knock-out mouse models have recently shed light on the underlying molecular mechanisms, and suggest that this may be the result of an innate autoimmune response. Based on these new findings we present a novel model of immune redundancy and duality in reperfusion injury. Natural antibody, mannan-binding lectin and toll-like receptor 4 are three pre-formed innate immune receptors that recognise pathogenic molecular patterns. Removing either significantly ameliorates reperfusion injury. We propose that these three receptors serve as key parallel recognition elements that respond to the same or similar ischaemic neo-antigens, of which at least one may have a lipopolysaccharide-like motif. This would fit both with the ligand preference of the three receptors, and the observation that giving monoclonal antibody to lipopolysaccharide reduces reperfusion injury. The consequent injury caused by receptor activation appears to be mainly related to the complement anaphylatoxins, and less to phagocytes, oxidative radicals, and the membrane attack complex. C5a levels in particular are predictive of overall injury, and we suggest this anaphylatoxin causes most of reperfusion injury via both direct toxic effects and a generalised immune activation. The former is illustrated by the recent observation that excess C5a alone can cause cardiac dysfunction. As for the latter, there is evidence that adaptive immunity (especially CD4+ cells) and other serum cascades (coagulation and kallikrein) are involved, and may have been recruited by complement. Furthermore, excess C5a can cause innate immune overactivation that paralyses neutrophils, reduces complement lytic function, and leads to systemic inflammation. This is analogous to what happens in sepsis, and would explain the passive role in IRI of normal immune effectors. Finally, there is a duality complement's function in reperfusion, as some elements are conductive of damage, whilst others may help inflammatory resolution. Most important among the latter are the opsonins, like C3b and apparently C1q, which help macrophages clear apoptosing cells before they undergo secondary necrosis. This model has important implications for clinical interventions. Firstly, redundancy means that inhibiting multiple receptors may achieve a larger mortality reduction than the small and inconsistent one seen in the published monotherapy trials. Secondly, duality means that a non-specific inhibition of complement would reduce both injury and resolution. Therefore, a specific inhibition of the lectin pathway and/or an inhibition of the downstream effectors upon which the receptors converge (e.g. C5a) seem to be a better interceptive strategy.

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.

The Bayesian approach improves the electrocardiographic diagnosis of broad complex tachycardia.

Despite numerous attempts at devising algorithms for diagnosing broad complex tachycardia (BCT) on the basis of the electrocardiogram (ECG), misdiagnosis is still common. The reason for this may lie with difficulty in implementing existent algorithms in practice, due to imperfect ascertainment of ECG features within them. An attempt was made to approach the problem afresh with the Bayesian inference by the construction of a diagnostic algorithm centered around the likelihood ratio (LR). Previously studied ECG features most effective in discriminating ventricular tachycardia (VT) from supraventricular tachycardia with aberrant conduction (SVTAC), according to their LR values, were selected for inclusion into a Bayesian diagnostic algorithm. A test set of 244 BCT ECGs was assembled and shown to three independent observers who were blinded to the diagnoses made at electrophysiological study. Their diagnostic accuracy by the Bayesian algorithm was compared against that by clinical judgement with the diagnoses from EPS as the criterial standard. Clinical judgement correctly diagnosed 35% of SVTAC, 85% of VT, and 47% of fascicular tachycardia. In comparison, by the Bayesian algorithm devised, 52% of SVTAC, 95% of VT, and 97% of fascicular tachycardia were correctly diagnosed. The Bayesian algorithm devised has proved to be superior to the clinical judgement of the observers who participated in this study, and theoretically will obviate the problem of imperfect ascertainment of ECG features. Hence, it holds the promise for being an effective tool for routine use in clinical practice.

[Long-term monitoring of patients with a syncope of obscure etiology with an implantable monitoring device]. / Dlouhodobé monitorování pacientu se synkopou nejasné etiologie pomocí implantabilního záznamového zarízení.

INTRODUCTION: Generally available methods for the diagnosis of syncopal conditions such as Holter monitoring, the tilt test and invasive electrophysiological examinations, lead to the assessment of the cause of sporadic syncopes only in some patients. The implantable monitoring device REVEAL protracts significantly the monitoring period. METHODS, RESULTS: The authors implanted the implantable monitoring device REVEAL in the course of 14 months to 19 patients with syncopes of obscure origin. During this period it was possible to prove the cause of the syncope in a total of 10 patients (53%), in 8 patients the cause was arrhythmia, in another two an arrhythmic cause was ruled out. During monitoring the authors did not record any serious undesirable events. CONCLUSION: Implantable monitoring devices are an asset in the diagnosis of sporadic syncopes where currently available invasive and non-invasive methods fail. Its use in patients without obvious structural cardiovascular disorders is safe.

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.

Recurrent syncope due to complete atrioventricular block, a rare presenting symptom of otherwise silent coronary artery disease: successful treatment by PTCA.

A patient presented with recurrent syncope and episodes of AV block preceded by asymptomatic ST segment elevation on ambulatory monitoring. Coronary angiography revealed a severe stenosis in the midsegment of the right coronary artery (RCA). Successful PTCA and stent insertion abolished further episodes of syncope.

The optimal pacing rate: an unpredictable parameter.

A three phase relation has been demonstrated between increasing heart rate and cardiac output at rest. Phase I with cardiac output increasing with increasing heart rate, phase II a plateau, and phase III decreasing cardiac output with any further increase in heart rate. The "optimal rate" can be defined as the heart rate at the onset of phase II. Twenty patients were studied, 13 male, mean age 60 years (range 31-71 years). All had chronic complete heart block and established DDD pacing. A maximal exercise test was performed to determine peak sinus rate. Exercise hemodynamics were measured using an ambulatory monitor (Capintec Vest), which permits measurement of relative cardiac output and relative ejection fraction. The patients were programmed to VVI pacing at a rate of 60 beats/min and performed three exercise tests at different workloads. The order of workloads was randomized and selected from a range (0, 25, 50, or 75 W) depending on fitness. After 3-minute stabilization, the VVI pacing rate was increased at 1-minute intervals until higher than peak sinus rate giving a total exercise time of 12 minutes. The "optimal rate band" was determined at each workload. The mean of this "optimal rate band" for each workload varied in a nonlinear manner. There was no correlation between "mean optimal rate" and age or the peak rate predicted by the Astrand formula. Current definitions of chronotropic incompetence are inaccurate. Are some of these people at their "optimal rate" already? The arbitrary selection of rate response curves on age related criteria may lead to an impaired hemodynamic response.

Normal coronary angiograms: financial victory from the brink of clinical defeat?

OBJECTIVE: To examine the hypothesis that, in patients undergoing coronary angiography for suspected ischaemic heart disease, a normal angiographic result is associated with a fall in consumption of health care resources following the angiogram. DESIGN: Retrospective cost-benefit analysis comparing the 12 month periods before and after coronary angiography. SETTING: Tertiary cardiac referral centre. SUBJECTS: 69 consecutive patients investigated in the financial year 1991-92 whose angiograms were normal. MAIN OUTCOME MEASURES: Drug and hospital admission costs in the 12 month periods before and after angiography; urgent and elective consultations with general practitioner in that time. RESULTS: The mean cost of care per patient in the year before investigation was 656.89 pounds. A highly significant fall in all indices of resource consumption was observed in the year following investigation, the mean resulting difference in the cost of care being 35.15 pounds per month. The cost of coronary angiography would, if this fall were maintained, be recouped in a mean time of 18 months. CONCLUSIONS: Patients suspected on clinical grounds to have coronary atherosclerosis who are found at angiography to have normal coronary arteries are heavy consumers of health care resources. Early investigation for these patients is safe and has beneficial resource consequences in the medium term.

Effect of sequential radiofrequency ablation lesions at fast and slow atrioventricular nodal pathway positions in patients with paroxysmal atrial fibrillation.

OBJECTIVE: To examine the hypothesis that the anatomic equivalents of the fast and slow pathways identified in patients with atrioventricular (AV) nodal tachycardia may be universal and represent the principal sites of atrial input into the normal compact AV node. METHODS: 15 patients undergoing complete AV junction ablation for paroxysmal atrial fibrillation were studied. Radiofrequency energy was delivered first in the anterior "fast pathway" position so as to prolong the atrium to bundle of His (AH) interval by over 50% of baseline (protocol 1) and then to the "slow pathway" position using the anatomical technique (protocol 2). RESULTS: Ablation protocol 1 resulted in prolongation of AH interval in all patients. Subsequent lesions at the level of the coronary sinus produced complete heart block in four patients, and in five caused a further increase in AH interval above that produced by protocol 1. Four of these latter patients developed complete block after delivery of RF energy slightly anterior to the level of the coronary sinus os, as did three further patients in whom ablation at the level of the coronary sinus had no effect. In four patients complete heart block could not be achieved by protocol 2. CONCLUSIONS: A discrete anterior "fast" pathway and a posterior "slow" pathway or network of posterior pathways form the principal inputs to the compact AV node in most patients with atrial fibrillation. The absence of dual AV nodal physiology in the majority of these patients may be related to the functional properties of the individual components of this posterior network.

Shuttle walking test: a new approach for evaluating patients with pacemakers.

OBJECTIVE: To validate an incremental field walking test, the shuttle walking test, as a means of assessing pacing modes and to aid programming of rate responsive pacemakers. DESIGN: Three separate groups of patients were recruited. Reproducibility (n = 10) of the shuttle walking test was assessed by performing three consecutive tests. Comparison of the shuttle walking test with a 10 min walk was assessed in 20 patients. In the third group (n = 10) patients with rate responsive pacemakers were programmed to either VVI fixed rate 70 beats/min or VVIR with the optimal rate response to show the discriminative value of the test. SETTING: Pacing clinic in a regional cardiothoracic centre. PATIENTS: 30 patients with chronotropic competence and dual chamber pacemakers with varying functional capacity and 10 patients with rate responsive pacemakers. INTERVENTIONS: Continuous haemodynamic monitoring was obtained using an ambulatory nuclear monitor, the Capintec VEST. Two exercise tests either shuttle walking test or 10 min corridor walk. The shuttle walk is an incremental walking test conducted on a 10 m course where the walking speed is dictated by bleeps on an audio cassette. RESULTS: Reproducibility was demonstrated over three consecutive tests with mean (1 SD) exercise times of 7.6 (1.7) min, 7.7 (1.6), and 7.7 (1.7) min. During the shuttle walk the test patients walked for a mean of 8.3 (1.2) min producing peak relative cardiac outputs of 78 (21) end diastolic volume/min compared with 64.9 (17) end diastolic volume/min for the 10 min walk (P < 0.001); peak heart rates were 118 and 104 beats/min (P < 0.03) respectively. In the third group relative peak cardiac output was significantly greater in VVIR (70 (24) v VVI 52 (15) end diastolic volume/min) (P < 0.009) as were exercise times (VVIR 8.8 (1.3) min v VVI 8.1 (1.3) min) (P < 0.003). CONCLUSIONS: The shuttle walk is an easy test to administer, requiring little equipment. It produces a symptom limited maximal performance and will be a useful aid to pacemaker programming as it is reproducible and able to show differences in exercise capacity between pacing modes.

An approach in the assessment of pacing hemodynamics: a comparison of VVI and DDD.

Previous methods for assessment of pacemaker hemodynamics have been limited to a rigid hospital environment. An alternative is the ambulatory ventricular function monitor (C-VEST) that, with a single injection of technetium-99m, permits the continuous measurement of relative ejection fraction (EF) and cardiac output (CO) during the activities of daily living. A study of reproducibility and a comparison of dual chamber (DDD) and fixed rate ventricular (VVI) pacing are presented. Reproducibility was assessed in six patients (4 males; mean age 58, range 27-78 years) with a mean EF of 48.5% (range 34%-62%) and DDD pacemakers, implanted for conduction abnormalities. In addition, 11 patients (7 males; mean age 55.5, range 34-75 years) with a mean EF of 48.5% (range 34%-65%), chronic complete heart block, and DDD pacemakers were used for the comparative study. After an initial multigated scan, the monitor was positioned over the left ventricle and kept in place with the plastic C-VEST. The patients undergoing the reproducibility study performed three shuttle walking tests with 20 minutes of rest in between. The patients in the comparative study were randomized to either VVI or DDD mode and performed one shuttle walking test in each pacing mode. The results confirmed that the C-VEST produces reproducible results with no significant difference in peak CO between the three shuttle walks. In addition, it confirmed previous hemodynamic studies showing that DDD pacing was superior to VVI pacing both at rest (P < 0.004) and at exercise (P < 0.002). These findings show the C-VEST to be an extremely useful tool for the hemodynamic assessment of pacemaker patients.

Clinical experience with a new lead combining active fixation with steroid elution.

The Medtronic lead engineering model number 10335A represents a new concept in lead design combining active fixation with steroid elution. It aims for immediate stability and low chronic thresholds. Twenty-one leads, 9 atrial and 12 ventricular, were implanted in 13 patients (10 males, mean age 68; range 22-91 years). The atrial leads showed no rise in pulse width threshold at a voltage of 1.6 volts (mean thresholds at implant, 1, and 26 weeks; 0.1 +/- 0.09 msec, 0.15 +/- 0.04 msec, and 0.1 +/- 0.03 msec, respectively). The ventricular leads had a small but significant rise between implant and 1 week at an output of 1.6 volts (0.07 +/- 0.03 msec increasing to 0.11 +/- 0.04 msec; P < 0.02) but no significant later rise (0.1 +/- 0.04 msec at 2 weeks and 0.1 +/- 0.05 msec at 6 months). These low chronic thresholds would allow early reprogramming of the unit to low voltages resulting in a battery saving with prolongation of the unit's life. There were no significant changes in the P and R wave amplitudes, but there was a fall in lead impedance in the ventricular leads between implantation and 1 week (P < 0.02) but none subsequently, and there was no significant change in atrial impedance. There were no sensing failures and no lead displacements. Despite impressive pacing characteristics, the study was suspended because of a high level of mechanical complications. Of the 96 patients implanted worldwide with 136 leads there were eight helix deformations, which will require redesign.(ABSTRACT TRUNCATED AT 250 WORDS)

Plaque herniation through an intracoronary stent.

We present a case where a Wiktor intracoronary stent was inserted for 'poor angiographic result' following balloon angioplasty. Despite appropriate positioning and repeated dilation of the stent a suboptimal result was achieved because of plaque herniation through the stent. The case emphasizes that the choice of stent used is important and will become more so as the number of choices available increases.

Failure of provision of antibiotic prophylaxis for 'at risk' cardiac patients: impetus for improvement required from cardiologists.

We conducted a survey by questionnaire to assess whether patients 'at risk' from infective endocarditis are aware of the need for good dental hygiene and antibiotic prophylaxis, and receive appropriate advice or treatment. Of 189 patients surveyed, half had told a dentist about their heart, 8% were aware of a dental problem, 12% had attended a dentist within one year, but 39% had not attended a dentist in 5 years. Only 21% accurately recalled instructions on prophylaxis and 44% recalled receiving antibiotics prior to treatment. Of replies from 262/480 general practitioners, half took a dental history but only 3% gave antibiotic advice in writing. Fifty-seven percent prescribed antibiotics recommended by the British Society for Antimicrobial Chemotherapy. Of the general practitioners and 72/240 dentists who replied, half were unaware of some of the cardiac conditions requiring prophylaxis, and did not receive adequate advice from their cardiac centre. We conclude most at-risk patients are unaware of the need for good dental hygiene and antibiotic prophylaxis. Communication needs to be improved to address these problems. A new 'endocarditis risk' card is proposed for patients to carry, with an identical 'sticker' to attach to medical notes.