The composition and fluidity of adipocyte membranes prepared from young and adult rats.

Membranes from adipocytes of adult and young rats have been compared. Phospholipid fatty acids from adult rats were more saturated than those from young rats. This difference was associated with a decreased fluidity in the membranes of the adult rats, which was inferred from measurements of fluorescence polarisation of the fluorescent probe, 1,6-diphenylhexa-1,3,5-triene.

Ligand affinities in mutant metmyoglobins.

Ligand binding to the wild-type and a series of mutant porcine myoglobins, expressed and purified from Escherichia coli cells, has been studied using UV-VIS absorption spectroscopy. The proximal pocket mutation, F7 Ser-->Leu (F7), causes an increased affinity for OH- and N3- binding to metmyoglobin. A hydrogen bond between the F7 serine residue and the imidazole side-chain of the proximal histidine has been removed by this mutation. It is suggested that this allows the imidazole group to reorientate, reducing the steric clash between itself and the haem pyrrole nitrogen atoms and leading to a shortening of the bond between the proximal histidine and the haem iron. Other conformational changes further away from the haem pocket have also been induced, but the mutant still crystallizes under the same conditions as for the wild-type protein. A series of distal pocket mutants, E11 Val-->Thr (VT), E7 His-->Val (HV) and a mutant with both of these substitutions (M2) all have greatly reduced the OH- and N3- binding affinity. These effects have been interpreted by considering several factors: the changed stability of the aquometmyoglobin form, hydrogen-bond formation between the ligand and the E7 residue, and electrostatic repulsion between the ligand and the E11 threonine residue.

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 intravenous adenosine on verapamil-sensitive "idiopathic" ventricular tachycardia.

The mechanism of ventricular tachycardia (VT) that occurs in the absence of structural heart disease ("idiopathic" VT) is unknown, but may involve triggered activity or reentry through calcium channel-mediated conduction pathways. It has been suggested that termination of VT by adenosine is specific to ventricular arrhythmias caused by cyclic adenosine monophosphate-mediated triggered activity. The effects of vagotonic maneuvers, and intravenous adenosine (up to 0.25 mg/kg in incremental doses) and verapamil (0.145 mg/kg) administered to 9 patients with "idiopathic" VT were studied during electrophysiologic study. Seven patients had inducible fascicular VT and 2 had incessant right ventricular outflow tract tachycardia. Vagal maneuvers did not have any effect on any VT. Adenosine interrupted both right ventricular outflow tract tachycardias for a period (2 to 15 seconds) that was dependent on the dose of adenosine, but had no effect on VT in any patient with fascicular VT. Verapamil produced stuttering termination of right ventricular outflow tract tachycardia with no preceding change in RR interval in patients with this arrhythmia. Administration of verapamil to patients with fascicular VT was followed by gradual slowing of the arrhythmia (cycle length increased from 397 +/- 45 to 506 +/- 86 ms; p < 0.01) in all 7 patients and by termination of VT in 6. In conclusion, the differential response of fascicular and right ventricular outflow tract tachycardias to both adenosine and verapamil suggests that: (1) These 2 forms of idiopathic VT have different mechanisms. (2) Fascicular VT is unlikely to be due to cyclic adenosine monophosphate-mediated triggered activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of intravenous adenosine in sinus rhythm as a diagnostic test for latent preexcitation.

In a proportion of patients with left free wall accessory connections, preexcitation is apparent only during atrial arrhythmias or atrial pacing (latent preexcitation). These patients may be at risk of a rapid ventricular response to atrial fibrillation despite the absence of preexcitation in sinus rhythm. The ability of intravenous adenosine to unmask latent preexcitation was evaluated in 22 patients with a history of documented supraventricular tachycardia and a normal electrocardiogram during sinus rhythm. Preexcitation was unmasked in response to adenosine in 4 patients: all 4 were shown to have latent preexcitation at electrophysiologic study. In 12 patients atrioventricular (AV) nodal conduction delay or block was induced without preexcitation after adenosine (first-degree AV block in 8, second-degree block in 4): at subsequent electrophysiologic study none of these patients was found to have latent preexcitation. Five patients had little or no PR prolongation in response to adenosine: of these, 2 were shown to have latent preexcitation at electrophysiologic study. Atrial fibrillation was induced in 1 patient and a narrow complex regular tachycardia in another after intravenous adenosine. Intravenous adenosine during sinus rhythm is capable of producing AV nodal conduction delay or block in 73% of patients with a history of supraventricular tachycardia: in these patients adenosine provides a diagnostic test that is both 100% sensitive and 100% specific for latent preexcitation. In those patients in whom adenosine does not produce AV conduction delay or block, further investigation is required to establish or refute the diagnosis of latent preexcitation.

Reproducibility of the signal averaged P wave: time and frequency domain analysis.

OBJECTIVE: To assess the reproducibility of time and frequency domain variables derived from the signal averaged P wave. DESIGN: Longitudinal within patient study. SETTING: Regional cardiothoracic centre. PATIENTS: 20 patients (10 with documented paroxysmal atrial fibrillation and 10 normal controls) were studied on three occasions to assess the reproducibility of repeated signal averaged P wave recordings. Digital P wave recordings were made on a further 10 patients on a single occasion and the recordings signal averaged twice in order to assess the reproducibility of the averaging system itself in the absence of biological variation. MAIN OUTCOME MEASURES: P wave duration, spatial velocity, and energies contained in frequency bands from 20, 30, and 60-150 Hz of the P wave spectrum were measured after P wave specific signal averaging. Coefficients of reproducibility were calculated for paired signal averaged P waves derived by signal averaging the same digital recordings on two separate occasions, for recordings performed in the same patients immediately after each other ("back to back") and those performed one week apart. RESULTS: System reproducibility when the same digital P wave recordings were signal averaged on two separate occasions was high (< 11% for all variables). For P wave duration the coefficient of reproducibility was 11.4% for back to back recordings and 13.1% for those one week apart. The reproducibility of spatial velocity and P wave energy was low. Variation in P wave morphology was noted when successive P waves from the same subject were examined. If recordings with the same P wave morphology were analysed the reproducibility of spatial velocity and P wave energy improved but remained significantly poorer than that for P wave duration. CONCLUSIONS: P wave duration is reproducible within subjects in the short and medium term. Frequency domain and spatial velocity analysis are poorly reproducible, due more to spontaneous variation in P wave morphology than to instability of the signal averaging process. This may limit the utility of signal averaged P wave variables other than duration for the prediction of atrial arrhythmia.

New training guidelines: what are the implications for cardiological research?

The recognition of the importance of research experience is welcomed; committed research supervisors should be identified for each trainee and research planning should start as early as possible in the traineeship. It would be welcome if employing authorities and postgraduate deans were to provide personal support for up to one year and modest research expenses for trainees undertaking research. In the absence of such support, application would need to be made to grant-giving bodies well in advance. Certain posts may need to be earmarked for the training of future clinical scientists. Academic units should regard themselves as challenged, but not necessarily threatened, by the new proposals. With appropriate consultation and involvement, and a modest allocation of funding, the overall result should enhance the quality of both service and academic communities.

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.

Signal averaged P wave compared with standard electrocardiography or echocardiography for prediction of atrial fibrillation after coronary bypass grafting.

OBJECTIVE: To define the clinical value of the signal averaged P wave (SAPW) and to compare it with the standard electrocardiogram (ECG), echocardiogram, and clinical assessment for the prediction of atrial fibrillation after coronary bypass grafting (CABG). DESIGN: Prospective validation cohort study. SETTING: Regional cardiothoracic centre. PATIENTS: 201 unselected patients undergoing first elective CABG were recruited over six months. Patients requiring concomitant valve surgery were excluded. MAIN OUTCOME MEASURES: Age, sex, cardiothoracic ratio, and cardioactive drugs were noted. P wave specific SAPW recordings, ECG, and M mode echocardiograms from which left atrial diameter was measured were performed within 24 hours of surgery. Filtered P wave duration (SAPWD), spatial velocity, and energy were calculated from the SAPW. From the ECG, lead II P wave duration, P terminal force in lead V1, total P wave duration, and isoelectric interval were measured. Patients had Holter monitoring for 48 hours postoperatively and daily ECGs until discharge. RESULTS: Two patients died (1%) and 10 were unsuitable for analysis (5%). Of the remaining 189, 51 (27%) had atrial fibrillation (AF) lasting > 1 hour at a mean of 2 (0.5 to 7) days after CABG. Of the variables examined, only SAPWD (AF group 148 (SD 12), v 142 (14) ms, P = 0.008) and male sex (AF group 96%, v 78%, P < 0.01) were significantly different. A prospectively defined SAPWD of > 141 ms predicted atrial fibrillation with positive and negative predictive accuracies of 34% and 83%. Logistic regression analysis identified both male sex and SAPWD as significant independent predictors of postoperative atrial fibrillation. CONCLUSIONS: Signal averaged P wave duration was a better predictor of atrial fibrillation after coronary bypass grafting than standard electrocardiographic or echocardiographic criteria. The predictive value of this test is such that it is likely to be useful in the design of prospective trials of prophylactic antiarrhythmic treatment but is of limited use using current techniques in the clinical management of individual patients.

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.

Management of hypertension in general practice: agreements with and variations from the British Hypertension Society guidelines.

A random sample of 200 East Anglian general practitioners was surveyed to establish current trends in the management of hypertension, including measurement of blood pressure (BP), patient investigation, treatment and follow-up. A total of 125 (62.5%) completed questionnaires was returned. Responses were used to assess the range of self-reported management practice and the extent of conformity with the British Hypertension Society guidelines. Although there was a broad spectrum of reported practice, many respondents adhered closely to the guidelines in relation to BP measurement, use of non-pharmacological treatment, treatment goals, choice of drug and patient investigation. Not surprisingly, the greatest disparity between reported and recommended practice occurred in areas where guidelines have only recently become available: treatment of isolated systolic hypertension and of the elderly hypertensive. Here, the survey provides a useful baseline against which to monitor future changes in management.

Dynamics of QT dispersion during myocardial infarction and ischaemia.

We studied the dynamics of QT dispersion over the first few days of myocardial infarction and during coronary angioplasty. Ten patients with anterior myocardial infarction and an equal number with inferior infarction had electrocardiograms (ECGs) recorded on admission to hospital (day 1), on the subsequent 2 days (day 2, 3), and prior to discharge (day 6). Ten patients undergoing therapeutic coronary angioplasty were studied; ECGs were recorded prior to, during, and after balloon inflation. Simultaneous 12-lead ECGs were scanned into a personal computer; specially designed software skeletonised and joined each image. The images were then available for user-interactive measurement of QT dispersion. Mean (S.D.) QTc dispersion on day 1 of acute myocardial infarction was 107 (44.8) ms, rose further over the next 48 h, reaching a maximum on day 3 (QTc dispersion, 162.3 (64.8) ms, P < 0.01), and was falling by hospital discharge (QTc dispersion, 117.4 (67.4) ms). There was no difference in QT dispersion measurement during coronary angioplasty. It is unlikely that acute ischaemia plays an important role in the dynamic changes seen in QT dispersion over the first few days of myocardial infarction. These rapid changes in QT dispersion have important implications in the design of any study of QT dispersion after myocardial infarction, and in comparison of studies.

The signal averaged P wave in atrioventricular block--evidence for abnormal atrial conduction?

The incidence of atrial fibrillation in patients with atrioventricular block (AVB) appears increased over that for the unpaced population even if atrioventricular synchrony is maintained by dual chamber pacing. To assess whether atrial fibrillation in these patients might be due to concurrent abnormality in atrial activation we performed signal averaged P wave (SAPW) recordings in 15 patients with dual chamber pacemakers implanted for AVB and compared the results to those from 21 unpaced controls. The median (range) age was 69 (53-89) years for patients and 60 (51-78) years for controls. Eleven patients and 12 controls were male. All patients were pacing in VDD mode at the time of study. SAPW recordings were obtained using our previously reported selective P wave averaging system. We measured P wave duration after high pass filtering at 40 Hz, the rate of change of P wave voltage over time (spatial velocity) and low and high frequency spectral energy after Fourier transformation of the P wave signal. We found increased P wave duration, mean spatial velocity and lower frequency energy in patients with AVB compared to controls [duration, 144 (5) vs. 134 (2) ms, p<0.05; mean spatial velocity, 5.6 (0.4) vs. 4.6 (0.1) mV/s, p<0.05; energy 20-150 Hz, 57.4 (8.2) vs. 36.3 (2.8) muV2.s, p<0.01. All values mean (SEM)]. These results suggest that the increased incidence of atrial fibrillation in patients paced for AVB may be related to intrinsic abnormalities of atrial activation and not solely to the pacing mode. Ensuring sequential atrioventricular pacing in these patients may not completely abolish the increased incidence of atrial fibrillation.

A procedure for the redefinition of equivocal results in thyroid function tests.

A retrospective analysis has been made of patients who had been classified (on the basis of measurements of serum thyroxine and thyroid hormone uptake test) as equivocal thyrotoxic (273 patients) or as equivocal hypothyroid (352 patients). The final diagnosis of these patients has been traced from their medical records. The results illustrate that control groups of euthyroid, thyrotoxic, and primary hypothyroid subjects differ from these equivocal groups. The populations initially classified as equivocal have been used to redefine the combinations of values obtained in the serum thyroxine and thyroid hormone uptake test which must be classed as equivocal. Using this redefinition, it is shown that a number of additional tests had been carried out when it could now be predicted with confidence that no useful new information would be obtained. The procedure described is not limited to tests of thyroid function and could easily be applied in most laboratories to redefine the ranges of results classified as equivocal.

The effects of adenosine on sinus node reentrant tachycardia.

The effects of adenosine given during sinus node reentrant tachycardia were investigated in two patients. Both patients received intravenous bolus doses of 0.1 mg/kg and 0.15 mg/kg. Adenosine slowed the atrial rate in both patients and terminated the tachycardia in one. These effects of adenosine on sinus node reentrant tachycardia suggest that sinus nodal tissue (as opposed to perinodal atrial tissue) is involved in the tachycardia circuit and that these effects should be considered when adenosine is used as a diagnostic agent in narrow-complex tachycardia.