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The effect of dazoxiben, a thromboxane synthetase inhibitor, on cold- induced forearm vasoconstriction was determined in two groups of human volunteers, those in whom dazoxiben abolished the platelet aggregation and release reaction induced by sodium arachidonate (group I) and those in whom it did not (group II). Dazoxiben abolished cold-induced forearm vasoconstriction in group I volunteers but not in those of group II. These results imply a correlation between platelet behaviour and cold- induced changes in vascular tone. In the group I volunteers the effect of dazoxiben on cold-induced vasoconstriction was abolished by 1800 mg of aspirin, but not by 40 mg. Since the lower dose of aspirin inhibits platelet cyclo-oxygenase but has no effect on cyclo-oxygenase in blood vessel walls, it is possible that platelets play no part in the modulation of vascular tone by dazoxiben. It is more likely that the effects of dazoxiben are confined to the vessel wall. [ABSTRACT FROM AUTHOR]

1 In healthy male volunteers dazoxiben (UK 37248), an inhibitor of thromboxane synthetase, abolished the arterial and venous vasoconstriction produced in the forearm by cold stimulation. 2 Aspirin alone had no effect on this vasoconstriction but negated the effect of dazoxiben. 3 In vitro dazoxiben increased the production of prostacyclin by human arteries and veins. 4 By reducing the synthesis of thromboxane A2, a potent vasoconstrictor, and by increasing the synthesis of prostacyclin, a potent vasodilator, dazoxiben may have a therapeutic role in conditions associated with abnormal vasoconstriction. [ABSTRACT FROM AUTHOR]

1 We have studied the effects on platelet behaviour of ingestion of the thromboxane synthetase inhibitor dazoxiben (UK 37248), by healthy subjects, and compared the results with the effects of a low dose of aspirin (a cyclo-oxygenase inhibitor), and of a combination of dazoxiben and a low dose of aspirin. 2 Dazoxiben ingestion prevented the release reaction induced by sodium arachidonate (NaAA) in platelet- rich plasma (PRP) from some individuals ('responders') but not in PRP from others ('non-responders'). In vitro testing of PRP from the same subjects, incubated with 10(-4)M dazoxiben, correlated with the effect of dazoxiben ingestion on NaAA-induced release. Platelets from 'non- responders' tended to undergo a more extensive release reaction than platelets from 'responders' even in the absence of any drug although there was some overlap between the results in the two groups. Platelets from 'non-responders' required significantly lower concentrations of NaAA to induce release reaction than platelets from 'responders'. Platelets from 'responders' and 'non-responders' did not differ in the amount of malondialdehyde (MDA) produced or in the effectiveness with which dazoxiben ingestion inhibited MDA production. 3 Low dose aspirin had comparable effects on NaAA-induced release to dazoxiben, but in contrast to dazoxiben, the effectiveness of low-dose aspirin in inhibiting NaAA induced release reaction was related to its effectiveness in inhibiting MDA generation. 4 Neither dazoxiben nor low- dose aspirin significantly affected the release reaction induced by adenosine diphosphate (ADP), although both drugs significantly inhibited adrenaline-induced release. 5 A combination of dazoxiben and low dose aspirin had a greater effect on platelet behaviour in response to NaAA, ADP, and adrenaline than either drug alone. [ABSTRACT FROM AUTHOR]

The Work and Social Adjustment Scale (WSAS) is a simple widely used 5-item measure of disability whose psychometric properties need more analysis in phobic disorders. The reliability, factor structure, validity, and sensitivity to change of the WSAS were studied in 205 phobic patients (73 agoraphobia, 62 social phobia, and 70 specific phobia) who participated in various open and randomized trials of self-exposure therapy. Internal consistency of the WSAS was excellent in all phobics pooled and in agoraphobics and social phobics separately. Principal components analysis extracted a single general factor of disability. Specific phobics gave less consistent ratings across WSAS items, suggesting that some items were less relevant to their problem. Internal consistency was marginally higher for self-ratings than clinician ratings of the WSAS. Self-ratings and clinician ratings correlated highly though patients tended to rate themselves as more disabled than clinicians did. WSAS total scores reflected differences in phobic severity and improvement with treatment. The WSAS is a valid, reliable, and change-sensitive measure of work/social and other adjustment in phobic disorders, especially in agoraphobia and social phobia.

Chronic heart failure is widely recognised as a common and escalating problem that causes major disability and often shortens life. Diuretics and digoxin have formed the mainstay of treatment for many years. Clinical trials have demonstrated that angiotensin converting enzymes and beta-blockers, in selected patients, improve symptoms and reduce mortality. Angiotensin-II antagonists and spironolactone may also have a role in certain individuals. Newer pharmacological approaches to the management of this complex disease are being developed, but await full evaluation.

Background: The objective measurement of exercise tolerance is an important component of heart failure trials. The use of laboratory-based treadmill exercise testing has attracted criticism, however, as being unrepresentative of patients' true capabilities., Aim: To examine the relationships between tests of exercise capacity, quality of life and haemodynamics in patients with stable symptomatic heart failure., Methods: Thirty-six patients with mild-moderate chronic heart failure were studied. Exercise capacity was assessed in the laboratory by maximal treadmill tests and self-paced corridor walk tests, and in the patients' homes by hip-borne pedometers. Quality of life was assessed by a disease-specific questionnaire. Cardiac output and limb blood flow were measured by non-invasive techniques., Results: Customary activity as assessed by pedometer scores correlated with quality of life questionnaire scores (r(S) = 0.47, P = 0.04), and both variables correlated with limb (calf) blood flow (pedometer scores: r(S) = 0.39, P = 0.03; quality of life scores: r(S)= 0.50, P = 0.04). The laboratory-based maximal treadmill test correlated with the self-paced corridor walk test, but neither of these tests correlated with pedometer scores, quality of life or haemodynamics., Conclusions: Different methods of assessing exercise capacity do not appear to give comparable results and bear different relationships to haemodynamic variables and quality of life. Pedometer scores of customary activity may better reflect patients' quality of life and appear to be more closely related to limb blood flow than the maximal treadmill exercise test or the corridor walk test. The sole use of laboratory-based exercise tests in therapeutic trials may give a misleading assessment of treatment efficacy in heart failure patients.

Objective: To characterise the central and regional haemodynamic effects of insulin in patients with chronic heart failure., Design: Single blind, placebo controlled study., Setting: University teaching hospital., Patients: Ten patients with stable chronic heart failure., Interventions: Hyperinsulinaemic euglycaemic clamp and non-invasive haemodynamic measurements., Main Outcome Measures: Change in resting heart rate, blood pressure, cardiac output, and regional splanchnic and skeletal muscle blood flow., Results: Insulin infusion led to a dose dependent increase in skeletal muscle blood flow of 0.36 (0.13) and 0.73 (0.14) ml/dl/min during low and high dose insulin infusions (p < 0.05 and p < 0.005 v placebo, respectively). Low and high dose insulin infusions led to a fall in heart rate of 4.6 (1.4) and 5.1 (1.3) beats/min (p < 0.05 and p < 0.005 v placebo, respectively) and a modest increase in cardiac output. There was no significant change in superior mesenteric artery blood flow., Conclusion: In patients with chronic heart failure insulin is a selective skeletal muscle vasodilator that leads to increased muscle perfusion primarily through redistribution of regional blood flow rather than by increased cardiac output. These results provide a rational haemodynamic explanation for the apparent beneficial effects of insulin infusion in the setting of heart failure.

Objectives: To document the degree of cognitive impairment in stable heart failure, and to determine its relation to the presence of Cheyne-Stokes respiration during sleep., Subjects: 104 heart failure patients and 21 healthy normal volunteers., Methods: Overnight oximetry was used (previously validated as a screening tool for Cheyne-Stokes respiration in heart failure). Cognitive function was assessed using a battery of neuropsychological tests. Left ventricular function was assessed by echocardiography., Results: Heart failure patients performed worse than the healthy volunteers in tests that measured vigilance. Reaction times were 48% slower (0.89 (0.03) s v 0.60 (0.05) s p < 0.005) and they hit twice as many obstacles on the Steer Clear simulator (75 (6.4) v 33 (4.6); p < 0.005). Cognitive impairment within the heart failure group was unrelated to either the presence of Cheyne-Stokes respiration, the degree of left ventricular dysfunction, or indices of nocturnal oxygenation., Conclusions: Vigilance was impaired in heart failure but this did not appear to be related to the presence of Cheyne-Stokes respiration during sleep. Impaired vigilance as measured on the Steer Clear test has been associated with an increased risk of motor vehicle accidents. The issue of fitness to drive in heart failure requires further attention.

Background: Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure are well recognized, there are theoretical advantages in combining ACE inhibition with angiotensin (AT)1 receptor antagonism., Methods: Twenty patients with mild to moderate heart failure and maximally treated with an ACE inhibitor were randomly assigned to losartan or placebo. Patients underwent repeated assessment of exercise tolerance, quality of life, central and regional hemodynamics, and neurohumoral and biochemical parameters over a period of 12 weeks., Results: Losartan treatment was well tolerated in terms of adverse events, heart rate, and blood pressure response, and there were no significant changes in serum creatinine or potassium. After 12 weeks of treatment, no significant differences were observed between the losartan and placebo groups in exercise tolerance, quality of life, central and regional hemodynamics, or neurohumoral parameters., Conclusions: In patients with mild to moderate heart failure already maximally treated with an ACE inhibitor, additional treatment with losartan is well tolerated, but we have not observed any significant improvement in exercise capacity, quality of life, central and regional hemodynamics, or neurohormones. Our data suggest that the combination of losartan with an ACE inhibitor does not offer any substantial advantages over treatment with an ACE inhibitor alone in these patients.

Objective: To measure health-related quality-of-life (HRQoL) in elderly symptomatic heart failure patients following treatment with an angiotensin II receptor antagonist (losartan) vs. an angiotensin-converting-enzyme (ACE) inhibitor (captopril)., Methods: Patients (age > or = 65 years) were randomised to losartan, titrated to 50 mg once daily, or captopril, titrated to 50 mg three times daily, as tolerated. Sickness Impact Profile (SIP) and Minnesota Living with Heart Failure (LIhFE) questionnaires were administered at baseline, weeks 12 and 48. Composite hypothesis testing of change in HRQoL from baseline for completers, and withdrawal for unfavourable events (death, clinical/laboratory adverse experience) was used to account for differential dropout rates., Results: In 203 patients completing the substudy (week 48), significant and comparable improvements in HRQoL from baseline were observed for both treatment groups (p < or = 0.001). Although there was a trend favouring losartan vs. captopril for the composite HRQoL endpoint (unadjusted p = 0.018, one-sided), this was not considered significant after adjusting for multiple testing. Significantly more captopril patients in the substudy subset withdrew for unfavourable reasons (19.6 vs. 10.9%, p = 0.038)., Conclusions: Significant improvements in HRQoL were observed in elderly patients with symptomatic heart failure treated with losartan and captopril long-term. A trend favouring losartan in the composite measure of drug tolerability/quality of life was not significant, but losartan was generally better tolerated than captopril in that significantly fewer losartan patients discontinued therapy.

Background: The AT1 receptor antagonists differ from the angiotensin converting enzyme inhibitors by achieving a more complete blockade of angiotensin II's actions and by not affecting bradykinin metabolism. There is little information on whether this causes clinically significant differences in haemodynamics, neurohormones and exercise tolerance in heart failure., Aims: To compare the effects of losartan and captopril upon central and regional haemodynamics, neurohormones and exercise capacity in heart failure., Methods: In a double-blind, randomised trial 18 patients aged > or =65 years with symptomatic heart failure were allocated to treatment with losartan (10 patients) or captopril (eight patients). Patients underwent assessment at baseline, after the first dose, at 12 weeks and at 24 weeks., Results: Systolic blood pressure fell by - 10.7% 1 h after captopril 6.25 mg (P = 0.007) and by - 4.8% 3 h after losartan 12.5 mg (P = 0.02). The blood pressure reduction was sustained with losartan at 12 and 24 weeks. Systemic vascular resistance fell acutely after captopril (-16.4%, P = 0.01). Captopril caused an acute and sustained rise in superior mesenteric artery blood flow (+ 22.9%, P = 0.04), and a slower rise in renal artery blood flow (+31.7%, P = 0.01). Losartan had no acute effects on regional haemodynamics but had increased superior mesenteric artery blood flow by 38.1% at 12 weeks (P = 0.02). There were no substantial differences between losartan and captopril, and no changes occurred in neurohormones or exercise capacity., Conclusion: No substantial differences were observed between losartan and captopril on central or regional haemodynamics, neurohormones or exercise capacity in elderly patients with stable symptomatic heart failure.

Aims: Mortality in patients with heart failure remains high and is difficult to predict. QT interval parameters on a 12-lead ECG have been shown to predict arrhythmic events in patients with a variety of myocardial diseases. There is some, but not consistent, evidence that QT interval parameters may act as predictors of mortality, in particular sudden death, in patients with heart failure. In an adequately powered prospective study we have studied QT interval parameters in patients with stable chronic heart failure in order to determine whether they are predictive of all-cause mortality or mode of death., Methods and Results: Five hundred and fifty-four ambulant outpatients with chronic heart failure were recruited. A 12-lead ECG, chest radiograph, echocardiogram, 24 h ambulatory electrocardiogram and serum for biochemical analysis were obtained at baseline. Patients were followed for 471+/-168 days. QT intervals were measured in all leads blinded to patient's characteristics and outcome, were corrected for heart rate, and the maximum QT intervals, and QT dispersion (range of QT intervals) were determined. The same parameters were determined for JT intervals. The primary end-point was all-cause mortality, secondary end-points were sudden cardiac death and death due to progressive heart failure. Multivariate analysis with the Cox's proportional hazards model was used to determine which variables were independently related to outcome. Four hundred and ninety-five patients had analysable ECGs at study entry and of these 71 died during follow-up. The heart rate corrected QT dispersion and maximum QT interval were significant univariate predictors of all-cause mortality (P=0.026 and <0.0001 respectively), and also of sudden death and progressive heart failure death, but were not related to outcome in the multivariate analysis. The independent predictors of all-cause mortality were cardiothoracic ratio (P=0.0003), creatinine (P=0.0009), heart rate (P=0.007), echocardiographically derived left ventricular end-diastolic dimension (P=0.007) and ventricular couplets on 24 h electrocardiographic monitoring (P=0.015)., Conclusion: In an adequately powered prospective study none of the QT or JT parameters were shown to be independent predictors of outcome in patients with mild to moderate congestive heart failure. These variables do not therefore add to the prognostic information which can be gained from simple radiographic, biochemical, echocardiographic and Holter data in this group of patients., (Copyright 1999 The European Society of Cardiology.)

Many clinical trials unintentionally include patients with a low risk of the trial endpoints. PRIME II (The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy) was a large international randomised double blind trial comparing the addition of ibopamine or placebo to the therapy of patients with advanced heart failure. The trial was stopped prematurely because ibopamine was associated with an increased fatality rate, but the protocol achieved its objective of including high-risk patients. Here we describe the protocol details that enabled patients with the desired degree of risk to be included. We also amplify our definition of mode of death. The PRIME II protocol was designed with the intention that patients in the placebo group would have an annual fatality rate of 20%. Since the study was to be conducted in some 200 centres in 13 European countries, the inclusion criteria had to be simple and flexible, allowing for different clinical practice. The inclusion criteria, together with the use of simple investigations (which did not have to include angiographic or radionuclide ventriculography) are described. The annual fatality rate in the placebo group was just over 20%. Six categories of mode of death were used, but while they were reasonably easy to apply they did not reveal the reason for the unexpected adverse effect of ibopamine. The inclusion and exclusion criteria used for PRIME II, and the definitions of mode of death, were effective. The PRIME II protocol can be used as a model for future heart failure studies.

Objective: To examine the relation between patterns of ventricular remodelling and haemodynamic and neurohormonal variables, at rest and during symptom limited exercise, in the year following acute myocardial infarction in patients not receiving angiotensin converting enzyme (ACE) inhibitors., Design: A prospective observational study., Patients: 65 patients recruited following hospital admission with a transmural anterior myocardial infarction., Methods: Central haemodynamics and neurohormonal activation at rest and during symptom limited treadmill exercise were measured at baseline before hospital discharge, one month later, and at three monthly intervals thereafter. PATIENTS were classified according to individual patterns of change in left ventricular end diastolic volumes at rest, assessed at each visit using transthoracic echocardiography., Results: In most patients (n = 43, 66%) ventricular volumes were unchanged or reduced. Mean (SEM) treadmill exercise capacity and peak exercise cardiac index increased at month 12 by 200 (24) seconds (p < 0.001 v baseline) and by 0.8 (0.4) l/min/m2 (p<0.05 v baseline), respectively, in this group. In patients with limited ventricular dilatation (n = 11, 17%) exercise capacity increased by 259 (52) seconds (p < 0.001 v baseline) and peak exercise cardiac index improved by 0.8 (0.7) l/min/m2 (NS). In the remaining 11 patients with progressive left ventricular dilatation, exercise capacity increased by 308 (53) seconds (p< 0. 001 v baseline) and peak exercise cardiac index similarly improved by 1.3 (0.7) l/min/m2 (NS). There were trends towards increased atrial natriuretic factor (ANF) secretion at rest and at peak exercise in this group., Conclusions: Ventricular dilatation after acute myocardial infarction is a heterogeneous process that is progressive in only a minority of patients. Compensatory mechanisms, including ANF release, appear capable of maintaining and improving exercise capacity in most patients for at least 12 months, even in those with a progressive increase in ventricular size.

Background: There has been conflicting evidence of the effect of angiotensin-converting enzyme (ACE) inhibitors on exercise tolerance. Meta-analysis of published results has suggested that a beneficial effect of ACE inhibitors is demonstrated if a trial design is adequate., Setting: Multicentre International Trial., Methods: In a double-blind, randomized, multicentre trial, 292 patients with moderate (New York Heart Association Grades II and III) heart failure were treated with trandolapril or placebo in addition to diuretics, and followed for 16 weeks. Exercise tolerance on a treadmill was assessed at baseline and after 4, 8, 12 and 16 weeks of treatment. Both a modified Bruce and a modified Naughton protocol were used., Results: Exercise tolerance improved in both treatment groups, with no significant benefit from trandolapril treatment., Conclusion: Trandolapril does not improve exercise tolerance as measured by treadmill testing.

Objectives: To compare the value of a series of cardiovascular measurements in patients with symptomatic disease receiving an effective treatment (rate responsive pacing)., Patients: 12 pacemaker dependent patients with VVIR units., Interventions: Single blind crossover between VVI and VVIR., Outcome Measures: Exercise capacity was assessed by treadmill tests (modified Bruce protocol and a fixed workload protocol) with respiratory gas analysis. Self paced corridor walk tests were also undertaken. Quality of life (QOL) was assessed by questionnaire. Daily activity was measured in the patients' homes using shoe and belt pedometers., Results: Treadmill tests and QOL questionnaires correctly identified the clinical benefit associated with VVIR. The modified Bruce protocol was superior to the fixed workload protocol as it was better tailored to the fairly well preserved exercise capacity of the patients. Symptom scores, but not walking times, were improved with VVIR during corridor walk tests. VVIR did not improve daily activity measured using either the belt or shoe pedometers., Conclusions: VVIR pacing improved some but not all measures of exercise capacity. This finding illustrates the difficulty of selecting an instrument to measure symptomatic improvement in clinical research; and raises the question, what is the best way of measuring exercise capacity?

Aims: To assess whether a domiciliary programme of specific inspiratory muscle training in stable chronic heart failure results in improvements in exercise tolerance or quality of life., Methods and Results: We conducted a randomized controlled trial of 8 weeks of inspiratory muscle training in 18 patients with stable chronic heart failure, using the Threshold trainer. Patients were randomized either to a training group inspiring for 30 min daily at 30% of maximum inspiratory mouth pressure, or to a control group of 'sham' training at 15% of maximum inspiratory mouth pressure. Sixteen of the 18 patients completed the study. Maximum inspiratory mouth pressure improved significantly in the training group compared with controls, by a mean (SD) of 25.4 (11.2) cmH2O (P=0.04). There were, however, no significant improvements in treadmill exercise time, corridor walk test time or quality of life scores in the trained group compared with controls., Conclusion: Despite achieving a significant increase in inspiratory muscle strength, this trial of simple domiciliary inspiratory muscle training using threshold loading at 30% of maximum inspiratory mouth pressure did not result in significant improvements in exercise tolerance or quality of life in patients with chronic heart failure.

Background: Cheyne-Stokes respiration disrupts sleep, leading to daytime somnolence and cognitive impairment. It is also an independent marker of increased mortality in heart failure. This study evaluated the effectiveness of oxygen therapy for Cheyne-Stokes respiration in heart failure., Methods: Eleven patients with stable heart failure and Cheyne-Stokes breathing were studies. Oxygen and air were administered for 4 weeks in a double-blind, cross-over study. Sleep and disordered breathing was assessed by polysomnography. Symptoms were assessed using the Epworth Sleepiness Scale, visual analogue and quality of lift scores. Cognitive function was assessed by neuropsychometric testing. Overnight urinary catecholamine excretion was used as a measure of sympathetic nerve activity., Results: Ninety-seven percent of apnoeas were central in origin. Oxygen therapy reduced the central apnoea rate (18.4 +/- 4.1 vs 3.8 +/- 2.1 per hour; p = 0.05) and periodic breathing time (33.6 +/- 7.4 vs 10.7 +/- 3.9% of actual sleep time; p = 0.003). Oxygen did not improve sleep quality, patient symptoms or cognitive failure. Oxygen reduced urinary noradrenaline excretion (8.3 +/- 1.5 vs 4.1 +/- 0.6 nmol.mmol-1 urinary creatinine; p = 0.03)., Conclusion: Oxygen stabilized sleep disordered breathing and reduced sympathetic activity in patients with heart failure and Cheyne-Stokes respiration. We were unable to demonstrate an effect on either patient symptoms or cognitive function.

Aims: To assess the effects of dietary creatine supplementation on skeletal muscle metabolism and endurance in patients with chronic heart failure., Methods: A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction was measured using handgrip dynanometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of maximum voluntary contraction or until exhaustion. Blood was taken at rest and 0 and 2 min after exercise for measurement of lactate and ammonia. After 30 min the procedure was repeated with fixed workloads of 7 kg, 14 kg and 21 kg. Patients were assigned to creatine 20 g daily or matching placebo for 5 days and returned after 6 days for repeat study., Results: Contractions (median (25th, 75th interquartiles)) until exhaustion at 75% of maximum voluntary contraction increased after creatine treatment (8 (6, 14) vs 14 (8, 17), P = 0.025) with no significant placebo effect. Ammonia per contraction at 75% maximum voluntary contraction (11.6 mumol/l/contraction (8.3, 15.7) vs 8.9 mumol/l/contraction (5.9, 10.8), P = 0.037) and lactate per contraction at 75% maximum voluntary contraction (0.32 mmol/l/contraction (0.28, 0.61) vs 0.27 mmol/l/contraction (0.19, 0.49), P = 0.07) fell after creatine but not after placebo., Conclusions: Creatine supplementation in chronic heart failure augments skeletal muscle endurance and attenuates the abnormal skeletal muscle metabolic response to exercise.

Objective: To determine the prevalence of sleep disordered breathing within a United Kingdom heart failure population., Subjects: 104 patients and 21 matched normal volunteers., Methods: Overnight home pulse oximetry with simultaneous ECG recording in the patient group; daytime sleepiness was assessed using the Epworth sleepiness scale (ESS); 41 patients underwent polysomnography to assess the validity of oximetry as a screening test for Cheyne-Stokes respiration., Results: Home oximetry was a good screening test for Cheyne-Stokes respiration (specificity 81%, sensitivity 87%). Patients with poorer New York Heart Association (NYHA) classes had higher sleepiness scores (p < 0.005). Twenty three patients had "abnormal" patterns of nocturnal desaturation suggestive of Cheyne-Stokes respiration. The mean (SEM) frequency of dips in Sao2 exceeding 4% was 10.3 (0.9) per hour in the patients and 4.8 (0.6) in normal controls (p < 0.005). Ejection fraction correlated negatively with dip frequency (r = -0.5, p < 0.005). The patient subgroup with > or = 15 dips/hour had a higher mean (SEM) NYHA class (3.0 (0.2) v 2.3 (0.1), p < 0.05), and experienced more ventricular ectopy (220 (76) v 78 (21) beats/hour, p < 0.05). There was no excess of serious arrhythmia., Conclusions: Nocturnal desaturation is common in patients with treated heart failure. Low ejection fraction was related to dip frequency. Lack of correlation between dips and ESS suggests that arousal from sleep is more important than hypoxia in the aetiology of daytime sleepiness in heart failure. Overnight oximetry is a useful screening test for Cheyne-Stokes respiration in patients with known heart failure.

Aim: Patients with heart failure have a reduced sensitivity to insulin's actions on glucose metabolism and a compensatory increase in endogenous plasma insulin levels. As insulin has a selective vasodilatory action in skeletal muscle, we have studied the association between insulin sensitivity and central and regional haemodynamics in patients with heart failure., Methods: Ten patients with stable symptomatic heart failure were studied. We used non-invasive techniques to measure cardiac output, forearm blood flow, superior mesenteric artery blood flow and right renal artery blood flow. Blood samples were assayed for noradrenaline, renin and atrial natriuretic peptide levels. Insulin sensitivity was assessed using the low dose short insulin tolerance test., Results: There was a significant inverse correlation between forearm blood flow and insulin sensitivity (r = -0.67, P = 0.03), patients with lesser degrees of insulin sensitivity having the greater forearm blood flows. There was no correlation with the other haemodynamic or neurohumoral parameters. Patients with greater insulin resistance tended to have higher circulating endogenous insulin levels, although this relationship did not reach statistical significance (r = -0.53, P = 0.12)., Conclusions: Insulin sensitivity appears to be an important determinant of skeletal muscle blood flow in heart failure. We speculate that this is secondary to the increased circulating endogenous insulin levels, and suggest that the therapeutic potential of exogenous insulin merits further investigation.

Objectives: We sought to assess the role of insulin in postprandial blood pressure regulation in the elderly., Background: Insulin is both a positive inotropic and chronotropic hormone that also vasodilates skeletal muscle vasculature. Insulin may thus mediate aspects of postprandial cardiovascular homeostasis., Methods: Ten healthy elderly subjects were studied in the fasting state on three separate days. After baseline supine hemodynamic and neurohumoral measurements were taken (cardiac output and superior mesenteric artery blood flow were measured using Doppler ultrasound, and calf blood flow was measured using venous occlusion plethysmography), subjects ate on one occasion a 2.5-MJ high carbohydrate meal and on the other two occasions, an isoenergetic high fat meal. One high fat meal was accompanied by an insulin infusion reproducing the plasma insulin profile seen after a high carbohydrate meal while maintaining the glycemic profile seen after a high fat meal alone. After meal ingestion, measurements were repeated every 20 min for 2 h., Results: After the three meals, there were similar increments in cardiac output and heart rate. After the high carbohydrate meal and high fat meal with insulin, mean arterial blood pressure fell by between 8 to 10 mm Hg, but did not change after the high fat meal. After the high carbohydrate meal and the high fat meal with insulin, calf vascular resistance did not change, whereas after the high fat meal, it increased by 15.5 +/- 4.4 U (mean +/- SEM)., Conclusions: Insulin contributes to the failure of calf vasoconstriction seen after a high carbohydrate meal. By this vasodepressor action, insulin is at least in part responsible for the fall in blood pressure after a high carbohydrate meal.

The cardiovascular (CV) responses to meal ingestion and orthostasis are well established. The effect of meal ingestion and meal composition on the CV responses to orthostasis are unknown. The effect of high carbohydrate (HC) and high fat (HF) meal ingestion on the CV responses to simulated orthostatic stress (using graded lower body subatmospheric pressure (LBSP)) was assessed in nine healthy young volunteers. Cardiac output (CO), forearm blood flow (FABF) heart rate (HR) and blood pressure (BP) were measured before and during LBSP while fasted and after eating HC and HF meals. Ingestion of both meals led to an increase in CO and HR. Both meals resulted in a fall in total peripheral resistance but only HC led to a significant fall in BP (p < 0.05). HF had no effect on the CV responses to LBSP, whereas HC resulted in attenuated FABF and forearm vascular resistance responses (p < 0.05). Thus, ingestion of an HC meal significantly attenuates the forearm vascular response to orthostatic stress and the hypotensive effect of orthostasis is additive to that occurring after an HC meal.

The role of calcium antagonists in patients with ischemic heart failure is currently unclear. We examined the effects of amlodipine on exercise capacity and central and regional hemodynamics in 32 patients with mild to moderate chronic heart failure in a single-center, double-blind, randomized placebo-controlled trial. All were taking at least 40 mg of furosemide daily with an angiotensin-converting enzyme inhibitor. Ischemic heart disease was the most common cause of heart failure, but no patient had symptom-limiting angina. Mean treadmill exercise capacity in patients taking amlodipine increased by 96 seconds (95% confidence interval -23 to 215) and 50 seconds (-34 to 135) in the placebo group; mean difference in change between treatments was 70 seconds (-90 to 233), p = 0.38. Active treatment with amlodipine did not affect self-paced corridor walking times. Similarly, there were no significant effects on cardiac output, oxygen uptake, heart rate, and mean arterial pressure at rest or during exercise. Calf and renal blood flow were also unchanged by treatment. The lack of significant effect demonstrated by these data suggests a limited role for amlodipine in patients with ischemic cardiomyopathy, although it may prove beneficial in those with nonischemic disease. More data are required before amlodipine can be recommended for all patients with chronic heart failure.

Patient referrals from general practice for suspected heart failure are increasing the demand for echocardiograms, many of which are normal. We investigated whether general practitioners could be more selective by referring only patients with abnormal electrocardiograms for echocardiography. The electrocardiograms of 200 patients attending a heart failure clinic were analysed by a consultant cardiologist and two general practitioners. All three assessors examined the electrocardiograms independently and unaware of the echocardiography results. The correlation between abnormal electrocardiograms and left ventricular systolic dysfunction on echocardiography was assessed, together with the concordance between the assessors in their electrocardiogram interpretations. One hundred and sixty-five patients had echocardiographic evidence of left ventricular systolic dysfunction. When interpreted by a cardiologist, the electrocardiogram had a sensitivity of 89.1% and a specificity of 45.7% in predicting left ventricular systolic dysfunction. The general practitioners' results were comparable to the cardiologist's. We estimate that using the electrocardiogram to select patients could reduce the number of open access echocardiograms performed for suspected heart failure by up to 43% but would miss 10% of those with significant left ventricular systolic dysfunction. We therefore do not recommend selecting patients for open access echocardiography on the basis of electrocardiographic abnormalities.

Symptom-limited, laboratory-based exercise tests are often used to define prognosis in patients with chronic heart failure, but they do not relate to measures of normal daily activity. Invasive measures of central hemodynamics similarly relate poorly to outcome. Pedometer scores of weekly walking are markedly reduced in patients with heart failure, but whether this less artificial measure of exercise capacity is important in predicting prognosis is not known. Eighty-four patients with chronic heart failure were followed for a mean of 710 days during which 44 died and 3 underwent cardiac transplantation. Symptom-limited treadmill exercise capacity using 2 different protocols did not predict survival, whereas reduced weekly pedometer scores were strong predictors of death (p < 0.001). Other variables that predicted death included resting cardiac output, arterial blood pressure, diuretic requirements, New York Heart Association class, increased bilirubin, and hyponatremia (all p < 0.01). Reduced levels of daily activity are strong predictors of death in chronic heart failure and appear more powerful than laboratory-based exercise tests. This type of assessment is valuable in identifying patients at high risk and provides an objective measure of incapacity during normal daily life. The exercise capacity of patients unable to exercise in the laboratory could also be assessed using this technique. This may prove invaluable in clinical and mortality trials.

We compared the effects of the orally active dopamine agonist ibopamine with the loop diuretic frusemide as first-line therapy in patients with mild congestive heart failure. Fourteen patients with New York Heart Association class II congestive heart failure were enrolled in a double-blind, cross-over study. After baseline measurements of clinical and symptomatic status, modified Bruce exercise time, high-level exercise time, corridor walk time, regional blood flow, pedometer scores, 24 h urine volume and sodium excretion and neurohumoural factors, patients were randomly allocated to receive either frusemide 40 mg o.d. or ibopamine 100 mg t.d.s. for 8 weeks. Assessments were performed at 2 weekly intervals. After 8 weeks, patients crossed over into the alternate treatment arm for a further 8 weeks, with further assessments performed every 2 weeks. There were four exacerbations of heart failure during ibopamine treatment and none during frusemide treatment. After 8 weeks of treatment, modified Bruce exercise time was 901 +/- 73 s with frusemide and 646 +/- 134 s with ibopamine (P < 0.05). Twenty-four hour urinary sodium excretion at weeks 2 and 4 (P < 0.05), and 24 h urinary volume at week 2 (P = 0.0001) were lower during ibopamine treatment. At week 8, supine (P = 0.076) and erect renin (P = 0.05) were lower with ibopamine treatment. In conclusion, ibopamine is ineffective as first line therapy for congestive heart failure, probably because of a lesser diuretic potency than frusemide.

Patients with heart failure are often inadequately investigated and treated in general practice. To improve the management of heart failure locally we initiated a specialist clinic in 1994. After its first 18 months, we audited the outcome of general practitioners' referrals to the clinic to examine its effectiveness in improving the diagnosis and treatment of heart failure. Eighty-five patients were referred with suspected heart failure. However, only 48% had echocardiographic evidence of left ventricular systolic dysfunction. Following referral, 80% of these patients were given a trial of angiotensin-converting enzyme inhibitors compared with 27% before referral. Six patients were receiving angiotensin-converting enzyme inhibitors unnecessarily, and five patients had significant structural cardiac disorders. Referral to a specialist clinic improved the accuracy of diagnosis and the number of patients on appropriate treatment. Greater use of open access echocardiography prior to referral might have allowed a more selective (and cost-effective) utilisation of the clinic.

Background: To determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of heart failure over angiotensin-converting-enzyme (ACE) inhibition with captopril, the ELITE study compared losartan with captopril in older heart-failure patients., Methods: We randomly assigned 722 ACE inhibitor naive patients (aged 65 years or more) with New York Heart Association (NYHA) class II-IV heart failure and ejection fractions of 40% or less to double-blind losartan (n = 352) titrated to 50 mg once daily or captopril (n = 370) titrated to 50 mg three times daily, for 48 weeks. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 26.5 mumol/L or more (> or = 0.3 mg/dL) on therapy; the secondary endpoint was the composite of death and/or hospital admission for heart failure; and other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina., Findings: The frequency of persisting increases in serum creatinine was the same in both groups (10.5%). Fewer losartan patients discontinued therapy for adverse experiences (12.2% vs 20.8% for captopril, p = 0.002). No losartan-treated patients discontinued due to cough compared with 14 in the captopril group. Death and/or hospital admission for heart failure was recorded in 9.4% of the losartan and 13.2% of the captopril patients (risk reduction 32% [95% CI -4% to + 55%], p = 0.075). This risk reduction was primarily due to a decrease in all-cause mortality (4.8% vs 8.7%; risk reduction 46% [95% CI 5-69%], p = 0.035). Admissions with heart failure were the same in both groups (5.7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22.2% vs 29.7%)., Interpretation: In this study of elderly heart-failure patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. A further trial, evaluating the effects of losartan and captopril on mortality and morbidity in a larger number of patients with heart failure, is in progress.