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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]

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.

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.

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.

Objective: To investigate abnormalities of skeletal muscle metabolism in patients with congestive heart failure., Setting: A university teaching hospital., Methods: 43 patients (22 New York Heart Association (NYHA) grade II, 21 grade III) and 10 controls were studied. A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction (MVC) was measured using handgrip dynamometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of MVC 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., Results: MVC (kg, mean (SEM)) was lower in patients than in controls (control 42.45 (2.3); NYHA II 34.13 (1.3), P = 0.003; NYHA III 33.13 (1.94), P = 0.008). Resting lactate (mmol/l) was higher in patients than controls (control 0.65 (0.06); NYHA II 0.84 (0.08), P = 0.13; NYHA III 1.18 (0.1), P = 0.002). Resting ammonia (mumol/l) was higher in NYHA III (65.7 (6.0)) than in NYHA II (48.0 (3.7), P = 0.016); no difference was found between controls (48.0 (7.1)) and patients. The overall lactate and ammonia response to exercise was greater in NYHA III than in NYHA II and controls (P < 0.05). At volitional exhaustion, peak lactate (mmol/l: NYHA III 3.31 (0.26); NYHA II 2.56 (0.16); controls 2.71 (0.22); P = 0.022 NYHA III v NYHA II) and ammonia (mumol/l: NYHA III) 126.4 (8.97); NYHA II 92.9 (7.23); controls 109 (16.3); P = 0.006 NYHA III v NYHA II) were higher in severe congestive heart failure., Conclusions: Skeletal muscle metabolism is abnormal at rest in congestive heart failure. During exercise, the degree of metabolic abnormality is related to the symptomatic status of the patient.

Objectives: This study aimed to explore the hemodynamic responses to ingestion of meals of different composition in patients with chronic stable angina and to assess the effect of these meals on time to onset of > 1-mm ST segment depression and limiting angina pectoris during exercise., Background: To our knowledge, no study has assessed the effect of meal composition and timing of exercise in patients with coronary artery disease., Methods: Fifteen patients with chronic stable angina visited our laboratory in the fasted state on three occasions. Measurements of cardiac output, heart rate and blood pressure were taken while patients were standing. A modified Bruce exercise test was then carried out, during which time to onset of > 1-mm ST segment depression and limiting chest pain were recorded. Patients then ate a 2.5-MJ high fat or high carbohydrate meal; on the third occasion, no meal was taken. At 30 min and 1 h after eating the meals, rest hemodynamic measurements and exercise tests were repeated., Results: The high fat meal did not affect exercise variables, whereas the high carbohydrate meal resulted in a reduction in time to onset of ST segment depression of 74.4 +/- 22.2 s (mean +/- SEM) during exercise at 30 min (p < 0.01), and at both 30 and 60 min after the high carbohydrate meal, limiting chest pain occurred 50 to 90 s earlier than when patients fasted (p < 0.01)., Conclusions: One hour after a high carbohydrate meal, the onset of angina during exercise occurs earlier than in the fasted state. Despite similar hemodynamic adjustments, a high fat meal does not affect exercise time.

Objective: To assess the significance of changes in respiratory muscle endurance in relation to respiratory and limb muscle strength in patients with mild to moderate chronic heart failure using a threshold loading technique., Subjects: 20 patients with chronic heart failure (17 male) aged 63.8 (SD 7.4) years and 10 healthy men aged 63.1 (5.6) years. Heart failure severity was New York Heart Association (NYHA) grade II (n = 11) and NYHA grade III/IV (n = 9)., Methods: Respiratory muscle strength was measured from mouth pressures during maximum inspiratory effort (MIP) at functional residual capacity (FRC) and limb muscle strength was measured using a hand grip dynamometer. Inspiratory muscle endurance was measured using a threshold loading technique. The total endurance duration, the maximum threshold pressure achieved (P-Max), and the inspiratory load (% ratio of P-Max/MIP) were recorded in all subjects., Results: Inspiratory muscles were weaker in patients with heart failure than in the controls [MIP 53.6 (16.5) v 70.9 (20.2) cm H2O, P < 0.05]. Hand grip strength was similar in both subject groups [31.6 (SD) v 36.1 (15.9) dynes]. Total endurance duration was significantly reduced in the patient group [494 (223) v 996 (267) s, P < 0.01], as was the maximal threshold pressure achieved [P-Max 18.5 (6.4) v 30.7 (6.6) cm H2O, P < 0.01]. When expressed as a percentage of MIP, P-Max was also lower in the patients [35.2 (11.8) v 44.8 (11.4)%, P < 0.05]. There was no significant correlation between any measure of endurance and limb muscle strength., Conclusions: Respiratory muscle endurance is reduced in patients with chronic heart failure. These changes probably reflect a generalised skeletal myopathy and provide further evidence of respiratory muscle dysfunction in patients with this disease. Respiratory muscle endurance needs now to be related to symptoms and the effects of treatment and respiratory muscle training should also be explored.

The proportion of patients reported to die suddenly or from progressive circulatory failure is not consistent among studies of heart failure. Lack of an adequate or consistent classification of how patients die contributes to the current confusion over the mode of death in heart failure. Defining how patients with heart failure die could be important in developing strategies to reduce the continuing high mortality associated with this condition. We identified 27 studies that reported 50 or more deaths among patients with heart failure to ascertain how death was classified. Definitions of sudden death appeared heterogeneous and the majority of studies failed to publish or make reference to how circulatory failure was defined. A framework for the classification of the mode of death has been developed in which clear separation of the activity and place at the time of death, cause of death, mode of death, and events prior to death is made (ACME: Activity, Cause, Mode and Event). This mode of classifying death has been successfully piloted in two mortality studies; AIRE and NETWORK. Classifying mortality in this way will help identify pathways leading to death and hence suggest therapies and strategies to reduce mortality in patients with heart failure, a group of patients whose prognosis remains poor.

Background: Several studies have suggested that the respiratory muscles are weak in patients with heart failure, but the aetiology and clinical relevance of this weakness are unclear. In order to see if respiratory muscle weakness in this context is part of a more generalised myopathic process, respiratory and limb muscle strength were compared in patients with heart failure. The relation between respiratory muscle strength, breathlessness on exercise, and exercise capacity was also examined., Methods: Twenty patients (three women) with New York Heart Association (NYHA) class II-IV heart failure of mean age 63 years were studied. Respiratory muscle strength was assessed using maximum inspiratory and expiratory mouth pressures (MIP and MEP) and transdiaphragmatic pressure during sniffs (sniff PDI). These parameters were compared with cardiac output (indirect Fick) and with limb muscle strength as assessed by grip strength. The patients also performed two exercise tests during which they rated their breathlessness on a Borg scale., Results: Mean (SD) cardiac index was 2.2 (0.4) l/min/m2. MIP and MEP were 66 (27) and 99 (29) cm H2O respectively. Sniff PDI was 103 (21) cm H2O and was positively correlated with grip strength and cardiac output (Spearman rank correlation coefficients 0.527 and 0.451, respectively). None of the indices of respiratory muscle strength were related to exercise time or breathlessness during exercise., Conclusions: The respiratory muscles are weak in patients with heart failure. This weakness reflects a more generalised myopathic process, possibly related to reduced cardiac output. However, respiratory muscle weakness does not appear to be an important factor in the aetiology of breathlessness on exercise.

Objective: To determine how many lives would be saved if patients were routinely treated with ACE inhibitors after myocardial infarction according to the criteria of four recent major clinical trials, and to estimate the costs and benefits of these approaches., Design: Retrospective survey., Setting: The Nottingham Health District., Patients: Data from 7855 patients admitted between 1989 and 1990 were combined and the selection criteria of four major clinical trials (AIRE, SAVE, GISSI-3, and ISIS-4) were applied., Results: Of the patients admitted in Nottingham with confirmed myocardial infarcts 39% were eligible for AIRE and 8% for SAVE. In patients with suspected myocardial infarction as defined by the major trials, 60% would have been eligible for GISSI-3 and 63% for ISIS-4. Treating appropriate patients in accordance with these trials would have saved 20 (AIRE), 3 (SAVE), 4 (GISSI-3) and 5 (ISIS-4) lives each year in Nottingham at a drug cost of 5400 pounds, 33 pounds 791, 2730 pounds, and 4116 pounds per life per year saved respectively., Conclusions: Short-term treatment with ACE inhibition appears to be cheaper but such an approach would save fewer lives. The AIRE study is the most applicable to current clinical practice but ACE inhibitors should be offered routinely to patients satisfying the criteria of any of the four major clinical trials.

Background: The pathogenesis of dyspnoea in patients with chronic heart failure is poorly understood. Static lung compliance is reduced in chronic heart failure. The relation between static lung compliance and exercise capacity and dyspnoea in chronic heart failure has been investigated., Methods: Static lung compliance was calculated from expiratory pressure-volume curves in 18 patients with chronic heart failure (three women, mean age 62 years). Catheter mounted pressure transducers were used to measure changes in oesophageal pressure. Changes in lung volume were determined by integrating flow at the mouth, measured by a pneumotachograph. New York Heart Association (NYHA) class for dyspnoea was determined by a single observer. Patients underwent treadmill exercise to symptom limited maximum using staged and fixed rate protocols. Borg ratings for dyspnoea at submaximal exercise were measured., Results: Static lung compliance, whether expressed as % total lung capacity (TLC)/cm H2O or % predicted TLC/cm H2O, was unrelated to NYHA class. Similarly, there was no relation between static lung compliance and exercise capacity with either protocol or with Borg ratings for dyspnoea at submaximal exercise, with the exception of that measured after 11 minutes of the staged protocol., Conclusions: Static lung compliance at rest has no relation with treadmill exercise capacity in chronic heart failure, and its relation with measures of dyspnoea is variable. No role for lung elasticity in determining the symptomatology of chronic heart failure was found.

Objectives: To determine the effects of captopril and oxygen on sleep quality in patients with mild to moderate cardiac failure., Design: An open observational study., Patients: 12 patients with New York Heart Association class II-III heart failure were studied at baseline. 9 of these patients were then examined at the end of 1 month of treatment with captopril; 9 of the patients were separately assessed during a single night of supplementary oxygen., Main Outcome Measures: Sleep patterns by polysomnography, overnight oximetry, and subjective sleep assessment using visual analogue scores., Results: Abnormal sleep was present in all baseline studies. Complete polysomnograms after treatment with captopril were obtained in 8 patients. Light sleep (stages 1 and 2) was reduced (mean (SEM) 61%(8)% to 48%(6)% actual sleep time, P < 0.05) but slow wave (stages 3 and 4) and REM (rapid eye movement) sleep increased (25%(6)% to 31%(5)%, 14%(2)% to 21%(5)% actual sleep time, P < 0.05). Apnoeic episodes (242(59) to 118(30), P < 0.05), desaturation events (171(60) to 73(37), P < 0.05), and arousals (33(5) to 18(3) P < 0.01) were reduced. Visual analogue scores of sleep quality increased 49(5) to 69(5), P < 0.01). Complete polysomnograms were obtained in 7 patients treated with oxygen. Light sleep duration was reduced (55% (7)% to 42%(5)% actual sleep time, P < 0.05) and slow wave sleep increased (30%(5)% to 38%(6)% actual sleep time, P < 0.05). REM sleep duration was not significantly different. Total arousals (33(6)% to 20(2) P < 0.05), desaturation events (140(33) to 38(10), P < 0.01), and apnoeic episodes (212(53) to 157(33), P < 0.05) were reduced. Visual analogue scores of sleep quality were unchanged., Conclusions: Captopril and oxygen may improve sleep quality and reduce nocturnal desaturation in patients with mild to moderate cardiac failure. Improved sleep quality could explain the reduction in daytime symptoms seen after treatment in patients with chronic heart failure.

Objectives: To determine the effects of enoximone on mortality and quality of life in patients with severe end stage heart failure., Design: A randomised, double blind, placebo controlled trial of the addition of enoximone to conventional treatment. Planned minimum follow up of one year., Setting: District general hospitals and cardiological referral centres in the United Kingdom., Patients: Planned 200 patients with severe, symptomatic heart failure despite treatment with diuretics and where appropriate and tolerated angiotensin converting enzyme inhibitors and digoxin., Results: The study was ended early by the ethics committee after 151 patients had been recruited because of an excess mortality in the enoximone group: 27 deaths compared with 18 in the placebo group (P < 0.05). Quality of life measured with a disease specific questionnaire showed a clinically significant improvement at week 2 with a mean increase score of 0.48 in the enoximone treated patients compared with 0.14 in those receiving placebo (P = 0.0086). With the Nottingham health profile questionnaire the physical mobility score was improved after three months in the enoximone group, median 21.3 compared with 41.8 in the placebo group (P = 0.008)., Conclusions: In patients with severe heart failure who remain incapacitated despite conventional treatment enoximone reduced survival but had a beneficial effect on the quality of life. Drugs that improve symptoms in severe end stage heart failure should not be discarded lightly.

We describe the results of two placebo-controlled trials (MIL-1077 and MIL-1078) designed to evaluate the clinical efficacy of oral milrinone administered together with converting enzyme inhibitors to patients with congestive heart failure. Although these trials were terminated prematurely, they provide the only controlled data regarding the effect of oral milrinone on exercise capacity in patients receiving converting enzyme inhibitors. Of the 254 patients randomized, 140 completed one of the trials or reached an end point and are the basis of this report. In both trials, there was a clear trend for an increase in exercise capacity in the milrinone-treated patients (+26 +/- 8% vs. +5 +/- 7% in MIL-1077 and +11 +/- 5% vs. +2 +/- 4% in MIL-1078). Symptoms of congestive heart failure were decreased in one trial but not the other. Quality of life, as assessed by a questionnaire, was not effected in either trial. There was an increased incidence of adverse events in milrinone-treated patients. Adverse events related primarily to hypotension and vasodilation led to discontinuation of drug in 18 milrinone-treated patients vs. 1 placebo-treated patient. Milrinone had little or no proarrhythmic effect and cardiovascular deaths were distributed equally between the milrinone and placebo groups. These data suggest that when used in combination with a converting enzyme inhibitor, oral milrinone improves exercise capacity but is associated with a high incidence of adverse events that appear to be related to excessive vasodilation.

Background: Transdiaphragmatic pressure (sniff PDI) during maximal sniffs is a useful clinical test of inspiratory muscle function. Although a normal range has been established for sniff PDI using air filled balloons, no comparable data are available for catheter mounted pressure transducers., Methods: Using a single catheter with two pressure transducers 15 cm apart, oesophageal and gastric pressures were recorded in 50 normal volunteers (25 women), five of each sex from each decade between the third and seventh decades of life. Each subject performed 10 maximal sniffs at functional residual capacity., Results: Mean (SD) sniff PDI was 149 (32) cm H2O in men and 127 (22) cm H2O in women. The lower limits of normal for sniff PDI (mean -1.96 x SD) after logarithmic transformation of the data were 95 and 78 cm H2O in men and women respectively., Conclusions: With this technique transdiaphragmatic pressure can be measured using a single catheter which can easily be cleaned and reused. The values for sniff PDI are similar to those recorded previously with air filled balloons, suggesting that the method of recording pressure does not significantly affect the values obtained.

Background: In patients with chronic heart failure there is no relation between cardiac output and symptom limited exercise tolerance measured on a bicycle or treadmill. Furthermore, the increase in cardiac output in response to treatment may not be matched by a similar increase in exercise tolerance. More important in determining exercise capability is blood flow to skeletal muscle. This implies that the reduction in skeletal muscle blood flow is not directly proportional to the reduction in cardiac output and that there are regional differences in blood flow in patients with heart failure., Methods: Cardiac output and regional blood flow measured in 30 patients with chronic heart failure were compared with values obtained from 10 healthy controls. Measurements were made at rest and in response to treadmill exercise and were all made non-invasively., Results: Cardiac output was lower in the patients at rest and during exercise. Blood flow in the superior mesenteric and renal arteries was also lower in the patients and represented a different proportion of cardiac output than in the controls. In response to exercise the increase in blood flow to the calf and therefore to skeletal muscle, was reduced in the patients. In the patients there was no correlation between resting cardiac output and blood flow in the superior mesenteric artery, renal artery, or calf., Conclusions: Because blood flow to skeletal muscle and to the kidneys is likely to be important in determining patients' symptoms this factor may explain why central haemodynamic variables do not correlate with the exercise tolerance in patients with chronic heart failure.

Background: The precise mechanism leading to the post-prandial worsening of angina has yet to be adequately defined. It has been attributed to an increase in double product but is perhaps more likely to be related to an increase in cardiac output after food. This study was designed to evaluate the effects of food on patients' exercise tolerance and compare these with changes in haemodynamic variables., Methods: 23 patients with chronic stable angina who had post-prandial worsening of their angina were studied. The patients were evaluated on two occasions and at each visit they underwent two symptom limited treadmill exercise tests. They remained fasting on the first visit and were given a 1400 kcal meal 60 minutes before the second exercise test on the second visit. Time to onset of 1 mm ST segment depression, heart rate, systemic arterial blood pressure, and cardiac output were measured at rest and during exercise., Results: There were no differences in any of the variables during the two exercise tests on the day the patients remained fasting. After the meal exercise tolerance fell significantly by 136 seconds and the stage at which 1 mm ST segment depression was first seen was also significantly reduced. Resting cardiac output increased significantly by 0.86 1/min with the patients sitting and by 0.89 1/min standing. The exercise times after food were significantly related to cardiac output even when fasting times were taken into account. Resting heart rate increased significantly by 8.3 beats per minute sitting and 10.4 beats per minute standing. There was little change in blood pressure and no evidence that the double product predicted the post-prandial exercise time., Conclusions: Worsening of angina was related to the increase in cardiac output after a meal and successful treatment will depend upon the prevention of this increase.