A. J. Cowley

Relation of daily activity levels in patients with chronic heart failure to long-term prognosis.

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.

The effect of lorcainide on arrhythmias and survival in patients with acute myocardial infarction: an example of publication bias

Ninety-five patients with suspected acute myocardial infarction were randomly allocated on admission to hospital on a double blind basis to treatment with lorcainide, a Class 1C anti-arrhythmic drug, or matching placebo. Treatment was continued for 6 weeks. Twenty-four-hour ECG tape recordings were made immediately on admission, on the sixth or seventh day after admission, and again just before the end of the treatment period. Lorcainide was shown to be an effective anti-arrhythmic agent. The study was not designed to evaluate the effect of lorcainide on survival, but there were nine deaths among the 49 patients treated with lorcainide compared with only one in the patients given placebo. These findings are consistent with the results of the First and Second Cardiac Arrhythmia Suppression trials (CAST and CAST-II). This study was carried out in 1980 but was not published at the time: it now provides an interesting example of publication bias.

Sleep‐disordered breathing in a general heart failure population: relationships to neurohumoral activation and subjective symptoms

The aim of this study was to determine the prevalence of sleep‐related breathing disorders (SDB) in a UK general heart failure (HF) population, and assess its impact on neurohumoral markers and symptoms of sleepiness and quality of life. Eighty‐four ambulatory patients (72 male, mean (SD) age 68.6 (10) yrs) attending UK HF clinics underwent an overnight recording of respiratory impedance, SaO2 and heart rate using a portable monitor (Nexan). Brain natriuretic peptide (BNP) and urinary catecholamines were measured. Subjective sleepiness and the impairment in quality of life were assessed (Epworth Sleepiness Scale (ESS), SF‐36 Health Performance Score). SDB was classified using the Apnoea/Hypopnoea Index (AHI). The prevalence of SDB (AHIu2003>u200315 eventsu2003h−1) was 24%, increasing from 15% in mild‐to‐moderate HF to 39% in severe HF. Patients with SDB had significantly higher levels of BNP and noradrenaline than those without SDB (mean (SD) BNP: 187 (119) versus 73 (98) pgu2003mL−1, Pu2003=u20030.02; noradrenaline: 309 (183) versus 225 (148) nmol/24u2003h, Pu2003=u20030.05). There was no significant difference in reported sleepiness or in any domain of SF‐36, between groups with and without SDB (ESS: 7.8 (4.7) versus 7.5 (3.6), Pu2003=u20030.87). In summary, in a general HF clinic population, the prevalence of SDB increased with the severity of HF. Patients with SDB had higher activation of a neurohumoral marker and more severe HF. Unlike obstructive sleep apnoea, SDB in HF had little discernible effect on sleepiness or quality of life as measured by standard subjective scales.

Depressor Action of Insulin on Skeletal Muscle Vasculature: A Novel Mechanism for Postprandial Hypotension in the Elderly

OBJECTIVESnWe sought to assess the role of insulin in postprandial blood pressure regulation in the elderly.nnnBACKGROUNDnInsulin is both a positive inotropic and chronotropic hormone that also vasodilates skeletal muscle vasculature. Insulin may thus mediate aspects of postprandial cardiovascular homeostasis.nnnMETHODSnTen 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.nnnRESULTSnAfter 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).nnnCONCLUSIONSnInsulin 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.

Reduced customary activity in chronic heart failure: assessment with a new shoe-mounted pedometer

Although many methods exist to assess the degree of incapacity of patients with chronic heart failure during normal daily activities, all have their limitations. In this study we describe a new shoe-mounted pedometer and compare it with body worn pedometers in normal volunteers and in patients with chronic heart failure. Ten young normal healthy volunteers participated in a comparison of the new shoe-mounted device with body born pedometers and counting a direct footfall. Seventeen patients with chronic heart failure and 10 aged-matched healthy elderly subjects participated in a comparison of both pedometers over 7 days. In the young volunteers the shoe-mounted pedometers were more accurate than the body-borne devices. With both pedometers the patients with chronic heart failure had a reduced level of activity compared with the normal volunteers over the 1 week period (P = 0.01). In both the patients and volunteers the shoe-mounted device recorded a higher score than the body borne pedometers (P < 0.01). The electronic shoe mounted pedometers are a more accurate way of assessing customary activity. In patients with chronic heart failure customary activity is substantially reduced compared with fit healthy elderly subjects.

Haemodynamic and hormonal response to a stream of cooled air

Many patients with angina note that their symptoms deteriorate in cold weather, although the precise physiological mechanism that explains this remains unclear. Exposure of the face to cool winds may be a contributory factor. The cardiovascular and hormonal response to a localised stream of room (22°C) and cold (4°C) air during submaximal treadmill exercise was therefore studied in nine normal subjects. Cardiac output and respiratory gases were measured with a mass spectrometer, using the indirect Fick principle. Blood samples were taken for plasma noradrenaline. A localised stream of air at 5 m · s−1 produced significant cardiovascular effects at rest, some of which persisted during exercise. In response to cold air, stroke volume, cardiac output, blood pressure and oxygen uptake increased (allP < 0.05). There was a trend towards a reduction in heart rate at rest and increase in plasma noradrenaline. Room air caused a reduction in blood pressure (P = 0.01) but stroke volumes and oxygen uptake were unchanged. The results of this study demonstrate significant cardiovascular effects of a cooled air facial stimulus at rest and during exercise. They may, in part, explain the effects of cold winds on patients with angina.

Clinical efficacy of flosequinan in heart failure

The effects of the new arterial and venous vasodilator flosequinan have been evaluated in a variety of ways in different groups of patients with chronic heart failure. Flosequinan improved the central hemodynamic effects of heart failure in one group, with benefits still apparent up to 24 hours after a single oral dose. In another group it also improved calf blood flow and, therefore, blood flow to skeletal muscle. Also, using a number of different tests, it improved the exercise performance of the patients. In a further group the improvement in exercise tolerance produced was similar to that of captopril. Flosequinan has the necessary properties of a drug that is likely to be of benefit in the treatment of patients with chronic heart failure.

Comparison of the effects of captopril and enoximone in patients with severe heart failure: a placebo controlled double-blind study

The effects of enoximone, a new cyclic adenosine monophosphate phosphodiesterase inhibitor, were compared with those of captopril in a double-blind study in a group of 10 patients with severe heart failure. Four weeks treatment with enoximone improved symptom-limited exercise tolerance from a mean value of 11.33 to 13.36 minutes (P less than 0.05) and 4 weeks of captopril treatment from 11.01 to 13.92 minutes (P less than 0.05). Four of the patients had a greater exercise tolerance taking enoximone, the remaining 6 while taking captopril. Both drugs reduced perceived exertion during submaximal exercise. Minute ventilation measured at rest and during submaximal exercise was also reduced by both drugs. Resting and post exercise calf blood flow was increased to a similar extent with captopril (P less than 0.03) and enoximone (P less than 0.005). There was no difference in calf blood flow and calf vascular resistance between the drugs suggesting that the peripheral haemodynamic effects of enoximone are due to peripheral vasodilatation. Enoximone is a useful drug for the treatment of patients with severe heart failure.

Breathlessness and exercise capacity in heart failure: the role of bronchial obstruction and responsiveness

The cause of the breathlessness and reduced exercise capacity that occur in patients with chronic heart failure remains obscure. We examined the hypothesis that airway obstruction and bronchial hyper-responsiveness, which are recognised features of chronic heart failure, might contribute to the breathlessness and reduced exercise capacity in this condition. We studied 37 patients (7 female) with chronic heart failure, of mean age 61 years. Each patient underwent: (i) lung function testing with spirometry and expiratory flow volume loops. (ii) Measurement of bronchial responsiveness to methacholine. (iii) Symptom-limited treadmill exercise capacity using both incremental and fixed workload protocols, with measurement of Borg scores for breathlessness. Lung function was not significantly related to either exercise time, or Borg symptom scores in either exercise protocol. Bronchial hyper-responsiveness to methacholine was demonstrated in 12 patients. Exercise time did not correlate with the degree of bronchial hyper-responsiveness in these 12 patients. Group mean exercise time and Borg scores were not significantly different in these 12 patients when compared to the 25 patients in whom bronchial hyper-responsiveness was not found. We conclude that airway obstruction and bronchial hyper-responsiveness are not likely to be important determinants of reduced exercise capacity and breathlessness in chronic heart failure.

Placebo-controlled trial of flosequinan in moderate heart failure. The possible importance of aetiology and method of analysis in the interpretation of the results of heart failure trials

One hundred-thirty five patients with moderate heart failure, recruited from 18 centres, were included in a double blind, placebo controlled study to evaluate the effects of flosequinan on symptom limited tread-mill exercise tolerance. Fifteen patients in the placebo group were withdrawn from the study compared with 14 from the group given flosequinan. New York Heart Association classification was improved at week 16 in the flosequinan group relative to those randomised to placebo (P < 0.01). Depending how the other results are analysed flosequinan either appeared to have no effect on symptom limited exercise tolerance in those who completed the study; a suggestion of superiority if an analysis at endpoint is used (P = 0.09), or, if a covariate analysis at endpoint is used, then a significant improvement can be demonstrated (P = 0.04). Subset analysis suggests that the aetiology of the heart failure and the dose of diuretics used might have a major effect on the response to treatment. The best way of analysing clinical trials in heart failure is not clear as the results can be profoundly influenced by the way data from withdrawn patients are handled. The aetiology and diuretic requirement of patients may influence their response to treatment.