The importance of abnormalities of liver function tests in predicting mortality in chronic heart failure.

A number of simple clinical and laboratory variables were analysed in a group of patients with chronic heart failure to evaluate their prognostic significance. Five hundred and fifty-two patients were followed for a maximum of 13 years with a total exposure time to death or censored survival of 1148 years. Of the clinical variables, diuretic dose and NYHA class were related to mortality (P < 0.01), and ischaemic heart disease was associated with a worse prognosis than other aetiologies (P < 0.05). Of the laboratory variables, abnormalities of liver function tests including bilirubin (P < 0.01), aspartate transaminase (P < 0.005), gamma glutamyl transpeptidase (P < 0.005) and alkaline phosphatase (P < 0.01) were all related to mortality as was plasma urate (P < 0.01). Multivariate survival analysis of all variables showed aspartate transaminase (chi 2 17.36, P < 0.001) accounted for the greatest variance followed by serum bilirubin (chi 2 14.35, P < 0.005). Thus, abnormalities in liver function tests have prognostic importance in chronic heart failure.

The integrated response of the cardiovascular system to food.

To obtain information about the integrated response of the cardiovascular system to food, cardiac output and regional blood flow (superior mesenteric artery, renal artery and calf blood flow) were measured in 14 normal young healthy subjects after an overnight fast and following a standard 800-kcal meal. Results were compared with 8 subjects who remained fasted throughout the study. Cardiac output increased from a mean (SEM) fasting value of 4.8 (0.3) l/min to a peak after 30 min of 6.1 (0.5) l/min (p < 0.001). Superior mesenteric blood flow increased from a fasting value of 463 (45) to a peak of 854 (110) ml/min also after 30 min (p < 0.001). These changes were accompanied by a significant fall in both systemic vascular resistance and superior mesenteric vascular resistance (p < 0.001). Only at the 15-min postprandial measurements was there a significant relationship between the increase in cardiac output and superior mesenteric artery blood flow (r = 0.62, p = 0.02). Calf blood flow increased and vascular resistance fell postprandially (p < 0.05), but there was little change in right renal artery blood flow. There was an insignificant fall in renal vascular resistance. Heart rate increased from a resting value of 65 (3) to a peak of 77 (4) beats/min after 15 and 30 min (p < 0.001), diastolic blood pressure fell postprandially with little change in systolic blood pressure. These results suggest that in healthy young subjects the increase in gut blood flow is met by an increase in cardiac output, with little evidence of redirection from other vascular beds. The early postprandial increase in superior mesenteric blood flow may account for the increase in cardiac output, although the magnitude of the change is much greater for cardiac output than superior mesenteric artery blood flow.

Cardiovascular responses to high-fat and high-carbohydrate meals in young subjects.

We compared the cardiovascular, glucose, insulin, and catecholamine responses to high-fat (F) and high-carbohydrate (C) meals in healthy young subjects (mean age 23 yr, range 19-39). Cardiac output rose 30 min after C by 32% [95% confidence interval (CI) of the increase +0.32 to +1.64 l/min] and after F by 22% [95% CI +0.30 to +1.96 l/min; P = 0.03, analysis of variance (ANOVA)]. Superior mesenteric artery blood flow rose by 87% 15 min after C (95% CI +119 to +258 ml/min) and by 122% (95% CI +138 to +392 ml/min) 45 min after F, with significantly different patterns of response (interaction effect P less than 0.05, ANOVA). Calf blood flow fell and remained low for 60 min after F but only fell 15 min after C, with a return to fasting levels thereafter (interaction effect P less than 0.03, ANOVA). Thirty minutes postprandially the change of calf blood flow from baseline after C was significantly different than after F (95% CI of differences +0.1 to +2.04 ml.100 ml-1.min-1). Glucose, insulin, and norepinephrine levels increased more after C than after F. Thus there are different regional vascular responses to C and F despite similar cardiac output increases.

Post-prandial worsening of angina: all due to changes in cardiac output?

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.

Exercise capability in heart failure: is cardiac output important after all?

The exercise capability of 39 patients with severe chronic heart failure was assessed in several ways and compared with measurements of cardiac output. The relation between cardiac index and exercise tolerance measured on a treadmill was poor (r = 0.191, p = 0.245). However, exercise tolerance measured with a series of self-paced corridor walk tests showed moderate correlations with cardiac index (r = -0.404, p = 0.015 to r = -0.516, p = 0.001) and customary activity assessed by step counting correlated better with cardiac index (r = 0.537, p less than 0.001). Cardiac output therefore seems to be a factor determining patients' exercise capability when they choose their own walking speed but not when they undergo formal treadmill tests in the laboratory.

Exercise tolerance in patients with heart failure--how should it be measured?

The exercise capability of 12 patients with heart failure was investigated by a variety of different methods before and after treatment with the vasodilator flosequinan. Two treadmill protocols were used, a modified Bruce with incremental workloads and a fixed workload protocol. On placebo, mean exercise time was greater with the Bruce protocol, 526 (64) s, than with the fixed protocol, 359 (59) s, P less than 0.005. Flosequinan increased exercise time more with the fixed protocol, so after 5 weeks' treatment exercise time was the same with both protocols; 680 (64) s with the Bruce and 673 (147) s with the fixed protocol. When the results are expressed as work, the patients achieved less with the Bruce protocol, 7.8 (1.9) kJ, than with the fixed protocol 12.5 (1.5) kJ on placebo, P less than 0.01. After flosequinan, the respective values were 14.5 (2.8) and 25.3 (5.1) kJ. Flosequinan improved corridor walk test times but there was no relationship between this and either treadmill test. Pedometer scores of customary activity were unchanged by flosequinan and were not correlated with any other exercise test. Different methods of assessing exercise capability provide different measures of patients' incapacity.

Effects of enoximone in patients with heart failure uncontrolled by captopril and diuretics.

Ten patients with severe heart failure, symptomatic despite treatment with diuretics and captopril, completed a study of the effect of adding enoximone to their normal treatment. Enoximone or matching placebo was given for 4 weeks in randomized double-blind order following a single-blind placebo run-in period. Exercise capability was measured with two different treadmill protocols, a corridor walk test and by step-counting with body-worn pedometers. Cardiac output and limb blood flow were assessed non-invasively by measuring respiratory gases and by venous occlusion plethysmography. Measurements were made at rest and in response to treadmill exercise. The mean exercise tolerance measured using the modified Bruce treadmill protocol was increased from the placebo value (498 +/- 91 seconds) after both 2 weeks (573 +/- 94 seconds, P = 0.051) and 4 weeks of enoximone (572 +/- 100 seconds, P = 0.057). Enoximone increased exercise duration in fixed workload tests from the placebo value (252 +/- 75 seconds) after 2 weeks' treatment (431 +/- 98 seconds, P = 0.011) and after 4 weeks (381 +/- 85 seconds, (P = 0.01). The percentage improvement with the fixed workload test was greater than with the modified Bruce protocol at week 2 (P = 0.03) and at week 4 (P = 0.051). Enoximone increased the speed of walking 100 m at self-selected slow, normal and fast paces. It had little effect on customary activity of the patients. Enoximone increased cardiac output measured at rest and during submaximal exercise (P = 0.001). It also improved blood flow to the calf muscle at rest and after exercise (P = 0.01). Enoximone has a beneficial effect in chronic heart failure symptomatic despite treatment with diuretics and captopril. The magnitude of its effect, however, depends upon the technique used to assess it.

Effects of food on the central and peripheral haemodynamic response to upright exercise in normal volunteers.

The central and peripheral haemodynamic effects of a modest meal were investigated in healthy volunteers at rest and in response to submaximal exercise. The meal increased heart rate, cardiac output, oxygen consumption, carbon dioxide production, and minute ventilation at rest and during exercise. The effects of food were additive to those induced by the exercise. Food had no effect on limb blood flow and lowered total systemic vascular resistance suggesting that there were no compensatory changes in regional blood flow to help redirect blood to the gut. An increase in cardiac output, and therefore myocardial work, is the predominant cardiovascular response to eating and this may help explain the postprandial deterioration in symptoms of some patients with cardiovascular disorders.

Flosequinan in heart failure: acute haemodynamic and longer term symptomatic effects.

There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.