Differences between acute and long-term metabolic and endocrine effects of oral beta-adrenoceptor agonist therapy with pirbuterol for cardiac failure.

The metabolic, hormonal and haemodynamic effects of oral pirbuterol, a new beta 2-adrenoceptor agonist, were studied acutely (n = 19) and after 3 months treatment (n = 11) in patients with severe heart failure receiving chronic frusemide therapy. In the acute study fasted patients (n = 10) showed reductions in plasma K+ (P less than 0.005) and cortisol (P less than 0.01) and increases in plasma glucose (P less than 0.005), insulin (P less than 0.01), lactate (P less than 0.005) and pyruvate (P less than 0.0025). These acute changes were less in unfasted subjects (n = 9). Maximal increase in stroke volume occurred at approximately half the plasma pirbuterol concentration required for maximal effect on plasma insulin. Treatment with pirbuterol for 3 months was associated with sustained increases in stroke volume and fasting plasma glucose and insulin, but there was loss of all other acute metabolic effects. Despite concurrent frusemide and digoxin therapy acute hypokalaemia caused no adverse effects. Hypokalaemia did not occur with chronic pirbuterol administration.

Captopril in a case of severe congestive heart failure and peripheral vascular disease.

A case of chronic congestive cardiac failure and peripheral vascular disease due to thromboembolism was treated with captopril. Marked improvement was noted in the cardiac status and peripheral vascular lesion both acutely and in the long-term follow-up.

Cardiac arrhythmias following acute myocardial infarction: associations with the serum potassium level and prior diuretic therapy.

The relationship between the initial serum potassium level and the incidence of cardiac arrhythmias following myocardial infarction has been reviewed in a coronary care unit setting. The incidence of arrhythmias in general, and ventricular fibrillation, ventricular tachycardia and frequent ventricular ectopic beats in particular, were inversely related to the initial serum potassium level. Hyperkalaemia was also significantly associated with ventricular fibrillation and ventricular tachycardia. Hypokalaemia was significantly more common in patients previously treated with diuretics, though most patients with hypokalaemia had not been so treated. The occurrence of an acute hypokalaemic syndrome, independent of, but exacerbated by, diuretic therapy, is further supported by these results.

Symptoms, haemodynamics, and exercise capacity during long term treatment of chronic heart failure. Experience with pirbuterol.

An open study of long term treatment with an oral beta 2 agonist (pirbuterol 20 mg three times daily) was undertaken in 63 patients with severe chronic heart failure. During three months of treatment 20 (32%) patients died, of whom 16 were taking the drug at the time of death. Mortality was related to initial functional class (New York Heart Association classification: 23% in grade III and 75% in grade IV). Concomitant treatment with digoxin did not affect mortality. The drug was well tolerated by most patients but unwanted side effects necessitated withdrawal of the drug in six (10%). Thirty-five patients were continuing to take the drug after three months, of whom 22 reported symptomatic improvement and only four deterioration. There was a relation between symptomatic improvement and increase in exercise capacity. At initial haemodynamic assessment a single dose of pirbuterol increased the cardiac index by 34% and the stroke index by 21%. Left ventricular filling pressure fell by 23% and systemic vascular resistance by 22%. Haemodynamic reassessment after three months of continuous treatment in 29 patients showed maintained improvement in the group as a whole, although individual variation was considerable. There was no apparent relation between haemodynamic improvement and improvement in exercise duration and symptoms. Severe heart failure has a poor prognosis. Identification of those patients who may derive benefit from treatment with a particular drug is not yet possible.

Acute haemodynamic comparison of amrinone and pirbuterol in chronic heart failure. Additional effects of isosorbide dinitrate.

A randomised, within patient comparison was made in patients with severe chronic heart failure, to study the acute haemodynamic effects of oral agents which have inotropic and vasodilator properties. A non-glycosidic non-adrenergic positive inotropic agent with vasodilator properties (amrinone) was compared with a beta-agonist which has vasodilator and positive inotropic effects (pirbuterol). To assess whether combined treatment with a venodilator might be advantageous, the effect of adding isosorbide dinitrate was studied. Oral amrinone or pirbuterol were given in random order to each of 13 patients, on successive days, and oral isosorbide dinitrate was added after two-and-a-half hours. Control values before amrinone or pirbuterol were similar, and both drugs increased cardiac index while reducing left ventricular filling pressure, right atrial pressure, and systemic vascular resistance. Heart rate and blood pressure were unchanged. The magnitude of the changes caused by amrinone and pirbuterol were not significantly different. The addition of isosorbide dinitrate caused further falls in left ventricular filling pressure and right atrial pressures, and a fall in heart rate with each drug. Other measurements remained unchanged. Although amrinone and pirbuterol have different pharmacological properties, their acute haemodynamic effects in patients with chronic heart failure are indistinguishable.

Effects of dazoxiben on exercise performance in chronic stable angina.

1 We have performed a double-blind, randomized, 7-d cross-over study of the thromboxane synthetase inhibitor dazoxiben (UK 37248) in 20 patients with stable coronary heart disease. 2 All patients had a history of exertional angina of greater than two years duration and no patient had suffered a myocardial infarction in the preceding twelve months. 3 All patients had a positive exercise stress test for myocardial ischaemia and 15 had undergone coronary angiography. All these patients had a 50% narrowing in at least one vessel. 4 All patients were on conventional anti-anginal medication and the doses of their various therapies remained unchanged in the three months prior to and during the study period. 5 Therapy with dazoxiben 200 mg four times daily produced no alteration in the subjective or objective features of angina in these patients. There was no alteration in angina attack rate, glyceryl trinitrate consumption or duration of treadmill exercise. 6 Dazoxiben produced a highly significant reduction in both the resting and the post-exercise levels of serum thromboxane B2 levels, although there was no significant difference between the pre-exercise and post-exercise values. 7 Dazoxiben is an effective inhibitor of the synthesis of thromboxane but it has no effect on the subjective or objective features of stable coronary disease. This would suggest that the production of thromboxane and the development of circulating platelet aggregates play no part in the mechanism of angina in patients with stable coronary heart disease.

The relationship between serum potassium and cardiac arrhythmias following cardiac infarction in patients aged over 65 years.

A retrospective analysis was performed of 405 patients, over the age of 65 years, who had been admitted with proven myocardial infarction to a coronary care unit, to investigate the relationship between the serum potassium level on admission and the incidence of cardiac arrhythmias. On admission, 173 (42.7%) patients had a serum potassium of less than 4.0 mmol/l. During the first 24 hours in hospital, 57% of all patients exhibited a disturbance of cardiac rhythm. The incidence of total arrhythmias was independent of the initial serum potassium level, but the mortality rate was 46.2% in those patients with a serum potassium less than 4.0 mmol/l while it was 34.5% in those with a potassium of 4.0 mmol/l or greater. Twelve patients with a serum potassium less than 4.0 mmol/l experienced at least one episode of ventricular fibrillation (6.9%), but only 1 patient with a serum potassium of 4.0 mmol/l or greater had this arrhythmia. The difference in incidence of this arrhythmia was highly significant (p less than 0.001). No patient who experienced ventricular fibrillation was on existing cardiac medication with either a diuretic, beta-adrenoreceptor blocking drug or digoxin. There was no significant difference in the occurrence of other cardiac arrhythmias between low and normal serum potassium groups.

Effects of verapamil on exercise performance in chronic angina pectoris.

We have studied the effects of chronic oral verapamil therapy on exercise performance in 26 patients with arteriographically proven coronary disease and positive exercise stress tests. Maximal, multistage treadmill exercise tests were performed before and after 2, 4, and 8 weeks therapy with verapamil 120 mg t.i.d. The time to angina and the distance walked increased from 279 to 452 sec and from 255 to 443 meters respectively. The frequency of anginal attacks decreased from 24 to 9 per week after 8 wk treatment while the nitroglycerin consumption decreased from 20 to 8 tablets per week. Functional aerobic impairment improved from 42.7% to 29.3% whilst there was no change in pressure-rate product, cumulative ST segment depression or EEV1/FVC ratios.

Treatment of chronic heart failure with pirbuterol: acute haemodynamic responses.

Fifty-nine patients with severe chronic heart failure were given pirbuterol, a beta agonist with vasodilator and positive inotropic properties. The acute haemodynamic responses to both single (20 patients) and incremental doses (39 patients) were measured. Pirbuterol increased cardiac index and reduced left ventricular filling pressure and systemic vascular resistance with only small changes in heart rate and blood pressure. Maximal effects were observed at an average of 170 minutes after a single oral dose of pirbuterol. In the incremental dose studies the plasma pirbuterol concentration was found to increase with increasing doses and was related to the magnitude of the haemodynamic response. Pirbuterol was well tolerated, and no drug-related side effects were recorded. Oral pirbuterol clearly improved pump performance in these patients, the haemodynamic changes being consistent with vasodilatation as the dominant mechanism rather than a direct inotropic effect.

Haemodynamic effects of prazosin in CHF.

The acute haemodynamic effects of oral prazosin have been studied, at cardiac catheterization, in 11 patients with CHF. In all patients there was a significant fall in left ventricular end-diastolic pressure, mean aortic and pulmonary artery pressure and systemic vascular resistance, 60 minutes after 3.5 mg of prazosin. There was no significant change in heart rate but there was a significant increase in cardiac index and left ventricular stroke work index. The patients received chronic therapy with prazosin one mg 3 times a day and CO was measured serially by the nitrous oxide whole body plethysmograph method. There was s sustained increase in cardiac index of 82% during the 8 week study period. Twelve months after the initial haemodynamic study 5 patients had improved sufficiently to return to normal work. A further 3 patients were improved symptomatically but were unable to return to their previous employment. Three patients died of a myocardial infarction. Prazosin has proved to be beneficial in CHF resistant to digitalis and diuretics.

Provocation of postural hypotension by nitroglycerin in diabetic autonomic neuropathy?

The effect of nitroglycerin on heart rate and systolic blood pressure was compared in 5 normal subjects, 12 diabetic subjects without autonomic neuropathy, and 5 diabetic subjects with autonomic neuropathy. The magnitude and time course of the increase in heart rate and the decrease in systolic blood pressure after nitroglycerin were similar in the normal and diabetic subjects without autonomic neuropathy, whereas a lesser increase in heart rate and a greater decrease in systolic blood pressure occurred in the diabetic subjects with autonomic neuropathy. It is therefore suggested that caution should be exercised when prescribing vasodilator drugs in diabetic patients, particularly those with autonomic neuropathy.

The effects of alpha- and beta-adrenergic receptor blockers on the pressure responses to isometric exercise in hypertensive patients.

1. The cardiovascular responses to handgrip exercise have been studied in ten patients with uncomplicated essential hypertension in a randomized crossover study of propranolol and prazosin. 2. Isometric handgrip exercise was performed with a calibrated strain gauge dynamometer at 30% of maximum voluntary contraction for 3 min. 3. Blood pressure and heart rate were measured in the supine position at rest and in the last 10 s of the exercise period. 4. These exercise studies were undertaken at the end of a run-in period and at the end of 1 month's optimal therapy with the two drugs. 5. The active treatment periods were separated by a 2 weeks placebo washout period. 6. Both drugs lowered the supine and standing systolic and diastolic pressures and there was no difference between these drugs in their effect on these variables. 7. Propranolol lowered the resting heart rate and neither drug suppressed the pressor response to isometric exercise. 8. The degree of pressure rise was similar with both drugs but propranolol suppressed isometric exercise-induced tachycardia.

Non-invasive assessment of left ventricular response to Valsalva manoeuvre in normal and diabetic subjects using praecordial accelerocardiography.

The left ventricular response to the Valsalva manoeuvre was studied in 5 normal subjects (group 1), 6 diabetics without autonomic neuropathy (group 2), and 5 diabetics with autonomic neuropathy (group 3), using the maximum amplitude of the praecordial accelerocardiogram (DE) as a noninvasive index of left ventricular performance. During the Valsalva manoeuvre DE decreased in all 3 groups. In groups 1 and 2, DE increased significantly above the control value after release of the manoveuvre (DE overshoot) but this did not occur in group 3. It is suggested that the overshoot of DE in groups 1 and 2 reflects an increase in left ventricular contractility after release of the Valsalva manoeuvre and the absence of an overshoot in DE in the patients with autonomic neuropathy is the result of loss of cardiac adrenergic innervation. The ability to detect an abnormal cardiovascular response to the Valsalva manoeuvre using the non-invasive technique of praecordial accelerocardiography may be of practical value in the assessment of left ventricular function.

The effects of exercise on the amplitude of the first heart sound in normal subjects.

The cardiovascular responses to isometric and dynamic exercise have been studied in six normal subjects, before and after intravenous propranolol, using the amplitude of the first heart sound (S1), measured from an ultra-low frequency phonocardiogram, as an index of left ventricular mechanical performance. Dynamic exercise caused significant increases in heart rate and S1 amplitude which were largely inhibited by beta-adrenergic blockade. Isometric exercise also produced increases in heart rate and blood pressure, but a decrease in S1 amplitude. Propranolol had no significant effect on the cardiovascular response to isometric exercise. These results confirm previous suggestions that, in contrast to dynamic exercise, the normal cardiovascular responses to isometric exercise are relatively independent of the beta-adrenergic nervous system. Possible reasons why the improvement in left ventricular performance, which has previously been shown to occur during isometric handgrip, was not reflected in the phonocardiogram, are also discussed.

Correlation between praecordial accelerocardiogram and left ventricular pressure.

The praecordial accelerocardiogram possesses important practical advantages over more familiar techniques of recording praecordial pulsations. We have compared the amplitude of the P wave of the praecordial accelerocardiogram in 6 normal subjects (group 1) and 21 patients with heart disease (group 2) at rest and after 3 minutes of isometric handgrip at 30 per cent maximum voluntary contraction. At rest in group 2 there was a significant linear correlation between the amplitude of the P wave of the accelerocardiogram, relative to the maximum systolic amplitude (P/DE), and the left ventricular end-diastolic pressure (P less than 0-01). However, comparison of the data for P/DE showed that the mean value (+/-SEM) of 29+/-5 per cent in group 1 was not significantly different from the mean value of 37+/-4 per cent in group 2 (P g .reater than 0-30). During handgrip the mean amplitude of the P wave did not increase significantly in group 1 (P greater than 0-20) but increased significantly in group 2 (P less than 0-02). In group 2 there was a significant linear correlation between the percentage increase in the amplitude of the P wave of the accelerocardiogram during handgrip and the percentage increase in the left ventricular end-diastolic pressure (P less than 0-01).

Effects of sustained isometric handgrip on praecordial accelerocardiogram in normal subjects and in patients with heart disease.

The effects of isometric exercise on the maximum amplitude of the praecordial accelerocardiogram (as represented by the DE deflection) have been compared in 6 normal subjects (group 1), 12 patients with aortic stenosis (group 2), and 16 patients with myocardial disease (group 3). Whereas the tachycardia and pressor effects of isometric exercise were identical in all three groups, the normal subjects showed a significant decrease in DE during handgrip of 10 +/- 4 per cent (P less than 0.05) as compared with the insignificant increases of 8.5 +/- 6 per cent (P greater than 0.5), and 4 +/- 3.5 per cent (P greater 0.3) observed in the patients in groups 2 and 3. This response in the normal subjects differed significantly from the responses observed in the patients in groups 2 (P less than 0.02) and 3 (P less than 0.01). Of the patients in each of groups 2 and 3, 50 per cent responded abnormally to handgrip in that they showed a significant increase in DE. In the patients with aortic stenosis this subgroup of patients differed from the remainder in that they had a higher resting cardiac index (P less than 0.05). In the patients with myocardial disease this subgroup was characterized by a significantly lower resting left ventricular end-diastolic pressure (P less than 0.02). It seems, therefore, that those patients who increase DE in response to handgrip tend to have better left ventricular function at rest than those who do not. We suggest that this may be because of increased beta adrenergic activity at rest and during isometric exercise in the subgroup who respond to handgrip with an increase in DE.