Responses of the rabbit epicardial coronary artery to acetylcholine and adrenoceptor agonists.

STUDY OBJECTIVE--The aim was to identify the role of the endothelium in mediating the responses to acetylcholine in the rabbit coronary artery, and to determine whether alpha or beta adrenergic stimulation may cause relaxation via endothelial receptors in the coronary arteries of this species. DESIGN--Responses to acetylcholine and adrenoceptor agonists were compared in isolated ring preparations with and without endothelium. The adrenoceptor agonists were examined in the presence of phentolamine or propranolol to block alpha and beta adrenoceptors, respectively. EXPERIMENTAL MATERIAL--30 New Zealand white rabbits (2.3-3.4 kg) were killed by an overdose of barbiturate and exsanguination, and the left epicardial coronary artery was dissected free. Ring preparations were suspended in organ baths under isometric tension and, where required, the tone of the preparations was raised by KC1. MEASUREMENTS AND MAIN RESULTS--Concentrations of acetylcholine up to 10(-6) mol.litre-1 produced dose dependent relaxation of the preparations with endothelium intact, but no relaxation in preparations denuded of endothelium. At higher concentrations, a marked vasoconstrictor response was seen in all preparations regardless of the presence of endothelium. At basal tone, acetylcholine produced vasoconstriction which reached a maximum of 1.0 (SEM 0.14)g tension in preparations with endothelium and 1.74(0.27) g tension in those without endothelium (p less than 0.05). In coronary arteries pretreated with 50 mumol.litre-1 phenoxybenzamine to block alpha adrenoceptors, noradrenaline, isoprenaline, and salbutamol produced dose dependent relaxation of the preparations; this was unaffected by the absence of endothelium. In vessels not pretreated with phenoxybenzamine, propranolol inhibited the relaxation to noradrenaline and isoprenaline but again there was no difference between vessels with and without endothelium. CONCLUSIONS--In the rabbit isolated epicardial coronary artery, acetylcholine produces an endothelium dependent relaxant response over a limited concentration range; a vasoconstrictor response via smooth muscle dominates at higher concentrations. beta Adrenoceptors mediating relaxation are present on the smooth muscle, but there was no evidence for either alpha or beta adrenoceptor mediated responses via the endothelium. Important differences with coronary arteries from other species are discussed.     

Influence of R wave analysis upon diagnostic accuracy of exercise testing in women.

Exercise electrocardiography in women with chest pain is associated with a high incidence of false positive ST segment depression. The recent observation that changes in R wave amplitude during exercise can also be used diagnostically may improve the value of stress testing in women. The results of 12 lead treadmill exercise and coronary angiography were reviewed in 62 women, mean age 51 years, presenting with "angina" without previous myocardial infarction. These were compared with exercise results in 14 healthy asymptomatic volunteers with a mean age of 26 years. In addition to conventional ST analysis, R wave amplitude changes during exercise, measured in leads II, III, a VF, and V4 to 6, were examined. While the sensitivity and specificity of ST and R wave changes were similar at about 67%, their combined interpretation was helpful. If both ST and R wave criteria were negative the predictive accuracy for normal coronary angiography was 94% (17/18). Alternatively, in tests showing both ST depression and an abnormal R wave response, coronary angiography was always abnormal (13/13). None of the normal volunteers developed ST segment depression and 93% (13/14) had a normal R wave response. If both were positive, however, coronary angiography was always abnormal (13/13). Although stress test interpretation in women is difficult, R wave analysis is a useful adjunct to ST change and can improve the predictive accuracy of the test in a significant number of patients.     

Use of electromagnetic flow probes to assess myocardial performance in man

Aortic blood flow was measured in 14 patients by means of an electromagnetic flow probe placed around the ascending aorta during cardiac surgery. High fidelity left ventricular pressure was monitored directly, 8 different indices of left ventricular function were derived from these measurements, and compared. Peak aortic blood flow correlated with the conventional indices of left ventricular function derived from left ventricular pressure, but better correlations were obtained for the maximum rate of change of power with respect to time. The clinical advantage of the derivation of this index is small and for clinical purposes peak aortic blood flow and the maximum rate of change of flow provide indices of myocardial performance which are directly available from the instrument.     

The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors

OBJECTIVES: The object of the study was to assess the relationship between erythrocyte sedimentation rate (ESR) and inflammatory cytokine production in chronic heart failure (CHF). Our findings lead us to re-evaluate the prognostic value of the ESR in assessing patients with CHF. BACKGROUND: The search for simple prognostic markers in CHF that can be assessed anywhere at low cost is important. Increases in ESR are related to the acute phase response in states of inflammation and infection. METHODS: Initially, we studied ESR in relation to plasma levels of inflammatory cytokines in 58 CHF patients. The findings prompted us to analyze the mortality predictive power of ESR compared with established risk factors in these patients and (retrospectively) in a second group of 101 clinically stable CHF patients who had ESR measured. RESULTS: In all 159 CHF patients (age 62+/-2 years, New York Heart Association [NYHA] class 2.7+/-0.1), ESR ranged from 1 to 96 mm/h (median 14 mm/h). The ESR was correlated with tumor necrosis factor (TNF)-alpha (r = 0.31, p<0.05), soluble TNF receptor-1 (r = 0.48, p<0.0005), soluble TNF receptor-2 (r = 0.39, p<0.005) and interleukin 6 (r = 0.45, p<0.005) levels. High ESR levels indicated a poor prognosis (p<0.0001), and this was independent of age, NYHA class, ejection fraction and peak oxygen consumption (p < 0.005). Patients with ESR above median (> or =15 mm/h) compared with patients with ESR <15 mm/h had an impaired survival (hazard ratio 2.62, 95% confidence interval 1.58-4.36, p<0.0001). CONCLUSIONS: Our study demonstrates that in CHF a high ESR is an unfavorable prognostic sign, independent of patients' symptomatology and ventricular function. These results are in diametrical contrast to previous results. This may reflect a change in the underlying pathophysiology due to today's treatment with angiotensin-converting enzyme inhibitors.     

Vasodilatation with captopril and prazosin in chronic heart failure: double blind study at rest and on exercise

A double blind cross over study was performed to compare the long term hormonal, haemodynamic, and clinical responses to specific inhibition of the renin-angiotensin-aldosterone system (captopril) and of the alpha 1 adrenoceptors of the sympathetic system (prazosin) both at rest and during upright exercise in patients with chronic heart failure. Sixteen patients completed one month's treatment with each drug. During conventional diuretic treatment (control) plasma renin activity, aldosterone, and noradrenaline were increased at rest and on exercise. Control left ventricular filling pressures were raised, and correlated significantly with plasma renin activity both at rest and on exercise. Systemic vascular resistance was increased at rest, and its reduction during exercise correlated inversely with the increase in plasma renin activity and plasma noradrenaline. After one month's treatment with captopril there were reductions in plasma aldosterone, weight, left ventricular filling pressure, and systemic vascular resistance at rest and on exercise. Dyspnoea was relieved and exercise capacity increased. The greater fall in systemic vascular resistance on exercise no longer correlated with the increase in plasma renin activity. During treatment with prazosin there were increases in plasma noradrenaline and, transiently, in plasma aldosterone. Fluid retention occurred, and left ventricular filling pressure was unchanged. Compared with control values systemic vascular resistance was reduced at rest but not on exercise. Dyspnoea and exercise capacity did not improve. In chronic heart failure, vasodilatation by inhibition of the alpha adrenergic system with prazosin causes compensatory stimulation of the renin-angiotensin-aldosterone system and does not result in clinical benefit. Inhibition of the renin-angiotensin-aldosterone system with captopril causes secondary vasodilatation at rest and on exercise and results in improvement in symptoms and exercise capacity.     

Variation in severity and type of sleep-disordered breathing throughout 4 nights in patients with heart failure

BACKGROUND: Over 50% of patients with chronic heart failure (CHF) have sleep-disordered breathing (SDB). Any variation in the type of SDB in CHF will have implications for patient management. Currently there is good evidence for treatment of obstructive sleep apnea (OSA) in CHF with continuous positive airway pressure; however, for central sleep apnea (CSA) the treatment is less clear. AIMS: The aim of this study was to investigate the variation in the severity and type of SDB (OSA vs. CSA) throughout 4 consecutive nights in CHF patients with SDB. METHODS: Nineteen male CHF patients (mean+/-sd: age 61+/-9 years; left ventricular ejection fraction: 34+/-10% and percent predicted peak VO2: 67+/-19%) underwent cardiorespiratory monitoring in their own home throughout 4 consecutive nights. RESULTS: There was minimal variation in apnea-hypopnea index (AHI) throughout 4 nights in CHF patients with SDB [intraclass correlation coefficient (95% confidence interval (CI)): 0.97 (95% CI 0.76 and 0.97)]. Eight patients [42% (95% CI 20% and 64%)] demonstrated a shift in the type of their SDB, from CSA to OSA or vice versa; these patients had significantly smaller neck circumference (group mean+/-sd) 42+/-2 vs. 44+/-2 cm; p=0.04), and had significant variation in the central AHI [intraclass correlation coefficient: 0.51 (95% CI 0.16 and 0.85)]. CONCLUSIONS: A single night of cardiorespiratory monitoring is representative of moderate-to-severe SDB in patients with CHF. However, a high proportion of patients shift their type of SDB over 4 nights. These findings may have implications for the management of SDB in CHF.     

Endothelium dependent and independent responses in coronary artery disease measured at angioplasty.

OBJECTIVE--To investigate the effects of substance P and papaverine, two drugs that increase coronary blood flow by different mechanisms, on vasomotion in stenotic coronary arteries at percutaneous transluminal coronary angioplasty (PTCA). DESIGN--Coronary blood flow responses to substance P and papaverine were measured in stenotic coronary arteries at the time of PTCA with quantitative angiography and a Doppler flow probe. SETTING--A cardiothoracic referral centre. PATIENTS--15 patients undergoing elective PTCA of a discrete epicardial coronary artery stenosis. INTERVENTIONS--Pharmacological coronary flow reserve was determined with papaverine 5-10 minutes before and after successful PTCA. Endothelium dependent responses to 2 minute infusions of substance P (10-15 pmol.min-1) were assessed immediately before PTCA. MAIN OUTCOME MEASURES--Coronary blood flow responses and changes in epicardial coronary artery area at stenotic, proximal, and distal sites with papaverine and substance P. RESULTS--Stenotic sites dilated with papaverine before PTCA (17.7%(6.9%) (mean (SEM)) area increase, p < 0.05 v baseline). Substance P dilated stenotic sites (16.8%(5.7%) area increase, p < 0.05) and proximal (14.3%(5.4%), p < 0.05) and distal sites (41.7%(9.3%), p < 0.005). Coronary flow reserve increased but did not reach normal values after PTCA (2.3(0.4) before PTCA v 3.0(0.4) after PTCA, p < 0.05) and was associated with an increase in peak flow with papaverine. Angioplasty did not alter baseline flow. After PTCA papaverine caused significant vasoconstriction at the stenotic site (-13.6%(4.3%) area decrease, p < 0.05). There was a negative correlation (r = -0.68, p < 0.05) between the dilator response with papaverine before PTCA and the constrictor response after PTCA. CONCLUSIONS--Substance P causes endothelium dependent dilatation in atheromatous coronary arteries, even at sites of overt atheroma. The cause of the paradoxical constrictor response to papaverine after PTCA is uncertain, but unopposed flow mediated vasoconstriction (the myogenic response) after balloon induced endothelial denudation may be one of several contributory factors.     

Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics

The clinical and neuroendocrine response to diuretic treatment was assessed at rest and on exercise in 12 patients with heart failure. Before treatment all patients were limited by breathlessness on exercise; one was oedematous. Plasma renin activity and aldosterone were normal but plasma noradrenaline was raised both at rest and on exercise. After one month's treatment with frusemide (40 mg) and amiloride (5 mg) weight was significantly reduced by a mean of 3.5 kg and exercise capacity had doubled. Plasma noradrenaline fell to normal at rest but remained abnormally raised on exercise. Plasma renin activity and aldosterone increased significantly both at rest and on exercise. Diuretics bring about a considerable clinical improvement in patients with chronic heart failure but they stimulate the renin-angiotensin system. Activation of the renin-angiotensin system in moderate heart failure occurs as a response to diuretic treatment rather than as a result of the disease process itself.     

Direct measurement of skeletal muscle fatigue in patients with chronic heart failure

Skeletal muscle function was measured as force production and fatigue in both the quadriceps (a large locomotive muscle) and adductor pollicis (a small intrinsic hand muscle) in five healthy volunteers, five patients with mild chronic heart failure, and five patients with severe chronic heart failure. The quadriceps of patients with chronic heart failure had a reduced muscle cross sectional area, a reduced maximum isometric force production, and an increased tendency to fatigue. Isometric force production and fatigue of the adductor pollicis, however, were not significantly different between the three groups under control conditions. But during circulatory occlusion fatigue in the adductor pollicis increased more in the patients with severe chronic heart failure. These differing findings in quadriceps and adductor pollicis suggest that skeletal muscle atrophy and reduced isometric force production are not a necessary consequence of chronic heart failure per se, because they were only present in the large locomotive muscle. The normal values for muscle fatigue observed in adductor pollicis in patients with chronic heart failure imply that skeletal muscle blood flow must increase normally during muscle activation when only a small muscle mass is used. These results are not compatible with the concept of a generalised impairment of normal vasodilatation within active skeletal muscle. In contrast, activation of a large muscle, such as quadriceps, results in the rapid onset of fatigue in patients with severe chronic heart failure. This fatigue may be related to the inability of the cardiovascular system to provide the required blood flow for the activation of a large muscle mass. The finding of a relatively greater increase in fatigue of adductor pollicis during circulatory occlusion in patients with severe chronic heart failure supports the hypnosis of an intrinsic abnormality of skeletal muscle in these patients.