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SummaryA dynamic thrombotic process, coronary spasm or both can be responsible for recurrent episodes of transient reduction of coronary blood flow in unstable angina. We have investigated the temporal relationship between episodic platelet activation, as detected by increased urinary excretion of 11-dehydro-TXB2, and spontaneous myocardial ischemia, assessed by continuous electrocardiographic monitoring and recording in 21 patients with unstable angina pectoris. In order to validate measurements of metabolite excretion as a reflection of intracoronary platelet activation, we have also performed repeated urine sampling from 8 patients undergoing PTCA and from 6 patients with peripheral vascular disease. The latter showed a 16% coefficient of variation in 3 consecutive 8-h urine samples. 11-dehydro-TXB2 increased significantly, by up to 15-fold, in the 2.5- to 5.0-h urine collection encompassing PTCA and decreased by > 50% during the following 2-h period. Patients with unstable angina were characterized by episodic increases (>2 SD of controls) in metabolite excretion, in successive 6-8 h specimens. Paired measurements of 11-dehydro-TXB2 and 2, 3-dinor-TXB2 in 15 urine samples did not reveal evidence of altered metabolic disposition of endogenously released TXB2. A total of 125 ECG ischemic episodes were recorded, of which 64% asymptomatic. We have compared these biochemical and ECG changes in patients randomized to i. v. low-dose aspirin or i.v. isosorbide dinitrate and oral diltiazem. Twenty-five of 56 (i.e. 45%) urine samples obtained in aspirin-free periods showed increased metabolite excretion as compared to 15 of 88 (i.e. 17%) samples collected during aspirin. Of the former, only 3 episodes of enhanced 11-dehydro-TXB2 excretion were associated with ST-segment changes, 7 with chest pain, and 15 with no ECG or clinical changes. Metabolite excretion was approximately 70% lower during aspirin administration than during coronary dilators. However, despite > 95% suppression of platelet cyclooxygenase activity, as monitored ex vivo, incomplete suppression of in vivo TXB2 biosynthesis was occasionally seen during low-dose aspirin therapy. We conclude that in unstable angina, episodic platelet activation is infrequently associated with spontaneous myocardial ischemia. Although the two events may represent functional expressions of the same coronary lesion, they are likely to be triggered by independent mechanisms through different mediators.

SUMMARY Factors determining the symptoms of breathlessness and fatigue in patients with congestive heart failure were investigated by comparing the response to slow and fast exercise. Symptom limited oxygen consumption (maximal); minute ventilation, mean pulmonary capillary wedge pressure; and arterial blood gases, pH, and lactate concentrations were measured during treadmill exercise using a slow protocol in 25 men (age 34-67 years) with congestive heart failure (New York Heart Association class II-III). Ten of these patients were also exercised according to a rapid protocol. Exercise was terminated by fatigue in 23/25 patients after the slow test and by breathlessness in all patients after the rapid test. Exercise capacity (maximal oxygen consumption and exercise duration) was not related to resting or exercise pulmonary capillary wedge pressure or the change in pulmonary capillary wedge pressure during exercise, nor was there any difference in pulmonary capillary wedge pressure at the end of exercise within individuals between the fast and slow tests. Minute ventilation was greater (51 vs 43 1/min), peak exercise lactate concentration higher (3-7 vs 2-2 mmol/1), and the change in pH from the resting state was greater (0-06 vs 0 02) during the rapid test than during the slow test. The sensation of breathlessness in congestive heart failure is not simply related to raised pulmonary capillary wedge pressure, but may in part be due to stimulation of peripheral chemoreceptors in response to metabolic acidosis.The cause of exercise intolerance in congestive heart failure is poorly understood. Patients treated with diuretics are limited more by fatigue than by breathlessness. Several studies have suggested that fatigue is related to an inadequate oxygen supply to skeletal muscle,'-3 because during exercise patients with heart failure have a reduced cardiac output, an early increase in lactate concentration, and augmented limb oxygen extraction.3 Common experience suggests that untrained normal subjects performing rapid exercise (for example running) often stop because of breathlessness, whereas when they exercise slowly (for example walking) they stop because of fatigue. In this study we have investigated whether the response to exercise in patients with congestive heart failure is similar, and if so whether differences in the metabolic, haemodynamic, and ventilatory reRequests for reprints to Professor Philip A

SUMMARY In some patients symptoms improve after the restoration of sinus rhythm from atrial fibrillation. To assess the size and mechanism ofsuch change, exercise capacity and pulsed Doppler left ventricular inflow velocities were assessed in 20 patients with established atrial fibrillation. Treadmill exercise capacity was assessed by measuring maximal oxygen consumption and anaerobic threshold before and on day 1 and 28 days after elective DC cardioversion. The relative contribution of atrial contraction to left ventricular filling was determined by relating the maximum height ofthe A wave to the maximum height of the E wave (A/E) ofthe Doppler velocity time curve. Cardioversion was successful in 14 patients. Maximal oxygen consumption and anaerobic threshold were unchanged on day 1 and increased by day 28 in all 14 patients. The percentage improvement was inversely related to the baseline values; however, the absolute improvement was small in all patients. The mean A/E ratio increased significantly from day 1 to day 28 in all 14 patients.Thus the restoration of sinus rhythm was associated with a delayed improvement in exercise capacity that may in part be due to a slow improvement in atrial contractility and peak cardiac output after cardioversion.Direct current cardioversion of atrial fibrillation is often performed to improve cardiac output and exercise capacity by regularising the heart beat and restoring the atrial systolic contribution to ventricular filling. The magnitude and time course of this improvement are controversial and the relative contribution of atrial systole to stroke volume is still uncertain." The purpose of the present study was to assess the mechanism and size of the increase in exercise capacity after cardioversion of atrial fibrillation to sinus rhythm. Patients and methodsWe studied 20 patients (18 men and 2 women; mean (SD) age 58(8) years). Atrial fibrillation had been present for 6-14 weeks and was associated with previous aortic or mitral valve surgery in five patients (performed 6-12 (mean 8) months before entry to the study), dilated cardiomyopathy in four patients, Present address and requests for reprints to Dr D P Lipkin, Department of Cardiology, Royal Free Hospital, Pond Street, London NW3 6QG.Accepted for publication 12 October 1987 coronary artery disease in seven patients, hypertrophic cardiomyopathy in two patients, and hypertension in one patient. Fibrillation was idiopathic in the remaining patient. The exercise tolerance of the patients was limited only by dyspnoea or fatigue. Patients were excluded if they had had a myocardial infarction during the previous six months, had evidence of myocardial ischaemia or ventricular tachycardia on exercise testing, or had chronic lung disease. There were four patients in New York Heart Association class I, 12 patients in class II, and four in class III. Resting left ventricular fractional shortening was assessed by M mode echocardiography recorded at the mitral valve leaflet tips (with cross sectional echocardiographic control)...