Early exercise testing after treatment with thrombolytic drugs for acute myocardial infarction: importance of reciprocal ST segment depression.

OBJECTIVE: To investigate the clinical importance of reciprocal ST depression induced by exercise testing early after acute myocardial infarction in patients treated with thrombolysis. DESIGN: Prospective observational study. SETTING: District general hospital in London. SUBJECTS: 202 patients (170 men) aged 33-69 with acute myocardial infarction treated with thrombolysis. MAIN OUTCOME MEASURES: All patients underwent exercise testing and coronary arteriography. ST depression induced by exercise was classified as either reciprocal (associated with ST elevation) or isolated (occurring on its own). The relation between reciprocal ST depression and the following end points was studied: characteristics of the infarct, left ventricular ejection fraction, extent of coronary artery disease on arteriography, and presence of angina induced by exercise. RESULTS: Reciprocal ST depression occurred almost exclusively in Q wave infarctions and was associated with a lower overall ejection fraction than isolated ST depression. It tended to be associated with persistent occlusion of the coronary artery related to the infarct and did not indicate remote ischaemia due to multivessel coronary disease. Unlike isolated ST depression, reciprocal ST depression was not associated with angina induced by exercise. CONCLUSIONS: Reciprocal ST depression induced by exercise is usually associated with extensive Q wave infarctions and persistent occlusion of the artery related to the infarct. It does not seem to indicate reversible ischaemia and should not be used as a non-invasive marker of multivessel disease in the assessment of requirements for further investigation soon after acute myocardial infarction.

Reexamination of the role of endogenous opiates in silent myocardial ischemia.

OBJECTIVES: This study was designed to examine the role of beta-endorphin and met-enkephalin in the pathophysiology of silent myocardial ischemia, with emphasis on their role in the physiologic response to stress. BACKGROUND: Silent myocardial ischemia is more common in patients whose perception of pain is reduced. Whether endogenous opiates can contribute to this process remains uncertain largely because of the conflicting findings of previous studies. METHODS: Forty-three patients with coronary artery disease and ischemia on treadmill stress testing underwent electrical pain tests and exercise treadmill tests during naloxone and placebo infusion in a randomized, double-blind crossover study. Thirty-one patients developed angina during both treadmill tests (group A), and 12 had silent ischemia (group B). Plasma beta-endorphin, metenkephalin, epinephrine, norepinephrine and cortisol were measured before and after exercise in a subgroup of 17 patients. RESULTS: Naloxone reduced electrical pain tolerance (1.40 +/- 0.10 [mean +/- SEM] vs. 1.72 +/- 0.19 mA, p = 0.04) but did not affect the time to angina in group A (260 +/- 20 vs. 248 +/- 20 s, p = 0.72) or induce angina in group B patients. Beta-endorphin and met-enkephalin levels during placebo infusion were not significantly different in groups A and B at baseline and after exercise, although beta-endorphin levels were significantly increased during naloxone infusion, confirming effective opiate receptor blockade. Norepinephrine and cortisol increased with exercise, but catecholamines and cortisol were similar in both groups and were unaffected by naloxone. CONCLUSIONS: Beta-endorphin and met-enkephalin were similar in patients with painful and silent ischemia, and naloxone infusion did not influence anginal symptoms despite effective opiate receptor blockade and a reduction in somatic pain tolerance. These findings suggest that endogenous opiates do not play an important role in modulating symptoms in myocardial ischemia. The increase in beta-endorphin with exercise that coincided with an increase in plasma cortisol is most likely due to its release from the anterior pituitary gland as part of the physiologic stress response.

Reassessment of treadmill stress testing for risk stratification in patients with acute myocardial infarction treated by thrombolysis.

OBJECTIVES: To evaluate the role of a treadmill stress test for identifying patients at risk of recurrent ischaemic events after acute myocardial infarction treated by thrombolysis. BACKGROUND: The natural history of myocardial infarction has changed with the introduction of thrombolytic treatment; there is a lower mortality but a higher incidence of recurrent thrombotic events (reinfarction, unstable angina). The treadmill stress continues to be recommended for risk stratification after acute myocardial infarction even though its value has never been formally reassessed in the thrombolytic era. METHODS: Prospective observational study in which 256 consecutive patients who presented with acute myocardial infarction treated by thrombolysis underwent an early treadmill stress test and were followed up for 10 (range 6-12) months. RESULTS: Recurrent ischaemic events occurred in 41 patients (unstable angina 15, reinfarction 21, death five) and a further 21 required revascularisation. Both ST depression at a low workload and low exercise tolerance (< 7 metabolic equivalents of the task (METS) were predictive of recurrent events, with respective hazard ratios of 1.93 (95% confidence interval (95% CI) 1.17-3.20; p < 0.01)) and 1.67 (95% CI 1.0-2.78; p < 0.05). These variables identified 50% and 70% of patients who subsequently sustained a recurrent ischaemic event, but the corresponding values for positive predictive accuracy were only 26% and 21%. Thus they are of limited value as a screening measure for identifying patients likely to benefit from invasive investigation and revascularisation. None of the other variables (ST elevation, haemodynamic responses, ventricular extrasystoles, angina) was significantly associated with recurrent ischaemic events. CONCLUSIONS: The treadmill stress test is of limited value for identifying patients at risk of recurrent ischaemic events after acute myocardial infarction treated by thrombolysis.

Silent myocardial ischemia: role of subclinical neuropathy in patients with and without diabetes.

OBJECTIVES: Silent myocardial ischemia is common in patients with diabetes. This study was designed to assess the role of subclinical autonomic impairment in diabetic patients with silent ischemia. BACKGROUND: Studies have suggested that silent ischemia is more common in diabetic patients with microvascular complications, but this has not been a consistent finding. METHODS: Twenty-two diabetic and 30 nondiabetic patients with proved coronary artery disease and a history of angina and ischemia on treadmill stress testing underwent clinical tests of autonomic function and measurement of 24-h heart rate variability. Diabetic patients with a history of microvascular complications were excluded. RESULTS: Although all 52 patients manifested ischemia during treadmill testing, only 36 patients experienced angina (angina group), whereas 16 did not (silent ischemia group). Diabetic and nondiabetic patients were similar in age (59 +/- 1 vs. 61 +/- 2 years, p = 0.56) and extent of coronary artery disease. However, clinical tests showed reduced parasympathetic function in the diabetic patients (Valsalva ratio 1.38 +/- 0.07 vs. 1.60 +/- 0.06; p = 0.007). Patients in the silent ischemia group were more often diabetic (33% vs. 63%, p = 0.05) and had prolonged time to ischemia on treadmill testing (200 +/- 20 vs. 271 +/- 20 s, p = 0.03). In addition, autonomic function was impaired in the silent group (supine/standing heart rate ratio 1.15 +/- 0.02 vs. 1.05 +/- 0.02, p = 0.002). Subgroup analysis showed that abnormalities of autonomic function were confined to the diabetic patients in the silent group. CONCLUSIONS: Despite the absence of overt microvascular complications, diabetic patients with silent exertional ischemia have evidence of significant autonomic impairment compared with findings in symptomatic patients. This difference is not seen in nondiabetic patients and indicates that subclinical neuropathy is an important cause of silent ischemia in patients with diabetes.

Significance of reciprocal ST depression in acute myocardial infarction: a study of 258 patients treated by thrombolysis.

OBJECTIVE: To investigate the clinical significance of reciprocal ST depression on the presenting electrocardiogram in patients with acute myocardial infarction treated by thrombolysis. DESIGN: A prospective cohort analytical study. SETTING: A London district general hospital. SUBJECTS: Two hundred and fifty eight consecutive patients with acute myocardial infarction treated with thrombolysis. INTERVENTIONS: All patients underwent treadmill stress testing after a mean (SEM) of 10 (3) days; 200 patients (78%) were referred for coronary arteriography at 30 (16) days. MAIN OUTCOME MEASURES: Relation between reciprocal ST depression at presentation and several endpoints: time from start of chest pain to hospital presentation, electrocardiographic changes during early treadmill stress testing, presence of multivessel coronary disease, and clinical outcome in terms of recurrent ischaemic events (death, reinfarction, and unstable angina) during a 10 (range six to 12) month follow up. RESULTS: Presentation was generally early, but in this group of patients reciprocal ST depression was significantly related to the time from the start of symptoms, those with reciprocal change presenting on average one hour earlier than those without. Although reciprocal change on the presenting electrocardiogram was weakly associated with ST depression on treadmill stress testing, it was not indicative of remote ischaemia as a result of multivessel coronary disease or high grade collateralisation of the infarct related artery. There was no association between reciprocal change and the incidence of recurrent ischaemic events. CONCLUSION: Reciprocal ST depression on the presenting electrocardiogram seems to be a benign electrical phenomenon related to the time from the start of symptoms. It does not necessarily predict an adverse prognosis in patients treated by thrombolysis.

Free radical activity and left ventricular function after thrombolysis for acute infarction.

BACKGROUND: Experimental data suggest that reperfusion injury involving free radicals contributes to the impairment of left ventricular function after successful thrombolysis. METHODS: In 72 patients presenting with acute myocardial infarction, markers of free radical activity were measured before streptokinase and two hours later. Thiobarbituric acid reactive material (TBA-RM) reflects lipid peroxidation by free radicals, and the concentration of plasma total thiols (34 patients) reflects oxidative stress. Coronary arteriography was performed at 18-72 hours after thrombolysis to determine coronary patency, and left ventricular function was assessed by ventriculography and from QRS scoring of the electrocardiogram. RESULTS: The infarct related artery was patent (Thrombolysis In Myocardial Infarction Trial grade 2 or better) in 60 (83%) and occluded in 12. In the 60 with a patent artery, the concentration of TBA-RM increased after streptokinase by (mean (SD)) 9.2 (14.0) nmol/g albumin, whereas in the 12 with an occluded artery TBA-RM decreased by 7.0 (11.3) nmol/g albumin (p < 0.01 between groups). In those with a patent artery the rise in TBA-RM associated with thrombolysis correlated with left ventricular ejection fraction (R = -0.41, p < 0.002), and with the QRS score (R = +0.38, p = 0.003). Plasma total thiol concentrations decreased by 12.7 (31.1) mumol/l in those with a patent artery, and this decrease associated with thrombolysis correlated with left ventricular ejection fraction (R = +0.39, p < 0.02) but not with the QRS score (R = -0.2, NS). CONCLUSIONS: These findings suggest that reperfusion injury mediated by free radicals may be of clinical importance in humans.

An epidemiological and clinical investigation of pulmonary function and respiratory symptoms in patients with rheumatoid arthritis.

Several studies have investigated lung function in patients with rheumatoid arthritis but have reached different conclusions. The main discrepancy has been between airways disease reported in 38-65 per cent of patients and interstitial pulmonary disease reported in 30-41 per cent. These variable results have probably arisen because specific lung disorders have often been diagnosed on the basis of non-specific tests of lung function which, when considered in isolation, are subject to different interpretations. We adopted a combined epidemiological and clinical approach to investigate lung function and respiratory symptoms in patients with rheumatoid arthritis. Epidemiological data showed that rheumatoid arthritis is associated with a mild restrictive lung defect with reductions in mean FEV1 and FVC of 0.26 l and 0.29 l respectively and a normal FEV1/FVC ratio. The reduction in mean maximum mid-expiratory flow rate of 0.34 l/s could be explained on the basis of lung restriction and there was no evidence of widespread airways dysfunction other than that which could be explained by cigarette smoking. The clinical study showed that abnormal lung function tests in individual patients were caused by a heterogeneous group of conditions which are frequently caused, or exacerbated, by cigarette smoking. Cigarette smoking, and not the rheumatoid process, was the most frequent cause of abnormal lung function in rheumatoid arthritis.

Streptokinase induced defibrination assessed by thrombin time: effects on residual coronary stenosis and left ventricular ejection fraction.

OBJECTIVE: To evaluate laboratory markers of defibrination early after thrombolytic therapy and to determine their relation to residual stenosis and left ventricular ejection fraction measured angiographically before discharge from hospital. DESIGN: Prospective analysis of defibrination after streptokinase measured by fibrinogen assay and thrombin time to provide a comparison of these coagulation variables for predicting angiographic responses to treatment in patients with acute myocardial infarction. SETTING: The coronary care unit of a district general hospital. PATIENTS: 44 patients with acute myocardial infarction treated by streptokinase infusion, all of whom underwent paired blood sampling before and one hour after streptokinase and cardiac catheterisation at a median of six (interquartile range 3-9) days later. MAIN OUTCOME MEASURES: Assay of thrombin time and plasma fibrinogen concentrations one hour after streptokinase infusion. Relations between these coagulation variables and residual stenosis in the infarct related coronary artery and left ventricular ejection fraction. Separate analyses are presented for all patients (n = 44) and those with patency of the infarct related artery (n = 35). RESULTS: Streptokinase infusion produced profound defibrination in every patient as shown by changes in thrombin time and circulating fibrinogen. Thrombin time after streptokinase infusion correlated significantly with both residual stenosis (r = -0.43, p < 0.005) and left ventricular ejection fraction (r = 0.38, p < 0.02). The importance of these correlations was emphasised by the interquartile group comparison which showed that a thrombin time > or = 49 seconds predicted a residual stenosis of 74% and an ejection fraction of 65%, compared with 90% and 49% for a thrombin time < or = 31 seconds (p < 0.01). When the analysis was restricted to patients with patency of the infarct related artery, the correlation between thrombin time and residual stenosis remained significant and group comparisons continued to show that patients in the highest quartile range had more widely patent arteries and better preservation of ejection fraction. Analysis of the fibrinogen data, on the other hand, showed insignificant or only marginally significant correlations with these angiographic variables. CONCLUSIONS: Early after streptokinase infusion for acute myocardial infarction, the level of defibrination measured by thrombin time has an important influence on residual coronary stenosis and left ventricular ejection fraction at discharge from hospital, values above 49 seconds being associated with the best angiographic result.

Clinical impact of introducing thrombolytic and aspirin therapy into the management policy of a coronary care unit.

PURPOSE: To evaluate the impact of introducing thrombolytic and aspirin therapy into the management policy of a coronary care unit, with particular reference to its effects on the hospital course of nonselected patients with acute myocardial infarction. End points chosen were the utilization of thrombolytic and aspirin therapy, hospital mortality, discharge diuretic requirements, and the incidence of ventricular fibrillation and cardiogenic shock. PATIENTS AND METHODS: A total of 336 patients with acute myocardial infarction were studied, comprising consecutive admissions to the coronary care unit over two separate 12-month periods: January to December 1986 (n = 158) and September 1989 to August 1990 (n = 178), before and after thrombolytic and aspirin therapy had been introduced into the management policy of the unit. RESULTS: Thrombolytic and aspirin therapy was given to 87% and 93%, respectively, of all patients in the 1989/1990 cohort. This high treatment rate led to substantial improvements in morbidity and mortality. Thus, comparison of the 1986 and 1989/1990 cohorts showed reductions in hospital mortality (24% to 11%, p less than 0.005), ventricular fibrillation (22% to 13%, p = 0.05), and cardiogenic shock (20% to 6%, p less than 0.001), particularly in patients aged over 60. Reductions in the incidence of lesser degrees of heart failure are reflected in the proportions of patients discharged with diuretic requirements, which declined from 43% in 1986 to 22% in 1989/1990 (p less than 0.001). The duration of hospital stay for patients who survived showed no change between 1986 and 1989/1990, but time spent in the coronary care unit decreased from 3.1 +/- 1.8 to 2.1 +/- 1.4 days (p less than 0.001). CONCLUSION: The great majority of nonselected patients with acute myocardial infarction are candidates for thrombolytic and aspirin therapy, which can be given safely, leading to profound reductions in mortality and the incidence of major complications, particularly in the older age group.

Thrombolytic treatment in acute myocardial infarction: neutrophil activation, peripheral leucocyte responses, and myocardial injury.

OBJECTIVE: To examine early leucocyte responses and neutrophil activation in acute myocardial infarction treated by streptokinase and to relate the findings to coronary recanalisation and indices of myocardial damage in order to provide further information about the role of neutrophils in the evolution of injury. DESIGN: Group analysis of paired blood samples, obtained before streptokinase treatment and one hour after it, and of three indirect measures of myocardial injury: left ventricular ejection fraction, QRS score, and peak creatine kinase. SETTING: The coronary care unit of a district general hospital. PATIENTS: 39 patients with acute myocardial infarction who underwent paired blood sampling (before streptokinase and one hour after streptokinase) and cardiac catheterisation 5 (3-8) days later. END POINTS: Changes in peripheral white cell and neutrophil counts and plasma elastase one hour after streptokinase infusion. Comparison of these variables in patients with and without patency of the infarct related coronary artery. Correlations between these variables and indirect measures of myocardial injury. RESULTS: Neutrophil activation, as reflected by plasma elastase, increased sharply one hour after streptokinase. Total white cell and neutrophil counts also increased. Changes tended to be more pronounced in patients with patency of the infarct related artery, though the trend was not statistically significant. Neutrophil activation before streptokinase was unrelated to indirect indices of myocardial injury but only one hour after streptokinase a weak negative correlation with left ventricular ejection fraction had developed. Peripheral neutrophil responses showed a similar relation to ejection fraction and also correlated with peak creatine kinase and QRS score. CONCLUSIONS: Thrombolytic treatment in acute myocardial infarction is associated with an abrupt reactive neutrophil response which provides an early measure of injury. It is also associated with neutrophil activation, probably in response to coronary recanalisation and myocardial reperfusion. Activated neutrophils are recognised as mediators of reperfusion injury in experimental infarction and the data in the present study provide preliminary evidence of a similar pathogenic role in the clinical setting.

Aging, autonomic function, and the perception of angina.

OBJECTIVE: To determine the effects of age and autonomic function on the perception of angina. DESIGN: Prospective evaluation of the relations between anginal perceptual threshold, autonomic function, and systolic blood pressure in patients with symptomatic coronary artery disease. Statistical analysis was by non-parametric techniques. SETTING: Cardiology departments of a district general hospital and a post-graduate teaching centre. SUBJECTS: 82 non-diabetic men with typical exertional angina and coronary artery disease confirmed by arteriography (n = 64) or a history of Q wave infarction (n = 18). MAIN OUTCOME MEASURES: Age, anginal perceptual threshold, autonomic function, and blood pressure. Anginal perceptual threshold was defined as the time from onset of 0.1 mV ST depression to the onset of angina during treadmill stress testing. Autonomic function was measured as the ratio of peak heart rate during the Valsalva manoeuvre to the minimum rate after release. RESULTS: Anginal perceptual threshold showed a weak but significant correlation with age, with older patients tending to have a longer interval between the onset of ST depression and the onset of angina. Comparison of patients in the upper and lower quartile age ranges showed a difference of 50 seconds between median threshold measurements. Blood pressure and heart rate responses to the Valsalva manoeuvre also correlated with age, but neither variable correlated with the anginal perceptual threshold. CONCLUSIONS: In non-diabetic men with coronary artery disease the perception of angina tends to deteriorate with advancing age. The mechanism is unclear but is not attributable solely to alterations in blood pressure or autonomic function.

The perception of angina in diabetes: relation to somatic pain threshold and autonomic function.

Silent ischemia is common in diabetic patients with coronary heart disease. These patients may also have more subtle alteration in the perception of angina as reflected by prolongation of anginal perceptual threshold--the time from onset of 0.1 mV ST segment depression to the onset of chest pain during treadmill exercise. Silent ischemia may be associated with a generalized hyposensitivity to pain, although the pathophysiologic mechanism is obscure. The purpose of the present study was to determine whether diabetic patients with prolonged anginal perceptual thresholds are also hyposensitive to painful stimuli and to investigate whether this is associated with autonomic neuropathy. Nineteen diabetic and 25 nondiabetic patients with exertional angina were exercised on a treadmill to measure anginal perceptual threshold. Somatic pain threshold was measured by calf sphygmomanometry. The cuff was inflated rapidly until pain occurred, and six repeat inflations were done to test reproducibility. Because there was no significant difference between measurements (coefficient of variation = 0.156) the mean value for each patient provided a measure of somatic pain threshold. The diabetic group had a longer anginal perceptual threshold (138 +/- 64 seconds vs 34 +/- 51 seconds, p less than 0.001), which correlated positively with the somatic pain threshold (r = 0.5, p = 0.03); patients with more prolonged anginal perceptual thresholds tended to have higher somatic pain thresholds. In the diabetic group anginal perceptual (r = -0.3, p = NS) and somatic pain (r = -0.4, p = 0.05) thresholds tended to increase as the ratio of peak to minimal heart rate during the Valsalva maneuver fell below 1.21, but these variables were unrelated in the nondiabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged anginal perceptual threshold in diabetes: effects on exercise capacity and myocardial ischemia.

Anginal perceptual threshold (the time from onset of 0.1 mV of ST segment depression to onset of angina during treadmill exercise) is prolonged in diabetic patients with coronary artery disease. In the present study, the functional significance of this perceptual abnormality was evaluated by analysis of its effect on exercise capacity and the severity of myocardial ischemia. Treadmill exercise in 32 diabetic patients and 36 nondiabetic control patients showed a close linear correlation between the time to onset of electrical ischemia (ST segment depression) and exercise capacity in both groups (r = 0.8 and 0.9, respectively; p less than 0.001). However, the slope of the relation was flatter in the diabetic group because prolongation of the anginal perceptual threshold permitted continued exercise as ischemia intensified. The anginal perceptual threshold itself showed a close linear correlation with exercise capacity in the diabetic group (r = 0.8, p less than 0.001), although in the nondiabetic group these variables were unrelated. The permissive effect of a prolonged anginal perceptual threshold on exercise capacity is undesirable as reflected by its correlation with ischemia at peak exercise (r = 0.6, p less than 0.001): the longer the threshold, the greater the exercise capacity and the more severe the ischemia. Indeed, the inverse relation between the severity of ischemia at peak exercise and exercise capacity in the nondiabetic group (r = 0.4, p less than 0.02) was completely lost in the diabetic group. Thus, in diabetic patients with coronary artery disease, anginal perceptual threshold is a major determinant of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)