Peter Horlock

Transient ST-segment depression as a marker of myocardial ischemia during daily life

Patients with angina and coronary artery disease (CAD) have many episodes of transient ST-segment depression during ordinary daily life, and these are often asymptomatic. To investigate this signal as a marker of myocardial ischemia, 30 patients with chronic stable angina and CAD underwent positron tomography, recording the regional myocardial uptake of rubidium-82, pain and ST-segment changes before, during and after 59 technically satisfactory exercise tests, 35 cold pressor tests and 22 episodes of unprovoked ST depression. Exercise resulted in 53 episodes of ST depression with angina and in 5 episodes without pain. After cold pressor tests, there were 3 episodes of ST depression and pain and 12 of painless ST depression. Only 9 episodes of unprovoked ST depression were accompanied by pain. Tomography showed independent evidence of ischemia in 63 (97%) of the total 65 episodes of ST depression with angina and in all 30 episodes of painless ST depression. In each patient perfusion defects occurred in the same myocardial segment during painful and painless ST depression and responses were significantly different from those in 16 normal subjects studied in the same way. These findings support the use of transient ST depression in continuous monitoring to assess the activity of CAD, but only in patients with typical angina pectoris, ST depression during exercise and proved CAD. They strengthen the evidence derived from ambulatory monitoring for a wider picture of the disease than is generally appreciated, with more frequent episodes of silent myocardial ischemia than of angina pectoris.

SILENT MYOCARDIAL ISCHAEMIA DUE TO MENTAL STRESS

Patients with angina and coronary disease have many episodes of symptomless transient myocardial ischaemia, most of which cannot be explained by physical exertion. 16 patients with typical stable angina pectoris were examined to test the hypothesis that these episodes can be triggered off by ordinary daily events, such as changes in mental activity. Regional myocardial perfusion and ischaemia were assessed by measurement of the uptake of rubidium-82 with positron tomography after mental arithmetic and physical exercise. With mental arithmetic, 12 (75%) patients had abnormalities of regional perfusion, accompanied in only 6 by ST-segment depression and in 4 of these 6 by angina, leaving 6 patients with perfusion abnormalities but neither pain nor electrocardiographic changes. After exercise, all the patients showed abnormal regional myocardial perfusion in the segments that became ischaemic with mental arithmetic. This was accompanied by ST depression in all and angina in 15. The association between mental activity and myocardial ischaemia may operate frequently during everyday life and may explain many of the transient and symptomless electrocardiographic changes in patients with coronary disease.

Relation between regional myocardial uptake of rubidium-82 and perfusion: absolute reduction of cation uptake in ischemia.

Experiments were undertaken using rubidium-82 and position tomography to examine the relation between myocardial perfusion and cation uptake during acute ischemia. Rubidium-82 was repeatedly eluted from a strontium-82-rubidium-82 generator. In six dogs emission tomograms were used to measure the delivered arterial and myocardial concentrations at rest and after coronary stenosis, stress and ischemia. There was a poor overall relation between regional myocardial uptake and flow measured by microspheres and a large individual variability. Extraction of rubidium-82 was inversely related to flow. Significant regional reduction of cation uptake was detected in the tomograms when regional flow decreased by more than 35 percent. This reduction was significantly greater when ischemia was present. A small but significantly greater when ischemia was present. A small but significant decrease (33.0 +/- 9.1 percent, mean +/- standard deviation) in the myocardial uptake of rubidium-82 was detected only when flow was increased by more than 120 percent in relation to a control area after administration of dypiridamole. The technique using rubidum-82 and tomography was applied in five volunteers and five patients with angina pectoris and coronary artery disease. Myocardial tomograms recorded at rest and after exercise in the volunteers showed homogeneous uptake of cation in reproducible and repeatable scans. In contrast, the patients with coronary artery disease showed an absolute mean decrease of 36 +/- 14 percent in regional myocardial uptake of rubidium-82 after exercise. These abnormalities persisted in serial tomograms for more than 20 minutes after the symptoms and electrocardiographic signs of ischemia.

Direct effects of smoking on the heart: silent ischemic disturbances of coronary flow

Cigarette smoking is strongly associated with ischemic heart disease and acute coronary events. The effect of smoking a single cigarette on regional myocardial perfusion was studied in 13 chronic smokers with typical stable angina pectoris using positron emission tomography and rubidium-82 (82Rb). Findings were compared with the effects of physical exercise. After exercise, 8 patients (61%) had angina, ST depression and abnormal regional myocardial perfusion. Uptake of 82Rb increased from 49 +/- 8 to 60 +/- 7 in remote myocardium, but decreased from 46 +/- 3 to 37 +/- 5 in an ischemic area. The remaining 5 patients (39%) had homogeneous increases in 82Rb uptake without angina or ST depression. After smoking, 6 of the 8 patients with positive exercise test responses had a decrease in 82Rb uptake, from 47 +/- 3 to 35 +/- 6 in the same segment of myocardium affected during exercise. However, in contrast to exercise, the events during smoking were largely silent. The absolute decreases in regional 82Rb uptake after smoking occurred at significantly lower levels of myocardial oxygen demand than after exercise. This suggests that an impairment of coronary blood supply is responsible. Thus, in smokers with coronary artery disease, each cigarette can cause profound silent disturbances of regional myocardial perfusion that are likely to occur frequently during daily life. Such repeated insults may represent an important mechanism linking smoking with coronary events.

The effects of nifedipine on acute experimental myocardial ischemia and infarction in dogs.

We studied 25 anesthetized and thoracotamized dogs before and during 5 hours of acute regional myocardial ischemia. Krypton-81m (81mKr) was infused constantly into the aortic sinuses. The myocardial equilibrium of this tracer was used to image and assess the distribution of regional myocardial perfusion using a gamma camera and digital computer. The epicardial ECG was recorded, S-T segment elevation and the loss of R and appearance of Q waves were measured, and the plasma activity of creatine kinase (CK) was determined in aortic and coronary venous blood throughout these experiments. Ten dogs underwent left anterior descending coronary artery (LAD) narrowing for 5 hours and received no drugs. Five dogs received nifedipine 13 μg/kg, and another five received 1.0 μg/kg intravenously 30 minutes after LAD narrowing. Those dogs receiving nifedipine, 13 μg/kg, showed a 30% fall in aortic pressure, a 12% rise in heart rate, and an extension of regional ischemia. The ECG showed an extension of infarct size, and CK release into the coronary vein appeared earlier than in the controls. Dogs receiving nifedipine, 1 μg/kg, showed a 12% fall in blood pressure, no rise in heart rate, an improvement in regional perfusion, and ECG signs that suggested limitation of infarct size. There also was delayed release of coronary venous CK. The effects of nifedipine on the natural history of regional myocardial perfusion, the electrocardiogram, and enzyme release from the heart were dose related and cannot be generalized. These observations warrant further clinical investigation to improve the use of this agent in man. Circ Res 44: 16-23, 1979

Quantitative Measurement of Blood—Brain Barrier Permeability Using Rubidium-82 and Positron Emission Tomography

In normal brain, the blood–brain barrier (BBB) is highly impermeable to K+ cations, their transport being controlled by ATPases situated in the endothelial cell membranes. 82Rb+ is a positron-emitting analogue of K+ with a half-life of 75 s. Using a steady-state model and positron emission tomography, quantitative extraction data for 82Rb+ transport across the BBB have been obtained both in normal human subjects and in a variety of conditions of cerebral pathology. A mean cerebral Rb extraction of 2.1% was found for normal subjects, corresponding to a mean value of 1.1 × 10−6 cm s−1 for 82Rb+ cation permeability across the BBB. No increase in cerebral Rb extraction was observed for patients with diffusely raised intracranial pressure secondary to obstructive hydrocephalus and benign intracranial hypertension, or for patients with multiple sclerosis or cerebral systemic lupus erythematosus. Cerebral tumours that were enhanced on computed tomography scanning showed a significant increase in local Rb uptake. No correlation between tumour size, or grade of glioma, and tumour Rb extraction was found. Nonenhancing tumours showed no increase in local Rb extraction, and regions of perifocal tumour oedema also had Rb extraction values in the normal range. It is concluded that increased Rb extraction occurs only where tight junction integrity in the BBB breaks down locally, that is, in the microcirculation of enhancing tumours but not in that of perifocal regions of tumour oedema or nonenhancing tumours.

Character of transient ischemia in angina pectoris

There is growing interest in the possible therapeutic and prognostic significance of silent myocardial ischemia in coronary artery disease (CAD) and its detection by ambulatory electrocardiographic (ECG) monitoring. In 100 apparently healthy normal subjects (20 with angiographically normal coronary arteries), Holter monitoring revealed significant ST-segment depression in only 2 (both over 40 years, one with positive treadmill test, the other with risk factor for CAD). No significant ECG changes were found in those with normal coronary vessels. In 30 patients with documented CAD, significant ST-segment depression during 1,934 episodes over 446 days of monitoring over 18 months was found. Only 24% of the episodes were associated with angina. Asymptomatic and symptomatic episodes were associated with comparable changes in perfusion detected by positron emission tomography. Heart rate increases greater than 10 beats/min preceding the onset of the ST-segment changes occurred in only 23% of the episodes. There was considerable variability in the ST-segment changes in the same patient monitored serially over long periods of time. The data indicate that it is extremely uncommon for patients without CAD to exhibit silent myocardial ischemia, whereas patients with stable angina exhibit frequent, variable and often asymptomatic ECG evidence of myocardial ischemia rarely triggered by increases in heart rate. These findings are likely to be of therapeutic and prognostic significance.

Semi-automated preparation of a 11C-labelled antibiotic-[N-methyl-11C]Erthromycin A lactobionate☆

A fast semi-automated method is described for labeling the antibiotic, erythromycin A (1), with the short-lived positron-emitting radionuclide, 11C (t 1/2 = 20.4 min), in order to permit the non-invasive study of its tissue uptake in vivo. Labelling was achieved by the fast reductive methylation of N-demethylerythromycin A (2) with [11C]formaldehyde, itself prepared from cyclotron-produced [11C]-carbon dioxide. Rapid chemical and radiochemical purification of the [N-methyl-11C]erythromycin A (3) were achieved by HPLC and verified by TLC with autoradiography. The purified material was formulated for human i.v. injection as a sterile apyrogenic solution of the lactobionate salt. The preparation takes 42 min from the end of radionuclide production and from [11C]carbon dioxide produces [N-methyl-C11]erythromycin A lactobionate in 1-12% radiochemical yield, corrected for radioactive decay.

Radioassay problems associated with the clinical use of a 82Rb radionuclide generator

The short-lived positron emitting radionuclide 82Rb (t1/2 1.27 min) is conveniently available from a 82Sr/82Rb generator system. The parent nuclide (t1/2 25.5d) produced from the spallation of molybdenum, has associated with it varying quantities of other long-lived strontium radionuclides, namely 85Sr, 89Sr and 90Sr. It is important therefore in the clinical use of such material that the levels of strontium radionuclides being administered to patients is carefully assayed and controlled. The problems associated with these measurements are discussed with special reference to the radiation dose received by the patient and the problems in resolving overlapping peaks with different FWHMs.

The half-life of 68Ge

Abstract The half-life of 68Ge has been remeasured using a high-pressure ionisation chamber resulting in a value of 270.82 ± 0.27 days.