A study of cold cardioplegic myocardial protection in rats: an experimental model using the uptake of technetium 99m pyrophosphate and enzyme activity as parameters of injury.

This study compares the use of St Thomas' cardioplegia and cold saline cardioplegia at 4 degrees C for protection against global myocardial ischaemia in a model of heterotopic cardiac transplantation in rats of isogeneic strain. The parameters of myocardial injury applied were the uptake of Technetium 99m pyrophosphate (Tc 99m Pyp) in the transplanted heart and the measurement of serum total creatine kinase (CK) and creatine kinase MB (CK:MB) isoenzyme activity. The findings indicate that St Thomas' cardioplegic solution confers improved myocardial protection compared with normal saline as judged by statistically significant differences between: (a) the uptake of Tc 99m Pyp between the two solutions at 30 min storage: and (b) the peak total serum creatine kinase enzyme activity at 90 min storage. Excellent correlation was present between the uptake of Tc 99m Pyp and peak total serum creatine kinase activity. Further application of this model is described.

Clinical significance of "reciprocal" S-T segment depression in acute myocardial infarction. Relative contributions of infarct size and ischemia at a distance.

The early electrocardiographic results in 100 patients surviving their first myocardial infarction who thereafter underwent serial radionuclide ventriculography were reviewed. Site of infarction was anterior in 46 and inferior in 54, with lateral extension in two patients. Those with "reciprocal" S-T segment depression of more than 1 mm in the acute phase (n = 53) sustained larger infarcts on the basis of enzyme criteria (mean peak serum creatine kinase, +/- SD, 2,203 +/- 1,271 versus 1,544 +/- 1,197 IU/liter, p less than 0.02), with a higher incidence of ventricular akinesis and dyskinesis. Reciprocal change was more common during inferior infarction (n = 33) than anterior infarction (n = 20). Despite equivalent peak enzyme levels following anterior and inferior infarction with reciprocal S-T depression (mean peak creatine kinase 2,330 versus 2,128, NS), there was marked sparing of left ventricular function in the latter group (mean left ventricular ejection fraction 0.31 +/- 0.14 versus 0.42 +/- 0.09, p less than 0.01). Of 17 patients who died within two years of infarction, 14 had reciprocal changes. Patients who died after anterior infarction with reciprocal changes (n = 5) had poor left ventricular function compared with those who died after inferior infarction (n = 9; left ventricular ejection fraction, +/- SD, 0.21 +/- 0.05 versus 0.38 +/- 0.11, p less than 0.01). One third of those recovering from inferior infarction with reciprocal changes subsequently had positive results on exercise testing, and of the nine patients who died, five had good left ventricular function (left ventricular ejection fraction 0.44 to 0.50). Infarct size and ventricular wall motion abnormality proved to be of major importance in the production of inferior reciprocal S-T change during anterior infarction, and subsequent mortality was related to poor left ventricular function. The proximity of the precordial leads to left ventricular myocardium may increase the detection of concomitant anterior ischemia during inferior infarction, and those who exhibit reciprocal change are presumably at risk from left main stem or anterior descending lesions but with reasonably good ventricular function represent a more attractive population for invasive investigation.

The influence of ectopic heart beats in gated ventricular blood-pool studies.

Direct data collection from ventricular blood-pool studies were stored in frame mode in a computer and by means of a modified tape recorder, the blood-pool image and ECG were recorded on tape. At the end of the study the tape data were replayed into the computer. The ECG signal was passed through a trigger circuit that detected the R wave which was sampled by the computer once every msec. Contractions outside of the desired range could be rejected along with the subsequent contraction. Of seven patients whose calculated ejection fractions were changed by more than 0.03, all had frequent (one in 20) ectopic contractions. The distorted ventricular volume curves were effectively restructured by the constraining procedure, changing the end-systolic volume and EF. Computer modeling showed a linear relationship between the percent of ectopic contractions and the underestimate of ejection fraction. One ectopic beat in ten led to a 5% underestimate of EF.

Effective penetration of the lung periphery using radioactive aerosols: concise communication.

Radioactive microspheres could offer several advantages over gases in the investigation of pulmonary ventilation. Monodisperse microspheres of human serum albumin have been produced using a spinning-disc generator, and kits were prepared for subsequent labelling with technetium-99m. The average labeling efficiency was 88% and unlabeled Tc-99m was removed before aerosol delivery. A simple system was constructed to nebulize and deliver dry monodisperse microspheres. The ventilation images obtained were compared quantitatively with the corresponding krypton-81m images, subdividing the lung regions into inner, central, and peripheral zones. No significant difference was found in the proportions of the total counts for any lung region. There was good agreement between the distributions of microspheres obtained on separate days (r = 0.97, p less than 0.0001), An "aerosol penetration index" was defined as the ratio of the peripheral to the inner counts for the microspheres normalized by the corresponding ratio for krypton-81m. The mean value of this index for 16 normal subjects was 0.98 +/- 0.23 (s.d.), indicating that the microspheres had achieved penetration of the lung periphery. For patients with chronic obstructive lung disease, more localized defects were observed with the microspheres than with krypton-81m. The mean penetration index for this group was only 0.69 +/- 0.21 (s.d.). This was significantly different from the value for normal subjects (p less than 0.002).

The use of felodipine in the treatment of severe hypertension.

To investigate the use of felodipine in severe hypertension 2 separate studies were carried out. In the first study, 101 patients on a fixed combination of atenolol 100mg and chlorthalidone 25mg who required additional or 'third line' therapy for proper control, were randomised to either felodipine or hydralazine and the dosage was increased if the supine diastolic blood pressure was greater than 90mm Hg. Felodipine reduced blood pressure more effectively than hydralazine and the incidence of adverse reactions was similar in both groups. In the second study, 17 patients with severe hypertension (WHO stage III), who had not been controlled by therapy with atenolol, thiazide diuretic and hydralazine, prazosin or nifedipine were studied. Patients were subsequently controlled by a combination of atenolol, frusemide or bumetanide, and minoxidil. Once stabilised, the patients then took part in a double-blind crossover study comparing minoxidil and felodipine. The patients' blood pressure was the same on both treatment regimes but their bodyweight was lower after felodipine administration. Felodipine is probably more effective than hydralazine and as effective as minoxidil in treating severe hypertension. As felodipine is usually well tolerated it should prove a useful drug in treating refractory hypertension.

Left ventricular function after anisoylated plasminogen streptokinase activator complex.

Limitation of the reduction in left ventricular function after acute myocardial infarction is an important indicator of benefit following thrombolytic therapy. Therefore, left ventricular function was studied by radionuclide ventriculography in 91 patients entering 3 separate studies of anisoylated plasminogen streptokinase activator complex (APSAC) administered within 4 hours of acute myocardial infarction. Global left ventricular ejection fraction was measured at 10 days and at 6 months to assess early and late effects of therapy, with particular emphasis on the timing of treatment and the site of infarction. Successful therapy with APSAC in anterior infarction resulted in preservation of left ventricular function at 10 days. The magnitude of benefit declined with increasing symptom duration before treatment, and was maintained at 6 months in those patients without reocclusion. The benefit of successful therapy was less marked in the inferior infarct group at 10 days. By 6 months, no significant benefit was detected because of an increase in ejection fraction in the placebo and occlusion or reocclusion group with inferior infarction. Early therapy results in greater preservation of left ventricular function, and recovery of function may be more rapid than with later treatment. More emphasis on early administration of thrombolytic therapy is indicated.

Effects of felodipine on resistance and capacitance vessels in patients with essential hypertension.

The acute cardiovascular effects of oral felodipine (0.05 mg/kg and 0.1 mg/kg) were studied using radionuclide methods in 14 hypertensive patients. Eight were previously untreated and 6 had been treated with atenolol 100mg daily for a least 1 month. The maximal effects were observed 60 minutes after the first oral dose and no greater effect was observed with the higher dose. Felodipine caused a reduction in systemic vascular resistance, with a fall in blood pressure and an increase in cardiac output and left ventricular ejection fraction. Those responses were presumably mediated by the reduction in afterload, as they were not modified by pretreatment with atenolol. There were no changes in venous capacitance and the overall pattern of response was similar to that noted with hydralazine. Thus, in hypertensive subjects felodipine acts as a potent arteriolar vasodilator. The results suggest the drug may be an effective means of controlling hypertension, particularly when given in combination with other antihypertensive therapy.

Pulmonary hypertension and right ventricular function in patients with COPD.

In 100 patients with chronic obstructive pulmonary disease (COPD), we found no significant correlation between simultaneous measurements of right ventricular ejection fraction, using radionuclide ventriculography, and pulmonary arterial pressure. There was, however, a weak but significant correlation between right ventricular ejection fraction and the pulmonary vascular resistance (r = 0.40, p less than 0.005). In 52 of these patients, 37 with pulmonary hypertension, right ventricular end-systolic volume index was 53 +/- 21 ml.m-2 and end-diastolic volume index was 86 +/- 27 ml.m-2, compared with a calculated mean of 33 ml.m-2 and 79 ml.m-2, respectively, for normal subjects. In 24 of these patients where the measurements were made at rest and on exercise, the mean right ventricular end-systolic volume increased from 66 +/- 20 ml.m-2 to 87 +/- 32 ml.m-2, with an increase in right ventricular systolic pressure from 28 +/- 9 mm Hg to 55 +/- 15 mm Hg. Analysis of the slope of the right ventricular end-systolic pressure volume relationship at rest and on exercise suggested relatively normal right ventricular contractility in the majority of patients. Thus, in these patients with stable COPD, despite the presence of pulmonary hypertension, right ventricular contractility remained relatively normal.

Long-term effects of cold cardioplegic myocardial protection in the rat.

The long-term histologic effects of the use of two cold cardioplegic solutions (St. Thomas' and saline) were studied and compared in a model of heterotopic cardiac transplantation in rats of isogeneic strain. After cold cardioplegic arrest, hearts were stored for varying times ("minimal," 30, or 90 minutes) in one of the solution prior to transplantation, giving a total of six groups (five animals in each group). Early assessment of myocardial injury 48 hours after transplantation was by the uptake of technetium 99m pyrophosphate and by measurement of serum creatine kinase activity. Late assessment of myocardial injury at 3 months after transplantation was by quantitative histologic examination. The findings indicated that significant myocardial fibrosis occurred in hearts stored in both solutions for the longest storage period (90 minutes) and that St. Thomas' cardioplegic formula conferred better myocardial protection after 90 minutes' storage than did cold saline, as judged by the degree of histologic injury at 3 months (p less than 0.025). Significant correlation was found between long-term histologic changes at 3 months and the uptake of technetium 99m pyrophosphate (p less than 0.001) and serum creatine kinase activity (p less than 0.05) assessed at 48 hours. Uptake of technetium 99m pyrophosphate and increased serum creatine kinase activity was demonstrated 48 hours after injury in animals having no detectable histologic injury at 3 months. These observations indicate that there may be technetium 99m pyrophosphate uptake and enzyme release from reversibly damaged myocardial cells.

Roentgenographic study of blood flow redistribution in acute pulmonary edema in dogs.

Acute pulmonary edema was induced in anesthetized vertically suspended dogs by inflating a ballon catheter in the descending thoracic aorta and infusing saline. Indices measured included pulmonary arterial pressure, left ventricle end-diastolic pressure, and cardiac output. Pulmonary blood-flow distribution was determined in frozen tissue after injecting radioactive macroaggregates labelled with 125-I, 131-I, and 99m-Tc. Randomized serial chest roentgenograms were interpreted by three radiologists not taking part in the physiologic studies. When left ventricular end-diastolic pressure was raised initially, roentgenograms usually revealed only interstitial edema. As alveolar edema increased, blood-flow to the lung bases decreased as measured physiologically. The roentgenographic and physiologic data show that in acute experiments on normal lungs, blood-flow redistribution occurs in association with alveolar edema rather than interstitial edema.

The use of captopril and captopril plus frusemide as antihypertensive agents in non-insulin dependent diabetes.

After all previous antihypertensive treatment had been stopped, blood pressure and glucose tolerance were measured in 16 hypertensive non-insulin treated diabetics before and again six weeks after treatment with captopril, an angiotensin-converting enzyme inhibitor. Supine blood pressure fell from 184 +/- 4.1/103 +/- 2.6 to 165 +/- 5.2/88 +/- 2.1 mmHg (P less than 0.001) and erect from 179 +/- 5.2/102 +/- 3.2 to 158 +/- 5.6/87 +/- 2.6 mmHg (P less than 0.005). The area under the oral glucose tolerance curve fell from 2313.6 +/- 154 to 2192.8 +/- 146 mmol/min/l (P less than 0.02). There was no change in plasma insulin, total glycosylated haemoglobin or fructosamine. Four patients who failed to show lowering of supine diastolic pressure below 95 mmHg were additionally given oral frusemide with further improvement in blood pressure and no alteration in carbohydrate intolerance. It was concluded that captopril alone is usually an effective antihypertensive agent in non-insulin dependent diabetes with the addition of frusemide benefiting resistant cases. Glucose intolerance did not worsen with either captopril alone or captopril plus frusemide.

Acute effects of intravenous phosphodiesterase inhibition in chronic heart failure: simultaneous pre- and afterload reduction with a single agent.

Intravenous phosphodiesterase inhibition with milrinone is known to have a beneficial effect on haemodynamics in chronic heart failure. Its effect on lower limb capacitance vessels has not been previously investigated. We have studied the effect of intravenous milrinone in 10 patients with severe chronic heart failure. Thirty minutes after commencement of treatment mean cardiac index had risen by 26% and pulmonary artery wedge pressure, systemic vascular resistance and right atrial pressure had fallen by 51, 24 and 89%, respectively (p less than 0.05 for all changes). These changes were maintained for the 2 h observation period with no evidence of tolerance and were accompanied by a 17% increase in venous volume (p less than 0.01) and a 42% increase in ejection fraction (p less than 0.001) at 30 min; at 120 min the improvement in ejection fraction had been maintained and a further increase in venous volume to 38% above baseline was evident. The increase in venous volume was strongly correlated with the decrease in mean pulmonary artery wedge pressure and mean right atrial pressure at 30 min and 2 h (r = -0.80 and -0.69 for mean pulmonary artery wedge pressure, r = -0.88 and -0.56 for mean right atrial pressure). Milrinone therefore has clinically important venodilating properties, in addition to its known effects as an arterial vasodilator and a positive inotrope.

Clinical effects and kinetic properties of intravenous APSAC--anisoylated plasminogen-streptokinase activator complex (BRL 26921) in acute myocardial infarction.

Fifty patients with a first myocardial infarction presenting within 4 hours of the onset of symptoms were treated with intravenous anisoylated plasminogen-streptokinase activator complex (APSAC-BRL 26921). Vessel patency with good flow was documented in 88%. The left ventricular ejection fraction declined with the duration of symptoms before treatment (r = -0.53, P less than 0.001). The correlation persisted for the group with anterior infarction (r = -0.46, P less than 0.05) where the mean left ventricular ejection fraction prior to discharge from hospital was 36 +/- 9% compared to 49 +/- 7% for the group with inferior infarction. Reinfarction developed in 12% and mortality at 6 months for the whole group was 6%. A degree of systemic fibrinolysis did occur with a fall in mean plasma fibrinogen from 3.20 g/l to 1.08 g/l. A pharmacokinetic study was performed in six patients demonstrating a clearance half-life of fibrinolytic activity of 87.5 +/- 5.0 min. APSAC is an effective intravenous thrombolytic agent with a relatively long half-life of fibrinolytic activity.

Sample collection and processing for the assay of plasma renin activity. A comparison of anticoagulants and inhibitors.

Plasma renin activity was measured in samples collected in lithium heparin, sodium heparin, and ethylenediaminetetraacetate. The samples were incubated under two widely used sets of conditions to generate angiotensin I, and the results were compared. Under certain incubation conditions, the absence of ethylenediaminetetraacetate from the sample tube produced low plasma renin activity values. This was obviated by using an alternative incubation medium and was not, therefore, due to direct inhibition of renin by heparin. These lower values were not seen in samples from patients receiving captopril. This suggests that the discrepant values were due to some angiotensin I conversion to angiotensin II and lower homologues in the incubates. Sodium heparin samples compared closely with lithium heparin samples, indicating that the presence of lithium is not significant. These results show that, provided the incubation conditions are suitably modified, samples collected into lithium or sodium heparin can be used for measurement of plasma renin activity.

A rotating transducer real-time scanner for ultrasonic examination of the heart and abdomen.

A mechanical real-time ultrasonic scanner utilizing a rotating transducer head has been successfully applied clinically to visualize the heart and abdomen. The design features of this scanner are discussed. The small dimensions and the 90 degree field of view of the sealed oil-filled transducer head optimize visualization of the heart avoiding bone and lung. The single point of entry aspect of this scanner results in a good field of view from any point on the abdominal surface. For example, in upper abdominal studies the liver and kidney can be readily viewed. Rapid and thorough searching of the abdomen is easily carried out and good quality selected sections can be captured by optimizing frame rate and angle of view. In obstetrical applications the complete mature fetus can be visualized using the alternative large 180 degree field of view.

The preparation and in vivo behaviour of 111In-oxine labelled neutrophils separated from whole blood using mono-poly resolving medium.

using a single step separation procedure, we have developed a method for labelling human neutrophils with 111In-oxine. This method allows a rapid separation of neutrophils from whole blood, with negligible mononuclear or red cell contamination. Preliminary studies using 111In-labelled neutrophils show minimal lung retention and early accumulation in the spleen consistent with viable cells. In addition, focal accumulation of 111In has been imaged in patients with localized inflammation or sepsis.

Radionuclide studies of left ventricular function in normal subjects.

The effects of age and exercise on cardiac function in a normal male population have been assessed by ECG-gated radionuclide ventriculography. Fifty-nine subjects aged from 25 to 54 years were studied (mean 44 +/- 10 S.D. years). Resting left ventricular ejection fraction (LVEF) was 0.54 +/- 0.07 and this increased by 0.07 +/- 0.05 during supine submaximal exercise at 75 watts. The mean increase in cardiac output on exercise was 93 +/- 30%. Stroke volume increased on exercise by 23 +/- 13% and end-systolic volume decreased by 10 +/- 16%. There was a weak correlation (P less than 0.05) between age and change in LVEF on exercise but the increase in cardiac output on exercise was not age dependent. It is important to use an age matched control population in any study of cardiac function.

Left ventricular function and the distribution of pulmonary and total blood volume in hypertensive and normotensive man.

Using radionuclide methods the relationship between total and central blood volume and left ventricular function was studied in 12 patients with untreated essential hypertension and contrasted with the findings in eight normotensive subjects. The principal findings were of an increased stroke volume and end-diastolic volume with an increase in the ratio of pulmonary to total blood volume in the hypertensive patients. Left ventricular ejection fraction was similar in both groups but end-systolic volume was increased presumably in response to the increased afterload of the ventricle. The increased pulmonary blood volume may be secondary to altered left ventricular mechanics and not a primary determinant of cardiac function.

Regional tidal volume assessed by gated lung imaging.

We have measured regional lung tidal volumes and functional residual capacities by accumulating and framing iso-volumic images while the patient rebreathes 127Xe. As the lung changes shape during ventilation corrections for changes in geometry were obtained by simultaneous collection of 99Tcm counts from the gated perfusion scan. Regions of interest were made to vary throughout the respiratory cycle so that a region had always the same value of 99Tcm counts. From the corrected 127Xe counts regional tidal volumes (TVr) and functional residual capacities (FRCr) were derived. In patients with established chronic bronchitis and emphysema FRCr were greater and the ratio TVr/FRCr decreased compared with patients with relatively normal static and dynamic lung volumes. Preliminary studies suggest that this ratio was a better discriminator between normal and abnormal regional function than estimates of regional xenon washout. Studies with xenon-133 have contributed to our understanding of the physiology of ventilation but have contributed somewhat less to routine clinical practice. This results in part from the unsatisfactory physical properties of xenon-133. Its relatively low gamma ray energy of 80 keV results in significant self-absorption losses and the activity which may be administered is limited by the radiation dose from the associated beta particles so that relatively poor counting statistics are obtained. With inhaled technetium-99m (99Tcm) microspheres imaging conditions are greatly improved but the distribution of these particles may not equate with the distribution of ventilation particularly if wet particles are used. Moreover, simultaneous microsphere perfusion scans with technetium-99m as a label are impossible. Krypton-81m gas has a suitable energy but the short half-life of the rubidium-81m generator (4.7 h) makes supply difficult and the ultrashort half-life of the krypton-81m gas (13 s) leads to problems in calculating the indices of ventilation. Xenon-127 (127Xe) gas has a more favourable dosimetry profile than xenon-133 because it does not have associated beta particles. Further it has an energy (203 keV) suitable for modern gamma cameras and may be used in the presence of injected 99Tcm microspheres to provide simultaneous ventilation/perfusion imaging. Conventional techniques have assumed that a static image of a dynamic process is adequate. As the lungs move during imaging, some account of this respiratory movement should be made.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic arterial and venous effects of captopril in congestive cardiac failure.

OBJECTIVE: To determine whether captopril alters peripheral venous tone in patients with congestive cardiac failure. DESIGN: Open study of patients at start of captopril treatment and three months later. SETTING: A hospital gamma camera laboratory. PATIENTS: 16 Men with congestive cardiac failure in New York Heart Association class II or III, aged 57-73. INTERVENTIONS: Patients were initially given 500 micrograms sublingual glyceryl trinitrate followed by 25 mg oral captopril. The study was then repeated after three months' captopril treatment. MAIN OUTCOME MEASURES: Previously validated non-invasive radionuclide techniques were used to measure changes in central haemodynamic variables and peripheral venous volumes in the calf. RESULTS: After 25 mg captopril there were falls in blood pressure and relative systemic vascular resistance and increases in cardiac index and left ventricular ejection fraction. This was accompanied by a 16% increase in peripheral venous volume (95% confidence interval 13.4% to 18.4%, p less than 0.01), which compared with an 11% increase after 500 micrograms glyceryl trinitrate (10% to 12%, p less than 0.01). Eleven patients were restudied after three months' continuous treatment with captopril. The resting venous volume was higher than it had been initially, by about 10%, and increased by a further 8.4% after 25 mg captopril (5.4% to 11.4%, p less than 0.05). CONCLUSIONS: Captopril is an important venodilator. Venous and arterial dilatation are produced short term and during long term treatment.