Effects of lymphatic transport of enzyme on plasma creatine kinase time-activity curves after myocardial infarction in dogs.
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Biomedical subjects
Publications and source records attributed to R Roberts.
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To determine whether nifedipine, a calcium antagonist, protects ischemic myocardium, conscious dogs were subjected to coronary occlusion and given nifedipine by intravenous infusion beginning 30 minutes after the onset of ischemia and lasting for 24 hours while systemic arterial pressure, left atrial pressure, and cardiac output were monitored. Local myocardial perfusion at selected intervals after coronary occlusion was assessed with radioactive microspheres injected into the left atrium. In regions of myocardium exhibiting moderately depressed flow 29 minutes after occlusion in control dogs (n = 8), flow was significantly greater 3 and 23.5 hours later, reflecting increases in collateral perfusion. Corresponding zones of myocardium in treated dogs (n = 9) exhibited significantly greater increases in flow at each interval after occlusion (P less than 0.05). Furthermore, myocardial creatine kinase depletion (which correlated well with morphometric estimates of necrosis) in myocardium matched for ischemia prior to treatment was 1.5 to 3 times less in treated than in control dogs (P less than 0.05). Thus, nifedipine produced sustained increases in collateral flow and reduced myocardial ischemic injury.
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A radioimmunoassay for the MB isoenzyme of creatine kinase (myocardial isoenzyme) has been developed based on an antibody to the B subunit. The antibody cross-reacts with MB but exhibits no cross-reactivity with MM C.K. even when present in 20 000 molar excess over MB C.K. unlabelled MB but not MM (up to 85 000 mI.U./ml) competitively displaces precipitable counts. This sensitive and specific radioimmunoassay accurately detects MB in a concentration of 0-01 mI.U./ml. Plasma MB C.K. in 100 healthy controls averaged 1 mI.U./ml+/-0-6 (S.D.), similar to results in 20 patients with chest pain without infarction. In contrast, in 50 patients with myocardial infarction MB C.K. values averaged 97+/-30 mI.U./ml. When hourly blood-samples from 10 of these patients admitted within an hour of chest pain were analysed by R.I.A., a 100% increase in MB was detectable within four hours of the onset of chest pain, generally before total C.K. exceeded the normal range. Development of an R.I.A. suitable for assay of an isoenzyme in plasma provides a specific and sensitivity assay of MB C.K., facilitating analysis of multiple samples and early detection of myocardial infarction. It may also serve as a prototype for radio-immunoassay of multiple forms of other enzymes of clinical importance.
To determine whether coronary dilatation and decreased myocardial oxygen requirements resulting from administration of verapamil, a calcium and slow current antagonist, protect ischemic myocardium in conscious dogs, we studied 15 treated and 15 control animals after coronary occlusion. Verapamil (0.2-0.7 mg/kg/h) was given by continuous infusion for 17 h beginning 5 h after the initial plasma creatine kinase (CK) elevation after coronary occlusion. Observed infarct size and infarct size predicted before verapamil were estimated from hourly plasma CK values and infarct size was estimated also from myocardial CK depletion measured directly, 24 h after occlusion. Changes in heart rate, blood pressure, and frequency of premature ventricular complexes (recorded every 30 min) after occlusion were similar in treated and control dogs. Coronary flow after verapamil, measured with radioactively labeled microspheres, did not increase in ischemic zones but increased by 90% in normal myocardium (p less than 0.05). The differences between observed and predicted infarct size estimated from plasma CK changes in treated and controls were similar (3.0 +/- 2.2 (S.E.) and 2.0 +/- 1.4 CK-g-eq), and myocardial CK depletion was also comparable in the two groups (25 +/- 2% and 23 +/- 2%). Thus although verapamil, administered five hours after the initial plasma CK elevation, increased coronary flow in normal myocardium, it did not augment flow in ischemic tissue or limit the extent of infarction.
Antibodies specific for the B and M subunits of creatine kinase (ATP: creatine N-phosphotransferase, EC 2.7.3.2) isoenzymes were obtained by immunization of rabbits with canine BB and MM creatine kinase. A radioimmunoassay capable of measuring picomolar amounts of creatine kinase isoenzymes has been developed which measures concentrations of intact isoenzymes rather than activity. It should aid in elucidating the metabolism and breakdown of creatine kinase isoenzymes.
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The diagnostic significance of Q waves in Leads II, III, and aVF when analyzed retrospectively remains controversial. Persistence of the Q wave on inspiration is said to reflect inferior infarction. Studies in the past, which have evaluated respiratory variation as a means to separate normal from abnormal Q waves, were performed utilizing the ECG only, were often retrospective, and frequently there was inadequate documentation of myocardial infarction. The present study was performed prospectively and utilized both electrocardiographic and vectorcardiographic analysis of the first 30 msec. vector before and after inspiration in 33 patients with documented acute myocardial infarction and in 22 normal volunteers. Inferior myocardial infarction was documented prospectively by ECG, VCG, by conventional enzymes, and by MB CPK. The VCG demonstrated increased sensitivity over that of the ECG, but the effect of inspiration noted on ECG and VCG was variable and extremely unreliable as a means of separating normal from abnormal Q waves.
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Although technetium-99m stannous (99mTc[Sn]) pyrophosphate has been shown to be a specific and sensitive index of myocardial infarction, abnormal images have been reported in patients with unstable angina or ventricular aneurysm. Sixty-one subjects--33 patients subjected to maximal treadmill stress testing, 23 normal subjects and 5 patients with a calcified aortic or mitral valve--underwent imaging with 99mTc(Sn) pyrophosphate to determine whether abnormal images are associated with (1) exercise-induced ischemia, (2) delayed clearance of tracer from the blood pool, or (3) calcified intracardiac structures. Myocardial injury was excluded on the basis of normal MB creatine kinase (CK) values in all patients with stress testing. All eight patients with an abnormal exercise stress test had normal images. Four of 25 patients with a normal exercise stress test had diffusely abnormal images. In some normal subjects diffusely abnormal images were present 60 minutes after injection of the tracer, but became normal 90 to 120 minutes after injection. Variations in clearance of tracer from the blood pool were noted in this group. Patients with a calcified aortic or mitral valve had normal images. We conclude that (1) exercise-induced ischemia is not associated with abnormal 99mTC(SN) pyrophosphate images; (2) images are not necessarily abnormal in patients with a calcified valve; and (3) delayed removal of tracer from the cardiac blood pool may result in diffusely abnormal images even in normal subjects; in these cases, repeat images should be obtained at least 2 hours after injection of the tracer to avoid false abnormal images.
This study was designed to evaluate the effects of dobutamine, a new cardioselective beta adrenergic agonist, on cardiac performance and myocardial injury in patients with evolving myocardial infarction. Results in 16 patients given dobutamine (1 to 40 microng/kg per min for 24 hours) were compared with those in two groups of control patients: one of 16 patients matched for predicted infarct size, and the other of 16 patients matched for early ventricular dysrhythmia, analyzed by computer. Infarct size was predicted from plasma creatine kinase (CK) values during the first 7 hours after the initial elevation, before infusion of dobutamine. Overall observed infarct size was estimated from hourly CK values for 48 hours (including those before and after administration of dobutamine). In all patients technetium-99m (stannous) pyrophosphate scans were positive for myocardial infarction. Dobutamine increased cardiac output (assessed by thermodilution) from 4.9 +/- 0.37 (mean +/- standard error) to 6.0 +/- 0.38 liters/min (P less than 0.05) and decreased pulmonary arterial occlusive pressure from 21.5 +/- 2.7 to 16.7 +/- 1.6 mmHg (P less than 0.01) without significantly altering heart rate or systemic arterial blood pressure. The ratio of observed to predicted infarct size, the frequency of independently detected reinfarction or extension of infarction and the frequency of premature ventricular complexes were similar in control and treated patients. Thus administration of dobutamine in doses sufficient to improve ventricular performance after myocardial infarction does not exacerbate myocardial injury or ventricular dysrhythmia.
Estimates of infarct size based on serial plasma creatine kinase (CK) changes have been made utilising the disappearance rate of CK from blood (kd) as one parameter. This study was performed to evaluate the effects on CK disappearance of myocardial infarction per se and selected drugs often used in the management of patients with myocardial infarction. Fifty-six conscious dogs were studied. Canine myocardial CK was isolated and radioactively labelled. Experiments were performed with intravenous injections of unlabelled CK or with radioactively labelled material. After injection, plasma CK activity declined monoexponentially (r = -0.95, n = 30) exceeding the rate of CK disappearance in vitro in whole blood or plasma. Three successive daily determinations of kd differed by less than or equal to 10% in the same dog (n = 5). Removal of radioactively labelled protein from plasma paralleled disappearance of plasma CK enzyme activity for several hours after i.v. injection of 14C-CK (n = 5). Myocardial infarction after occlusion of the left anterior descending coronary artery altered kd by less than 10% (n = 5) estimated after i.v. injection of 14C-CK. Administration of large doses of Nembutal (30 mg-kg-1), morphine (2 mg-kg-1), or Valium (1 mg-kg-1) decreased kd markedly (n = 17), but low doses of morphine (0-2 mg-kg-1) or Valium (0-1 mg-kg-1) did not substantially diminish kd. Thus, enzymatic estimates of infarct size are not likely to be influenced by changes in kd occurring during myocardial infarction. However, modification of estimates may be required when pharmacological interventions are employed, capable of altering CK disappearance.
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Coronary bypass surgery may be associated with an increased perioperative mortality rate in patients with unstable compared to stable angina. The mortality rate is excessively high when surgery is performed during evolving myocardial infarction. Elevated plasma MB CPK isoenzyme activity is a remarkably sensitive and specific marker of myocardial damage. Accordingly, we studied 111 patients with unstable angina to determine whether exclusion of patients with initially elevated MB CPK improves the perioperative mortality rate. Plasma MB CPK activity was assayed prior to catheterization and every 2 hours therafter. Of the 111 patients, 16, with initially elevated MB CPK activity, were excluded and managed medically. Catheterization was performed in 59 patients, and severe vessel obstruction was documented in 55. Coronary bypass surgery performed in 47 patients was associated with a mortality rate of 4 per cent. Thus, after exclusion of patients with evolving infarction by MB CPK isoenzyme analysis, catheterization and coronary bypass surgery in patients with unstable angina resulted in a mortality rate comparable to that in patients with stable angina.