Cardiac and Skeletal Muscle Myoglobin Release After Reperfusion of Injured Myocardium in Dogs With Systemic Hypotension
Background Myoglobin (Mb) is an intramyocardial protein that is released into the systemic circulation and rapidly cleared via the kidneys after myocardial injury. Arterial Mb concentration–time curves have been studied in humans and dogs in the setting of acute coronary artery occlusion, and the rate of rise of Mb is both sensitive and specific as an indicator of successful coronary artery reperfusion. Systemic hypotension may alter Mb kinetics and impact on the utility of this method by causing Mb release from ischemic skeletal muscle and by decreasing renal Mb clearance. This study was undertaken to determine whether analysis of Mb kinetics remains accurate in identifying coronary reperfusion in the setting of systemic hypotension.
Methods and Results Eighteen chronically instrumented dogs were made hypotensive by being bled via a large-bore femoral artery catheter into a reservoir adjusted to maintain a constant mean arterial pressure of 50 mm Hg for 8 hours. After the first hour of hypotension, each dog was studied under one of the following three protocols: group 1, 2 hours of mid–left anterior descending artery (LAD) occlusion followed by 5 hours of unlimited reperfusion; group 2, 7 hours of mid-LAD occlusion without reperfusion; or group 3, 7 additional hours of hypotension alone. Systemic lactate extractions demonstrated a shift to anaerobic metabolism in skeletal muscle and confirmed that shock was established in all animals. Regional arteriovenous Mb differences in group 1 animals demonstrated release of large amounts of Mb from reperfused myocardium; in contrast, smaller amounts of Mb were released both from skeletal muscle rendered ischemic by hypotension and from myocardium rendered ischemic by coronary occlusion without reperfusion. In group 1 dogs, arterial Mb rose rapidly immediately after reperfusion, with peak Mb occurring 108±24 minutes (mean±SEM) after vessel reopening. In group 2 and group 3 dogs, arterial Mb rose more slowly, such that peak Mb was not reached within 8 hours in 11 of 12 animals. The linear rate of rise of arterial Mb over the first hour of reperfusion in group 1 dogs was 51±16 ng · mL−1 · min−1. This slope was significantly greater than slopes determined over the same time period in dogs occluded and not reperfused (group 2, 1.2±0.6 ng · mL−1 · min−1) and in those hypotensive alone (group 3, 0.8±0.5 ng · mL−1 · min−1). All the slopes of group 2 and group 3 dogs fell below the range of slopes of group 1 dogs. In contrast to slopes of the Mb concentration–time curves, linear creatine kinase slopes were significantly less sensitive in predicting reperfusion.
Conclusions Analysis of plasma Mb kinetics allows early identification of coronary reperfusion after myocardial injury even in the presence of significant systemic hypotension.
Myoglobin (Mb) is an intramyocardial protein that is released into blood after myocardial injury.1 2 3 4 5 6 7 8 The kinetics of plasma Mb concentration after coronary artery occlusion and reperfusion have been well defined.8 9 10 11 After reperfusion of a 2-hour mid–left anterior descending artery (LAD) occlusion in animals, Mb concentration rises rapidly, with the peak value occurring within 40 minutes.12 Mb concentration–time curves fit well to a one-compartment biexponential equation that can be used to calculate an appearance rate time constant (ka).13 14 The magnitude of ka correlates with reperfusion and has differentiated successful reperfusion from nonreperfusion in both human and animal studies.15 In addition, estimates of ka based on the slope of the rapid rise of Mb have also predicted reperfusion in humans with good specificity compared with patency demonstrated by angiography.15
The utility of this noninvasive method for predicting coronary reperfusion has not been investigated in the setting of systemic hypotension. Hypotension can impact on Mb kinetics by (1) decreasing blood flow to the kidneys (the sole site of Mb clearance)16 and (2) causing Mb release from ischemic skeletal muscle. These factors could decrease the sensitivity of this method in identifying coronary reperfusion and thereby attenuate its utility in patients who develop hypotension after acute myocardial infarction.
The present study was undertaken to determine whether analysis of Mb kinetics remains useful in demonstrating coronary reperfusion after myocardial injury in the presence of systemic hypotension and to compare Mb and creatine kinase (CK) kinetics in this setting. To elucidate the effects of hypotension on differential Mb release from myocardium and skeletal muscle, regional arteriovenous (A-V) Mb differences were analyzed.
Eighteen mongrel dogs weighing 20 to 27 kg were sedated with fentanyl and thiamylal sodium, anesthetized with nitrous oxide and halothane, and ventilated through a Narkovet positive-pressure ventilator. Under sterile conditions, a left thoracotomy was performed in each, and one or two pneumatic occluders were placed on the LAD just distal to the first or second diagonal branch. Electrodes were sewn onto the epicardium in the distribution of the LAD. Catheters were placed in the aorta and left atrium for monitoring of blood pressure and withdrawal of arterial blood specimens, respectively. In 12 animals, an extravascular Doppler probe was placed around the LAD distal to the occluders. All animals were allowed to recover for at least 7 days so that elevated Mb and CK levels secondary to skeletal muscle injury could return to normal. Intramuscular butorphanol tartrate was used for postoperative pain control for up to 72 hours.
On the day of the acute study, each animal was sedated with sodium pentobarbital, anesthetized with nitrous oxide and halothane, and ventilated with a Harvard positive-pressure respirator. A cutdown was performed on the external jugular vein and a catheter advanced through the coronary sinus under fluoroscopic control into the great cardiac vein, thereby allowing semiselective sampling from the area of myocardial injury in the distribution of the LAD. Catheters were also placed through cutdowns into the left femoral vein and the right femoral artery. The former was used for sampling of venous blood from a large skeletal muscle bed and the latter for arterial connection via a large-bore tube to a saline-filled reservoir. Each animal was anticoagulated with 10 000 U IV heparin followed by 5000 U every 2 hours throughout the acute study. Coronary Doppler flow and the epicardial electrogram were monitored throughout the experiment. Intravenous succinyl choline was used as required to prevent skeletal muscle contraction.
Hypotension was established in each animal by opening the femoral artery line and allowing free flow of blood into the reservoir. Aortic pressure was monitored continuously, and the mean arterial pressure (MAP) was maintained near 50 mm Hg throughout each experiment by manual adjustment of the height of the reservoir. The heart rate, MAP, and volume of blood shifting between dog and reservoir were measured at 20-minute intervals.
Three different protocols were carried out, with six dogs in each group. After 1 hour of hypotension, animals in group 1 underwent a 2-hour LAD occlusion followed by 5 hours of unlimited reperfusion. After a similar 1-hour equilibration period, animals in group 2 underwent a 7-hour LAD occlusion without reperfusion. Animals in group 3 underwent 8 hours of hypotension alone without coronary artery occlusion.
Animals that underwent LAD occlusion (ie, those in groups 1 and 2) were pretreated with an IV bolus of 2 mg/kg lidocaine given just before occluder inflation. Any subsequent ventricular arrhythmia was treated with up to 500 mg IV procainamide as needed (given in 100-mg increments). LAD occlusion was verified in each case by the Doppler flow probe and by ECG changes indicative of myocardial injury, including ST-segment elevation, loss of R-wave voltage, and/or widening of the QRS complex. In each animal, a stable sinus rhythm was established within 20 minutes of LAD occlusion. Two animals (one in group 1 and one in group 3) required addition of normal saline to the reservoir because of a persistent MAP below 50 mm Hg despite reinfusion of all the reservoir blood.
Arterial, venous, and coronary sinus blood samples were drawn every 20 minutes for determination of Mb and every hour for determination of CK. Immediately after reperfusion in group 1 dogs, Mb and CK samples were drawn more frequently (Mb samples from all sites at 10-minute intervals for 2 hours and CK samples from all sites at 30-minute intervals for the duration of the experiment). Arterial and venous specimens were also drawn hourly in every animal for determination of lactate concentration. CK specimens were preserved with EDTA and 2-mercaptoethanol, both in 10-mmol/L concentrations. Lactate specimens were preserved with 2 g% sodium fluoride. All specimens were stored at −7°C between collection and analysis.
Standard radioimmunoassay methods developed in our laboratory and previously reported were used to determine Mb concentrations.16 The lower limit of detection of this assay is 32 ng/mL. Reproducibility studies in our laboratory demonstrated a mean difference of duplicate measurements of 8.6±0.9% (SEM). Standard enzymatic methods were used to determine total CK activities and lactate concentrations (Sigma Chemical Co).17 18 The lower limit of detection of CK activity was 2 IU/L, with a mean difference of duplicate measurements of 3.2±0.2%.
Arterial Mb concentration–time curves were constructed for each animal. The curves generated in group 1 animals were fit by least-squares analysis to the biexponential equation
where ka is the appearance rate constant, kd the disappearance rate constant, t0 the time of initial Mb appearance in blood after occluder release, and A a scaling factor related to peak arterial Mb concentration. The slope of the rapid-rise portion of the curve was calculated two different ways: (1) The slope of the tangent at the midpoint of the first hour of reperfusion was determined from the first derivative of the biexponential equation and (2) linear slopes were determined from first-order least-squares regression lines fit to the actual data points during the first hour after reperfusion. Because curves in groups 2 and 3 animals could not be fit to the biexponential equation (see below), slopes were determined for these curves only by least-squares regression lines using the data points over the fourth hour of hypotension. This time period correlated with the time period analyzed in group 1 animals. Hence, slopes determined by linear regression over the fourth hour of each experiment were used to compare group 1 animals with those in groups 2 and 3. Time to peak arterial Mb concentration was also determined in each animal.
CK kinetics were also evaluated. Straight-line slopes were determined over the fourth hour of each experiment by least-squares analysis, and CK slopes in group 1 were compared with those in groups 2 and 3. Time to peak CK was also determined in each animal.
In all animals, Mb A-V differences were determined across the myocardium in the LAD distribution and across skeletal muscle in the left femoral artery distribution. A-V Mb differences for myocardial and skeletal muscle were analyzed to determine the site of predominant ischemic injury in each animal. Systemic A-V lactate differences were also measured in each animal to verify the presence of physiologically significant shock.
Plasma volumes were determined in nine animals at baseline and at hours 4 and 8 of the experimental protocol. For each determination, a known amount of indocyanine green (ICG) was injected into the femoral vein. Arterial samples were withdrawn every minute for 5 minutes and then every 5 minutes for the next 15 minutes. Plasma was obtained by centrifugation, and the spectrophotometric optical density of each sample was read at 805 nm. ICG concentrations were determined from a standard curve of serial dilutions of ICG in dog plasma, and a semilogarithmic plot of concentration versus time was constructed for each set of determinations. The terminal linear portion of each curve was extrapolated to time zero, and each plasma volume was determined by dividing the total amount injected by the concentration at time zero and then multiplying by 1.14 to correct for trapped plasma and body/venous hematocrit ratio.19
All values used for comparison are reported as mean±SEM. Unpaired two-tailed t tests and ANOVA were used to analyze the grouped data. Standard Pearson correlation coefficients were used to determine the degree of correlation between matched sets of data. Statistical significance is defined as P<.05.
This study is in compliance with FDA guidelines and the animal welfare regulations of our institution and conforms to the guiding principles of the American Physiological Society.
For each group of animals, mean heart rate and MAP at baseline and at hours 1, 4, and 8 are listed in Table 1⇓. In each animal, heart rate increased early in the course of hypotension. MAP was successfully held near 50 mm Hg throughout each experiment. Also shown in Table 1⇓ are mean plasma volume data. There were no statistical differences between groups in mean plasma volume at 0, 4, or 8 hours. The trend in each group, however, was a fall in plasma volume with hemorrhage followed by an increase (albeit to subnormal levels) later in the experimental protocol.
Skeletal muscle lactate extractions were determined hourly in each animal by dividing the A-V lactate difference by the arterial lactate level. The mean percent lactate extraction for each hour of the study was calculated for each group. Before hypotension, lactate extraction was similar in all three groups (9.2±7.8%, 15.3±7.3%, and 11.9±2.8%, respectively; P>.80). During hypotension, there was a rapid and persistent shift to anaerobic metabolism in every animal such that lactate was released from skeletal muscle into venous blood during hours 2 through 8. In all three groups, lactate release was demonstrated in hour 2 of hypotension (−29.7±14.6%, −14.0±7.7%, and −10.3±2.2%, respectively), and lactate extraction values remained negative through the end of the experiment. There was no significant variation in skeletal muscle lactate extraction after the second hour in any group.
Representative Mb concentration–time curves from an animal in each group are illustrated in Figs 1 though 3. In group 1 animals (Fig 1⇓), Mb levels remained relatively low at all three sites through coronary occlusion until unlimited reperfusion was established at hour 3 by release of the LAD occluders. After reperfusion, there was a rapid rise in Mb concentration at all three sites, with peak Mb levels occurring at 108±24 minutes (Table 2⇓). Coronary sinus Mb levels rose more quickly and to a higher level than either arterial or venous Mb. Although some Mb may have been released from skeletal muscle because of hypotension, any such skeletal muscle release was most likely obscured by the high circulating levels of Mb released from the myocardium into the coronary sinus.
In group 2 animals (Fig 2⇓), Mb levels remained relatively low for several hours after LAD occlusion. There was perceptible Mb release into the coronary sinus beginning in the third hour after occlusion, but the absolute level and the rate of rise of coronary sinus and arterial Mb were much lower than in the reperfused (group 1) animals. Beginning approximately 5 hours after LAD occlusion, Mb levels began to rise, but at a rate an order of magnitude lower than in the reperfused animals.
In group 3 animals (Fig 3⇓), a gradual rise in Mb occurred in hours 6 through 8 of hypotension, also at a rate an order of magnitude lower than in group 1 animals. Because of the absence of coronary artery occlusion in group 3 animals, a skeletal muscle A-V Mb difference is appreciated. This finding supports the hypothesis that systemic hypotension leads to skeletal muscle ischemia with Mb release into the systemic circulation; nonetheless, the amount released and its rate of appearance in blood are substantially lower than that released from the myocardium after coronary artery reperfusion.
Arterial Mb concentration–time curves in each reperfused (group 1) animal were fit to a biexponential equation by methods outlined above. The slope of the rapid-rise portion of the curve was calculated two different ways (Fig 4⇓). The slope of the tangent at the midpoint of hour 1 of reperfusion was determined from the first derivative of the biexponential equation. To compare group 1 animals with group 2 and group 3 animals (see below), slopes were also determined for least-squares regression lines fit to the actual data points during hour 1 of reperfusion. As shown in Table 2⇑, these straight-line slopes correlate well with the midpoint tangent lines (r=.82).
Straight-line slopes were also determined over hour 4 in the other two groups of animals (Table 2⇑). The slopes of groups 2 and 3 animals (1.2±0.6 and 0.8±0.5 ng · mL−1 · min−1, respectively) were significantly lower than the slopes of group 1 animals (51±16 ng · mL−1 · min−1; P<.02). Furthermore, each slope in the group 2 and group 3 dogs fell below the range of slopes of group 1 dogs (Fig 5⇓).
Straight-line slopes of CK activity versus time were determined over hour 4 of each experiment. The slopes of group 1 animals (3.10±2.64 IU · mL−1 · min−1) were somewhat greater than those of group 2 and group 3 animals (0.07±0.06 and 0.65±0.43 IU · mL−1 · min−1, respectively; .05<P<.10). However, there was some overlap of individual CK slopes between group 1 animals and the animals in groups 2 and 3.
Time to peak CK was analyzed in a fashion similar to time to peak Mb. Peak CK occurred late in the study protocol in one group 1 animal (270 minutes) and was not reached before completion of the study in the other five. Similarly, peak CK was not reached in any group 2 or group 3 animal.
This study shows that analysis of Mb kinetics is an accurate method of identifying coronary reperfusion after myocardial injury even in the presence of systemic shock. This conclusion is supported by the steeper Mb slopes during the first hour of reperfusion in group 1 animals compared with Mb slopes in group 2 and group 3 animals. This method of analysis is most useful because it relies only on data collected early in the course of myocardial infarction and reperfusion.
Parameters derived from the biexponential equation, such as ka and tangent slopes, were not used for comparison because they could not be consistently obtained during the first 4 hours in group 2 and group 3 animals. To fit Mb curves to such an equation, the downward portion of the curve must be available for analysis. Peak Mb concentration was infrequently reached in these animals before completion of the experiment. The close correlation of straight-line slopes to tangent slopes in group 1 animals (Table 2⇑) and the close fit of the data points to linear regression lines in all animals (mean, r=.80±0.06) lend credence to the use of straight-line slopes for comparison.
In two of six group 2 dogs that were occluded and not reperfused (Fig 2⇑), Mb levels rose late in the experiment. Slopes obtained during this period might falsely indicate successful reperfusion if the time of onset of coronary occlusion were erroneously determined to be 4 to 6 hours later than its actual occurrence. This late rapid rise is most likely a direct result of hypotension causing skeletal muscle Mb release (as indicated by regional Mb differences) late in the experiment. This observation suggests that analysis of Mb kinetics may be difficult in patients who develop hypotension 4 to 6 hours before administration of thrombolytics. Nonetheless, the method might be valid for the majority of patients who present for therapy before or soon after the onset of hypotension.
In group 1 dogs, time to peak Mb was substantially shorter than time to peak CK, and Mb slopes were much steeper than were CK slopes. These findings are consistent with results of normotensive animals occluded and reperfused in earlier studies and suggest that Mb rise is more sensitive than CK rise as an early indicator of reperfusion, even in the setting of hypotension. Of note is that time to peak Mb after reperfusion is longer in hypotensive animals (108±24 minutes) than in normotensive animals (25±2 minutes) previously studied under the same protocol.12 However, the rate of rise in Mb concentration after reperfusion is not significantly different in the hypotensive animals of the present study (slope, 51±16 ng · mL−1 · min−1) than in earlier normotensive animals (slope, 70±13 ng · mL−1 · min−1, P>.50). The longer time to peak Mb in animals with hypotension is most likely attributable to the effects of shock, including diminished myocardial perfusion and/or decreased Mb clearance due to diminished renal flow. Despite the delay of Mb appearance in hypotensive animals, time to peak Mb concentration still differentiates reperfusion from nonreperfusion, since peak Mb was not reached within 8 hours in nonreperfused animals.
In patients with significant hypotension, efforts often are made to maintain coronary perfusion pressure. At pharmacological doses, inotropes such as dopamine may sacrifice peripheral perfusion to maintain coronary perfusion pressure. Such efforts might create physiology intermediate between normal blood pressure and sustained central hypotension. The present study investigated the extreme example of unmitigated systemic shock with central and peripheral hypotension. Myoglobin is sensitive in detecting coronary reperfusion at normal physiological pressures and in sustained hypotension. We suspect it would also be sensitive in intermediate physiology caused by the use of inotropes or balloon counterpulsation.
The clinical benefits of reperfusion therapy after acute total coronary artery occlusion are well established. Recent literature suggests that the survival benefit of thrombolysis is not entirely dependent on patency of the infarct-related artery20 ; however, other studies have shown that reperfusion early after the onset of myocardial infarction improves left ventricular ejection fraction and contractility of the infarcted segment21 22 and reduces left ventricular dilatation.23 Since reduced left ventricular function and left ventricular dilatation impact negatively on prognosis after myocardial infarction, establishment of coronary artery patency remains the ultimate goal of reperfusion therapy. If failed reperfusion could be established within several hours of administration of a thrombolytic agent, therapy such as salvage angioplasty and/or urgent bypass surgery might improve prognosis, particularly in the setting of cardiogenic shock, in which the prognosis is extremely poor but somewhat improved by early angioplasty.24
Although several clinical indicators are currently used to predict reperfusion (resolution of ST elevation, relief of pain, reperfusion arrhythmia, rapid rise of CK), none are capable of accurately predicting reperfusion early in the course of myocardial infarction.25 A rapid latex agglutination kit that can determine Mb concentration in blood within 10 minutes is now widely available,26 such that Mb kinetics can be used during the first hours of a myocardial infarction to predict reperfusion and, if clinically indicated, to direct further management.
The dogs in this study were made hypotensive by being bled into a reservoir. This method was used because it allowed accurate control of blood pressure throughout the experiment. Establishing cardiogenic shock would not afford this control and would interfere with myocardial Mb concentrations and release after occlusion. We feel that our mode of hemorrhagic shock closely simulates cardiogenic shock. Physiological similarities between these two types of shock include (1) the presence of hypotension, (2) a fall in cardiac output, (3) increased catecholamines with a resultant tachycardia and increased systemic vascular resistance, (4) maximal vasodilation of the distal coronary arteries, and (5) lactic acidosis with a potential change to anaerobic metabolism. Possible differences between hemorrhagic shock in these animals and cardiogenic shock in a patient with a large myocardial infarction include (1) different blood flows to splanchnic and muscular beds, (2) splenic contraction (a response to shock in the dog), and (3) a potential change in coronary blood flow due to global hyperkinesis in hemorrhagic shock.
Shock was successfully established in each dog, as demonstrated by the rise of systemic lactate concentrations. Lactate has been shown to be the most sensitive indicator of systemic shock in laboratory animals.27 The shift from positive to negative lactate extraction across the skeletal muscle bed indicates a shift from aerobic to anaerobic metabolism, which is the hallmark of shock in both humans and laboratory animals.
Regional Mb A-V differences reveal that the myocardium was the major source of Mb released into the blood in group 1 animals. This is consistent with the reflow theory, which states that intracellular proteins released because of cellular injury remain in the interstitial space until reestablishment of blood flow, at which time they rapidly enter the general circulation. In group 3 animals, in contrast, skeletal muscle was the major source of Mb release; this release occurred late in the experimental protocol. A similar release of skeletal muscle Mb probably occurred in groups 1 and 2 animals, but this was not apparent because it was masked by the relatively larger amounts of Mb released from ischemic myocardium (Figs 1⇑ and 2⇑). Unfortunately, this proposed pattern of release cannot be further substantiated because myocardial and skeletal muscle Mb are immunologically identical.
The results of the plasma volume determinations showed a pattern of diminished plasma volume at 4 hours (compared with baseline) with a subsequent increase (albeit to a level less than baseline) at 8 hours. This pattern was consistent among the animals regardless of study protocol, and it correlated closely with results of a canine model of hemorrhagic shock by Chien et al.28 The late rise in plasma volume is thought to occur because of the direct vasodilatory effect of shock on systemic vessels with myogenic capacity.
A possible source of error is frequent sampling of blood. Because of flushing of lines, the volume of blood lost to sampling was replaced by an approximately equal volume of normal saline. The greatest dilutional error occurred in group 1 animals because of the larger number of blood samples drawn. This source of dilutional error may have resulted in an underestimation of both individual Mb values and slopes of the Mb concentration–time curves to a degree proportional to the number of blood samples drawn. If this dilutional error had an important effect on the data, it would have resulted in the greatest underestimation of the slopes in group 1 animals because of the larger number of blood specimens required in this protocol. Another possible source of error is shifting of blood between the animals and the reservoir. Plasma volume and the pattern of reservoir blood flow were similar in all experiments. Therefore, any dilutional effect that the reservoir would have had on Mb concentrations and slopes of the Mb concentration–time curves would be similar in all groups in terms of percent reduction. The greatest absolute underestimation again would have occurred in group 1 animals because of the greater absolute magnitude of these values.
In conclusion, analysis of Mb kinetics is an accurate method of identifying coronary reperfusion after myocardial injury even in the presence of significant systemic hypotension. This method must be used cautiously when the time of onset of shock is uncertain or when improper timing of specimen collection could lead to false-positive prediction of successful reperfusion. This study should be used as a foundation for proceeding with human studies in which the physiology is variable, the degree and duration of reperfusion are unknown, and efforts are made to maintain central blood pressure and coronary perfusion.
This study was supported by a Grant-in-Aid from the American Heart Association, New York State Affiliate. The authors wish to thank Felicia A. Bosinski, Kathleen Harris, Amy C. Johnson, and Deana J. Gretka for their technical assistance.
- Received October 24, 1994.
- Accepted December 13, 1994.
- Copyright © 1995 by American Heart Association
Stone MJ, Waterman MR, Harimoto D, Murray G, Wilson N, Platt MR, Blomqvist G, Willerson JT. Serum myoglobin level as a diagnostic test in patients with acute myocardial infarction. Br Heart J. 1977;39:375-380.
Willerson JT, Poliner L, Buja LM, Waterman MR, Gomez-Sanchez CE, Templeton GH, Stone MJ. Myoglobinemia as a clue to the presence of acute myocardial infarction. Clin Res. 1976;24:422A. Abstract.
Stone MJ, Willerson JT, Gomez-Sanchez CE, Waterman MR. Radioimmunoassay of myoglobin in human serum: results in patients with acute myocardial infarction. J Clin Invest. 1975;56:1334-1339.
Stone MJ, Waterman MR, Poliner LR, Templeton GH, Buja M, Willerson JT. Myoglobinemia is an early and quantitative index of acute myocardial infarction. Angiology. 1978;29:386-392.
Kaiser HF, Helmling E, Glunz H-G. Serum myoglobin in acute revascularization by systemic streptokinase: fast diagnosis of acute myocardial infarction and control of the efficiency of coronary thrombolysis by a new myoglobin latex test. Circulation. 1984;70(suppl II):II-153. Abstract.
Lwebuga-Mukasa JS, Libby P, Bloor CM, Maroko PR. The evaluation of serum myoglobin following experimental coronary occlusion. Circulation. 1973;48(suppl IV):IV-129. Abstract.
Ellis AK, Little T, Masud ARZ, Liberman HA, Morris DC, Klocke FJ. Early noninvasive detection of successful reperfusion in patients with acute myocardial infarction. Circulation. 1988;78:1352-1357.
Ellis AK, Saran BR. Kinetics of myoglobin release and prediction of myocardial myoglobin depletion after coronary artery reperfusion. Circulation. 1989;80:676-683.
Ellis AK, Little T, Masud ARZ, Klocke FJ. Patterns of myoglobin release after reperfusion of injured myocardium. Circulation. 1985;72:639-647.
Riggs DS. The Mathematical Approach to Physiologic Problems. Cambridge, Mass: MIT Press; 1963:193-220.
Dillon GA, Ellis AK, Klocke FJ. Rapid determination of coronary reperfusion in acute MI patients using plasma myoglobin measurements. Circulation. 1991;84(suppl II):II-115. Abstract.
Klocke FJ, Copley DP, Krawczyk JA, Reichlin M. Rapid renal clearance of immunoreactive canine plasma myoglobin. Circulation. 1982;65:1522-1528.
Marbach EP, Weil MH. Rapid enzymatic measurement of blood lactate and pyruvate. Clin Chem. 1967;13:314-325.
ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.
Shehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natta P, Passamani ER, Williams DO, Zaret B. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI phase I) Trial. Circulation. 1987;75:817-829.
Stack RS, O’Connor CM, Mark DB, Hinohara T, Phillips HR, Lee MM, Ramirez NM, O’Callaghan WG, Simonton CA, Carlson EB, Morris KG, Behar VS, Kong Y, Peter RH, Califf RM. Coronary perfusion during acute myocardial infarction with a combined therapy of coronary angioplasty and high dose intravenous streptokinase. Circulation. 1988;77:151-161.
Lee L, Bates ER, Pitt B, Walton JA, Laufer N, O’Neill WW. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation. 1988;78:1345-1351.
Califf RM, O’Neil W, Stack RS, Aronson L, Mark DB, Mantell S, George BS, Candela RJ, Kereiakes DJ, Abbotsmith C, Topol EJ, and the TAMI Study Group. Failure of simple clinical measurements to predict perfusion status after intravenous thrombolysis. Ann Intern Med. 1988;108:658-662.
Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation. 1970;41:989-1001.
Chien S, Dellenback RJ, Usami S, Burton DA, Gustavson PF, Magazinovic V. Blood volume, hemodynamic, and metabolic changes in hemorrhagic shock in normal and splenectomized dogs. Am J Physiol. 1973;225:866-879.