Experimental reversal of acute coronary thrombotic occlusion and myocardial injury in animals utilizing streptokinase

Fresh autologous thrombus, 1.0 to 1.5 ml, was injected into the left anterior descending and/or left diagonal coronary arteries of 19 open-chest dogs to produce evolving acute myocardial infarction (AMI). Thrombotic obstruction was documented by coronary angiography. Multilead epicardial ECGs showed ST segment elevations of affected left ventricular (LV) areas within 2 minutes after thrombus injection, and LV segmental wall cyanosis with hypocontraction was observed within 10 minutes in the myocardial areas supplied by the thrombosed artery. Ten animals then received an initial dose of streptokinase (STK), 250,000 U (intravenous), followed by STK, 1000 to 3000 U/min (intracoronary), while nine control dogs untreated with STK received normal saline infusion. All but one STK-treated animal (all nine animals receiving intracoronary STK) had reestablishment of blood flow in the previously occluded vessels within $\text{1}\text{1}\text{2}\text{hours}$, disappearance of ventricular cyanosis, return of normal LV contractile function, and normalization of elevated ST segments within 1 hour after intracoronary STK thearpy. In contrast, in the non-STK-treated control group, all animals had continued coronary obstruction, progressive ST elevations, and worsening LV cyanosis and hypocontraction until death or for more than 3 hours post thrombus; three control animals died of ventricular fibrillation (VF) within 1 hour of thrombus occlusion, three more died of VF within 2 hours post thrombus, and only three survived beyond 2 hours post thrombus. Postmortem examination of non-STK-treated animals revealed extensive residual coronary thrombus. All intracoronary STK-treated animals evidenced absence of residual thrombus at postmortem examination. These data provide clinically relevant evidence that early intracoronary STK effects thrombolysis in AMI by reopening coronary vessels occluded by fresh thrombus, thereby protecting myocardium from further ischemia and necrosis, preserving LV function, and also reversing cardiac muscle injury.     

Significance of serum enzyme changes after cardiac catheterization and selective coronary arteriography.

The serum creatine kinase (CK), aspartate transaminase (AST), lactic dehydrogenase (LD) and alpha-hydroxybutyric dehydrogenase (HBD) were determined before and 3, 6, 18, and 36 hours after cardiac catheterization and angiocardiography in 56 consecutive patients with ischaemic heart disease. Five of these patients whose serum enzyme levels were higher than normal before the procedure were excluded from the study. Forty-one of the remaining 51 patients had left ventriculography and also selective coronary arteriography. In these 41 patients (groups 1 and 2--see below), the mean serum CK levels increased after the procedure to exceed the upper limit of normal at every study interval. The mean serum AST, LD, and HBD levels generally remained within the normal range at all study intervals, though serum AST increased abnormally in 9 of the 41 patients (22%) and serum LD and HBD each increased above the normal limit in 2 of 41 patients (4.9%). In 24 patients (group 1) whose coronary arteriograms showed insignificant coronary narrowing (less than 75%) in any of the three major coronary arteries, the increase in serum CK was significantly higher than in 17 patients (group 2) with greater than 75% narrowings in at least one of the three major coronary arteries. However, the degree of serum CK elevation observed during the postangiographic period was much lower than that in another group of 30 consecutive patients with acute myocardial infarction. In 10 patients (group 3) who had the same procedure as groups 1 and 2 except without the selective coronary arteriography, the serum enzyme levels showed no noticeable increase after the procedure. The difference in postangiographic serum CK elevation between patients with and without selective coronary arteriography and the difference between group 1 (without significant coronory narrowing) and group 2 (with significant narrowing) strongly suggest that the raised serum CK levels represent some form of myocardial damage caused by the coronary arteriography, which, however, is different at least in degree from that of acute myocardial infarction.     

Significance of serum enzyme changes after cardiac catheterization and selective coronary arteriography.

The serum creatine kinase (CK), aspartate transaminase (AST), lactic dehydrogenase (LD) and alpha-hydroxybutyric dehydrogenase (HBD) were determined before and 3, 6, 18, and 36 hours after cardiac catheterization and angiocardiography in 56 consecutive patients with ischaemic heart disease. Five of these patients whose serum enzyme levels were higher than normal before the procedure were excluded from the study. Forty-one of the remaining 51 patients had left ventriculography and also selective coronary arteriography. In these 41 patients (groups 1 and 2--see below), the mean serum CK levels increased after the procedure to exceed the upper limit of normal at every study interval. The mean serum AST, LD, and HBD levels generally remained within the normal range at all study intervals, though serum AST increased abnormally in 9 of the 41 patients (22%) and serum LD and HBD each increased above the normal limit in 2 of 41 patients (4.9%). In 24 patients (group 1) whose coronary arteriograms showed insignificant coronary narrowing (less than 75%) in any of the three major coronary arteries, the increase in serum CK was significantly higher than in 17 patients (group 2) with greater than 75% narrowings in at least one of the three major coronary arteries. However, the degree of serum CK elevation observed during the postangiographic period was much lower than that in another group of 30 consecutive patients with acute myocardial infarction. In 10 patients (group 3) who had the same procedure as groups 1 and 2 except without the selective coronary arteriography, the serum enzyme levels showed no noticeable increase after the procedure. The difference in postangiographic serum CK elevation between patients with and without selective coronary arteriography and the difference between group 1 (without significant coronory narrowing) and group 2 (with significant narrowing) strongly suggest that the raised serum CK levels represent some form of myocardial damage caused by the coronary arteriography, which, however, is different at least in degree from that of acute myocardial infarction.     

Myocardial salvage by intracoronary thrombolysis in evolving acute myocardial infarction: evaluation using intracoronary injection of thallium-201

Immediate objective assessment of viabillty of reperfused myocardium following intracoronary (IC) thrombolysis by evaluation of ventricular function may be limited due to delay in restoration of function. Thus we assessed myocardial uptake of thallium-201 (TI-201) following IC injection postreperfusion as an index of myocardial salvage in 12 experimental dogs and in five patients with evolving acute myocardial infarction (AMI). In seven dogs with mean of 313 minutes of experimental coronary occlusion, immediate postreperfusion IC TI-201 images revealed absence of myocardial uptake in prevlously occluded zones. These TI-201 defects correlated with presence of necrosis as demonstrated by histochemical staining with triphenyl-tetrazolium chloride (TTC). In contrast, in five dogs with mean of 37 minutes of coronary occlusion, reperfused myocardium showed normal TI-201 uptake following its IC injection; this normal TI-201 uptake pattern correlated with absence of necrosis by TTC technique in all five dogs. In five patients with evolving AMI, control TI-201 images obtained following IV injection prior to IC thrombolysis showed myocardial perfusion defects corresponding to distribution of the occluded vessel. Following reperfusion, 30 to 50 mCi of TI-201 was injected into the reopened coronary artery. In two patients with mean symptom onset of reperfusion time of $\text{2}\text{1}\text{2}\text{hours}$, immediate postreperfusion IC TI-201 images demonstrated normal or improved TI-201 uptake in reperfused myocardium. By radionuclide ventriculography, segmental wall motion remained abnormal in the reperfused regions 6 hours postreperfusion and showed improvement by the time of 10-day study. In the remaining three patients with symptom onset to reperfusion time of 5 hours, immediate postreperfusion IC TI-201 images did not show improvement, correlating with persistent wall motion abnormalities 10 days postreperfusion. In all five patients, repeat 10-day IV TI-201 images were unchanged from the immediate postreperfusion IC TI-201 images. We conclude that (1) prereperfusion TI-201 imaging with repeat TI-201 injection into the reopened coronary artery appears to delineate the extent of myocardial salvage in both experimental and clinical studies and (2) this method of IC TI-201 imaging allows immediate assessment of myocardial viabillty which may facilltate decisions regarding the need for additional myocardial revascularization modalities.     

Collateral function in early acute myocardial infarction

The role of the collateral circulation < 6 hours after the onset of acute myocardial infarction (MI) was evaluated in 34 consecutive patients without previous MI. There were 19 patients with and 15 without collaterals. The group was subdivided into those with nonjeopardized collaterals (group A, 14 patients) and those with jeopardized collaterals (group B, 5 patients), and the group without collaterals into those with partially obstructed coronary arteries (group C, 5 patients) and those with totally obstructed coronary arteries (group D, 10 patients). These groups had similar sites of coronary stenoses and MI. Eleven of 14 collaterals in group A were poor, but MI mass measured by peak creatine kinase (CK) was smaller in group A than in group B (p < 0.01) or group D (p < 0.01), and cardiac function was significantly better in group A than in group D (cardiac index, p < 0.05; stroke index, p < 0.01; ejection fraction, p < 0.01; regional wall motion, p < 0.01). Group C was not statistically different from group A in myocardial function and CK. Group B was similar to group D in MI mass and cardiac function (cardiac index, stroke index, ejection fraction and regional wall motion). Thus, patients with nonjeopardized collaterals and those with partially obstructed coronary arteries had less myocardial damage and better cardiac function than did those with jeopardized collaterals and those with totally obstructed coronary arteries. A nonjeopardized collateral circulation may play a role in limiting MI mass and preserving myocardial function in the early stages of acute MI.     

Myocardial infarction in patients with coronary artery spasm demonstrated by angiography

Twelve cases of myocardial infarction (MI) were documented in 11 of 39 patients who had coronary artery spasm (CAS) that was observed by angiography either before MI (3 patients), after MI (5 patients), or both before and after MI (3 patients). MI corresponded in location to sites of ECG changes of myocardial ischemia during spontaneous angina pectoris in 7 of 7 patients and to the region of myocardium supplied by the vessel in which CAS was observed by angiography in each patient. MI occurred in the distribution of the right coronary artery in 8 patients and of the left coronary artery in 4 patients. Of 12 vessels that supplled infarcted regions of myocardium, 7 vessels had ≥50% diameter fixed coronary artery narrowing (CAN), but the remaining 5 vessels had minimal (10%) or no fixed CAN. In those patients who were studied after MI, coronary angiography demonstrated that only 3 of 9 vessels in the distribution of infarcted regions of myocardium were completely occluded. Clinical follow-up for an average of 1.3 years after MI showed that 7 patients continued to have chest pain, 2 patients were asymptomatic, and 2 patients died suddenly 9 weeks and 1 year, respectively, after MI. Therefore, among our patients with CAS demonstrated by angiography, Mis (1) were frequent (28%), (2) occurred in the distribution of observed coronary spasm, (3) were frequently (5 of 12 arteries) in the distribution of vessels having minimal or no fixed narrowing, and (4) were often (6 of 9 arteries) in the distribution of vessels that were demonstrated to be patent after MI.     

Effect of arterial pressure on left ventricular O2 consumption,coronary blood flow,and reserve capacity following coronary occlusion

The effect of mean systemic arterial pressure $\text{(}\text{SAP}\text{)}$ on myocardial O₂ consumption (MV?O₂) coronary blood flow (CBF) and the reduction of left ventricular (LV) reserve capacity resulting from coronary artery occlusion was studied in 25 open-chest pentobarbital anesthetized dogs with fixed cardiac output and controlled heart rate (HR) and $\text{SAP}$. In all animals, baseline MV?O₂ and CBF were obtained and LV reserve capacity was determined by identifying the HR and $\text{SAP}$ level which raised mean left atrial pressure to 12 mm. Hg. After uniform placement of a pericoronary snare, the dogs were randomized to five equal groups, and $\text{SAP}$ was set at 40, 70 (two groups), 100, and 130 mm. Hg. MV?O₂ and CBF were redetermined and the coronary artery was ligated in all except one group (70 mm. Hg) which served as sham control. Thirty minutes after coronary occlusion, MV?O₂, CBF, and LV reserve capacity were determined again. Percent of nonperfused myocardium did not differ among groups (27.6 ± 1%). MV?O₂ bore a linear relationship to $\text{SAP}$ setting whereas CBF bore a curvilinear relationship. Coronary occlusion did not modify these relationships. Significant, but similar decreases in tolerated HR (23.1 ± 4.7 min.^?1) and $\text{SAP}$ (41.9 ± 6.2 mm. Hg) from control values were observed in all four groups regardless of $\text{SAP}$ setting.We concluded that the impact of coronary ligation on MV?O₂, CBF, the loss of functional reserve capacity, and possibly the extent of ischemic injury of the left ventricle, is not modified by afterload changes. However, optimal O₂ supply-to-demand ratio appears at $\text{SAP}$ of about 100 mm. Hg.     

Experimental coronary arterial occlusion and release: Effects on enzymes,electrocardiograms, myocardial contractility and reactive hyperemia

After less than 1 hour of coronary arterial occlusion, the myocardium suffers irreversible changes as revealed by electron microscopy. Yet, the earliest clinical laboratory indexes of myocardlal infarction—elevated serum enzyme levels and significant Q waves on the electrocardiogram—are not detected until at least 6 hours after coronary occlusion. To study the early period after coronary occlusion in the dog, occlusion of the left anterior descending coronary artery for 1 to 3 hours was followed by release, and coronary sinus and venous enzyme levels, the electrocardiogram and myocardial contractility from the infarcted area, and reactive hyperemia were monitored. Coronary sinus enzyme levels rose within 15 minutes after release of occlusion in half of the experiments with $\text{1}\text{to}\text{1}\text{1}\text{2}$ hours and in all of those with 2 to 3 hours of occlusion, and this rise preceded the rise in venous levels by only 10 to 20 minutes. Significant Q waves appeared 15 to 30 minutes after release of occlusion as the serum enzymes were increasing. Thus, clinically, the delayed appearance of increased serum enzymes and significant electrocardiographic Q waves is probably largely due to a lack of circulation in the infarcted area rather than to prolonged survival time. Also, the venous enzyme level reflects the coronary sinus level minutes later. The presence of viable myocardium in the infarcted area was suggested by elevation of the S-T segment upon reclamping, and by residual myocardial contractility and retained capacity for reactive hyperemia. These findings occurred in some experiments even In the presence of a significant Q wave.     

Relationship between the Enzymatically Estimated Infarct Size and Clinical Findings in Acute Myocardial Infarction

ABSTRACT In 580 patients with a definite myocardial infarction (MI) and no previous MI, the enzymatically estimated infarct size was related to the clinical course including various complications. In all patients, heat-stable lactate dehydrogenase activity (EC 1.1.1.27, LD) was analyzed every 12 hours for 48–108 hours and in a subgroup (n=170) creatine kinase activity (EC 2.7.3.2, CK) and creatine kinase subunit B (CK B) were analyzed every 6 hours for 48 hours. The highest recorded enzyme activity was used as a rough estimate of infarct size. A positive correlation was found between serum enzyme activity and most of the clinical variables studied, such as incidence of congestive heart failure, treatment with furosemide, incidence of hypotension, cardiogenic shock, pericarditis, post myocardial infarction syndrome, AV block III, and the duration of hospitalization. We conclude that the enzymatically estimated infarct size determined by heat-stable LD, CK and CK B closely reflects the severity of the infarction.     

Progressive transmural electrographic,myocardial potassium ion/sodium ion ratio and ultrastructural changes as a function of time after acute coronary occlusion

The progressive transmural electrographic, biochemical and ultrastructural changes as a function of time after acute coronary occlusion were systematically assessed in eight dogs. Transmural plunge electrodes with poles 1 mm apart were placed in the ischemic and nonischemic zones, and coronary occlusion was maintained for 4 hours. Transmural full thickness biopsy specimens were obtained from each zone for electron microscopy before, and 1 and 4 hours after occlusion. Endocardial and epicardial layers were also obtained for assessment of myocardial potassium ion (K⁺) and sodium ion (Na⁺) concentrations. Before coronary occlusion, local Q waves were recorded an average depth of 1.0 ± 0.34 mm from the endocardial surface. After 1 hour of occlusion, Q waves appeared at an average depth of 3.8 ± 0.67 mm and progressed to a depth of 5.2 ± 0.7 mm at 2 hours, 6.2 ± 0.5 mm at 3 hours and 7.0 ± 0.5 mm at 4 hours. After 1 hour, ultrastructural changes of early ischemia, including a decrease in glycogen and mild mitochondrial swelling, were seen in the endocardial layer; the epicardial layer showed normal morphologic features. After 4 hours, the endocardial layer showed well developed ischemic changes marked by the loss of mitochondrial cristae, vacuolization, the appearance of amorphous mitochondrial densities, an increase in interfibrillary space and the appearance of I bands. In contrast, the epicardial layer at this time showed only early ischemic changes. At the end of 4 hours, the endocardial layer showed a marked decrease in myocardial K⁺ concentration and an increase in Na⁺ concentration leading to complete reversal of the $\text{K}{}^{\mathrm{+}}\text{Na}{}^{\mathrm{+}}$ ratio (0.7 ± 1.0; P < 0.001). In the epicardial layer, a smaller decrease in K⁺ concentration and an increase in Na⁺ concentration occurred, resulting in a diminution but not a reversal of the $\text{K}{}^{\mathrm{+}}\text{Na}{}^{\mathrm{+}}$ ratio (1.4 ± 0.2; P < 0.005).Thus, the dynamic evolution of an acute myocardal infarction involves a sequential progression from endocardium to epicardium as a function of time, resulting in an epicardial “border zone” in the early stages after acute coronary occlusion.     

Estimated appearance of raised serum enzyme activity in relation to onset of symptoms in acute myocardial infarction

In 709 patients with definite acute myocardial infarction (MI) the appearance of raised serum enzyme activity was related to onset of symptoms. Heat stable lactate dehydrogenase (LD), creatine kinase (CK) and CK B were analysed. A gradual increase in the incidence of raised enzyme activity in the first blood sample was seen for up to 18 hours after the onset of MI for all 3 enzymes. The incidence of raised enzyme activity in the first blood sample was higher for CK and CK B than for heat stable LD up to 24 hours after onset of MI, but thereafter a similar incidence was found. The median time between onset of symptoms and estimated appearance of raised serum enzyme activity was 6.2 hours for heat stable LD versus 4.3 hours for CK and 4.1 hours for CK B. A wide variation was however found. Infarct localization and chronic treatment with betablockade might affect these results. The clinical course including short- and long-term survival was similar in patients with early and later appearance of enzymes.     

Total, phasic, and regional myocardial blood flow in aortic stenosis.

The effect of aortic stenosis on total, phasic, and regional myocardial flow was studied in 16 anesthetized, open-chested dogs. An adjustable catheter device was used to produce increasing aortic obstruction, the severity of which was judged from the left ventricular aortic peak systolic gradient as mild (< 25 mm. Hg), moderate (26 to 50 mm. Hg) and severe (> 50 mm. Hg). The supply/demand index was estimated from the ratio of diastolic pressure time index to systolic pressure time index ($\text{DPTI}\text{SPTI}$). The ratio of diastolic to systolic coronary blood flow ($\text{DIAS}\text{SYS}$) was determined from the flow tracings. Total myocardial flow and endocardial/epicardial flow ratios ($\text{ENDO}\text{EPI}$) were determined by injecting four differently-labeled 7 to 9 micron microspheres in the left atrium during control, mild, moderate, and severe aortic stenosis.The supply/demand ($\text{DPTI}\text{SPTI}$) index decreased significantly at all levels of aortic stenosis because of a decrease in DPTI and an increase in SPTI. The $\text{DIAS}\text{SYS}$ coronary flow ratio and the $\text{ENDO}\text{EPI}$ myocardial flow ratio were not significantly changed during aortic stenosis. The total myocardial flow was significantly higher than control only during severe aortic stenosis.The results indicate that, for all degrees of experimental aortic stenosis, there were significant decreases in $\text{DPTI}\text{SPTI}$ but no significant changes in $\text{DIAS}\text{SYS}$ coronary flow ratio or the distribution of myocardial perfusion. Thus, in acute, experimental aortic stenosis, there is evidence of increased myocardial oxygen demand, but endocardial perfusion is not changed significantly.     

Relationship between Enzymatically Estimated Infarct Size and Short- and Long-term Survival after Acute Myocardial Infarction

Abstract In 585 patients with acute myocardial infarction (AMI) and no previous MI the maximal activity of serum heat-stable lactate dehydrogenase (LD) (EC 1.1.1.27) activity was related to 1-year and 2-year mortality rates. All patients participated in a double-blind trial with metoprolol during the first three months after an AMI. Thereafter both groups were treated in a similar way. A strong relationship was found between LD maximum activity and the in-hospital prognosis (p<0.001), the 1-year survival rate (p<0.001) and the 2-year survival rate (p<0.001). When the patients who were alive after primary hospitalization were analyzed as a separate group, the relationship between LD maximum activity and 1-year and 2-year survival rates remained (p<0.001). In a subsample of 171 patients the maximal activity of creatine kinase (CK) (EC 2.7.3.2) and CK subunit B did not correlate either with in-hospital, 1-year or 2-year survival rates. We conclude that, when a sufficiently large number of patients are investigated, there is a strong relationship between serum enzyme maximum activity and short- and long-term survival.     

Serotonin blockade during experimental coronary thrombosis.

The protective effect of methysergide on accumulating serotonin within the myocardium, during acute and chronic coronary thrombosis was evaluated in two groups of dogs. The first group of 15 dogs was pretreated with methysergide (100 μg/Kg. B.W., intravenously) and an equal number of dogs in the second group served as the control. An occluding intracoronary thrombus was produced in each dog by the closed chest placement of a thrombogenic wire into the left anterior descending (LAD) coronary artery, via catheter technique, under x-ray visualization. Blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral resistance (TPR), and contractile force ($\text{dP}\text{dt}$) were determined before and at 1, 3, and 5 hours (acute phase) after the onset of thrombosis. These variables were measured again at 1 and 8 days (chronic phase) after verified occlusion. The sums of the mean Q wave (ΣQ) and S-T segment (ΣS-T) amplitudes from 14 ECG precordial mapping sites were also calculated in six dogs of each group at these chronic time periods. Several biochemical variables were measured in the active phase from coronary venous blood specimens collected through the fifth hour. Histological examinations were also performed in the acute and chronic phases on control and pretreated hearts. During the aforementioned sampling times, certain hemodynamic variables decreased significantly (p < 0.05) in the control dogs, but less significant changes were found in the methysergide pretreated animals. There were similar differences in the mean concentration of certain biochemical variables between the two groups, in the acute stages of thrombosis, with less significant changes in the methysergide pretreated dogs. Generally, there were less necrotic changes in the methysergide hearts at the eighth day but histological differences between the two groups were inconclusive in the acute phase. It appears from this study that the cardiodynamic and biochemical integrity was sustained by blocking the action of serotonin within the affected myocardium during myocardial infarction due to thrombotic occlusion of the LAD coronary artery.     

Mechanisms contributing to myocardial accumulation of technetium-99m stannous pyrophosphate after coronary arterial occlusion.

The relation between the accumulation of pyrophosphate and technetium-99m in myocardium with reversible and irreversible ischmic injury was studied in dogs subjected to transitory or persistent coronary arterial occlusion. Among four dogs with coronary occlusion maintained for less than 20 minutes, none had either increased MB creatine kinase (CK) (the "myocardial" CK isoenzyme) activity serum or a positive 99mTc stannous pyrophosphate image. Seven dogs with coronary occlusion maintained for 30 or more minutes had elevated serum MB CK activity, and five of the seven had positive (abnormal) images. Thus, although false negative images may occur occasionally despite myocardial damage, both increased serum MB CK and abnormal images generally accompanied prolonged coronary occlusion. In contrast, ischemia without infarction was not associated with abnormal images. Both 99mTc and 32P labeled pyrophosphate were accumulated extensively and proportionally in myocardium from zones of infarction, and uptake of both tracers was comparable although modest in isolated mitochondria. Similar results were obtained after myocardial infarction in animals with induced profound leukopenia. Thus, phagocytosis of the radiopharmaceutical agent by leukocytes migrating into the infarct is not an essential mechanism accounting for uptake. These results indicate that abnormal images reflect uptake of pyrophosphate, associated with 99mTc, by irreversibly injured myocardium rather than leukocytic infiltration involved in the inflammatory response in the heart.     

Myocardial infarct extension: Prevalence,clinical significance,and problems in diagnosis

To examine the prevalence, clinical significance, and problems in the diagnosis of myocardial infarct (MI) extension, 103 patients with acute MI were studied. Each patient underwent enzymatic infarct sizing in the initial 72 hours and then had quantitative CK-MB (myocardial isoenzyme of serum creatine kinase) analysis at 8-hour intervals over the remaining hospitalization. In addition, daily standard 12-lead ECGs and documentation of prolonged (>15 minutes) resting ischemic chest pain were recorded. MI extension, by CK-MB methods, occurred in 32 (31%) of 103 patients at 5.9 ± 0.3 days after initial infarction. ECG changes suggesting MI extension occurred in 14 (14%), but only six of these patients had extension by CK-MB. Similarly, recurrent chest pain following initial MI occurred in 28 (27%), but enzymatic extension was evident in only 11 of these patients. MI extension resulted in significantly greater early in-hospital mortality (16%) compared to those patients without MI extension (2.8%, p < 0.05). Thus MI extension occurs commonly and may explain some early in-hospital deaths post MI. The usual clinical and ECG diagnostic parameters utilized are insensitive indicators of enzymatic MI extension.     

Serum creatine kinase B subunit activity in diagnosis of acute myocardial infarction.

The value of serum creatine kinase B subunit activity (CK B) in the diagnosis of acute myocardial infarction was studied in 238 consecutive cases. All were admitted to a coronary care unit because of suspected acute myocardial infarction. Serum CK B activity was determined by an immunoinhibition procedure, using a CK M subunit inhibiting antibody (anti-M). For the evaluation of serum CK B, patients were classified into acute myocardial infarction and non-acute myocardial infarction groups. This classification was based on electrocardiographic findings, on quantitative determinations of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total serum creatine kinase (CK) activities, and on qualitative electrophoretic determinations of serum CK and serum lactate dehydrogenase (LD) isoenzymes. The prevalence of acute myocardial infarction in the patient material was 0.47. Serum CK B subunit activity was found to be a highly selective indicator of acute myocardial infarction with a predictive value of a positive test result of 0.97 and a predictive value of a negative test result of 0.99. The serum CK B activity increased above the acute myocardial infarction discrimination limit within 12 hours from onset of symptoms. Two non-acute myocardial infarction patients, who were resuscitated after cardiac arrest, had increased serum CK B values caused by the transient presence of CK isoenzyme BB in serum.     

Effects of ortho-iodo sodium benzoate on acute myocardial ischemia, hemodynamic function, and infarct size after coronary artery occlusion in dogs

Ortho-iodo sodium benzoate (OISB) decreases the affinity of blood for oxygen, thus enhancing potential tissue oxygen delivery. To test the hypothesis that a change in oxygen affinity would ameliorate regional myocardial ischemic injury resulting from occlusion of the left anterior descending (LAD) coronary artery, experiments were carried out in 55 anesthetized dogs which received an intravenous infusion of OISB. In Protocol I studies (n = 9), preocclusion intravenous infusion of OISB (500 mg/kg) reduced epicardial S-T segment elevation 15 minutes after coronary occlusion, while a similar volume of normal saline solution did not affect this index of ischemic damage. In Protocol II experiments, 34 dogs were randomized to either an OISB or saline group, after which the LAD was ligated, the chest closed, and the animal allowed to recover from anesthesia. Myocardial infarction (MI) size was assessed after the animal died or was killed 8 to 24 hours later, and was found to be 29% smaller in dogs receiving OISB. In 6 dogs, blood P50 (the partial oxygen pressure at which hemoglobin is 50% saturated with oxygen) was increased by OISB infusion, confirming that its administration effected a rightward shift in the oxyhemoglobin dissociation curve. Protocol III studies assessed the effects of OISB on cardiac hemodynamic function and acute myocardial ischemic damage when infusion was begun 15 minutes after LAD occlusion: average epicardial S-T segment elevation was not altered by saline solution, but decreased when OISB was infused during the last 15 minutes of myocardial ischemia. Reductions in heart rate, left ventricular dP/dt, and cardiac output were observed in 7 dogs during OISB infusion, but there were no changes in these measurements during coronary occlusion in 5 dogs receiving a constant infusion of saline solution. There were no changes in regional myocardial blood flow (microsphere technique) to either ischemic or nonischemic zones in either the saline control or OISB treatment groups. Thus, both acute myocardial ischemic injury (assessed by epicardial electrocardiographic mapping) and ultimate MI size are reduced when OISB is infused before experimental coronary artery occlusion. OISB also reduces myocardial ischemic injury when its administration is begun 15 minutes after coronary occlusion, while effecting decreases in heart rate, left ventricular contractility, and cardiac output.     

Kinetics of antifibrillatory effects of bretylium: Correlation with myocardial drug concentrations

To determine the kinetics of the antifibrillatory effects of bretylium tosylate and to assess the relative importance of myocardial versus serum drug concentrations, studies were performed in 32 dogs after they received bolus injections of bretylium tosylate (6 mg/kg or 2 mg/kg body weight) or saline solution. Parallel determinations were made of drug concentrations in serum and myocardium, together with antifibrillatory and electrophysiologic effects, both with and without 2 minutes of coronary ischemia produced by temporary coronary ligation. Serum bretylium concentration decreased rapidly after intravenous injection, whereas myocardial concentrations increased gradually, peaking at 1.5 to 6 hours in both open and closed chest dogs. The ratio of myocardial to serum drug concentration increased to 6.4 to 12.6 at 12 hours. Parallel elimination of the drug in serum and myocardium occurred thereafter, with elimination half-life of 10.5 hours (closed chest dogs).Electrophysiologic and antifibrillatory effects paralleled myocardial rather than serum drug kinetics with peak effects at 3 to 6 hours. The ventricular effective refractory period was 24 to 26 ms greater at 3 hours in dogs treated with the drug than in those receiving saline solution. The ventricular fibrillation threshold increased 6 to 10-fold after 2 mg/kg of the drug was given at 3 to 6 hours in dogs both with and without ischemia in comparison with that in control animals treated with saline solution. The average increase in threshold exceeded 12-fold after administration of 6 mg/kg of the drug (2 minutes to 12 hours). The repetitive ventricular response threshold 3 hours after drug administration increased 5-fold after 2 mg/kg and 18-fold after 6 mg/kg of the drug was administered in dogs with or without ischemia.These studies elucidate canine serum and myocardial drug kinetics of bretylium, quantify the prolonged antifibrillatory effect of this drug with its delayed maximal effect and emphasize the importance of tissue levels of bretylium in determining drug action.     

Nuclear magnetic resonance analysis of acute and chronic myocardial infarction in dogs: Alterations in spin-lattice relaxation times

The purpose of this study was to evaluate the effects of acute and chronic ischemic injury on myocardial spin-lattice relaxation times (T₁) in dogs. Ligation of the left anterior descending coronary artery was performed on 23 dogs which were divided into four experimental groups and killed at 3 hours (n = 6), 4 days (n = 6), 21 days (n = 5), and 56 days (n = 6) after coronary occlusion. T₁ was measured in vitro with a 2.5 kg nuclear magnetic resonance (NMR) spectrometer using tissue from ischemic and control areas of the myocardium. Both the 3-hour and 4-day groups showed prolongations in T₁ (p < 0.01) for tissue from the ischemic area. In the 21-day group, two infarcts showed an increase in T₁, two showed a decrease in T₁, and one showed no significant change. The 56-day old infarcts had a lower mean value for T₁ than control myocardium (p < 0.01). The differences in myocardial water content between control and infarcted myocardium were found to parallel changes in T₁ values in each experimental group. Pathologic examination of the myocardial scar from 21- and 56-day-old infarcts revealed extensive fibrosis in the infarcts with lower T₁ values and tissue water contents than control myocardium. We conclude that myocardial edema in 3-hour and 4-day-old infarcts results in association with prolongations in T₁. Twenty-one-day-old infarcts may be edematous (with increased T₁) or fibrotic (with T₁ values lower than normal myocardium), while 56-day-old infarcts are fibrotic and have shorter T₁ values than normal myocardium. This study suggests that NMR imaging may have the capacity to evaluate myocardial edema and help define the duration of ischemic injury.