Coronary Artery Ligation In Dogs Research Articles

Triggered activity due to delayed afterdepolarizations in sites of focal origin of ischemic ventricular tachycardia.

This study for the first time systematically evaluated the site of origin of focal ventricular tachycardia (VT) induced 1-3 h after acute coronary artery ligation in dogs. We determined whether delayed afterdepolarizations (DADs) and triggered activity (TA) are more often recorded from ischemic endocardium excised from focal sites of VT origin. A total of 145 alpha-chloralose-anesthetized dogs were studied: in 54 dogs without inducible VT, normal or ischemic endocardium was investigated in vitro; in 91 dogs, inducible VT was studied by three-dimensional activation mapping, with in vitro study of 51 endocardial foci compared with 40 endocardial ischemic sites not of VT origin. Incidence of DADs (71% vs. 33%, P <0.05) and TA (32% vs. 11%, P <0.05) was greater in ischemic than in normal Purkinje tissues. Purkinje sites of origin of focal VT demonstrated the greatest frequency of DADs (92%, P <0.05) and TA (75%, P <0.05), with repetitive TA predominating. Similar results were obtained in endocardial sites of origin. Action potentials were mildly depolarized and prolonged in the focal sites of origin. These abnormalities were stable up to 2.5 h of recording. This study demonstrated that DADs and TA may underlie a majority of focal VTs in ischemic endocardium and Purkinje tissue.

Prediction of immediate ventricular arrhythmias after coronary artery ligation

Objectives. Our aim was to test the hypothesis that increased beat to beat morphologic variations in the body surface electrocardiogram (ECG) are associated with fragmented diastolic electrical activity that appears after coronary artery ligation and to correlate the appearance of spontaneous ventricular fibrillation after coronary ligation with the magnitude of the ECG beat to beat variability.Background. Unstable and variably delayed electrical activation precedes the development of ventricular fibrillation in dogs with acute ischemia. Detection of these highly variable low amplitude signals from the body surface is currently impossible. We have developed a system designed to measure the degree of beat to beat variability of the ECG.Methods. With high fidelity electrocardiography, subtle beat to beat ECG morphologic variations were detected in epicardial and body surface electrograms and quantified as the variance of the ECG voltage at specific points of the cardiac cycle. The ratio of the variance at the QRS offset to that of the QRS onset (beat to beat variability index) was then calculated.Results. Ventricular fibrillation developed in 12 of 27 dogs after left anterior descending coronary artery ligation. In 7 of the 12 dogs it occurred immediately (<15 min) after ligation; in the other 5 it developed late (15 min) after ligation. Dogs with subsequently immediate ventricular fibrillation had a significantly higher beat to beat variability index than that of dogs with late or no ventricular fibrillation both before coronary ligation (4.7 ± 1.4 vs. 1.1 ± 0.2 and 0.8 ± 0.1, respectively, p < 0.001) and after ligation (6.4 ± 2.6, 1.0 ± 0.6 and 1.2 ± 0.6, respectively, p < 0.001). In dogs that developed ventricular fibrillation immediately after coronary ligation, the arrhythmia was preceded by fragmented diastolic electrical activity on the epicardial electrogram and a simultaneous increase in the beat to beat morphologic variability of the terminal portion of the body surface ECG QRS complex.Conclusions. Beat to beat QRS offset morphologic variations appear to be increased before and further increased after coronary artery ligation in dogs that develop ventricular fibrillation immediately after ligation. Increased beat to beat variability index may be associated with the presence of electrophysiologic instability and can predict early ventricular fibrillation.

Analysis of bites on three-dimensional vectorcardiography after coronary artery ligation in dogs

The serial changes in the QRS loops of vectorcardiograms were investigated following ligation of a branch of the left anterior descending artery (LAD) by the three-dimensional rotation method in 18 dogs. Concave inflections of the QRS loop, defined as "bites," were best delineated when the loop was viewed from a left cranial or right caudal direction. Bites appeared 48 +/- 8 minutes after LAD ligation in all of the dogs, and their development was closely related to the temporal changes in the % sigma R and QRS point score on a standard 12-lead electrocardiogram. Q waves were not observed on the electrocardiograms in 9 dogs. In the remaining 9, they appeared 117 +/- 18 minutes after LAD ligation. The bite duration, area, and amplitude were compared with the anatomical extent of the infarcts. A significant positive correlation was found between bite duration and infarct size. The detection of bites on the three-dimensionally rotated vectorcardiogram appears to have a high sensitivity for anterior myocardial infarction and could potentially become a useful diagnostic tool.

Prevention of Spontaneous Sustained Ventricular Tachycardia in the Postinfarction Dog by Left Stellate Ganglionectomy

Suppression of Sustained VT by Left Stellectomy. Holter monitoring and ventricular pacing were used to examine control, right stellate ganglionectomy, and left stellate ganglionectomy treatment groups, 6‐24 hours after left anterior descending coronary artery ligation in dogs. In nine of 27 controls (33%), spontaneous ventricular triplets (358 ± 8 beats/min) initiated sustained monomorphic ventricular tachycardia (386 ± 16 beats/min), followed by ventricular fibrillation at 12.6 ± 1.4 hours. Ventricular pacing produced sustained monomorphic ventricular tachycardia in 13 of 18 survivors (73%) at 24 hours. Left but not right stellectomy performed 15 minutes before coronary artery ligation reduced the incidence of spontaneous sustained monomorphic ventricular tachycardia (2 of 27, 7%, P = 0.06; 7 of 27, 26%, P = 0.50, respectively) and reduced the maximal ventricular triplet rate (332 ± 12, P &lt;0.05 and 358 ± 10 beats/min, respectively, P = NS vs control). Neither left nor right stellectomy altered the incidence of ventricular triplets during the 6‐24 hour period (153 ± 58 and 222 ± 55/hour, respectively, vs control, 177 ± 59/hour, P = NS) nor prevented pacing‐induced sustained monomorphic ventricular tachycardia in the survivors at 24 hours (20 of 24, 75%; and 16 of 20, 80%, P = NS). The data demonstrate that left but not right stellectomy reduces spontaneous sustained ventricular tachycardia and ventricular fibrillation during the 6‐24 hour period following coronary artery ligation in the dog. Left stellectomy reduces the triggers for sustained monomorphic ventricular tachycardia (rapid ventricular triplets) without altering the underlying reentrant substrate for sustained ventricular tachycardia.

Thyroid hormone metabolism in nonthyroidal illness. I. Changes in thyroid hormone metabolism in dogs with experimental myocardial infarction and effect of thyroid hormone administration on their hemodynamics

To asses the changes in thyroid hormone metabolism after the onset of acute myocardial infarction (AMI), serum T4 and T3 levels were serially measured for 24 hours after the coronary artery ligation in dogs. The effect of thyroid hormone administration on hemodynamics in these dogs were also studied to clarify the possible usefulness of thyroid hormone therapy in nonthyroidal illness (NTI). Dogs were anesthetized with ketamine using "Micro-Mini" drip administration. Coronary artery ligation was performed in 8 dogs (MI group) Open chest operation was performed in 8 dogs, but their coronary arteries were not ligated and were used as control (cont. group). Blood samples were drawn before and 1, 3, 6, 12, 18 and 24 hours after coronary artery ligation, and serum levels of T4 and T3 were measured using the TDX T4 system and a commercial RIA kit, respectively. Various hemodynamic parameters (heat rate, mean blood pressure, max dp/dt, left ventricular end-diastolic pressure, cardiac output) were measured at the same time mentioned above. All the hemodynamic parameters remained within normal range for 24 hours in the control group. Serum T4 and T3 levels, however, showed slight, but significant decreases due to general anesthesia and open chest operation in the control group. On the other hand, hemodynamic parameters were maintained in the normal ranges only for 12 hours, and gradually deteriorated in the MI group. Moreover, it was remarkable that both T4 and T3 levels were decreased immediately after the ligation in this group, T4 being less than 0.1 micrograms/dl and T3 less than 10 ng/dl. They continued to show the low values thereafter. When T4 (30 micrograms/24 hours), and T3(7, 14 or 21 micrograms/24 hours) were continuously infused intravenously for 24 hours after the coronary artery ligation in 10 dogs, serum T4 levels were maintained in the normal range of the dog (1.5-3.6 micrograms/dl) and the serum T3 levels were increased to the low normal range. However, there were no significant differences in hemodynamic indices between the thyroid hormone treated groups and the non-treated group. These data show that T4 and T3 concentrations decrease prior to the deterioration of cardiac function. Moreover, the present findings also suggest that administration of thyroid hormone has no benefit in patients with NTI associated with low T4 and T3 levels.

Effect of ethanol on regional myocardial blood flow and hemodynamics, before and after coronary artery ligation in dogs.

The effects on regional myocardial blood flows (RMBF) and hemodynamics due to ethanol administered before and after acute coronary artery ligation (CAL) in 18 anesthetized dogs were studied. Ethanol was administered to seven dogs (group I) prior to CAL and to six dogs (group II) after CAL; five dogs (group III, control) received only saline before and after CAL. Uniform blood ethanol levels (180 +/- 30 mg/dl) were maintained in groups I and II after initial ethanol administration. In these groups the heart rate and rate-pressure product (which reflects myocardial oxygen consumption) remained stable, but pulmonary arterial pressures were elevated. Other hemodynamic parameters remained stable in all groups. Ethanol caused a significant transmural increase of RMBF (p less than 0.001) in both groups I and II. In group II the increase was significant in both nonischemic and ischemic tissues, with no apparent redistribution of flow among the myocardial layers. The percentage increase of RMBF due to ethanol was highest in group II nonischemic tissue (95-107%) compared to the corresponding ischemic tissue (57-60%) and the group I myocardial tissue (36-47%) prior to CAL (p less than 0.001). The observed differences between ethanol pre- and posttreatments suggest different interactions between ethanol and catecholamines. The results also confirm that vasodilatory reserve is present in the acutely ischemic myocardium and that the local availability of ethanol is important for coronary vasodilatation.

Effects of SK&F 93479 on experimentally induced ventricular arrhythmias in dogs, rats and mice.

The effects of SK&F 93479, a potent histamine H2-receptor antagonist, on ventricular arrhythmias induced by coronary artery ligation in dogs and rats, and by aconitine infusion in mice were investigated. It was found that SK&F 93479 in large doses, significantly prevented the occurrence of spontaneous ventricular fibrillation and the changes in ventricular fibrillation threshold following coronary artery ligation in dogs. In rats subjected to ligation of the main left coronary artery, it significantly reduced the incidence of ventricular fibrillation, and significantly prolonged the time of onset of ventricular tachycardia and ventricular fibrillation. On the contrary, SK&F 93479 did not significantly alter the incidence or the time of onset of cardiac dysrhythmias caused by aconitine infusion in mice. These findings suggest that SK&F 93479 lacks non-specific antiarrhythmic activity and that its protective effects against coronary artery ligation may be mediated by its histamine H2-receptor antagonizing action. They also support the hypothesis that histamine may contribute to the genesis of ventricular arrhythmias resulting from acute myocardial ischaemia.

Protection by SK&F 93479 against the haemodynamic effects of coronary artery ligation in dogs

The effects of SK&F 93479, a potent histamine H2-receptor antagonist, on the changes in haemodynamics induced by coronary artery ligation were investigated in anaesthetized dogs. Intravenous bolus injection of SK&F 93479 1 mg/kg followed by 1 mg/kg/h infusion caused transient decreases in systemic blood pressure, left ventricular pressure, and dLVP/dtmax, but did not significantly alter heart rate. Coronary artery ligation produced haemodynamic depression, and this was significantly prevented by pretreatment of the animals with SK&F 93479. These findings suggest that histamine may contribute to the haemodynamic changes arising from acute myocardial ischaemia.

Effect of diltiazem on ischemia in the perfused working rat heart.

We reported that diltiazem, a calcium antagonist, attenuated myocardial acidosis produced by coronary artery ligation in dogs (J.P.E.T. 222: 720, 1982). This finding suggests the beneficial effect of diltiazem on ischemic myocardium. The present study was undertaken to examine whether diltiazem protected the myocardium from irreversible ischemic damage in the isolated perfused working rat heart. Ischemia was produced by lowering afterload pressure of the perfused working rat heart until the heart was reperfused by raising the after-load. After ischemia, the following changes were observed: decreases in the pressure-rate product and coronary flow, depletion of ATP and CrP, and accumulation of lactate. The pressure-rate product and ATP level of the heart that had been made ischemic for 20 min did not return to the preischemic level during reperfusion, suggesting that irreversible ischemic damage occurred. Diltiazem (1, 5 and 10 mg/1) was provided to the heart 5 min before the onset of ischemia. In the presence of diltiazem, the levels of ATP and CrP did not decrease even after 20 min of ischemia. Reperfusion with the normal buffer after 20 min of ischemia recovered the pressure-rate product that had been decreased by ischemia, depending upon the concentration of diltiazem provided. These results indicate that diltiazem has a protective effect on the ischemic myocardium.

Non-hydrostatic pulmonary edema after coronary artery ligation in dogs. Protective effect of indomethacin.

Pulmonary edema which develops during acute myocardial infarction is generally believed to result solely from pulmonary microvascular hypertension. However, patient with myocardial infarction and pulmonary edema occasionally are found to have normal pulmonary wedge pressure. We report data indicating that pulmonary edema develops after coronary artery ligation despite stable microvascular pressure. Four groups of open-chest dogs were studied: (1) nine dogs with left anterior descending coronary artery ligation, (2) seven dogs with sham coronary ligation, (3) seven dogs ligated after beginning an infusion of indomethacin (5 mg/kg per hr), and (4) five dogs ligated after an infusion of the drug's vehicle was begun. Extravascular lung water and pulmonary blood volume were measured at hourly intervals during the 2 hours before and after coronary ligation or sham ligation. Gravimetric lung water was measured immediately thereafter. Changes of net pulmonary intravascular driving force (the difference of microvascular hydrostatic and oncotic pressure) after ligation or sham ligation were small and comparable in all groups. Pulmonary blood volume did not change in any group. Pulmonary extravascular water volume remained constant in the sham group but rose significantly in the ligated group. Gravimetric lung water also was significantly higher in the latter group. We interpret these results to indicate that factors other than microvascular pressure can mediate the formation of these results to indicated that factors other than microvascular pressure can mediate the formation of edema during acute myocardial infarction; increased pulmonary microvascular permeability may be responsible. Indomethacin infusion blocked the formation of edema after coronary ligation, even though net microvascular driving force was highest in this group. Infusion of the vehicle alone did not prevent edema. The mechanism by which indomethacin exerts this protective effect is unclear but is probably a result of its inhibition of cyclo-oxygenase or cyclic nucleotide phosphodiesterase.

Effect of glucose-insulin-potassium infusions on epicardial ECG changes and on myocardial metabolic changes after coronary artery ligation in dogs.

The effect of glucose-insulin-potassium infusion (GIK) on developing myocardial infarction in dogs was evaluated, commencing infusion 30 min after coronary artery ligation (CAL). The parameters studied were: early (60 min after CAL) and late (6 and one half h after CAL) epicardial ST segment elevation, the change in Q, R, and S waves and certain myocardial metabolic determinations (glycogen, sodium, potassium, dry-wet weight ratio, adenosine triphosphate, creatine phosphate, inorganic phosphate, and lactate). 6 and one half h after coronary ligation Q wave amplitude was less, the R wave amplitude was greater and the metabolic profile in hte infarct zone was less deranged; metabolic improvement was also found in the nonischaemic zone. Sites in which early ST-segment elevation was less with GIK did not predict all the sites in which there was eventual lessened Q wave formation. R wave fall and disturbance of myocardial metabolism. This study supports others showing an effect of GIK in improving the features of developing experimental myocardial infarction. Following the rate of Q wave development in relation to the early ST segment elevation may be of value in assessing GIK effects provided that a qualitative rather than quantitative relationship between the two parameters is accepted.

Depletion of myocardial creatine kinase, lactate dehydrogenase, myoglobin and K+ after coronary artery ligation in dogs

In order to compare the time-course of disappearance of macromolecules and electrolytes from ischaemic myocardium, measurements of creatine kinase and lactate dehydrogenase activity and myoglobin, K+ and Na+ concentration were made on myocardial extracts from dogs which had left anterior descending coronary artery ligation for 3, 6, 12 and 24 h (4 groups of 6 dogs each). Intensity of ischaemia was assessed by myocardial blood flow measured with 15+/- 5 micrometers microspheres at 15 min after ligation. Creatine kinase and lactate dehydrogenase activities and K+/Na+ concentration ratios were at all times correlated with the magnitude of collateral blood flow in the ischaemic myocardium, while myoglobin concentration was correlated with blood flow only at 12 and 24h. Comparisons of the intensity of depletion at the various times after ligation showed that K+, K+/Na+ and creatine kinase had all reached a steady state at 12 h after ligation while lactate dehydrogenase and myoglobin had still to reach a steady state at 24 h. We conclude that these indices are mutually supportive markers of the intensity of ischaemia of 24 h duration, but K+ or K+/Na+ may be the most reliable indices for shorter periods of ischaemia of 3 to 6 h duration.

Ventricular arrhythmias in acute coronary artery ligation in dogs: electrophysiological mechanism and its relation to the severity of myocardial ischemia.

Analysis of conduction characteristics within the ischemic myocardium and the incidence of ventricular arrhythmias for the first 30 minutes of coronary artery ligation identified two phases of ventricular arrhythmias with different electrophysiological mechanisms. The first phase appearing during 2-10 minutes (immediate ventricular arrhythmias: IVA) was closely related to the degree of epicardial delay and thus considered to be initiated by reentry within the ischemic epicardial zone. In contrast, the second or delayed phase (12-30 minutes, delayed ventricular arrhythmias: DVA) of ventricular arrhythmias appearing independently from epicardial delay was suggested to originate from the subendocardial Purkinje network, since endocardial activation of the ischemic zone consistently preceded the QRS complexes of ventricular arrhythmias. Measurements of myocardial adenosine triphosphate (ATP) contents demonstrated that in animals developing a profound myocardial ischemia by 3-5 minutes, epicardial delay was not observed and thereby IVA was not initiated. In contrast, epicardial delay and IVA were associated with a significant, but milder or slower ischemic process. At the time of DVA, myocardial ATP contents were at extremely low levels for both groups with and without DVA, supporting the concept that DVA is not originated from the ischemic myocardial cells, but from Purkinje fibers depressed secondarily by surrounding ischemic myocardial cells.

Acute changes of myocardial norepinephrine and glycogen phosphorylase in ischemic and non-ischemic areas after coronary ligation in dogs.

The myocardial norepinephrine (NE) content and glycogen phosphorylase activity were measured before and after coronary artery ligation in dogs anesthetized with pentobarbital. Coronary artery ligation was performed by ligating a branch of the left anterior descending coronary artery (LAD). Before coronary artery ligation, the NE content in the circumflex area (778.05 +/- 37.83 ng.g-1 wet tissue) was significantly higher than that in the LAD area (630.57 +/- 35.75 ng.g-1 wet tissue). The NE content in the circumflex area (non-ischemic area) decreased significantly 1.5, 3, 30. 60, and 420 min after coronary artery ligation, while that in the LAD area (ischemic area) did not decrease significantly except for the NE level obtained after 420 min of coronary artery ligation. The glycogen phosphorylase activity increased significantly 1.5 min after coronary artery ligation in both non-ischemic and ischemic areas. From the foregoing results, it is suggested that NE release occurs in both ischemic and non-ischemic areas within at least 1.5 min after coronary artery ligation, and that within 60 min after coronary artery ligation the NE content decreases in the non-ischemic area but not in the ischemic area probably because of very limited washout of the released NE in the ischemic area.

Prolonged epicardial mapping of myocardial infarction: The effects of propranolol and intra-aortic balloon pumping following coronary artery occlusion

A methods of prolonged epicardial surface mapping of myocardial infarction by serial epicardial ECG's is described. The progression of infarction following coronary artery ligation in dogs was monitored over a 4 day period and the early and late changes in the configuration of the epicardial ECG's associated with the underlying myocardial injury were defined. The determination of the infarct size by surface mapping in vivo correlated accurately with the final infarct size determined by dehydrogenase staining in vitro. Treatment with propranolol resulted in a significant reduction in the infarct size. Treatment with intra-aortic balloon pumping did not alter the size of the myocardial infarction induced in this experimental model.

Significance of spinal autonomic loci in post coronary ligation arrhythmia

Two-stage coronary artery ligation in dogs consistently induced ventricular ectopics and raised plasma catecholamine and free fatty acid levels. Ether or pentobarbitone anaesthesia completely abolished the cardiac irregularities and lowered the plasma catecholamine and free fatty acid levels. Chloralose anaesthesia, on the other hand, did not affect the ventricular ectopics, plasma catecholamines and free fatty acids. Haemorrhagic hypotension did not alter the incidence of ventricular ectopics following coronary artery ligation. In chloralose anaesthetized dogs, the neural factors concerned in the genesis of cardiac arrhythmias following coronary artery ligation were analysed by surgical and pharmacological procedures. Bilateral vagotomy, mid-collicular or spinal (C1) transection did not significantly influence the incidence of ventricular ectopics. Spinal (C4-T6) cord destruction completely abolished ventricular ectopics, restored normal rhythm and lowered plasma catecholamine and free fatty acid levels. Spinal anacsthesia with xylocaine was also found to completely abolish ventricular ectopics. Cardiac sympathectomy or bilateral adrenalectomy significantly inhibited the ventricular ectopics and lowered plasma catecholamines and free fatty acids. Ganglionic blockade, adrenergic neurone blockade or β-adrenoceptor blockade restored normal sinus rhythm. The results implicate the prime importance of spinal autonomic loci in the integration of reflex cardiac arrhythmia arising from myocardial ischaemia. The afferent and efferent pathways of the reflex seem to be in the sympathetics.

200) - Effects of propranolol on utilization of glycogen during coronary artery ligation in dogs

200) - Effects of propranolol on utilization of glycogen during coronary artery ligation in dogs

Regional metabolic changes in the myocardium following coronary artery ligation in dogs

Metabolic and hemodynamic changes were studied in dogs before and at 5 minute intervals following ligation of the anterior descending coronary artery. By placing catheters in the arterial (A), main coronary sinus (CS), and great cardiac vein (CV) positions, it was possible to collect simultaneous samples from the three sites and analyze the effluent for pH, Po 2, potassium, glucose, pyruvate, and lactate. Following coronary ligation, there was a significant decrease in pH and glucose and an increase in lactate and potassium in the CV samples. The Po 2 value did not change significantly. The CS drainage exhibited minor changes and only when the changes in the CV samples were marked. The hemodynamic changes included a slight fall in blood pressure, an increase in isovolumetric contraction period, and an increase in left ventricular end-diastolic pressure following coronary ligation. The results and the technique are discussed with emphasis on metabolic alterations in regional venous drainage following coronary artery ligation.

Responses of the ischemic myocardium to allopurinol

Allopurinol was found to have a profound effect on hemodynamic, ECG, and biochemical changes of experimental myocardial ischemia produced by coronary artery ligation in dogs and sheep. Following acute infarction, intravenously administered Allopurinol caused an increase of myocardial contractility and cardiac output, reversed or prevented electrocardiographic S-T changes of ischemic origin, and exhibited prolonged antiarrhythmic effects. It is suggested that prevention of the irreversible loss of purine base from the cell during hypoxic states is the biochemical action of this drug that results in rapid recovery of the stressed myocardium. The results of the experiments indicated that Allopurinol may be a useful agent for the treatment of coronary insufficiency.

Analysis of T-wave abnormalities associated with myocardial infarction using a theoretic model.

The physiological basis of serial T-wave abnormalities associated with myocardial infarction was studied. After coronary artery ligation in dogs, ventricular functional refractory periods (FRPs) were measured at five to eight epicardial, intramural, and endocardial sites. FRPs measured during acute ischemia shortened an average of 26 msec. FRPs measured 24 to 72 hr after coronary ligation were 24 msec longer at ischemic than at nonischemic sites. Alterations of recovery times were analyzed in terms of a repolarization model which related the form of the action potential downstroke to the form of the T wave of the body surface ECG. Observed FRPs were used to infer action potential duration and T waves were derived. Shortening FRPs in the anterolateral wall of the ventricle increased the amplitude of derived T waves in the X lead and caused T-wave inversion in the Z lead. Prolonging FRPs in the same area caused T-wave inversion in lead X and increased T amplitude in lead Z. The form of derived T waves qualitatively corresponded to serial T-wave abnormalities seen in patients with myocardial infarction.