Changes of regional myocardial blood flow during and after acute focal experimental ischaemia.

The regional blood flow through the myocardium of the left ventricle was measured in 11 dogs after ligation of the left anterior descending coronary artery, by means of a local injection of 133Xe depot and precordial detection of its washout 2 hours after ligation. Immediately after ligation the blood flow in the ischaemic area declined considerably but at the same time there was a significant increase of blood flow in the non-ischaemic left ventricular myocardium. The regional flow in the ischaemic and non-ischaemic area increased insignificantly for 2 hrs. These changes were not due to alterations in coronary artery pressure, as the mean arterial pressure declined significantly during the first hour. After temporary ischaemia by ligation of the left anterior descending coronary artery for 2--4 minutes, an intensive reactive hyperaemia developed in the ischaemic region (the blood flow reached 221% of control values on the average) which was the more intensive, the greater the drop of blood flow in the ischaemic area after ligation.     

Right ventricular function in acute myocardial ischaemia

A haemodynamic examination of 10 dogs was carried out at rest, during volume loading and after ligation of the right coronary artery in the presence of a closed pericardium. Ligation of the right coronary artery led to haemodynamic signs of depression of right ventricular function--a drop in systolic pressure and an increase in end diastolic pressure, together with a shift of the functional curve to the right and downwards. Overall performance of the heart (cardiac output and the mean systemic pressure, also fell. Our results show that the depression of the systolic function of the myocardium in the presence of right ventricular infarction can be an important factor in the genesis of low cardiac output syndrome observed in clinical situations. Its pathophysiological mechanisms and some of the clinical consequences are discussed.     

Cardiac telocytes were decreased during myocardial infarction and their therapeutic effects for ischaemic heart in rat

Recently, cardiac telocytes were found in the myocardium. However, the functional role of cardiac telocytes and possible changes in the cardiac telocyte population during myocardial infarction in the myocardium are not known. In this study, the role of the recently identified cardiac telocytes in myocardial infarction (MI) was investigated. Cardiac telocytes were distributed longitudinally and within the cross network of the myocardium, which was impaired during MI. Cardiac telocytes in the infarction zone were undetectable from approximately 4 days to 4 weeks after an experimental coronary occlusion was used to induce MI. Although cardiac telocytes in the non‐ischaemic area of the ischaemic heart experienced cell death, the cell density increased approximately 2 weeks after experimental coronary occlusion. The cell density was then maintained at a level similar to that observed 1–4 days after left anterior descending coronary artery (LAD)‐ligation, but was still lower than normal after 2 weeks. We also found that simultaneous transplantation of cardiac telocytes in the infarcted and border zones of the heart decreased the infarction size and improved myocardial function. These data indicate that cardiac telocytes, their secreted factors and microvesicles, and the microenvironment may be structurally and functionally important for maintenance of the physiological integrity of the myocardium. Rebuilding the cardiac telocyte network in the infarcted zone following MI may be beneficial for functional regeneration of the infarcted myocardium.     

Effect of chloroquine in experimental myocardial ischaemia

The cardiac effects of the phospholipase A2 inhibiting agent chloroquine were studied in dogs, rats and cats. During left anterior descending coronary artery occlusion produced in anaesthetized mongrel dog, chloroquine pretreatment considerably reduced the epicardial ST-segment elevation in the ischaemic area, as well as the number of premature ventricular contractions. In conscious male Sprague-Dawley CFY rats it diminished the duration and prolonged the latency of appearance of the early post-infarction arrhythmias and increased the survival rate following coronary artery ligation. Chloroquine failed to affect the ventricular fibrillation threshold in the normoxic cat heart. The cardioprotective action of chloroquine could be explained at least partly by its antiphospholipase activity.     

Anaesthetic-related occurrence of early ventricular arrhythmias during acute myocardial ischaemia in rats

The cardiovascular responses of rats anaesthetised with different anaesthetic agents to acute coronary artery ligation were studied. Before thoracotomy, urethane-anaesthetised animals exhibited significantly lower blood pressures. Ligation of the left coronary artery induced a high incidence of ventricular tachycardia or fibrillation in rats anaesthetised with pentobarbitone, urethane, or ether inhalation followed by chloralose. Ketamine-anaesthetised animals had a significantly lower incidence of ventricular arrhythmias. The mortality rate was also lower, though not statistically significant. However, all groups of rats showed essentially similar blood pressure and heart rate changes following coronary artery ligation as well as the time of onset of ventricular tachycardia or fibrillation. The findings demonstrate the influence of anaesthetics on the occurrence of early ventricular arrhythmias following acute coronary artery ligation in rats.     

Coronary ligation reduces maximum sustained swimming speed in Chinook salmon, Oncorhynchus tshawytscha

The maximum aerobic swimming speed of Chinook salmon (Oncorhynchus tshawytscha) was measured before and after ligation of the coronary artery. Coronary artery ligation prevented blood flow to the compact layer of the ventricular myocardium, which represents 30% of the ventricular mass, and produced a statistically significant 35.5% reduction in maximum swimming speed. We conclude that the coronary circulation is important for maximum aerobic swimming and implicit in this conclusion is that maximum cardiac performance is probably necessary for maximum aerobic swimming performance.     

Anti-arrhythmic action of adenosine and the cyclic nucleotide content of the myocardium of rats with ischemia

In anesthetized rats a 30-min intravenous infusion of adenosine (2.5 mg/kg/min) performed after the coronary artery ligation significantly decreased the incidence and severity of early ischemic arrhythmias. After the infusion of adenosine, there was an increase in cGMP level in the left ventricular myocardium, cAMP content remained unchanged.     

Effects of L-carnitine in acute myocardial ischaemia

Data in the literature suggest that exogenous L-carnitine improves the metabolic function of ischaemic heart cells: it enhances the transport of long-chain fatty acids into the mitochondria, stimulates the slowed beta-oxidation, and moderates the accumulation of amphiphilic acyl esters. A study has therefore been made of the cardiac effects of L-carnitine in dog experiments (n = 8). The left anterior descending coronary artery (LAD) was isolated in anaesthetized, thoracotomized animals in situ. After a control occlusion and equilibration period, the LAD was again ligated at the time of L-carnitine infusion (100 mg/kg iv. during 10 min). The agent diminished the maximal conduction delay and the degree of epicardial ST-segment elevation in the ischaemic myocardial region, and the free fatty acid concentration of the arterial blood, but it did not influence the frequency of ventricular extrasystoles. The anti-ischaemic effect of L-carnitine was manifest only during the infusion, and its discontinuation was immediately followed by an enhanced ST-segment elevation. In the dose applied, the substance did not affect the heart rate, systemic mean arterial pressure, left ventricular end-diastolic pressure (LVEDP), or left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of L-carnitine (100 mg/kg iv.) is very short, and it has no significant antiarrhythmic action.     

Electroacupuncture decreases the susceptibility to ventricular tachycardia in conscious rats by reducing cardiac metabolic demand

Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Clinical observations and experimental work with animals suggest that acupuncture may have therapeutic effects for individuals with coronary heart disease, certain arrhythmias, and myocardial ischemia. Therefore, we tested the hypothesis that electroacupuncture reduces the susceptibility to ischemia-reperfusion-mediated ventricular tachyarrhythmias. To test this hypothesis, we measured the susceptibility to ventricular tachyarrhythmias produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious rats under two experimental conditions: 1) control and 2) with electroacupuncture. Acupuncture was simulated by electrically stimulating the median nerves, corresponding to the Jianshi-Neiguan [pericardial meridian (P) 5-6] acupoints. Results document a significantly lower incidence of ventricular tachyarrhythmias with electroacupuncture (2 of 8, 25%) relative to control (14 of 14, 100%) rats. The decreased susceptibility to tachyarrhythmias with electroacupuncture was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST-segment elevation) during ischemia.     

Is Performance Time a Prerequisite for the Onset and Intensity of the Occlusion-Reperfusion Arrhythmias in Anaesthetised Rats?

The aim of the present study is to investigate the onset and the intensity of arrhythmias in anaesthetized rats as a function of time under a standardized experimental condition, which is composed of 30 min occlusion and 60 min reperfusion. Local bred rats (250-350 g) housed in a 12-h light-dark cycle (lights on at 09.00 h, lights off at 21.00 h) were anaesthetized by sodium thiopentone (60 mg kg^-1 i.p.) and left anterior descending coronary artery ligation method using 6/0 braided silk ligature was used to induce 30 min occlusion and 60-min reperfusion. Animals were randomly allocated into three groups to exposure to 30-min occlusion at 9.00 h and 60 min reperfusion at 9:30 h (Group I, n = 6); to 30 min occlusion at 15.00 h and 60 min reperfusion at 15:30 h (Group II, n = 6); and to 30 min occlusion at 21.00 h and 60 min reperfusion at 21.30 h (Group III, n = 6). ECG and haemodynamic parameters were recorded throughout the experiments. The onset of ventricular ectopic beats (VEBs), number of VEBs, incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) during the periods of occlusion-reperfusion were analysed. Total VF incidence during occlusion were lower than the VT incidence in all groups. Either VT or VF incidences during reperfusion showed same profiles in all groups but VT incidence was 2-fold higher than VF. Time-dependent application of occlusion-reperfusion induced by coronary artery ligation method in the anaesthetized rats did not result in a variation in the onset and the intensity of arrhythmias. The duration of the experimental ischaemia was the principal factor, which determines the time of onset and intensity of the occlusion-reperfusion arrhythmias.     

Effects of experimental coronary ligation of pH and lactate concentration in cardiac lymph.

Changes in pH and lactate concentration in the cardiac lymph and arterial blood were studied after ligation of the left coronary artery of the dog. After the coronary ligation, pH of the cardiac lymph dropped significantly accompanied by a rise in the lactate concentration, while the pH and lactate concentration of the arterial blood did not change throughout the experiments. This fall in pH in the cardiac lymph may reflect changes in the interstitial fluid of the ischemic myocardium.     

Effects of the lipolysis inhibiting agent beta-pyridylcarbinol (Ronicol) in acute myocardial ischaemia

The antilipolytic, nicotinic acid analogue beta-pyridylcarbinol (Ronicol) has previously been reported to decrease the free fatty acid (FFA) concentration of the arteria-blood, and to moderate the FFA-uptake and O2-consumption of the myocardium; on this basis, the drug may be expected to exert a cardioprotective action. The cardiac effects of Ronicol were therefore studied on a self-control, 'single-vessel' coronary artery ligature dog model. The left anterior descending coronary artery (LAD) was prepared in the in situ heart of anaesthetized, thoracotomized animals. Following the control ligation, a stabilization period and Ronicol infusion (1 mg/kg iv. during 10 minutes), the LAD was repeatedly ligated. The duration of the individual occlusions was 10 minutes. Ronicol significantly decreased the arterial FFA concentration and the epicardial ST segment elevation; its antilipolytic and anti-ischaemic effects were protracted and were still observed 120 minutes after pretreatment. The drug did not decrease the inhomogeneity of ventricular depolarization in the ischaemic myocardium and in the dose applied it had no influence on the heart rate, arterial blood pressure, left ventricular end-diastolic pressure and left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of Ronicol (1 mg/kg iv.) is about 120 minutes. It has the advantage that it does not possess the unwanted cardiovascular side-effects displayed by nicotinic acid observed by us too in this model earlier (Cardiol. Hung. 13, 33-41, 1984).     

Ventricular arrhythmias following coronary artery occlusion in the streptozotocin diabetic rat

The following investigation was designed to assess whether or not streptozotocin diabetes has an influence on the number and severity of ventricular arrhythmias following coronary artery occlusion in the conscious rat. In addition, electrocardiogram and haemodynamic data were compared between streptozotocin groups and control. Diabetes was induced in male Sprague-Dawley rats with streptozotocin (55 mg/kg iv) and left anterior descending coronary artery ligation was performed either 6 or 9 weeks later. Rats were allowed to recover from preparative surgery for 1 week prior to ligation. Streptozotocin diabetes (untreated or insulin controlled) appeared to have little influence on the variables tested. When exposed to equivalent degrees of ischaemia (the rat is a microangiopathy-resistant species), the streptozotocin diabetic rat heart was not appreciably more prone to arrhythmias of any type compared with control.     

Regional appearance of atrial natriuretic peptide in the ventricles of infarcted rat hearts

The appearance of atrial natriuretic peptide (ANP) in the ventricular myocardium was investigated in rat hearts subjected to severe left ventricular infarction. The left coronary artery was ligated for 1, 2, 3, 4 and 6 days and for 3 weeks, and the tissue was prepared for microscopic examination of immunoreactive ANP and for electron microscopy. In the normal and sham-operated hearts, and in hearts subjected to 1 day of coronary ligation, ANP immunoreactivity was restricted to a few ventricular myocytes of the conduction system. Following 2–3 days of coronary ligation, ANP immunoreactivity was detected in the viable myocardium of the lateral border of the infarct and in a few layers of viable cardiac myocytes located in the subendocardial areas of the ischemic left free ventricular wall. Further, during the following days and after 3 weeks of coronary ligation, a gradient of specific labeling was commonly seen across the lateral border area of the infarct. Thus, the strongest immunoreactivities were present in the cardiac myocytes located adjacent to the non-contracting myocardium. Electron microscopic examination of the immunoreactive cardiac myocytes confirmed the presence of electron-dense specific granules within these cells. The present findings suggest that the increased regional production of ANP within the ventricular myocardium is induced by increased mechanical stretch of the cardiac myocytes, and that this might contribute to the increased release of ANP in myocardial infarction.     

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.     

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.     

Circadian Variation of Myocardial Ischemia in Patients with Stable Coronary Artery Disease

The circadian variation of myocardial ischemia detected during 24-h ambulatory electrocardiographic monitoring (AEM) was analyzed in 123 patients with stable angina pectoris, positive exercise test, and angiographically proven coronary artery disease. A total of 437 ischemic episodes (ST-segment depression ≥ 1 mm and duration ≥ 1 min) were observed; 333 (76%) episodes remained asymptomatic, and only 104 (24%) episodes were accompanied by anginal pain. Ischemic episodes predominantly occurred during the morning hours, between 6 a.m. and noon, and another smaller peak was observed in the afternoon, between 4 and 5 p.m.; this diurnal pattern was influenced neither by the extent of coronary artery disease nor the degree of left ventricular dysfunction. The circadian variation was restricted to the 345 (78%) ischemic episodes preceded by increases in heart rate; the 92 (22%) episodes without prior heart rate changes occurred randomly throughout the day. The morning peak in ischemic episodes was not associated with less myocardial oxygen supply; in contrast, heart rate profile showed parallel increases during the morning and afternoon hours, indicating elevated myocardial demand during these periods. Ischemia-related ventricular arrhythmias were concentrated during the morning hours, but their overall prevalence was low–28 (6%) of 437 ischemic episodes. These findings may provide further insight into the pathomechanisms of acute clinical events in patients with coronary artery disease, since the circadian variation of myocardial ischemia is very similar to that observed for the onset of myocardial infarction and sudden cardiac death.     

Circadian Variation of Myocardial Ischemia in Patients with Stable Coronary Artery Disease

The circadian variation of myocardial ischemia detected during 24-h ambulatory electrocardiographic monitoring (AEM) was analyzed in 123 patients with stable angina pectoris, positive exercise test, and angiographically proven coronary artery disease. A total of 437 ischemic episodes (ST-segment depression ≥ 1 mm and duration ≥ 1 min) were observed; 333 (76%) episodes remained asymptomatic, and only 104 (24%) episodes were accompanied by anginal pain. Ischemic episodes predominantly occurred during the morning hours, between 6 a.m. and noon, and another smaller peak was observed in the afternoon, between 4 and 5 p.m.; this diurnal pattern was influenced neither by the extent of coronary artery disease nor the degree of left ventricular dysfunction. The circadian variation was restricted to the 345 (78%) ischemic episodes preceded by increases in heart rate; the 92 (22%) episodes without prior heart rate changes occurred randomly throughout the day. The morning peak in ischemic episodes was not associated with less myocardial oxygen supply; in contrast, heart rate profile showed parallel increases during the morning and afternoon hours, indicating elevated myocardial demand during these periods. Ischemia-related ventricular arrhythmias were concentrated during the morning hours, but their overall prevalence was low-28 (6%) of 437 ischemic episodes. These findings may provide further insight into the pathomechanisms of acute clinical events in patients with coronary artery disease, since the circadian variation of myocardial ischemia is very similar to that observed for the onset of myocardial infarction and sudden cardiac death.     

Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats

The response to myocardial ischemia is complex and involves the cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex, which plays a major role in the genesis of ventricular arrhythmias. For example, brief myocardial ischemia leads to ATP release, which activates cardiac spinal afferents through stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects against ischemia-induced ventricular arrhythmias. However, the role of afferent signals in the initiation of sustained ventricular tachycardia has not been investigated. Therefore, we tested the hypothesis that cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in adult (12-15 wk of age), conscious, male Sprague-Dawley rats. To test this hypothesis, the susceptibility to ventricular tachyarrhythmias produced by occlusion of the left main coronary artery was determined in two groups of conscious rats: 1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia) and 2) control (sham deafferentation). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Results document a significantly higher VAT in the deafferentation group (7.0 ± 0.7 min) relative to control (4.3 ± 0.3 min) rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST segment elevation) during ischemia.     

Age-related cardiovascular responses of rats to coronary artery ligation

The cardiovascular responses of rats of different ages, ranging from 4-15 weeks (body weight 115-490 g), to acute left coronary artery ligation under pentobarbitone anaesthesia were studied. In older animals, the responses included the occurrence of ventricular tachycardia and/or fibrillation, decrease in blood pressure, and a slight increase in heart rate. On the contrary, younger rats exhibited atrioventricular block followed by ventricular arrest, and decreases in both blood pressure and heart rate. The findings demonstrate the existence of age-related cardiovascular responses to acute myocardial ischaemia in rats, and suggest that 10-15-week-old male Sprague-Dawley rats are suitable experimental animals for producing early ventricular arrhythmias by acute coronary artery ligation.