Differences in mortality rate between abrupt and progressive carotid ligation in the gerbil: role of endogenous angiotensin II

Studies have shown that in comparison to rapid occlusion of a vessel, gradual occlusion produces less severe tissue ischemia due to a more effective development of collateral circulation. As other studies have shown that collateral circulation can be enhanced by stimulation of the endogenous renin-angiotensin II system, it was hypothesized that this system is involved in the mechanism of protection against ischemia that obtains during gradual vascular occlusion. To test this hypothesis, mortality rates were evaluated in gerbils subjected to gradual vascular occlusion by means of progressive carotid ligation while simultaneously infused with inhibitors of the renin-angiotensin II cascade--enalaprilat or saralasin. Groups of animals with either abrupt or progressive carotid ligation infused with saline served as controls. Results showed that (1) in saline-infused animals, there was a significant decrease in the mortality rate of progressive-ligated animals when compared to abrupt-ligated animals, and (2) administration of either enalaprilat or saralasin to progressive-ligated animals resulted in mortality rates that were indistinguishable from those of saline-infused abrupt-ligated animals. These results suggest that the endogenous renin-angiotensin system is indeed involved in an adaptive mechanism that occurs during progressive ligation of the carotid artery, and more specifically, that the relatively benign effect of progressive carotid ligation may be due to the action of angiotensin II to stimulate the development of collateral circulation and reduce the severity of focal brain ischemia.     

Common carotid artery stump pressure in the gerbil stroke model.

In 106 slightly anaesthetised adult mongolian gerbils one common carotid artery (CCA) was ligated and the blood pressure in the distal and in the proximal stump was monitored for 8 minutes. The mean distal CCA stump pressure of the 39 nonsurvivors was 15 (+/- 6) mm Hg, that of the 25 survivors with retinocerebral infarcts was 25 (+/- 6) mm Hg, and that of the 42 intact survivors was 31 (+/- 7) mm Hg. The corresponding mean arterial blood pressures (MABP), as measured in the proximal CCA stump, were 81 (+/- 12) mm Hg, 84 (+/- 13) mm Hg, and 87 (+/- 11) mm Hg, respectively. There were no differences between the samples concerning sex, body weight, rectal temperature, arterial blood gases, arterial pH, and haematocrit. Measurements in a second series of 10 awake gerbils showed that the mean values of MABP, heart rate, and respiratory rate of the nonsurvivors were less than those of the survivors during 90 minutes after CCA ligation. It is inferred that in the mongolian gerbil the lower threshold of the arterial blood pressure for the development of brain infarcts ranges within 22 and 25 mm Hg, that is, within the values found in monkeys and cats. The longlasting depression of respiration and circulation in the nonsurvivors is considered to be related to the phenomenon of diaschisis .     

Individual propensity for thrombosis: comparison of venous and arterial circulations

Introduction

The pathogenesis of venous thrombosis has been attributed to complex interaction between environmental and inherited variables. A basal predisposition for venous thrombophilia independent of environmental variables has not been previously defined experimentally. Both to address the existence of an individual propensity to venous thrombosis and to establish an animal model in which variables governing this propensity could be tested, we provoked venous thrombi in a cohort of pigs of uniform size and age. We furthermore sought to determine whether the thrombotic propensity in the venous circulation is associated with similar propensity for arterial thrombosis.

Materials and methods

Bilateral iliac venous stents were deployed and 2 h later, thrombi were harvested and weighed. The thrombotic response was compared to carotid arterial thrombi generated by crush injury within the same pig. Venous and arterial thrombus platelet deposition were measured by scintillation detection of autologous ¹¹¹In-platelet content.

Results

In a cohort of 27 pigs, venous thrombus weights and platelet content varied over greater trrhan 10-fold range from least to greatest responders. There was strong intra-individual correlation of thrombus platelet deposition (r = 0.86; p = 0.008) and thrombus weights (r = 0.68; p = 0.015) between stented iliac vein pairs. Venous thrombosis correlated with whole blood platelet counts but not carotid platelet-rich thrombus formation.

Conclusions

The wide variation in venous thrombotic response to a standardized injury appears to represent an intrinsic propensity of the individual. The poor correlation with arterial thrombosis implies unique mechanisms responsible for this propensity in arteries and veins.     

Stellate ganglion innervation of the vertebro-basilar arterial system demonstrated in the rat with anterograde and retrograde WGA-HRP tracing

Stellate ganglia projections to cerebral arteries have been investigated with wheatgerm-agglutinated horseradish peroxidase (WGA-HRP). Injections of WGA-HRP into the stellate ganglia resulted in labelling of nerve fibres on the vertebral and basilar arteries, and their side branches. The innervation was bilateral, but with an ipsilateral predominance. After WGA-HRP application on the basilar artery, retrogradely labelled cells appeared in both stellate ganglia, but most numerously in the right ganglion (70-75%). Failure to detect stellate projections to cerebral arteries in 6-hydroxydopamine (6-OHDA)-pretreated animals indicates that these fibres are of noradrenergic sympathetic character. It is suggested that the stellate fibres follow the vertebral arteries towards the basilar artery and its branches.     

Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease

Damage to the endothelium is an important component of atherosclerosis and can be quantified by measuring plasma markers, such as von Willebrand factor, thrombomodulin, intercellular adhesion molecule-1, and E-selectin. We hypothesized that increased levels of these markers would be related to objectively defined disease severity among patients with peripheral atherosclerosis or carotid atherosclerosis. To test this, we measured the markers by using ELISA in the plasma of 45 patients with intermittent claudication alone and in 53 patients presenting with transient ischemic attack. Disease severity in the former was by ankle-brachial pressure index and in the latter by ultrasound defined % stenosis. Any symptomatic dual disease or history or present coronary atherosclerosis warranted exclusion. Data were correlated according to Spearman's method. The only significant correlation was between von Willebrand factor and ankle-brachial pressure index (r = -0.39, p = 0.008). Our data suggest that von Willebrand factor is the most sensitive marker of peripheral atherosclerosis and that none of the plasma markers seems to be a useful marker of the degree of carotid artery stenosis.     

Association between arterial bifurcation anatomy and angiographic plaque ulceration among 4,627 carotid stenoses

Stability of atheromatous plaques is influenced by local mechanical and haemodynamic factors, such as plaque motion and shear stress. However, although blood vessel anatomy is an important determinant of haemodynamics, particularly at bifurcations, there have been no previous clinical studies of the association between arterial anatomy and plaque ulceration. We therefore studied arterial anatomy and plaque ulceration using angiograms of 4,627 carotid bifurcations with atheromatous disease from the European Carotid Surgery Trial (ECST). We studied the vessel diameter and area ratios that have been shown in flow models to affect local haemodynamics and shear stress, and which are known to vary widely between and within individuals (internal to common, external to common, external to internal carotid artery and outflow/inflow area). Angiographic plaque surface morphology was defined as ulcerated or not ulcerated. To avoid any potential bias due to selective inclusion of patients in the ECST, we studied the contralateral, and usually asymptomatic, as well as the symptomatic carotid artery. To correct for the effects of systemic factors that might influence plaque stability, we also studied the relationship between the degree of asymmetry of bifurcation anatomy within individuals and the presence of plaque ulceration. Despite considerable inter-individual variation in carotid anatomy, we found no association between the prevalence of angiographic plaque ulceration and any of the anatomical parameters studied in either symptomatic or contralateral carotid arteries. There were also no associations between ipsilateral bifurcation anatomy and plaque ulceration in individuals with unilateral plaque ulceration. Carotid arterial anatomy does not appear to be an important determinant of plaque stability. Other factors that influence local haemodynamics, such as the anatomy and composition of the plaque itself may be more important.     

Differences in CT findings between embolic and thrombotic cerebral artery occlusion of the internal carotid arterial system

Two hundred and one patients with embolic (EM) and 107 with thrombotic (TH) cerebral arterial occlusion of the internal carotid arterial system were subjected to the study. Diagnoses of EM and TH were made with our own diagnostic criteria, based on clinical and angiographic informations but not on CT findings, as previously described. Well-marginated hypodense areas in multiple vascular territories were observed only in patients with EM (13.9%). The following CT findings were more frequently seen in EM than in TH; a) a hypodense area involving the cortex, b) a sharply-marginated lesion, c) a shift of the mid-line structures and d) hemorrhagic infarction. Patients with TH were more frequently accompanied with watershed infarction, or infarct in the basal ganglia and/or deep white matter than those with EM. Watershed zone between cortical and perforating arteries was involved only by TH. Deep-seated infarct, however, was more likely to be embolic rather than thrombotic in nature, if it was sharply-marginated and accompanied with surrounding brain edema. Differences in CT findings of EM and TH appeared to reflect those of pathogenetic mechanisms such as rapidity of occlusive process, sites of occlusion, routes and availabilities of collateral circulation, presence of reopening of the previously occluded artery, etc. In the present study, it can be concluded that there is distinctive differences in CT findings between EM and TH, indicating the usefulness in differentiation of two diagnostic subtypes in the acute stage of cerebral infarction.     

Regional cerebral blood flow and stroke index after left carotid artery ligation in the conscious gerbil

We measured the regional cerebral blood flow in both hemispheres of Mongolian gerbil subjected to permanent left caratoid artery ligation, using [³H]nicotine as the tracer. At 1,3 and 6 h post-ligation, neurological signs were recorded and a stroke index score was tallied for each animal.In conscious control gerbils, mean cerebral blood flow on the left side was1.10 ± 0.08 (S.E.M.) ml·g⁻¹·min⁻¹ at the cerebral cortex0.58 ± 0.02 at the hippocampus and0.69 ± 0.04 at the diencephalon. Animals with a stroke index score exceeding 10 were considered symptomatic. We noted a close relationship between regional cerebral blood flow and the stroke index score. In symptomatic animals, regional cerebral blood flow in the ischemic hemisphere at 1,3 and 6 post-ligation was less than 0.21 ml·g⁻¹·min⁻¹ at the cortex and diencephalon, and less than 0.09 ml·g⁻¹min⁻¹ at the hippocampus.We suggest that unilaterally ligated gerbils manifesting a stroke index score greater than 10 represent a good experimental model for the study of ischemia.     

The effects of unilateral carotid occlusion on the responses to decapitation in the gerbil brain

The effects of partial ischemia (unilateral carotid artery occlusion) on the metabolic and electrical responses to decapitation were studied in the awake and anesthetized gerbils' brains. The gerbil was connected to the 2 channel fluorometer/reflectometer by flexible light guides implanted above the two hemispheres of the brain. The results show that: (1) the metabolic rate as measured by this present technique is lower in the gerbil than in the rat; (2) the metabolic rate of the ischemic hemisphere is lower as compared to that of the normoxic contralateral hemisphere.     

腔隙性脑梗死与血压变异性、颈动脉粥样硬化相关性研究

目的探讨腔隙性脑梗死(CLI)与血压变异性、颈动脉粥样硬化的关系。方法 96例原发性高血压并发CLI患者为观察组,88例原发性高血压患者为对照组。全部患者行头颅CT或MRI检查、动态血压监测、颈动脉超声检查,并进行颈动脉硬化分型及等级积分。结果年龄、性别、吸烟史、高血压、糖尿病、24h收缩压标准差(24h SBPsd)、总胆固醇、高密度脂蛋白胆固醇及颈动脉硬化积分均与脑梗死有显著相关关系,经多因素Logistic回归分析显示,24h SBPsd(r=0.4832,P<0.001)和颈动脉硬化积分(r=0.4960,P<0.001)与脑梗死呈显著正相关。结论 24h SBPsd、颈动脉硬化与脑梗死密切相关,是脑梗死发生发展的有效预测指标。     

2型糖尿病无症状性颅内动脉狭窄与颈动脉粥样硬化的相关性研究

目的 探讨2型糖尿病无症状性颅内动脉狭窄与颈动脉颅外段粥样硬化病变之间的关系.方法 采用经颅多普勒超声和颈动脉超声检测无脑卒中2型糖尿病患者颅内外动脉,分别判断颅内动脉狭窄及颈动脉颅外段内中膜厚度、斑块形成和狭窄程度(狭窄程度≥50%或完全闭塞),分析颅内动脉狭窄与颈动脉粥样硬化病变之间的关系及危险因素.结果 194例患者中42例(21.65%)发生颅内动脉狭窄,其中大脑中动脉受累者30例(15.46%);123例(63.40%)存在颈动脉粥样硬化性病变.颅内动脉狭窄组患者高龄(t=-3.054,P=0.003)、长糖尿病病程(U=2172.500,P=0.002)、合并高血压(x2=9.986,P=0.002)及颈动脉病变(x2=14.086,P=0.000)比例明显高于无狭窄组(均P＜0.01).单因素分析提示,颅内动脉和大脑中动脉狭窄与颈动脉粥样硬化病变程度相关(U=1929.000,1519.000;均P=0.000).多因素Logistic回归分析显示,合并高血压(OR=2.849,95%CI:1.247～6.508;P=0.013)和颈动脉病变(OR=4.838,95%CI:1.778～13.167;P=0.002)为2型糖尿病无症状性颅内动脉狭窄的独立危险因素.结论 2型糖尿病无症状性颅内动脉狭窄与颈动脉粥样硬化病变相关,颈动脉颅外段粥样硬化可能是国人2型糖尿病无症状性颅内动脉狭窄的独立预测因素.     

Cardiac and arterial lesions in carotid transient ischemic attacks

Two hundred fifty consecutive patients with carotid transient ischemic attacks (TIAs) and no previous stroke were assessed with cerebral angiography (95%), two-dimensional echocardiography (86%), electrocardiography (100%), and Holter monitoring (99 selected patients). Angiography disclosed a lesion appropriate to the TIAs in 84%. Lesions also occurred in the asymptomatic carotid artery, but stenosis of more than 75% of the lumen diameter and ulcers were significantly more frequent on the symptomatic side. Twenty-three percent of the patients had a potential source of emboli from the heart, usually in the context of symptomatic heart disease. Among the 205 patients who underwent full angiographic and cardiac investigations, 6% had an isolated potential cardiac source of emboli and 19% had a potential cardiac source of emboli associated with appropriate carotid disease. The search for a potential cardiac source of emboli is strongly indicated in patients with carotid TIAs and known heart disease. In the patients with no history of heart disease, the yield of this search is low, but our results suggest that at least 14 of such patients have an undetected potential cardiac source of emboli. Cardiac and arterial lesions commonly coexist in carotid TIAs.     

Unilateral carotid artery ligation in the Mongolian gerbil as a model for testing infarction-reducing therapies

This study evaluates infarct size measurement as an indicator of cerebral ischaemia outcome in a placebo-controlled trial of potential cerebral protection in the unilateral carotid artery ligation in the Mongolian gerbil. Ibuprofen was used in an effort to manipulate infarct size as this agent has been shown to reduce ischaemia in myocardial infarction. Using measurements obtained through an infarct-sizing technique and a statistical power analysis of the method, the sample sizes needed to obtain significant results were projected for this model. In this case, it was not possible to demonstrate an effect of ibuprofen on infarct size although a tendency towards larger infarct size in ibuprofen-treated compared with placebo-treated gerbils was observed (36.1 +/- 10.1% versus 30.0 +/- 17.5%). The sample sizes needed to find significant changes in infarct size indicate that this model finds a practical use in studying therapies which will alter infarct size by at least 50%. For example, to detect a 30% change in infarct size, 33 successfully infarcted gerbils per group would be needed, but a 50% change would require a more tenable 13 infarcted gerbils per group. However, given the 40% infarction rate of occluded gerbils seen in this study, almost 33 gerbils per group would be required to detect a 50% change. In addition, somatosensory evoked potential was compared with neurological examination as a predictor of infarction. It would be helpful to be able to pre-screen for infarcted gerbils immediately after occlusion in order to direct infarcted gerbils into control and treated groups. Somatosensory evoked potential successfully predicted infarction with a 90% accuracy in 21 gerbils compared with neurological evaluation which was 100% accurate. But the somatosensory evoked potential prediction was made within 15 min of occlusion as opposed to the 6 h of observation during which the neurological evaluation was made.     

Common carotid arterial stiffness and the risk of ischaemic stroke

In the present case-control study we aimed to investigate the association of common carotid arterial (CCA) stiffness with ischaemic stroke (IS) and to determine whether this relationship was independent of conventional risk factors including CCA intima-media thickness (CCA-IMT). CCA distensibility, defined as the change of CCA-diameter during the cardiac cycle, and CCA-IMT were evaluated by means of high-resolution B-mode carotid ultrasound examination in consecutive, first-ever IS patients (n=193) and in age- and sex-matched control subjects (n=106). The CCA distensibility (inverse of CCA stiffness) was significantly (P=0.007) lower in IS (0.353 mm, 95% CI: 0.326-0.379) than in control subjects (0.415 mm, 95% CI: 0.378-0.451) even after adjusting for blood pressure values, diastolic CCA-diameter and height. The multivariate logistic regression procedure selected CCA-IMT and CCA distensibility as the only independent predictor variables of IS. Each 1 SD increase in the CCA-IMT and each 1 SD decrease in the CCA distensibility independently increased the likelihood of IS by 167.0% (OR: 2.67, 95% CI: 1.80-3.96, P<0.001) and 59.0% (OR: 1.59, 95% CI: 1.22-2.07, P=0.001) respectively. Increased CCA stiffness is associated with IS independent of conventional risk factors and CCA-IMT. The causal interrelationship between the elastic properties of the CCA and the risk of stroke deserves further investigation by longitudinal studies.