Elevation of soluble intercellular adhesion molecule-1 levels in symptomatic and asymptomatic carotid atherosclerosis.

OBJECTIVE: Recent data suggest that the increased expression of intercellular adhesion molecule-1 (ICAM-1) in atherosclerotic plaque taken from the carotid bifurcation correlates with the development of neurological symptoms. As a result, the authors sought to compare the serum levels of soluble forms of ICAM-1 (sICAM-1) in patients who were asymptomatic with those who were symptomatic for carotid artery stenosis as well as in patients who were matched in terms of sex, age, and risk factors who did not have carotid artery disease. METHODS: Using enzyme-linked immunosorbent assay, serum sICAM-1 levels were prospectively determined in 54 patients scheduled to undergo carotid endarterectomy for either symptomatic or asymptomatic high-grade stenosis (> or =60%) and in 5 additional patient controls. Data are expressed as mean +/- standard error of the mean, with significance defined as P < 0.05 using the Mann-Whitney two-tailed test for two-column comparison or analysis of variance and Fisher protected least significant difference test. RESULTS: Using a univariate model, serum sICAM-1 levels were significantly elevated in patients with carotid artery stenosis as compared with control patients without stenosis (347 +/- 15 ng/ml versus 216 +/- 8.2 ng/ml) (P < 0.01). When the asymptomatic and symptomatic patients with carotid artery stenosis were considered separately, these levels were still elevated relative to those of control patients (asymptomatic [312 +/- 18 ng/ml] and symptomatic [376 +/- 22 ng/ml] patients; P = 0.06 for asymptomatic versus control patients, P < 0.01 for symptomatic versus control patients). Symptomatic patients also had significantly elevated sICAM-1 levels as compared with asymptomatic patients (P < 0.05). Despite the fact that female patients demonstrated higher ICAM-1 levels than male patients (P < 0.05), sex, age, and risk factors such as the presence of hypercholesterolemia, diabetes, hypertension, or a history of smoking did not confound these findings. CONCLUSION: Levels of sICAM-1 are higher in patients with carotid stenosis than in control patients. Symptomatic patients demonstrate significantly elevated levels as compared with asymptomatic patients. These data support the contention that ICAM-1 is a reliable marker of carotid disease progression and suggest that serum levels may be useful in following certain asymptomatic patients.

A modified transorbital baboon model of reperfused stroke.

BACKGROUND AND PURPOSE: Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. METHODS: Eight male baboons (weight, 22+/-2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide-narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride-stained sections. RESULTS: Infarction volumes (on T2-weighted images) were 32+/-7% (mean+/-SEM) of the ipsilateral hemisphere, and neurological scores averaged 29+/-9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (r=0.9, P:=0.003). CONCLUSIONS: Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.

Safety and efficacy of fixed-dose heparin in carotid endarterectomy.

OBJECTIVE: Although fixed dosage of heparin is frequently used during vascular surgery, there are very few studies that document the appropriateness of this type of dosing. We have undertaken a prospective study to determine the physiological response to a fixed dose of heparin, using a conventional measure of anticoagulation, and have correlated this measure with complications. METHODS: We studied 140 consecutive patients undergoing elective carotid endarterectomy. Serial activated clotting times (ACT values) were obtained in duplicate before administration of heparin, 15 minutes after application of a carotid artery cross-clamp, and 1 hour after administration of 5000 U of heparin by intravenous bolus. Postoperatively, patients were assessed for new neurological deficits (transient ischemic attack and stroke) and neck hematomas. A battery of neuropsychometric tests was performed in 49 patients at baseline and on the day after carotid endarterectomy to identify subtle new neurological deficits. RESULTS: ACT values were found to be highly reproducible, with less than a 1.5% difference between duplicate baseline samples. Although all patients received 5000 U of heparin, the dose received per kilogram of body weight varied considerably (44-116 U/kg), as did ACT values at both 15 minutes (178-423 s) and 1 hour (173-390 s). Nevertheless, there was a significant correlation between heparin dose per kilogram and ACT values at 15 minutes (r = 0.45) and at 1 hour (r = 0.38) postinfusion, as well as ACT ratios (final ACT/initial ACT) at 15 minutes (r = 0.43) and at 1 hour (r = 0.34) after heparin bolus. Eight patients (5.7%) developed postoperative wound hematomas, one of which (0.7%) required reoperation. No patient had a stroke, but one patient had a transient ischemic attack, and 19 (39%) of 49 patients demonstrated significant early postoperative neuropsychometric deficits. Although the incidence of neck hematoma was not influenced by the heparin dose (P = 0.23), the ACT value at 15 minutes (P = 0.71) or 1 hour (P = 0.61), or the ACT ratio (P = 0.68), the only severe hematoma requiring reoperation occurred when the maximal ACT value was more than 400 seconds. Although performance on neuropsychometric tests did not appear to be statistically influenced by heparin dosing, the ACT value, or the degree of ACT elevation, there was a trend for deficits to be associated with lower heparin doses. CONCLUSION: Fixed heparin dosing achieves safe and efficacious anticoagulation in the great majority of patients having carotid endarterectomy, with 5000 U expected to result in 15-minute and 1-hour ACT values of 175 to 425 seconds and 170 to 390 seconds, respectively. Although weight-based heparin dosing may reduce the incidence of subtle complications (hematoma formation or decline on neuropsychometric tests) and may result in more predictable 15-minute and 1-hour ACT values (85 U/kg; 225-375 and 200-340 s, respectively), no statistically compelling clinical advantage could be demonstrated. Therefore, either weight-based or fixed dosing is acceptable, with both obviating the need for routine pre-clamp ACT confirmation, thereby saving operative time and expense.

Titration of postischemic cerebral hypoperfusion by variation of ischemic severity in a murine model of stroke.

OBJECTIVE: Murine models using intraluminal occluding sutures to establish transient focal cerebral ischemia are becoming increasingly widespread, because of advances in transgenic technology and the advent of cerebroprotective strategies to ameliorate postischemic cerebrovascular no-reflow. We hypothesize that the degree of postischemic hypoperfusion is directly related to the severity of the initial ischemic insult. METHODS: Transient ischemia of 45-minute duration was produced using middle cerebral artery occlusion with 10-0 (n = 5), 9-0 (n = 5), 8-0 (n = 6), 7-0 (n = 8), 6-0 (n = 30), or 5-0 (n = 5) sutures. In separate experiments, transient vessel occlusion with 6-0 sutures was performed for 15 (n = 17), 30 (n = 16), or 45 (n = 30) minutes. Sequential laser Doppler measurements of relative cerebral blood flow were obtained, and stroke severity was assessed using neurological deficit scores and infarction volumes. RESULTS: Although relative cerebral blood flow at the time of occlusion and 24 hours thereafter was diminished in parallel with increasing suture diameters, only the use of larger sutures resulted in postischemic no-reflow. As the suture diameter was increased, the resultant reflow was decreased and the stroke outcome worsened. A more than twofold increase in infarction volume (8.0 +/- 3 versus 19.7 +/- 3%, P < 0.05) resulted when ischemia duration was increased from 30 to 45 minutes. CONCLUSION: Titration of the initial ischemic insult leads to corresponding variations in the magnitude of postischemic no-reflow and tissue damage. Therefore, critical control of the severity of the initial injury in studies using intraluminal suture occlusion is warranted.

Cigarette smoking and the development and rupture of cerebral aneurysms in a mixed race population: implications for population screening and smoking cessation.

BACKGROUND: Despite advances in the treatment of aneurysmal subarachnoid hemorhage (aSAH), major additional reductions in morbidity will require the identifications of unruptured aneurysms with a high propensity for bleeding. As screening the entire population is currently not cost-effective, risk factors for the presence of unruptured aneurysms must be identified, and if possible, these risk factors should be modified to reduce disease prevalence. METHODS: To examine whether cigarette smoking independent of arterial hypertension is a risk factor for the development of cerebral aneurysms rather than just being associated with aSAH and to determine whether smoking cessation decreases this risk, we conducted a case-control study comparing the prevalence and degree of smoking in a consecutive series of patients undergoing surgery for ruptured or unruptured aneurysm with age-, sex-, race-, and geographically matched control subjects culled from the New York Healthy Heart Study. RESULTS: Hypertension alone carries little additional risk for the development of ruptured or unruptured aneurysms. Smoking is a risk factor for not only aneurysmal subarachnoid hemorrhage (Relative Risk [RR]=2.83) but also aneurysm formation (RR=2.33). Coexistent hypertension increases the risk of smoking only minimally. Younger smokers are at threefold higher risk than middle-aged ones. Smoking cessation appears to reduce risk of aneurysmal rupture. The effect of smoking on aneurysm formation and rupture may be dose-dependent. CONCLUSIONS: Together these data suggest that smoking, independent of hypertension, plays a critical role in aneurysm development, especially in younger patients, but that physiological mechanisms exist for repair of the damage induced by this toxic insult if cessation is possible.

Does poly-L-lysine coating of the middle cerebral artery occlusion suture improve infarct consistency in a murine model?

BACKGROUND AND PURPOSE: Rodent models of stroke that employ an intraluminal suture to cause focal cerebral ischemia are associated with some variability of resultant infarct volumes, thus requiring increased numbers of animals to determine significant differences between experimental groups. A recent modification of the occluding suture by coating with poly-L-lysine has been shown to create more uniform infarct volumes in rats. METHODS: To evaluate the utility of this modification in murine models of both transient and permanent focal cerebral ischemia, male C57B16J mice were subjected to reversible middle cerebral artery occlusion (MCAo) for 45 minutes (n=42), or to permanent MCAo (n=25), with an intraluminal monofilament suture. Three types of sutures were used: untreated, partially coated, and completely coated with poly-L-lysine. Relative changes in regional cerebral blood flow, severity of neurological deficits, and infarct volumes were measured 24 hours after the ischemic injury. RESULTS: Animals subjected to 45 minutes of temporary occlusion with completely coated poly-L-lysine sutures had infarct volumes of 13.8%+/-5% compared with infarct volumes of 7.2%+/-4% in those subjected to partially coated sutures and 22.4%+/-6% in the group occluded with untreated sutures (P=ns). Use of completely coated sutures resulted in significantly less reperfusion following suture removal. Control animals undergoing permanent occlusion with untreated sutures had infarct volumes of 17%+/-7% compared with 14.1%+/-5% using completely coated sutures and 6.5%+/-3% in animals with partially coated sutures (P=ns). There were no significant differences in cerebral blood flow between the experimental groups undergoing permanent MCAo. CONCLUSIONS: Poly-L-lysine coating of intraluminal sutures does not increase the consistency of infarct volumes in a murine model of temporary/permanent MCAo. These findings are in marked contrast to findings in rats.