Adel M. Malek

Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium.

Fluid shear stress has been shown to be an important regulator of vascular structure and function through its effect on the endothelial cell. We have explored the effect of shear stress on the expression of the heparin-binding growth factors platelet-derived growth factor B chain (PDGF-B) and basic fibroblast growth factor (bFGF) in bovine aortic endothelial cells using a purpose-built cone-plate viscometer. Using morphometric analysis, we have mimicked the endothelial cell shape changes encountered in vivo in response to shear stress and correlated these with changes in gene expression. Steady laminar shear stress of 15 and 36 dyn/cm2 both resulted in endothelial cell shape change, but the higher shear stress induced greater and more uniform alignment in the direction of flow and nuclear protrusion after 24 h. Steady laminar shear stress of both 15 and 36 dyn/cm2 induced a significant 3.9- and 4.2-fold decrease, respectively, in PDGF-B mRNA at 9 h. In contrast, steady laminar shear of 15 dyn/cm2 induced a mild and transient 1.5-fold increase in bFGF mRNA while shear of 36 dyn/cm2 induced a significant 4.8-fold increase at 6 h of shear which remained at 2.9-fold at 9 h. Pulsatile and turbulent shear stress showed the same effect as steady laminar shear stress (all at 15 dyn/cm2 time-average magnitude) on PDGF-B and bFGF mRNA content. Cyclic stretch (20% strain, 20/min) of cells grown on silicone substrate did not significantly affect either PDGF-B or bFGF mRNA levels. These results suggest that expression of each peptide growth factor gene is differentially regulated by fluid shear stress in the vascular endothelial cell. These results may have implications on vascular structure and function in response to hemodynamic forces and present a model for the study of transduction of mechanical stimuli into altered gene expression.

Cerebral hyperperfusion syndrome after percutaneous transluminal stenting of the craniocervical arteries.

OBJECTIVE Cerebral hyperperfusion syndrome is a recognized complication of carotid endarterectomy, with a reported incidence of 0.3 to 1.2%. The incidence of cerebral hyperperfusion after endovascular revascularization procedures of the craniocervical arteries remains unknown. We evaluated the incidence of cerebral hyperperfusion syndrome in our endovascular revascularization series. To our knowledge, there are no previous studies evaluating the incidence of hyperperfusion syndrome after percutaneous transluminal angioplasty/stenting. METHODS Between March 1996 and February 2000, 140 patients underwent percutaneous transluminal angioplasty/stenting of the craniocervical arteries at our institution. In all patients, selective bilateral arteriography of the carotid and vertebral arteries was performed to document the sites of craniocervical stenosis and collateral blood flow and the results of the endovascular revascularization procedure. We then reviewed all pertinent medical records, arteriographic films, and sectional imaging studies to determine the incidence of cerebral hyperperfusion in this series. RESULTS Seven patients (5.0%) developed clinical or radiological manifestations of cerebral hyperperfusion. In the target group, percutaneous transluminal stenting achieved a 90 to 100% reduction in stenotic lesions (mean stenosis, 91%) of the carotid (n = 5) and vertebral (n = 2) arteries. All seven patients remained neurologically stable immediately after treatment. There was delayed development of clinical and radiographic findings, suggestive of cerebral hyperperfusion. Six patients showed evidence of ipsilateral hemispheric edema, including two patients who developed intracranial hemorrhage (one parenchymal, one parenchymal and subarachnoid) documented by computed tomographic brain scans. Symptoms resolved within 72 hours in the four patients without hemorrhage. The two patients with hemorrhage recovered during a more protracted period (range, 3 wk to 6 mo). There were no long-term sequelae or deaths during a cumulative follow-up of 84 months (mean follow-up, 12 mo). CONCLUSION Hyperperfusion syndrome is an uncommon but potentially serious complication of extracranial and intracranial angioplasty and stenting procedures. The clinical manifestations are similar to hyperperfusion syndrome after carotid endarterectomy; however, the prevalence may be greater in the high-risk cohort commonly referred for endovascular treatment. Our findings suggest that patients undergoing endovascular stenting procedures should be closely monitored for evidence of hyperperfusion, with careful monitoring of blood pressure, heart rate, and anticoagulation. Further research is needed to confirm that cerebral hyperperfusion is the pathogenesis of this condition.

Stent-supported coil embolization: the treatment of fusiform and wide-neck aneurysms and pseudoaneurysms.

OBJECTIVE We describe a consecutive series of patients treated with endovascular stent-supported coil embolization for symptomatic or enlarging wide-neck and fusiform aneurysms and pseudoaneurysms of the carotid and vertebrobasilar arteries. METHODS Seven stent-supported coil embolization procedures were performed for seven aneurysms in seven consecutive patients. There were five pseudoaneurysms, one dissecting aneurysm, and one berry aneurysm. Four aneurysms were located in the carotid artery, and three were located in the vertebrobasilar system. Three aneurysms were intracranial. Four patients were symptomatic, and three had angiographic evidence of increasing aneurysm size. RESULTS Technical success was achieved in six (86%) of seven patients. Entanglement of a coil with the stent struts necessitated partial coil delivery into the parent artery in one patient, but there were no neurological or other adverse sequelae. The 30-day rate of periprocedural stroke or mortality was 0%. At a mean clinical follow-up of 14.5 months, neurological status was at baseline or better in all patients. To date, all treated patients remain clinically asymptomatic with oral administration of aspirin only. CONCLUSION Stent-supported coil embolization represents an emerging therapeutic alternative to surgery for the treatment of symptomatic or enlarging wide-neck and fusiform aneurysms and pseudoaneurysms of the cervical and vertebrobasilar arteries, which are not amenable to conventional unsupported coil embolization. Experience with greater numbers of patients and long-term follow-up are required to further validate this technique.

Dural carotid cavernous fistula: definitive endovascular management and long-term follow-up.

PURPOSE To describe the endovascular treatment and clinical outcome in patients with indirect carotid cavernous fistulas (CCFs) over a 15-year period. To our knowledge, this is the largest series in the medical literature. DESIGN Interventional case series. METHODS A retrospective evaluation of 135 consecutive patients who underwent examination and treatment for indirect CCF was performed. Patients received independent evaluations by ophthalmologists, neurologists, or neuro-ophthalmologists before, during, and after endovascular treatment. Patients initially received noninvasive imaging followed by cerebral arteriography for definitive diagnosis and stratification by angiographic risk factors. Endovascular treatment was performed in 133 (98%) patients and clinical follow-up was achieved in 135 (100%) patients on an average of 56 +/- 4.3 months (range: 2 months-14 years). Angiographic follow-up was performed in 72 (54%) patients with ongoing symptoms or a history of fistula with high-risk angiographic features. Arteriographic cure with long-term clinical outcome is summarized by modified Rankin scale (mRS) and Barthel index (BI). RESULTS At a mean follow-up of 56 months, 121 (90%) patients were clinically cured. At latest clinical follow-up, 131 (97%) patients showed good recovery (mRS, 1-2; BI 90-100), one (1%) had moderate disability (mRS, 3; BI, 50-60), and three (2%) (mRS, 4; BI, 40-50) were severely disabled. Procedure-related permanent morbidity was 2.3%. There was no operative mortality. CONCLUSIONS With the observed favorable outcomes and low rate of procedural morbidity in this patient population with long-term angiographic and clinical follow-up, endovascular therapy should be the primary treatment for patients with indirect (dural) fistulas of the cavernous sinus.

Molecular aspects of signal transduction of shear stress in the endothelial cell

The cardiovascular system is constantly exposed to mechanical forces, which play a pivotal role in determining its structure and function [1,2]. In the blood vessel, anatomical correlation and surgical experiments have demonstrated that mechanical forces of haemodynamic origin play a crucial role in determining vessel structure (reviewed in [1,3]). In vitro experiments have been designed to duplicate both the shear forces resulting from blood flow [4] and the mechanical strain encountered in response to increased transmural pressure on various cell types, including endothelium [5—10], smooth muscle [11–13] and cardiac myocyte [14,15]. This review will be limited to the definition of fluid shear stress and its effect on endothelial cell function, gene expression, and the key second messenger systems, sensory structures and molecular mechanisms believed to be involved in the endothelial response to flow.

Control of endothelial cell gene expression by flow

The vessel wall is constantly subjected to, and affected by, the stresses resulting from the hemodynamic stimuli of transmural pressure and flow. At the interface between blood and the vessel wall, the endothelial cell plays a crucial role in controlling vessel structure and function in response to changes in hemodynamic conditions. Using bovine aortic endothelium monolayers, we show that fluid shear stress causes simultaneous differential regulation of endothelial-derived products. We also report that the downregulation of endothelin-1 mRNA by flow is a reversible process, and through the use of uncharged dextran supplementation demonstrate it to be shear stress- rather than shear rate-dependent. Recent work on the effect of fluid shear stress on endothelial cell gene expression of a number of potent endothelial products is reviewed, including vasoactive substances, autocrine and paracrine growth factors, thrombosis/fibrinolysis modulators, chemotactic factors, surface receptors and immediate-early genes. The encountered patterns of gene expression responses are classified into three categories: a transient increase with return to baseline (type I), a sustained increase (type II) and a biphasic response consisting of an early transient increase of varying extent followed by a pronounced and sustained decrease (type III). The importance of the dynamic character of the flow stimulus and the magnitude dependence of the response are presented. Potential molecular mechanisms of shear-induced gene regulation, including putative shear stress response elements (SSRE), are discussed. These results suggest exquisite modulation of endothelial cell phenotype by local fluid shear stress and may offer insight into the mechanism of flow-dependent vascular remodeling and the observed propensity of atherosclerosis formation around bifurcations and areas of low shear stress.

Endothelial expression of thrombomodulin is reversibly regulated by fluid shear stress.

The vascular endothelium, by virtue of its position at the interface between blood and the vessel wall, is known to play a critical role in the control of thrombosis and fibrinolysis. Thrombomodulin (TM) is a surface receptor that binds thrombin and is a potent activator of the protein C anticoagulant pathway. Although TM expression is known to be regulated by various cytokines, little is known about its response to ever-present biomechanical stimuli. We have explored the role of fluid shear stress, imparted on the luminal surface of the endothelial cell as a result of blood flow, on the expression of TM mRNA and protein in both bovine aortic endothelial (BAE) and bovine smooth muscle (BSM) cells in an in vitro system. We report in the present study that TM expression is regulated by flow. Subjecting BAE cells to fluid shear stress in the physiological range of magnitude of 15 (moderate shear stress) and 36 (elevated shear stress) dynes/cm2 resulted in a mild transient increase followed by a significant decrease in TM mRNA to 37% and 16% of its resting level, respectively, by 9 hours after the onset of flow. In contrast, shear stress at the low magnitude of 4 dynes/cm2 did not affect TM mRNA levels. The sensitivity of TM mRNA expression by flow was found to be specific to endothelium, since it was not observed in BSM cells exposed to steady laminar shear stress of 15 dynes/cm2. Furthermore, unlike BAE cells, BSM cells did not exhibit altered cell shape nor align in the direction of flow after 24 hours of shear stress at 15 dynes/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Balloon-assist Technique for Endovascular Coil Embolization of Geometrically Difficult Intracranial Aneurysms

OBJECTIVE The balloon-assist or neck-remodeling technique is an adjunctive method devised for the endovascular coil embolization of aneurysms characterized by a wide neck or unfavorable geometric features. Since its initial description, there have been few data to corroborate its utility, efficacy, and safety in aneurysm embolization. METHODS Twenty patients (19 female patients and 1 male patient) with 22 aneurysms (19 unruptured aneurysms and 3 ruptured aneurysms) underwent balloon-assisted coil embolization. The balloon-assist technique was performed in the same treatment session after conventional coil embolization had failed in 55% of cases (12 of 22 cases) and was the primary treatment in 45% of cases. The majority of aneurysms were located in the supraclinoid carotid artery (13 paraophthalmic and 3 superior hypophyseal aneurysms). The mean angiographic measurements included a fundus of 8.7 +/- 3.7 mm, a neck of 5.3 +/- 2.2 mm, and a comparatively unfavorable fundus/neck ratio of 1.33 +/- 0.23. RESULTS Technical success was achieved in 77% of cases (17 of 22). The rate of aneurysm obliteration at the end of the procedures was 97 +/- 3.8%. Angiographic follow-up data (mean follow-up period, 10.3 mo) obtained for 89% of the treated aneurysms (15 of 17) confirmed stable mean occlusion of 97.8 +/- 3.8%. Technical complications included two cases of asymptomatic distal vessel thromboembolism, which resolved angiographically within 24 hours, and one case of intraprocedural rupture of an arteriovenous malformation-related feeder artery aneurysm, which resulted in no neurological deficits and required no further treatment (transient complication rate, 13.6%; 3 of 22 cases). There were no deaths and no procedure-related 30-day or permanent morbidity. CONCLUSION The balloon-assist method of coil embolization is characterized by promising intermediate-term angiographic and clinical outcomes and acceptable morbidity and mortality rates. Although this adjunctive method requires the use of an additional microcatheter and consequently involves a higher level of technical complexity, it extends the range of aneurysms that can be successfully treated with electrolytically detachable coils via an endovascular approach.

Endovascular Treatment of Ruptured Posterior Circulation Cerebral Aneurysms: Clinical and Angiographic Outcomes

BACKGROUND AND PURPOSE We sought to describe the clinical outcome and angiographic results obtained in the endovascular therapy of ruptured posterior circulation cerebral aneurysms using Guglielmi detachable coils (GDC) over a 7-year period. METHODS A retrospective analysis was performed of 112 patients evaluated at the University of California at San Francisco Medical Center between June 1991 and August 1998. The Hunt-Hess grade at presentation of treated patients was I in 26 patients (24%), II in 24 (22%), III in 27 (25%), IV in 24 (22%), and V in 8 (7%). Clinical follow-up for the total population was achieved in 104 of 109 patients (96%), with a mean duration of 13.1 months. Angiographic follow-up for the subset excluding parent vessel occlusion cases was obtained in 93% of cases, with a mean duration of 7.2 months. RESULTS Technical success, defined as the ability to catheterize and embolize the aneurysm with GDC, was achieved in 109 of 112 of cases (97%). The mean angiographic occlusion rate, or projected area of the aneurysm occluded by the coils, for all 110 successfully treated aneurysms was 94.6%. At latest clinical follow-up, 81 of 109 patients (74%) achieved good recovery with Glasgow Outcome Scale (GOS) score of I, 10 of 109 (9%) were moderately (GOS II) and 5 of 109 (5%) were severely (GOS III) disabled, 1 of 109 (1%) remained in a vegetative state (GOS IV), and 12 of 109 (11%) were dead. Of the subset of 77 patients with Hunt-Hess grades I to III, 68 (88%) achieved a good clinical outcome (GOS I). A statistically significant correlation was demonstrated between Hunt-Hess grade at presentation and final GOS outcome score (chi(2)=41.4, P<0.0005). Procedure-related permanent morbidity was 2.8% (3/109 patients). Repeated hemorrhage was observed in a single patient (0.9%) with a partially treated aneurysm. CONCLUSIONS The observed favorable outcome and low morbidity in this group of high-risk patients point to GDC embolization as an effective method for the endovascular management of patients with ruptured posterior circulation aneurysms.

Treatment of Posterior Circulation Ischemia With Extracranial Percutaneous Balloon Angioplasty and Stent Placement

BACKGROUND AND PURPOSE Vertebrobasilar territory ischemia (VBI) leads to disabling neurological symptoms and poses a risk for stroke by an embolic or flow-related mechanism. We present our clinical experience in the endovascular treatment of patients with symptomatic VBI from severe atherosclerosis or dissection of the vertebral and subclavian arteries that was unresponsive to medical therapy. METHODS Twenty-one patients (9 female, 12 male) with a mean age of 65.7 years (range 47 to 81 years) underwent treatment with percutaneous endovascular balloon angioplasty and stent placement. Sixteen patients (76.2%) had evidence of contralateral involvement, and 9 (42.8%) demonstrated severe anterior-circulation atherosclerosis. Nine patients had a previous infarct in the occipital lobe, cerebellum, or pons before treatment. Follow-up was available for all patients. RESULTS Balloon angioplasty with intravascular stent placement was performed in 13 vertebral artery lesions (10 at the origin, 3 in the cervical segment) and in 8 subclavian lesions. The prestenting stenosis was 75% (50% to 100%) and was reduced to 4.5% (0% to 20%) after stenting. Six of the patients with proximal subclavian stenosis demonstrated angiographic evidence of subclavian steal, which resolved in all cases after treatment. All patients showed improvement in symptoms after the procedure except for 1 who developed a hemispheric stroke after thrombotic occlusion of an untreated cavernous carotid artery stenosis (rate of major stroke and mortality=4.8%). One patient (4.8%) had a periprocedural transient ischemic attack (TIA), and none had minor stroke. At long-term follow-up (mean=20.7+/-3.6 months) of the surviving 20 patients, 12 (57.1%) remained symptom-free, 4 (19%) had at most 1 TIA over a 3-month period, 2 (9.5%) had at most 1 TIA per month, and 2 (9.5%) had persistent symptoms. There were no clinically evident infarcts during the follow-up period. CONCLUSIONS Endovascular treatment using balloon angioplasty with intravascular stent placement for symptomatic stenotic lesions resulting in VBI that is unresponsive to medical therapy appears to be of benefit in this high-risk subset of patients with poor collateral flow.