Elizabeth Hitchner

Prospective neurocognitive evaluation of patients undergoing carotid interventions

OBJECTIVE Distal cerebral embolization is a known complication of carotid interventions. We prospectively investigated whether subclinical microembolization seen on postoperative magnetic resonance imaging (MRI) leads to cognitive deficits in patients undergoing carotid revascularization procedures. METHODS Patients undergoing carotid interventions and eligible for MRI scanning were recruited. Among 247 patients who received preoperative and postoperative MRI evaluations, 51 also completed neuropsychologic testing before and at 1 month after their procedure. Cognitive evaluation included the Rey Auditory Verbal Learning Test (RAVLT) for memory evaluation and the Mini-Mental State Examination (MMSE) for general cognitive impairment screening. RESULTS The 51 patients (all men), comprising 16 with carotid artery stenting (CAS) and 35 with carotid endarterectomy (CEA), were a mean age of 71 years (range, 54-89 years). Among them, 27 patients (53%) were symptomatic preoperatively, including 11 who had prior stroke and 16 who had prior preoperative transient ischemic attack symptoms. Most patients had significant medical comorbidities, including hypertension (96%), diabetes (31.3%), coronary artery disease (47%), and chronic obstructive pulmonary disease (15.7%). Two patients (4%) had prior ipsilateral CEA and eight had contralateral carotid occlusion (15.7%). Memory decline evident on RAVLT was identified in eight CAS patients and 13 CEA patients. Eleven patients had evidence of procedure-related microemboli. Although there was no significant difference in baseline cognitive function or memory change between the CEA and CAS cohorts, the CAS cohort had a significantly higher incidence of microembolic lesions. Multivariate regression analysis showed that procedure-related microembolization was associated with memory decline (P = .016) as evident by change in RAVLT. A history of neurologic symptoms was significantly associated with poor baseline cognitive function (MMSE; P = .03) and overall cognitive deterioration (change in MMSE; P = .026), as determined by Wilcoxon rank sum test and linear regression analysis, respectively. CONCLUSIONS Although CEA and CAS are effective in stroke prevention, with minimal neurologic complication, neurocognitive effects remain uncertain. Procedure-associated microembolization and pre-existing neurologic symptoms are associated with poor baseline cognitive function and memory decline after the procedures. Further comprehensive cognitive evaluation to determine the benefit of carotid interventions is warranted.

Intravascular ultrasound as a clinical adjunct for carotid plaque characterization

OBJECTIVE Virtual histology intravascular ultrasound (VH IVUS) is valuable for estimating minimal lumen diameter and plaque characterization. The clinical use of IVUS in carotid intervention is not well characterized. We aim to evaluate the role of IVUS in carotid plaque characterization and determine whether it could be predictive of procedure-related microemboli. METHODS From July 2010, patients with severe carotid stenosis who underwent elective carotid stenting procedures were prospectively enrolled. IVUS evaluation was performed before stent placement. Patient demographics, comorbidities, and preoperative images were recorded. Comparison of pre- and postoperative diffusion-weighted magnetic resonance images was used to identify the number of procedure-related microemboli. IVUS-derived minimal lumen diameter and vessel wall plaque characteristics were collected. Univariate and multivariate logistic regressions were used to search for associations between IVUS-derived VH data and incidence of microemboli. RESULTS A total of 38 high-risk patients receiving carotid stenting were enrolled. Among them, 25 patients had type I aortic arches and 17 of the patients were symptomatic (preoperative stroke or transient ischemic attack). VH IVUS data did not show strong associations with microemboli, however, a trend was found between the area of fibrous tissue and median or more incidence of microemboli (P = .099). IVUS-defined vessel diameter maximum was associated with median or more incidence of microemboli (P = .042). In addition, median or more incidence of microemboli showed trends with proximal common carotid artery calcification (P = .056) and with being over the age of 80 (P = .06). Contralateral carotid occlusion or high-grade stenosis was associated with postoperative contralateral microemboli (P = .036). CONCLUSIONS We demonstrate that periprocedural carotid IVUS is clinically feasible. VH IVUS may be helpful in better understanding plaque morphology and determining optimal stent placement. However, its use in predicting microembolization remains limited.

Volume of subclinical embolic infarct correlates to long-term cognitive changes after carotid revascularization

Objective: Carotid intervention is safe and effective in stroke prevention in appropriately selected patients. Despite minimal neurologic complications, procedure‐related subclinical microemboli are common and their cognitive effects are largely unknown. In this prospective longitudinal study, we sought to determine long‐term cognitive effects of embolic infarcts. Methods: The study recruited 119 patients including 46% symptomatic patients who underwent carotid revascularization. Neuropsychological testing was administered preoperatively and at 1 month, 6 months, and 12 months postoperatively. Rey Auditory Verbal Learning Test (RAVLT) was the primary cognitive measure with parallel forms to avoid practice effect. All patients also received 3T brain magnetic resonance imaging with a diffusion‐weighted imaging (DWI) sequence preoperatively and within 48 hours postoperatively to identify procedure‐related new embolic lesions. Each DWI lesion was manually traced and input into a neuroimaging program to define volume. Embolic infarct volumes were correlated with cognitive measures. Regression models were used to identify relationships between infarct volumes and cognitive measures. Results: A total of 587 DWI lesions were identified on 3T magnetic resonance imaging in 81.7% of carotid artery stenting (CAS) and 36.4% of carotid endarterectomy patients with a total volume of 29,327 mm3. Among them, 54 DWI lesions were found in carotid endarterectomy patients and 533 in the CAS patients. Four patients had transient postoperative neurologic symptoms and one had a stroke. CAS was an independent predictor of embolic infarction (odds ratio, 6.6 [2.1–20.4]; P < .01) and infarct volume (P = .004). Diabetes and contralateral carotid severe stenosis or occlusion had a trend of positive association with infarct volume, whereas systolic blood pressure ≥140 mm Hg had a negative association (P = .1, .09, and .1, respectively). There was a trend of improved RAVLT scores overall after carotid revascularization. Significantly higher infarct volumes were observed among those with RAVLT decline. Within the CAS cohort, infarct volume was negatively correlated with short‐ and long‐term RAVLT changes (P < .05). Conclusions: Cognitive assessment of procedure‐related subclinical microemboli is challenging. Volumes of embolic infarct correlate with long‐term cognitive changes, suggesting that microembolization should be considered a surrogate measure for carotid disease management.

Brain structural connectivity distinguishes patients at risk for cognitive decline after carotid interventions

While brain connectivity analyses have been demonstrated to identify ill patients for a number of diseases, their ability to predict cognitive impairment after brain injury is not well established. Traditional post brain injury models, such as stroke, are limited for this evaluation because pre‐injury brain connectivity patterns are infrequently available. Patients with severe carotid stenosis, in contrast, often undergo non‐emergent revascularization surgery, allowing the collection of pre and post‐operative imaging, may experience brain insult due to perioperative thrombotic/embolic infarcts or hypoperfusion, and can suffer post‐operative cognitive decline. We hypothesized that a distributed function such as memory would be more resilient in patients with brains demonstrating higher degrees of modularity. To test this hypothesis, we analyzed preoperative structural connectivity graphs (using T1 and DWI MRI) for 34 patients that underwent carotid intervention, and evaluated differences in graph metrics using the Brain Connectivity Toolbox. We found that patients with lower binary component number, binary community number and weighted community number prior to surgery were at greater risk for developing cognitive decline. These findings highlight the promise of brain connectivity analyses to predict cognitive decline following brain injury and serve as a clinical decision support tool. Hum Brain Mapp 37:2185–2194, 2016.

Utilization of Intravascular Ultrasound during Carotid Artery Stenting.

For patients at high risk for surgery, carotid artery stenting (CAS) is a viable alternative to help reduce risk of stroke for patients with high-grade carotid artery stenosis; however, a higher incidence of perioperative stroke has been observed in patients undergoing stenting compared to those undergoing open surgery. Intravascular ultrasound (IVUS) is commonly used during coronary artery procedures to help evaluate lesions and to guide stent placement. Multiple groups have sought to determine whether IVUS could also be used during CAS. While IVUS has been shown to be both feasible and safe during CAS, there is limited evidence that demonstrates direct improvement in procedural outcomes. Further studies focusing on clinical outcomes should be conducted in order to justify routine use of this technology during CAS.

A prospective evaluation of using IVUS during percutaneous superficial femoral artery interventions.

BACKGROUND The outcomes of endovascular interventions of the superficial femoral artery (SFA) are variable. Completion angiography is typically performed to confirm satisfactory outcomes after SFA angioplasty and/or stenting. However, two-dimensional angiography may not accurately reflect the extent of residual stenosis. We sought to determine whether intravascular ultrasound (IVUS) can help with residual disease assessment and procedure outcome. METHODS Patients with anticipated SFA disease were prospectively recruited to the study. Patients with primary SFA disease on diagnostic angiography were included. After SFA endovascular intervention with angioplasty and/or stenting, a completion angiogram was performed to confirm satisfactory results before IVUS evaluation. IVUS-detected maximal residual stenosis, maximal residual lesion volume, and number of nonconsecutive posttreatment SFA segments with >50% residual stenosis were evaluated. Periprocedural ankle-brachial indexes (ABIs), Short Form 36 (SF-36) surveys, and Walking Impairment Questionnaires were also collected. RESULTS Fifty-nine patients were prospectively enrolled. Thirty-three received angioplasty only, and 26 received angioplasty and stenting. All patients were men, mean age was 67 years, and major comorbidities included coronary artery disease (53%), active smoking (56%), hypertension (88%), and diabetes (68%). The angioplasty-only cohort had more nonconsecutive areas of >50% residual stenosis (P = 0.004), greater residual stenosis (P = 0.03), and smaller minimal lumen diameters after treatment (P = 0.01) than the angioplasty and stenting cohort. However, there was no significant difference in ABI between the 2 groups and no difference in ABI improvement after intervention. Sixty-four percent of all patients demonstrated a >0.2 increase in postintervention ABI. Improvement in ABI at 1 month after procedure significantly correlated with postintervention SF-36 survey physical scores (r = 0.435, P = 0.007). CONCLUSIONS IVUS evaluation provides more-accurate intraprocedural insight on the extent of residual stenosis after SFA interventions. Future studies are warranted to determine whether IVUS-guided postangioplasty and/or stenting can impact long-term interventional outcome.

Eotaxin Augments Calcification in Vascular Smooth Muscle Cells

Calcification of atherosclerotic plaques in elderly patients represents a potent risk marker of cardiovascular events. Plasma analyses of patients with or without calcified plaques reveal significant differences in chemokines, particularly eotaxin, which escalates with increased calcification. We therefore, hypothesize that eotaxin in circulation augments calcification of vascular smooth muscle cells (VSMCs) possibly via oxidative stress in the vasculature. We observe that eotaxin increases the rate of calcification significantly in VSMCs as evidenced by increased alkaline phosphatase activity, calcium deposition, and osteogenic marker expression. In addition, eotaxin promotes proliferation in VSMCs and triggers oxidative stress in a NADPH oxidase dependent manner. These primary novel observations support our proposition that in the vasculature eotaxin augments mineralization. Our findings suggest that eotaxin may represent a potential therapeutic target for prevention of cardiovascular complications in the elderly. J. Cell. Biochem. 118: 647–654, 2017.

Contralateral microemboli following carotid artery stenting in patients with a contralateral internal carotid artery occlusion.

Subclinical microembolization identified on diffusion-weighted magnetic resonance imaging is recognized as an important outcome measure for carotid revascularization procedures. It is generally believed that arch manipulation is the primary reason for developing microemboli in the contralateral hemisphere during carotid artery stenting. However, we identified three patients who developed postprocedure microemboli of the contralateral hemisphere despite a known chronic contralateral internal carotid artery occlusion. Our cases highlight that ipsilateral microemboli may be an underappreciated but an important source of contralateral lesions through patent intracranial collateral pathways.

Convergence Analysis of Micro-Lesions (CAML): An approach to mapping of diffuse lesions from carotid revascularization

Carotid revascularization (endarterectomy, stenting) prevents stroke; however, procedure-related embolization is common and results in small brain lesions easily identified by diffusion weighted magnetic resonance imaging (DWI). A crucial barrier to understanding the clinical significance of these lesions has been the lack of a statistical approach to identify vulnerable brain areas. The problem is that the lesions are small, numerous, and non-overlapping. Here we address this problem with a new method, the Convergence Analysis of Micro-Lesions (CAML) technique, an extension of the Anatomic Likelihood Analysis (ALE). The method combines manual lesion tracing, constraints based on known lesion patterns, and convergence analysis to represent regions vulnerable to lesions as probabilistic brain atlases. Two studies were conducted over the course of 12 years in an active, vascular surgery clinic. An analysis in an initial group of 126 patients at 1.5 T MRI was cross-validated in a second group of 80 patients at 3T MRI. In CAML, lesions were manually defined and center points identified. Brains were aligned according to side of surgery since this factor powerfully determines lesion distribution. A convergence based analysis, was performed on each of these groups. Results indicated the most consistent region of vulnerability was in motor and premotor cortex regions. Smaller regions common to both groups included the dorsolateral prefrontal cortex and medial parietal regions. Vulnerability of motor cortex is consistent with previous work showing changes in hand dexterity associated with these procedures. The consistency of CAML also demonstrates the feasibility of this new approach to characterize small, diffuse, non-overlapping lesions in patients with multifocal pathologies.

CONVERGENCE ANALYSIS OF MICRO-LESIONS (CAML) FOR DIFFUSE PATHOLOGIES

NAWM. For each subject, the periventricular WMH (red circles), deep WMH (green triangles), and NAWM (blue squares) are displayed on a ternary plot (created using ggtern package in R), with the location corresponding to the relative WM-GM-CSF fraction of the lesions (or normal WM). The relative tissue fraction is shown as a percentage along the left (WM-like), right (GM-like), and bottom (CSF-like) axes. Remarkably, the periventricular WMH, deep WMH, and NAWM appear in distinct clusters, exhibiting their different profiles with regard to relative tissue fractions obtained from SS3T-CSD diffusion data. able 1 ata presented as mean (SD) or number of males (%) for sex. Reported -values from student’s t-tests for age and intracranial volume (ICV), chiquare test for independence for sex, and one-way ANCOVA controlling for V for PVWMH (periventricular WMH), DWMH (deep WMH) and total MH volumes. No significant differences were observed between groups r age, gender, ICV, or DWMHvolume. PVWMHvolumewas significantly reater in AD compared to controls (as was total WMH volume, as xpected) HC (n 1⁄4 94) AD (n1⁄448) Test statistic p-value ge (years) 78.4 (7.4) 77.4 (8.3) t (140) 1⁄4 0.73 0.47 ex (male) 44 (46.8) 21 (43.8) X (1, n1⁄4142) 1⁄4 0.03 0.87