Structural Stability of Carotid Plaque and Symptomatology

Stroke Clinical Trial

Official title:

Structural Stability of Carotid Plaque and Symptomatology

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02476396
• Other study ID #: 2015-0289
• Secondary ID: A535700SMPH\NEUR
• Status: Recruiting
• Start date: November 9, 2015
• Est. completion date: December 2025

Study information

• Verified date: October 2023
• Source: University of Wisconsin, Madison
• Contact: Robert J Dempsey, MD
• Phone: 608-265-5967
• Email: dempsey[@]neurosurgery.wisc.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of the research is to understand structural plaque abnormalities that make a carotid plaque unstable and brake off (embolize) which would help to predict and treat individuals who are likely to suffer not only classic episodic major strokes but also cognitive impairment.

Description:

This study examines the relationship between the structural stability of carotid atherosclerotic plaque forming at the bifurcation of the common internal/external carotids and the ability of such lesions to cause disease. The theory behind this work is the hypothesis that carotid atherosclerotic stroke presents not only as a classical episodic clinical condition, but may also involve elements of a continuous process involving large and small vessel circulations, microcirculatory changes, cellular metabolic resistance to ischemia and micro embolic events. Recent studies suggest for every recognized clinical stroke, 5 silent strokes take place.

The patient implications are enormous as imaging suggests 11 million "silent strokes" occur yearly in the US with poor understanding of the pathophysiology or cognitive consequences for our patients. Within this framework, the investigators choose to study the hypothesis that carotid artery atherosclerosis is likely to cause microemboli, as well as classic macroemboli, which may result in more subtle disturbances than those ordinarily detected by more obvious clinical events such as stroke and transient ischemia attacks.

Understanding the structural plaque abnormalities that render a carotid plaque unstable and at risk of embolization would help to predict and treat individuals who are likely to suffer not only classic episodic major strokes, but also cognitive impairment from the contribution of microemboli to this overall disease process. The investigators have previously described a non-invasive ultrasound-based measure of plaque structural stability which will be further studied in this proposal. This study will expand on previous work performed at the University of Wisconsin-Madison, and will include patients with carotid artery stenosis, both with and without classic stroke symptoms, as well as a control group of patients without known atherosclerotic disease. Current treatments for carotid artery stenosis include either carotid endarterectomy to remove plaque or carotid stenting using a expandable metal coil to prevent the artery from narrowing.

In the previous version of this protocol, the investigators have enrolled 95 -subjects (75 patient-subjects and 20 control-subjects) with no safety concerns. Findings include new understanding of the relatively of atherosclerosis and cognition as well as the basic pathophysiology of atherosclerotic large to small vessel disease.

The study will run for 5 years from IRB approval with potential to further expand it. All patient-subjects will have a baseline and 1-year follow-up, ultrasound, TCD, blood collection and cognitive study to see if endarterectomy or stenting (endovascular) affected pre-op change. Change in cognition will be compared to report studies in the normal control group. In past, carotid patients have been recruited at a greater pace. Given the complexity of these studies the investigators anticipate recruitment and complete analysis of 20 patients/year. During this time initial psychological testing will be done pre-operatively. During the final year of the study, the data analysis of the plaque ultrasounds, and histopathology and 1-year follow-up the patient received in the last year of recruitment will take place. The investigators can recruit additional patients to fill any missing data points if these results identify a subset of classically asymptomatic patients with significant carotid plaques and microemboli causing vascular cognitive decline.

• Specific Aim 1: Atherosclerosis, plaque elasticity, strain defects and histopathology of plaque. This aim will study the relationship of structural instability in the carotid plaques with histopathologic evidence for fissuring of the plaques that may represent a micro-emboli source. The determination of a structural defect causing abnormal strain measurements in a carotid atherosclerotic plaque will be important in understanding the pathophysiology of this disorder, as well as, addressing future treatment strategies, which could include preventing angiogenesis, thrombosis, or abnormal cholesterol deposit within the plaque.

• Specific Aim 2: Plaque strain deficits and microemboli. In this aim, the investigators will preoperatively measure the structural stability of each plaque ultrasonically while simultaneously recording distally for the presence of microemboli over time within the carotid system. Statistical analysis will establish the structural instability signature that predicts ongoing subclinical microemboli.

• Specific Aim 3: Plaque strain deficits, microemboli, and cognition. This aim will analyze increased elasticity strain within carotid plaques as measured preoperatively with ultrasound and correlate these parameters with cognition

• Specific Aim 4: Blood RNA expression profiles can be used as biomarkers to identify the patients with a higher risk of plaque instability. This aim will analyze the mRNA and microRNA expression profiles of the blood and the excised plaque samples from patients with stable and ruptured carotid atherosclerotic plaques. The RNA analysis will be conducted with the microarrays.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria (Patients):

• Patients undergoing carotid endarterectomy or stenting (endovascular) for established clinical criteria

• Age > 18 years

• Male or Female

• English speaking

• Patients must sign written informed consent form

Inclusion Criteria (Controls):

• A spouse or sibling of a Patient Subject

• Age > 18 years

• Male or Female

• English speaking

• Control-Subject must sign a written informed consent form

Exclusion Criteria (Patients):

• Previous history of carotid artery surgery (endovascular or open) on the same side

• Previous cervical radiation

• Patients not felt be suitable for carotid endarterectomy or stenting (endovascular)

• Patients with impaired consent capacity

• Contraindication to MRI scans (impaired renal function, need for sedative medication during scans, inability to lie in scanner for 60 minutes)

• Prisoner status

Exclusion Criteria (Controls):

• Control-Subjects with impaired consent capacity

• Prisoner status

• Previous history of Stroke or TIAs

• Previous history of carotid artery surgery (endovascular or open)

Related Conditions & MeSH terms

• Carotid Artery Plaque
• Carotid Artery Stenosis
• Carotid Stenosis
• Cerebrovascular Accident
• Constriction, Pathologic
• Ischemic Attack, Transient
• Stroke
• Transient Ischemic Attack

Intervention

Procedure:
• Carotid Endarterectomy or Stenting
Carotid endarterectomy is a procedure to treat carotid artery disease. This disease occurs when fatty, waxy deposits build up in one of the carotid arteries. The carotid arteries are blood vessels located on each side of your neck (carotid arteries). This buildup of plaques (atherosclerosis) may restrict blood flow to your brain. Removing plaques causing the narrowing in the artery can improve blood flow in your carotid artery and reduce your risk of stroke. In carotid endarterectomy, you an anesthetic. Your surgeon makes an incision along the front of your neck, opens your carotid artery and removes the plaques that are clogging your artery. Your surgeon then repairs the artery with stitches or a patch made with a vein or artificial material (patch graft). Source: Mayo Clinic Carotid stenting uses a expandable metal coil to prevent the artery from narrowing.

Locations

Country	Name	City	State
United States	University of Wisconsin-Madison	Madison	Wisconsin

Sponsors (3)

Lead Sponsor	Collaborator
University of Wisconsin, Madison	National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (13)

Dempsey RJ, Vemuganti R, Varghese T, Hermann BP. A review of carotid atherosclerosis and vascular cognitive decline: a new understanding of the keys to symptomology. Neurosurgery. 2010 Aug;67(2):484-93; discussion 493-4. doi: 10.1227/01.NEU.0000371730.11404.36. — View Citation

McCormick M, Varghese T, Wang X, Mitchell C, Kliewer MA, Dempsey RJ. Methods for robust in vivo strain estimation in the carotid artery. Phys Med Biol. 2012 Nov 21;57(22):7329-53. doi: 10.1088/0031-9155/57/22/7329. Epub 2012 Oct 18. — View Citation

Rocque BG, Jackson D, Varghese T, Hermann B, McCormick M, Kliewer M, Mitchell C, Dempsey RJ. Impaired cognitive function in patients with atherosclerotic carotid stenosis and correlation with ultrasound strain measurements. J Neurol Sci. 2012 Nov 15;322(1-2):20-4. doi: 10.1016/j.jns.2012.05.020. Epub 2012 Jun 1. — View Citation

Shi H, Mitchell CC, McCormick M, Kliewer MA, Dempsey RJ, Varghese T. Preliminary in vivo atherosclerotic carotid plaque characterization using the accumulated axial strain and relative lateral shift strain indices. Phys Med Biol. 2008 Nov 21;53(22):6377-94. doi: 10.1088/0031-9155/53/22/008. Epub 2008 Oct 21. — View Citation

Shi H, Tu H, Dempsey RJ, Varghese T. Ultrasonic attenuation estimation in small plaque samples using a power difference method. Ultrason Imaging. 2007 Jan;29(1):15-30. doi: 10.1177/016173460702900102. — View Citation

Shi H, Varghese T, Dempsey RJ, Salamat MS, Zagzebski JA. Relationship between ultrasonic attenuation, size and axial strain parameters for ex vivo atherosclerotic carotid plaque. Ultrasound Med Biol. 2008 Oct;34(10):1666-77. doi: 10.1016/j.ultrasmedbio.2008.02.014. Epub 2008 May 19. — View Citation

Shi H, Varghese T, Mitchell CC, McCormick M, Dempsey RJ, Kliewer MA. In vivo attenuation and equivalent scatterer size parameters for atherosclerotic carotid plaque: preliminary results. Ultrasonics. 2009 Dec;49(8):779-85. doi: 10.1016/j.ultras.2009.06.004. Epub 2009 Jul 3. — View Citation

Tureyen K, Vemuganti R, Salamat MS, Dempsey RJ. Increased angiogenesis and angiogenic gene expression in carotid artery plaques from symptomatic stroke patients. Neurosurgery. 2006 May;58(5):971-7; discussion 971-7. doi: 10.1227/01.NEU.0000210246.61817.FE. — View Citation

Vemuganti R, Dempsey RJ. Carotid atherosclerotic plaques from symptomatic stroke patients share the molecular fingerprints to develop in a neoplastic fashion: a microarray analysis study. Neuroscience. 2005;131(2):359-74. doi: 10.1016/j.neuroscience.2004.08.058. — View Citation

Vemuganti R, Dempsey RJ. Increased expression of genes that control ionic homeostasis, second messenger signaling and metabolism in the carotid plaques from patients with symptomatic stroke. J Neurochem. 2006 Apr;97 Suppl 1:92-6. doi: 10.1111/j.1471-4159.2005.03516.x. — View Citation

Wang X, Jackson DC, Mitchell CC, Varghese T, Hermann BP, Kliewer MA, Dempsey RJ. Estimation of ultrasound strain indices in carotid plaque and correlation to cognitive dysfunction. Annu Int Conf IEEE Eng Med Biol Soc. 2014;2014:5627-30. doi: 10.1109/EMBC.2014.6944903. — View Citation

Wang X, Jackson DC, Varghese T, Mitchell CC, Hermann BP, Kliewer MA, Dempsey RJ. Correlation of cognitive function with ultrasound strain indices in carotid plaque. Ultrasound Med Biol. 2014 Jan;40(1):78-89. doi: 10.1016/j.ultrasmedbio.2013.08.001. Epub 2013 Oct 11. — View Citation

Wesley UV, Vemuganti R, Ayvaci ER, Dempsey RJ. Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling. Brain Res. 2013 Feb 16;1496:1-9. doi: 10.1016/j.brainres.2012.12.008. Epub 2012 Dec 14. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Thickness of the fibrous cap	Examination of fibrous cap of the atherosclerotic plaque to measure thickness.	obtained day of surgery
Other	Number of vascular channels	Histopathologic examination of vascular channels to determine the number of channels in the fibrous cap vs the plaque proper.	obtained day of surgery
Other	Percent diameter stenosis measured with MRI	The percent diameter stenosis will be determined with NASCET criteria.	baseline (pre-surgery)
Other	Maximum Plaque Thickness measured with MRI	Maximum plaque thickness was measured in the transverse plane, perpendicular to the center axis of the lumen	baseline (pre-surgery)
Other	Number of ulcerations measured with MRI	Ulceration will be determined by using a size threshold of 1 mm	baseline (pre-surgery)
Other	Intraluminal Thrombus measured with MRI	Intraluminal thrombus will be determined by a central filling defect	baseline (pre-surgery)
Other	Thinnest area of the enhancing FC	The thinnest area of the enhancing FC will be recorded with FC fissuring being defined as full thickness defects	baseline (pre-surgery)
Other	Carotid intraplaque hemorrhage (IPH)	Carotid IPH will be defined by MPnRAGE-positive plaque with =2-fold signal compared with the sternocleidomastoid muscle	baseline (pre-surgery)
Other	Volumetrics	Total volumes of plaque, lipid-rich necrotic core (LRNC), IPH, and neovascularity will be determined quantitatively with volumes manually segmented from multi-contrast scans	baseline (pre-surgery)
Other	White Matter Hyperintensity (WMH) Volumes	From brain MRI scans, WMH volume will be evaluated using semi-automated segmentation of T2-FLAIR images.	baseline (pre-surgery)
Other	Hemoglobin A1C		baseline
Other	High-sensitivity C-reactive protein (hs-CRP)		baseline
Other	Fasting Lipid Panel		baseline
Other	Compare DNA between blood, plaque, and genes		baseline
Primary	Change in Ultrasound Strain Measurements (Gray Scale Median Value) on Carotid Plaques	Ultrasound Radio frequency (RF) data will be acquired on patients, using both one-dimensional (1D) and two-dimensional (2D) wobbler and/or matrix array transducers to obtain four-dimensional (3D + time) RF data sets. The hypothesis is that plaques which have a lower gray scale median value and which during deformations of the cardiac cycles show larger stress concentrations in these regions are more vulnerable to rupture.	baseline (pre-surgery), 1 year follow up
Primary	Change in In-vivo velocity measured by Transcranial Doppler (TCD)	TCD will be utilized to acquire in-vivo velocity (peak systolic, mean, and end diastolic velocity information) measurements of blood flow in the right and left middle cerebral arteries.	baseline (pre-surgery), 1 year follow up
Primary	Change in Systolic to diastolic ratio measured by transcranial Doppler (TCD)	TCD will be utilized to acquire systolic to diastolic (S/D) ratio of blood flow in the right and left middle cerebral arteries.	baseline (pre-surgery), 1 year follow up
Primary	Change in Pulsatility index measured by transcranial Doppler (TCD)	TCD will be utilized to acquire pulsatility index (PI) measurements of blood flow in the right and left middle cerebral arteries.	baseline (pre-surgery), 1 year follow up
Primary	Change in Resistive index measured by transcranial Doppler (TCD)	TCD will be utilized to acquire resistive index (RI) measurements of blood flow in the right and left middle cerebral arteries.	baseline (pre-surgery), 1 year follow up
Primary	Histopathologic classification of carotid atherosclerotic plaque after removal for plaque ulceration	Histologic classification of plaques is made using the updated classification of atherosclerotic plaques recommended by the American Heart association.	obtained day of surgery
Primary	Change in Impairment Index - General Cognitive Morbidity	General cognitive morbidity will be derived by comparison of the Kaufman 4-subtest IQ and NART. The NART is brief standardized test that assesses an individual's ability to read irregular words (e.g., subtle). Performance on this test has been shown to be highly correlated with years of formal education and premorbid intellectual ability as assessed by traditional intelligence tests. Performance on NART will serve as a comparison against which to compare current IQ as determined by a brief 4-subtest version of the WAIS-R. This abbreviated IQ measure has been demonstrated to have very high correlation (r > .95) with the complete standard WAIS-R Full Scale IQ. Comparison of predicted versus obtained IQ will provide a measure of potential cognitive decline to be used in comparison of groups at study entry.	baseline (pre-surgery), 1 year follow up
Secondary	Change in Impairment Index - Number of Abnormal Test Scores	The 60-minute cognitive screen is the most thorough assessment with the greatest sensitivity to detect the cognitive disruption associated with vascular cognitive impairment (VCI). The cognitive domains to be assessed include executive function and activation, visuospatial ability, language/lexical retrieval, and memory/learning, for a total of 10 tests. A summary impairment index will be derived for each participant and include the proportion of abnormal test scores.	baseline (pre-surgery), 1 year follow up
Secondary	Change in Impairment Index - Cognitive Domain Z-scores	A summary impairment index will be derived for each participant in part using composite cognitive domain z-scores (executive function, visuospatial, language, memory).	baseline (pre-surgery), 1 year follow up