Early Detection of Vascular Dysfunction Using Biomarkers From Lagrangian Carotid Strain Imaging

The purpose of this research is assess imaging and identification of soft plaque that undergoes large deformations or strain will identify plaque vulnerable to rupture which could lead to 'silent strokes'. Validation of current study results with MRI will foster use of real-time ultrasound (US) strain imaging and strain indices as a screening tool for identifying normal human participants susceptible to increased vascular aging and developing plaque prone to rupture or micro-embolization.

Current research will evaluate Lagrangian carotid strain imaging (LCSI) for prediction of vascular health on volunteers. In this study, investigators will evaluate age-related strain variations (due to plaque deposition) in the carotid artery, establishing groundwork that will help identify typical and atypical values for these indices. Investigator's hypothesis is that plaques with higher strain indices (softer plaques) are more prone to rupture than plaques with lower strain indices (stiffer) plaques, thus requiring intervention. Clinical criteria for treatment has focused primarily on the degree of stenosis. Long-term objectives are to provide non-invasive methods for screening participants at risk for vascular aging or plaque rupture in asymptomatic participants, expanding upon current criteria for risk assessments based on focal transient ischemic attack (TIA) or strokes. Variations in vessel strain have been associated with, or are precursors to, plaque deposition, vascular aging, or cerebrovascular diseases. Increased arterial strain and pressure changes have been linked to brain aging using magnetic resonance imaging (MRI) based vascular indices, and memory deficits commonly linked to Alzheimer dementia. Stiffening and thickening of the arterial walls have also been associated with cerebrovascular disease. Investigators hypothesize that strain indices as vascular biomarkers can be utilized for screening possible 'vulnerable participants' validated with MRI, with the potential ability to improve endothelial function and reverse vascular aging. Strain indices may enable differentiating study participants with vascular cognitive impairment (VCI) from other dementias. Cognitive testing is unable to make this differentiation.

Study Overview

• Status: Completed
• Conditions: Healthy; Carotid Artery Diseases
• Intervention / Treatment: Device: Ultrasound imaging; Device: Magnetic Resonance Imaging (MRI); Other: Neurocognitive testing; Device: Transcranial Doppler (TCD); Device: Pulse Wave Doppler

• Study Type: Observational
• Enrollment (Actual): 217

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Department of Medical Physics, University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This research will enroll 280 adult participants. 40 participants will be invited to participate in the longitudinal Ultrasound and Magnetic Resonance Imaging study if they are determined to be "at-risk" per current clinical guidelines for being in the at risk population.

Description

Inclusion Criteria:

Aim 1 (Ultrasound (US) only):

• Adults at least 18 years
• Are able to provide written informed consent on their own behalf

Aim 2 (US and MRI):

• Participation in the US study (Aim 1)
• Determined by presence of hypoechogenic or echolucent lipid-rich soft plaque during initial ultrasound imaging session
• Adults willing to participate over 5 years

Exclusion Criteria:

Aim 1 (US only)

• Women that are currently pregnant
• Inability to cooperate with the ultrasound study, in particular those unable to sit without gross movement for the duration the ultrasound study (estimated at 60-90 minutes)
• Open wounds or sores in the anterior neck
• History of cancer treatment, vascular disease, cardiac disease, stroke or TIA
• History of medications that affect vascular wall and plaque
• History of statin medications*
• History of hypertension medications*

• History of anticoagulation, blood thinners

  • These criteria will not be exclusionary for the cohort that is greater than 70 years of age.

Aim 2 (US and MRI):

• Women that are currently pregnant
• Inability to cooperate with the ultrasound study, in particular those unable to sit without gross movement for the duration the ultrasound study (estimated at 60-90 minutes)
• Patients that require intravenous (IV) conscious sedation for imaging are not eligible; patients requiring mild, oral anxiolytics for research imaging will be allowed to participate as long as the following criteria are met:
• The participant has their own prescription for the medication;
• The informed consent process is conducted prior to the self-administration of this medication; and,
• The participant comes to the research visit with a driver
• Contraindications to MR
• Unable to lie in the MRI scanner for 45-60 minutes
• Patients with a contraindication to gadolinium based contrast agents, including allergy or impaired renal function (per University of Wisconsin Health Guidelines)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Aim 1: Ultrasound Only; Approximately 280 asymptomatic participants will participate in ultrasound (US) studies and blood work.	Device: Ultrasound imaging; Carotid artery ultrasound exam. US imaging will include complete clinical carotid ultrasound examination (B-mode, Doppler and color-flow modes), clinical strain and shear wave imaging study, backscattered and beam-steered radiofrequency (RF) data acquisition using research mode, and reference phantom RF data acquisition.
Aim 2: Ultrasound and MRI; A sub-group of 40 at risk volunteers determined from the clinical ultrasound scans and bloodwork from Aim 1 will be asked to participate in a longitudinal US and MRI study. Participants will be selected from a population of individuals that do not have significant atherosclerosis, but present with increased risk due to the presence of soft, lipid rich plaque that are hypoechogenic or echolucent on ultrasound B-mode images. These participants may also satisfy the current clinical guidelines of increased vessel diameter and decreased blood flow velocity with ultrasound that may result in plaque deposition for being in the at risk population. Participants will receive US, strain and shear wave imaging every 2 years after the first scan in Aim 1 and MRI Imaging in Year 1 and Year 5: separated by 4 years	Device: Ultrasound imaging; Carotid artery ultrasound exam. US imaging will include complete clinical carotid ultrasound examination (B-mode, Doppler and color-flow modes), clinical strain and shear wave imaging study, backscattered and beam-steered radiofrequency (RF) data acquisition using research mode, and reference phantom RF data acquisition.; Device: Magnetic Resonance Imaging (MRI); Head and Neck MRI exam with contrast; Other: Neurocognitive testing; Harmonization battery to assess executive function/attention, speeded psychomotor, verbal, and nonverbal memory, language, and visuospatial skills; Device: Transcranial Doppler (TCD); Use of a TCD system to monitor right and left middle cerebral artery Doppler waveforms in the volunteer for 60 minutes; Device: Pulse Wave Doppler; Pulse wave Doppler will be used to acquire a Doppler waveform in the right common carotid artery and the right femoral artery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterization of artery wall stiffness and possible plaque by capturing B-mode, Doppler and color-flow modes of Ultrasound	Participants will receive complete clinical carotid ultrasound examination. B-mode, Doppler and color-flow modes of Ultrasound will be captured. This measure will characterize artery wall stiffness and possible plaque by using Ultrasound.	up to 60 minute
Carotid artery ultrasound examination for Aim-1 participants: backscattered and beam-steered RF data acquisition using research mode	Participants will receive complete clinical carotid ultrasound examination. Backscattered and beam-steered RF data acquisition using research mode, and reference phantom RF data acquisition will be performed. This measure will characterize artery wall stiffness and possible plaque by using Ultrasound.	up to 60 minute
Fasting Lipid panel Analysis	For aim-1 participants, a single fasting (10-12 hours) blood sample will be collected for a fasting lipid panel	up to 13 hours
Hemoglobin A1C test for diabetes	For aim-1 participants, a single fasting (10-12 hours) blood sample will be collected for a Hemoglobin A1C test	up to 13 hours
High-sensitivity C-reactive protein (HS-CRP) test for inflammatory markers for Aim 1 participants	For aim-1 participants, a single fasting (10-12 hours) blood sample will be collected for High-sensitivity C-reactive protein (HS-CRP) test	up to 13 hours
Detection of Plaques by MRI- Accuracy of MRI detection method as compared to Ultrasound and blood work	Longitudinal Ultrasound strain and MRI study will be performed on on a sub-group of 40(aim-2) at risk participants determined from the clinical ultrasound scans and bloodwork from Aim 1. This subgroup meet the criteria for being in a higher risk group for atherosclerosis or those with softer lipid-rich plaque (hypoechogenic or lower brightness on ultrasound). Participants will be contacted on the phone to discuss these incidental findings and to request if they would be interested in participating in follow-up MRI, US and strain. MRI results will be compared to previous Ultrasound and blood work results to test the accuracy of MRI method in detecting plaques.	up to 60 minute
Characterization of artery wall stiffness and possible plaque by using radiofrequency ultrasound signals to estimate strain tensors, pulse wave velocity (PWV), and shear wave imaging	Participants will receive complete clinical carotid ultrasound examination. Clinical strain and shear wave imaging will be performed. This measure will characterize artery wall stiffness and possible plaque by using Ultrasound.	up to 60 minute

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Tomy Varghese, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2021
• Primary Completion (Actual): June 30, 2025
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: October 27, 2020
• First Submitted That Met QC Criteria: November 10, 2020
• First Posted (Actual): November 17, 2020

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: July 1, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Carotid Artery Diseases
• Other Study ID Numbers: 2020-0384; A534800 (Other Identifier: UW Madison); SMPH/MED PHYSICS (Other Identifier: University of Wisconsin, Madison); 1R01HL147866-01A1 (U.S. NIH Grant/Contract); 2/12/2025 (Other Identifier: Protocol Version)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes