Platelet Adhesion in the Pathobiology of Aortic Stenosis

Aortic stenosis (AS) is a serious and common condition that affects 2-3% of the population >65 years of age in Western countries. It is also responsible for extraordinarily high healthcare expenditures, estimated to be over $6 billion annually,2 in part because the primary treatment for severe AS is aortic valve replacement (AVR) which is resource-intensive. Valve abnormalities are frequently recognized before AS becomes severe, or before there is need for guideline-directed procedural intervention, thereby providing an opportunity for pharmacologic intervention to slow disease progression. Yet, all attempts to prevent AS progression in those with degenerative non-congenital forms of disease have failed. The only non-procedural intervention that benefits patients with moderate or greater AS is the aggressive treatment of hypertension, which reduces net left ventricular (LV) afterload (valvulo-arterial impedance [Zva]) and can slow secondary LV remodeling. The overall goal of this proposal is to integrate advanced imaging and vascular biology to study how von Willebrand factor (VWF) and platelet adhesion promote AS progression through many parallel pathways, thereby representing a potential therapeutic target. We are hypothesizing that blood markers of abnormal VWF proteolysis and platelet-derived factors, and abnormal valve shear patterns which can be detected by advanced analysis of spectral Doppler on echocardiography are predictors for progressive AS.

Study Overview

• Status: Recruiting
• Conditions: Aortic Valve Stenosis
• Intervention / Treatment: Diagnostic test: Echocardiogaphy

• Study Type: Observational
• Enrollment (Anticipated): 65

Contacts and Locations

• Study Contact: Name: Jonathan Lindner, MD; Phone Number: 434 297-9442; Email: jlindner@virginia.edu

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia
      • Contact: Jonathan Lindner, MD; Phone Number: 434-297-9442; Email: jlindner@virginia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 23 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

• Age-matched to the Aortic Valve Disease group
• Referred for echocardiography for a clinical indication
• Absence of valve disease

Description

Inclusion Criteria For AS group

• Age >25 years of age

• Mild or moderate calcific, non-congenital aortic stenosis by echocardiography within the prior 3 months defined as:

  • aortic valve area 1.0 cm2 - 1.9 cm2 and either
  • peak velocity of >2.5 m/s and <4.0 m/s with normal or mildly reduced stroke volume index (>25 ml/m2), or
  • VTI ratio (LVOT:AoV) of <0.5 and >0.25 with abnormal stroke volume (<35 ml/m2 or >60 ml/m2).
• Age and sex-matched control subjects undergoing echocardiography with no aortic stenosis, and no more than mild severity disease of other valves.

Inclusion criteria for Control Group

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Mild to moderate AS; Patients with mild to moderate AS by echocardiography	Diagnostic test: Echocardiogaphy; Assessment of high velocity low amplitude signals on Doppler echocardiography
Controls; Age and sex match controls with no AS by echocardiography	Diagnostic test: Echocardiogaphy; Assessment of high velocity low amplitude signals on Doppler echocardiography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evidence for High Shear Patterns on Echocardiography	Low-amplitude high velocity signals on spectral Doppler	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma markers of VWF	Plasma markers including VWF antigen, oxidation, cleavage; and ADAMTS13 activity	4 years

Collaborators and Investigators

• Sponsor: University of Virginia

Publications and helpful links

General Publications

• Ozawa K, Muller MA, Varlamov O, Hagen MW, Packwood W, Morgan TK, Xie A, Lopez CS, Chung D, Chen J, Lopez JA, Lindner JR. Reduced Proteolytic Cleavage of von Willebrand Factor Leads to Aortic Valve Stenosis and Load-Dependent Ventricular Remodeling. JACC Basic Transl Sci. 2022 Jun 29;7(7):642-655. doi: 10.1016/j.jacbts.2022.02.021. eCollection 2022 Jul. Erratum In: JACC Basic Transl Sci. 2023 Feb 27;8(2):237.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2023
• Primary Completion (Anticipated): August 30, 2027
• Study Completion (Anticipated): June 1, 2028

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: September 19, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): April 21, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Constriction, Pathologic
• Other Study ID Numbers: HSR220332

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: No