# Advanced Non-invasive Imaging in the Investigation of Aortic Stenosis Pathobiology

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $696,457

## Abstract

SUMMARY
Aortic stenosis (AS) is a serious condition that affects 2-4% of the elderly, and is responsible for U.S. healthcare
expenditures of over $6 billion annually attributable mostly to valve replacement procedures. Frequently, AS is
diagnosed by non-invasive imaging before it is severe or symptomatic. Yet there are no pharmacologic therapies
to slow progression of disease. The pathobiology of AS involves the myofibroblastic and osteoblastic
transformation of valvular interstitial cells (VICs) that mediate matrix remodeling and calcification. The plurality
of events and signaling pathways that influence VICs is one reason for lack of effective medical therapy. Using
in vivo molecular imaging of the aortic root and comprehensive echocardiography, we have found that mice that
lack the ability to cleave von Willebrand Factor (VWF) multimers from the endothelial surface develop
progressive AS and load-related left ventricular hypertrophy. Valve leaflets from these animals demonstrate
endothelial adhesion of platelets and platelet extracellular vesicles, and also typical patterns of VIC proliferation
and transformation. These findings are consistent with the idea that platelets contribute to AS by binding VWF
and acting in a juxtracrine fashion through local release of platelet-derived growth factors, cytokines, and reactive
oxygen species (ROS) which are known to stimulate VIC transformation. Accordingly, inhibiting platelet
interaction with VWF at the valve endothelial surface could prevent the activation of many parallel signaling
pathways that contribute to AS. Our overall goal is to integrate non-invasive imaging with histology,
transcriptomics, and blood markers to characterize this potentially treatable mechanism for AS. In Aim 1, we will
provide definitive evidence that platelet adhesion contributes to AS by longitudinal assessment of mice deficient
for the ADAMTS13 protease that cleaves shear-activated VWF from the endothelial surface. We will investigate
whether deletion of platelet GPIb, the counterligand for VWF; and treatment with recombinant ADAMTS13.
Because platelet-endothelial adhesion also contributes to vascular stiffness, a systems-biology approach will be
used with non-invasive imaging of arterial compliance, LV remodeling, and load-dependent indices of LV
function. In Aim 2, we will test whether novel pharmacologic approaches that reduce excess endothelial-
associated VWF multimers suppress the development of AS and LV remodeling in the murine models. Therapies
will include (i) n-acetylcysteine which inhibits VWF self-association, and (ii) an acetovanillone inhibitor of Nox2
which reduces the generation of ROS and, consequently, excess endothelial-associated VWF. In Aim 3, a proof-
of-concept prospective clinical trial will be performed in patients with mild or moderate AS to determine whether
blood markers of abnormal VWF proteolysis and platelet-derived signaling factors predict rapidly progressive AS
and arterial non-compl...

## Key facts

- **NIH application ID:** 10522099
- **Project number:** 1R01HL165422-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jonathan R Lindner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $696,457
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522099

## Citation

> US National Institutes of Health, RePORTER application 10522099, Advanced Non-invasive Imaging in the Investigation of Aortic Stenosis Pathobiology (1R01HL165422-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10522099. Licensed CC0.

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