# Neuropeptides reduce thrombosis risk in heart failure

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $437,500

## Abstract

Project Summary
In chronic heart failure patients, thromboembolic events are the most common complication, resulting in
increased hospitalization rates and mortality. Prevention of cardiac thrombosis in heart failure (HF) patients
with anticoagulant therapy is controversial because of the increased risk of bleeding. Cardiac endothelial cells
normally promote anticoagulation through multiple pathways including activated protein C (APC) generation on
their luminal surface. In HF, the endothelial surface becomes increasingly prothrombotic partly due to altered
endothelial anticoagulation. Alterations in APC and thrombin generation, and increased von Willebrand factor
(vWF) extrusion from the endothelium, are likely consequences of a prothrombotic endothelium. A
recombinant form of APC has been used in clinical trials but is associated with an increased risk of bleeding.
An alternative therapeutic approach may involve promotion of multiple endogenous endothelial anticoagulant
pathways. Cardiac sympathetic nerves make close appositions with endocardial endothelial cells (EECs) that
line the cardiac chambers; these direct connections are unlike those with vascular endothelium where smooth
muscle separates nerve from endothelial cell. Sympathetic nerves regulate many aspects of normal
endothelial function likely through release of norepinephrine (NE) and neuropeptides such as neuropeptide Y
(NPY) and galanin. We suspect that neuropeptides promote the anticoagulant function of endothelial cells.
We hypothesize that neuropeptide release is suppressed in HF promoting endothelial dysfunction and a
reduction in anticoagulation function.
We test this hypothesis with human HF and control ventricular tissue and plasma, and in a mouse model of
HF. We will determine: (i) the spatial and functional link between endocardial thrombosis and aberrant
ventricular innervation; examined in HF mice with a novel combined contrast-enhanced ultrasound and
microPET approach; (ii) the mechanisms, both direct and indirect, through which neuropeptides promote
endothelial anticoagulation; examined in cultured human heart failure EECs; (iii) the promotion of endothelial
anticoagulant function by neuropeptide treatment in vivo in HF mice; (iv) whether plasma neuropeptide levels
in HF subjects can be used as early biomarkers of a prothrombotic state.
Significance: A critical link between subendocardial nerve activity and endothelial anticoagulant function will
be identified in these studies. Preliminary data suggest that neuropeptides promote endothelial anticoagulant
function, and this function is disrupted in HF. If this is the case, neuropeptide treatment may provide a novel
therapy for reducing thromboembolic complications in HF patients. Establishing a relationship between
circulating neuropeptide levels and thrombus formation will identify novel early biomarkers of thromboembolic
risk in HF patients.

## Key facts

- **NIH application ID:** 9869905
- **Project number:** 5R01HL139558-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Wohaib Hasan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2018-03-15 → 2020-12-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869905

## Citation

> US National Institutes of Health, RePORTER application 9869905, Neuropeptides reduce thrombosis risk in heart failure (5R01HL139558-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9869905. Licensed CC0.

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