# The Consequence of Impaired Lymphatic Drainage on Rejection in Cardiac Transplantation

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
The leading cause of chronic cardiac transplant rejection—coronary artery vasculopathy (CAV)—remains a
major factor limiting long-term survival in heart transplant patients worldwide. The disease causes concentric
intimal thickening along the coronary arteries leading to luminal narrowing and increased vascular resistance.
CAV pathophysiology is thought to involve chronic inflammation and various immunogenic factors, implicating
the lymphatic network as a potential therapeutic target. During heart transplantation, the lymphatic network is
severed upon donor heart excision and not surgically reconstructed. The consequence resulting from severed
lymphatic vessels in transplanted hearts is unknown. An intact lymphatic network is imperative in maintaining
heart health through immune cell trafficking and tissue-fluid homeostasis. Lymphangiogenesis drives lymphatic
reconstitution through the vascular endothelial growth factor (VEGF) family, where VEGF-C/VEGFR-3 signaling
predominates. Previous studies have shown the beneficial effects of augmenting lymphatic growth via VEGF-
C/VEGFR-3 signaling on cardiac function by simultaneously enhancing immune clearance and reducing
myocardial edema and fibrosis in a disease model of myocardial infarction. We hypothesize this disruption in
lymphatic drainage potentiates inflammation by impeding the egress of immune cells and pro-inflammatory
cytokines out of the donor heart exacerbating transplant rejection. Preliminary results in our retrospective human
study indicate significant differences in lymphatic area at earlier timepoints in an allograft’s lifespan between
transplant patients with and without a clear clinical diagnosis of CAV. These data suggest modulating lymphatic
development directly after cardiac transplantation may predetermine transplant outcomes by establishing critical
routes of drainage earlier in the process. The long-term goal of this study is to elucidate the consequence
of lymphatic dysfunction in heart transplant rejection and develop a localized, sustained
lymphangiogenic-focused therapy to combat the implications of this disease. In Specific Aim 1, we will
identify the effect of severed lymphatics on immune cell infiltration and rejection severity by inducing transplant
acceptance and rejection in a heterotopic abdominal heart transplant rodent model. In Specific Aim 2, we will
evaluate the effects of localized lymphatic augmentation on donor graft function utilizing VEGF-C encapsulated
in a poly(ethylene glycol)-based hydrogel. Understanding pathologic conditions associated with lymphatic
dysfunction in cardiac transplantation will provide novel therapeutic targets that enhance the longevity of donor
grafts and reduce mortality among the transplant community. Optimizing cardiac function and donor graft survival
is especially important for pediatric patients that require multiple heart transplants throughout their lifetime.

## Key facts

- **NIH application ID:** 10490963
- **Project number:** 5F31HL156495-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sydney C Ginn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490963

## Citation

> US National Institutes of Health, RePORTER application 10490963, The Consequence of Impaired Lymphatic Drainage on Rejection in Cardiac Transplantation (5F31HL156495-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10490963. Licensed CC0.

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