# The role of adrenergic signaling in cancer cachexia-associated cardiac remodeling

> **NIH NIH F30** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $53,974

## Abstract

Project Summary
Cachexia is a devastating state of malnutrition brought about by a synergistic combination of decreased appetite
and increased metabolism of fat and lean mass. Furthermore, multiple organs, including the heart, are impaired
by this debilitating condition. While many chronic diseases such as heart failure, kidney failure, and cirrhosis are
associated with cachexia, this condition is particularly prevalent in pancreatic ductal adenocarcinoma (PDAC).
Our lab and others demonstrated significant structural and functional remodeling of the heart in various models
of cancer cachexia. These maladaptive changes in the heart are also observed in chemotherapy-naïve cancer
cachexia patients, limiting tolerable therapeutic options and quality of life. However, there are currently no
effective treatments for cachexia and the mediators of adverse cardiac remodeling in cancer-associated
cachexia remain elusive.
The sympathetic nervous system (SNS) is responsible for the “fight-or-flight” response and primes the body to
fight disease. Chronic SNS overactivity is implicated in cachexia pathophysiology by browning white adipose
tissue and increasing basal metabolic rate. However, the role of the SNS in regulating cardiac remodeling during
cancer cachexia has not been investigated. Chronic elevation in SNS tone is a well-established driver of cardiac
pathology in patients with heart failure by direct stimulation of the heart. Elevated sympathetic tone to other
tissues, such as the bone marrow, also drives cardiovascular pathology by decreasing Cxcl12 expression in
bone marrow, resulting in augmented myelopoiesis and recruitment of inflammatory leukocytes to the
cardiovascular system. Using a model of PDAC-associated cachexia, I found a gene signature indicating adverse
structural remodeling and desensitization of adrenergic receptors in the heart. These observations are consistent
with direct SNS hyperactivity on the heart. Indeed, treatment with a non-selective adrenergic receptor blocker
was able to attenuate loss of cardiac tissue in animals with PDAC cachexia. Furthermore, I found increased
pool of neutrophils in the heart, which was accompanied by a downregulation of bone marrow Cxcl12 expression.
Therefore, based on my preliminary data and recent literature, I hypothesize that SNS hyperactivity mediates
adverse cardiac remodeling during cancer-cachexia. This project proposes to assess the effects of sympathetic
hyperactivity to the heart as well as bone marrow in driving cardiac remodeling during cachexia.
Collectively, this work has broad implications and is directly applicable to identifying new therapeutic targets for
treating cachexia and increasing survival in cancer patients. Achieving the goals of the proposal will: 1) enhance
our understanding of the root cause of cachexia induced cardiac remodeling, 2) provide novel therapeutic targets
for cachexia, and 3) describe novel mechanisms by which adrenergic signaling mediates cardiac stress ...

## Key facts

- **NIH application ID:** 11004608
- **Project number:** 5F30HL170476-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Parham Diba
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-08-25 → 2027-02-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11004608

## Citation

> US National Institutes of Health, RePORTER application 11004608, The role of adrenergic signaling in cancer cachexia-associated cardiac remodeling (5F30HL170476-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11004608. Licensed CC0.

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