# Macrophage-mediated interleukin-6 signaling drives ryanodine receptor 2 calcium leak in postoperative atrial fibrillation

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2024 · $49,244

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in the understanding of the molecular drivers of postoperative atrial fibrillation (poAF),
which is self-limited atrial fibrillation (AF) 2-4 days after surgery. The recurrence rate of AF is eight-fold greater
and mortality risk two-fold greater in poAF patients compared to those that remain in sinus rhythm after surgery.
Thus, it is apparent that current poAF treatments such as beta-blockers, while effective in reducing acute
arrhythmia-related symptoms, do not adequately target the underlying molecular drivers of poAF. As can be
expected after surgery, there is systemic inflammation secondary to tissue damage, and studies show that the
degree of systemic inflammation positively correlates with poAF risk. Current anti-inflammatory agents such as
non-steroidal anti-inflammatory drugs target a broad spectrum of inflammatory mediators and have unwanted
side effects such as acute kidney injury and immunosuppression. Therefore, the rationale for this project is that
targeting a precise molecular pathway within specific cell types has the potential of decreasing poAF and, more
importantly, recurrent AF risk without the unwanted side effects of current anti-inflammatory agents. To this end,
our lab has recently developed and published a novel poAF mouse model consisting of atrial pericardiectomy
and transient aortic clamping. We and others have shown that interleukin (IL)-6 is reproducibly and robustly
elevated in the atria of mice with poAF. In addition, we have found that atrial macrophages mediate atrial IL-6
signaling through production of the IL-6 receptor alpha (IL-6R), which activates Ca2+/calmodulin-dependent
protein kinase II (CaMKII) in nearby atrial cardiomyocytes (ACMs) and leads to arrhythmogenic ryanodine
receptor-2 (RyR2) Ca2+ leak. The overall objective of this proposal is to identify whether inhibiting atrial IL-6
signaling at multiple levels can abrogate arrhythmogenic RyR2 Ca2+ leak and poAF. We hypothesize that
macrophages, which infiltrate the atria 48-72 hours after cardiac surgery, promote IL-6 trans-signaling to ACMs
through release of IL-6R, resulting in STAT3-mediated CaMKII transcriptional upregulation and RyR2
phosphorylation at Ser2814 and Ca2+ leak. We will test this hypothesis with the following two aims. Aim 1 will
assess whether atrial IL-6 signaling mediated by macrophages is necessary for poAF. Aim 2 will test whether
STAT3 activation is required for RyR2 Ca2+ leak. This project will constitute a significant advancement in the
identification of a targeted treatment for poAF via the IL-6 signaling axis, which has broad impacts on other types
of arrhythmias as well as cardiovascular diseases such as heart failure and atherosclerosis that are also driven
by IL-6-mediated systemic inflammation.

## Key facts

- **NIH application ID:** 10994822
- **Project number:** 1F30HL172431-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Joshua Anthony Keefe
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,244
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994822

## Citation

> US National Institutes of Health, RePORTER application 10994822, Macrophage-mediated interleukin-6 signaling drives ryanodine receptor 2 calcium leak in postoperative atrial fibrillation (1F30HL172431-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10994822. Licensed CC0.

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