# Integration of structure and signaling in cardiac pacemaker function

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $665,608

## Abstract

PROJECT SUMMARY
Heart failure (HF), a leading cause of morbidity and mortality, involves significant dysfunction of the sino-atrial
node (SAN). SAN dysfunction (SND) can result from or worsen HF through a vicious cycle leading to HF
progression and/or death. However, mechanisms of HF-induced SND due to alterations in expression and
distribution of ion channels/receptors and their regulatory factors across the human SAN pacemaker complex
have not been studied in human hearts but rather only in animal models that possess significantly different 3D
SAN structure and molecular profile. To overcome these major obstacles, our multidisciplinary team has
established a vigorous human heart research program to acquire viable explanted hearts with the long-term goal
to develop a novel integrative framework to understand how structural and molecular remodeling contribute to
SND and arrhythmias in HF and other diseases. We developed an integrated approach of intramural optical
mapping, 3D structural imaging, and molecular mapping to examine the human SAN from molecular to organ
levels. Our initial results with this approach suggest that the human SAN complex consists of multiple and
redundant intranodal pacemakers and conduction pathways (SAN compartments), which allow for the robust
regulation of heart rhythm. Our results also suggest that HF-induced impairments of SAN compartments and
SND may be orchestrated in part by (1) fibrotic remodeling, (2) molecular remodeling in expression and
distribution of adenosine A1 receptors and the G protein-coupled channel IK.Ado (GIRK1/GIRK4)() and/or (3) If
pacemaker channels (HCN1/HCN4). Furthermore, our preliminary data suggest that HF-induced downregulation
of If pacemaker channels is linked to the upregulation of several microRNAs (or miRs) in animal models, where
SAN targeting treatment with antimiRs restored SAN function and alleviated HF. Finally, our preliminary data
demonstrates that these miRs are selectively upregulated in human failing SAN and represent promising targets
for SND treatment. Based on these recently published and preliminary data, our central hypothesis is that HF-
induced heterogeneous structural and molecular remodeling of SAN compartments impairs the robustness of
the human SAN complex and leads to SND. The overall objective is to define functional, structural, and molecular
features of the human SAN complex altered by HF to reveal novel targets for SND treatment. This translational
research will advance our understanding of human SAN function and expression profiles in normal and diseased
hearts that is essential for the development of new therapies against SND.

## Key facts

- **NIH application ID:** 9899286
- **Project number:** 5R01HL115580-07
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Vadim V Fedorov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $665,608
- **Award type:** 5
- **Project period:** 2013-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899286

## Citation

> US National Institutes of Health, RePORTER application 9899286, Integration of structure and signaling in cardiac pacemaker function (5R01HL115580-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899286. Licensed CC0.

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