# Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $632,382

## Abstract

ABSTRACT
Mechanical load is a fundamental regulator of cardiac function. The heart operates in a dynamically changing
mechanical environment, and alterations in intra-cardiac pressure and/or volume preload/afterload influence
cardiac performance to coordinate cardiac output with venous return and arterial blood supply. A crucial aspect
of this regulation is the modulation of heart rate, which is controlled by the sinoatrial node (SAN), the primary
pacemaker of the heart. The SAN anatomy and location within the heart enable it to detect fluctuations in both
coronary and atrial blood pressure, establishing a structural foundation for the regulation of heart rate through
SAN mechanosensitivity in response to hemodynamic changes. Although physiological stretch is an essential
component of the SAN autoregulatory feedback mechanism, chronically elevated stretch results in severe
myocardial remodeling and leads to SAN dysfunction (SND), also known as sick sinus syndrome. Conditions
associated with mechanical overload, such as hypertension, often exhibit SND, which manifests as bradycardia,
irregular atrial pauses, and sinus arrest/block. The upstream mechanisms of SND in the hypertensive heart are
unexplored and contribute to lack of preventative intervention. We will address this gap in knowledge by
employing a combination of several multi-level cutting-edge imaging modalities of cellular microarchitecture, Ca2+
and cAMP dynamics, electrophysiological measurements, biochemical studies, and computational modeling to
demonstrate an innovative concept that proposes a tight association between mechanical loading, SAN
pacemaking, and its regulation by the autonomic nervous system through a mechanosensitive caveolar
pacemaker signalosome. This caveolar domain provides the spatiotemporal foundation for mechano-
electrochemical signal transduction and heart rhythm regulation, which involves stretch-induced augmentation
of cAMP production and cAMP/PKA-mediated phosphorylation of Ca2+ handling and sarcolemmal proteins as
well as activation of caveolar mechano-sensitive ion channels. We propose that prolonged (chronic) atrial
overload leads to the degradation of caveolae, causing SND and an altered response to both mechanical and
autonomic stimulation, which forms the molecular basis for chronotropic incompetence. Preventing caveolae
degradation or restoring caveolae structures could alleviate SND phenotype and improve the SAN ability to
adequately respond to emotional or physical stressors. This research holds significant potential impact as it will
provide mechanistic insights that can serve as a foundation for developing innovative therapeutic strategies
aimed at preventing SND in hypertensive individuals.

## Key facts

- **NIH application ID:** 10803144
- **Project number:** 2R01HL141214-06
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Alexey V Glukhov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,382
- **Award type:** 2
- **Project period:** 2018-03-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803144

## Citation

> US National Institutes of Health, RePORTER application 10803144, Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling (2R01HL141214-06). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10803144. Licensed CC0.

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