# Cardiac Sensory-Sympathetic-Angiotensinergic Mechanisms in Hypertrophic Cardiomyopathy

> **NIH NIH F32** · UNIVERSITY OF IOWA · 2020 · $33,723

## Abstract

Sarcomere gene mutations cause hypertrophic cardiomyopathy (HCM), a common devastating disease.
HCM is characterized by cardiac/myocyte hypertrophy, myocyte disarray, fibrosis, diastolic dysfunction,
arrhythmias and risk of sudden cardiac death. While HCM may progress to heart failure, sudden death can
occur before heart failure develops. While an enormous amount of knowledge of genetics and molecular
mechanisms of cardiomyocyte dysfunction has been gained from animal models of HCM, very little is
known regarding the roles of cardiac innervation and its interactions with the cardiac renin-angiotensin
system (RAS) in HCM. We hypothesize that pathological remodeling of the heart, and cardiomyocyte
energy depletion in HCM induces dysregulation of cardiac sensory nerve activity leading to cardiac
sympathovagal imbalance, activation of cardiac RAS, and decreased baroreflex sensitivity, all of which
promote arrhythmias and accelerate progression to congestive heart failure and death.
We will utilize two established mouse models of HCM with cardiac-targeted human mutations and differing
phenotypes to test our hypothesis. Specific Aims of the project are to: (1) Determine roles of cardiac vagal
and ‘sympathetic’ afferent nerves, and arterial baroreflex in mediating autonomic and cardiac dysfunction in
HCM mice, and (2) Test the hypothesis that chronic infusion of the angiotensin peptide Ang-(1-7) to HCM
mice will inhibit cardiac sympathetic tone and oppose deleterious actions of angiotensin II, resulting in less
cardiac fibrosis and improved left ventricular (LV) function. Experimental approaches include telemetric
monitoring of blood pressure, assessment of sympathetic and parasympathetic tone, and baroreflex
sensitivity; assessment of cardiac function by echocardiograph, and LV pressure recordings; and chemical
ablation of cardiac ‘sympathetic’ afferent neurons. Additionally, the angiotensin peptide Ang-(1-7) will be
infused chronically to inhibit the cardiac RAS and sympathetic nerve activity for therapeutic benefit.
The significance of this research relates to understanding the key roles played by cardiac sensory and
sympathetic nerves, baroreflexes, and cardiac RAS in determining the severity of HCM and its progression
to heart failure. In addition, a novel treatment [Ang-(1-7) infusion] for HCM will be tested with potential
clinical implications.

## Key facts

- **NIH application ID:** 9851947
- **Project number:** 5F32HL140880-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Robert Arnold Larson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,723
- **Award type:** 5
- **Project period:** 2018-01-15 → 2020-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851947

## Citation

> US National Institutes of Health, RePORTER application 9851947, Cardiac Sensory-Sympathetic-Angiotensinergic Mechanisms in Hypertrophic Cardiomyopathy (5F32HL140880-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851947. Licensed CC0.

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