# Early Onset Diastolic Dysfunction in HCM:  Identifying New Mechanisms and Targets

> **NIH HL R01** · UNIVERSITY OF ARIZONA · 2026 · $605,684

## Abstract

Summary
Mutations in genes that encode the proteins of the cardiac sarcomere are a primary cause of
hypertrophic cardiomyopathy (HCM). HCM represents the most common genetic cardiac
disorder and is characterized by a complex and progressive clinical course exhibiting broad
phenotypic variability and, for patients carrying mutations in sarcomeric genes in particular,
significant morbidity and mortality. Recent longitudinal studies have begun to define the natural
history of HCM and revealed a “preclinical” stage in genotype-positive cohorts. Before the
availability of genetic testing the majority of patients presented with significant symptoms and
late stage cardiac remodeling, thus limiting their response to treatment. The ability to identify
patients before the onset of irreversible HCM opens a therapeutic window whereby genotype-
positive, phenotype-negative patients can be treated before the onset of pathogenic remodeling
and thus perhaps change the natural history of this lifelong disorder. This goal will require the
ability to precisely identify primary disease mechanisms at the level of the complex and dynamic
cardiac sarcomere. An enduring clinical challenge in HCM remains the treatment of patients
with diastolic dysfunction (impaired left ventricular relaxation) which manifests as shortness of
breath, often with minimal exertion and is one of the most common manifestations in this
otherwise diverse disorder, thus representing a significant unmet need. To date, our group has
focused on mutations in the regulatory thin filament and developed a program that combines
structural biophysics with in vitro experiment, in vivo animal models and an experimentally
validated all-atom computational model of the cardiac thin filament (cTF). As the thin filament is
the primary arbiter of cardiac relaxation at the molecular level we now propose to apply our
integrated approach to first, in Aim 1, fully characterize (at the atomic level) three specific
functional domains of 

## Key facts

- **NIH application ID:** 11248009
- **Project number:** 5R01HL172871-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Jil C Tardiff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $605,684
- **Award type:** 5
- **Project period:** 2024-12-15T00:00:00 → 2028-11-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11248009

## Citation

> US National Institutes of Health, RePORTER application 11248009, Early Onset Diastolic Dysfunction in HCM:  Identifying New Mechanisms and Targets (5R01HL172871-02). Retrieved via AI Analytics 2026-05-19 from https://api.ai-analytics.org/grant/nih/11248009. Licensed CC0.

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