# Hypertrophic Cardiomyopathy: Understanding the Heterogeneity of Disease Expression and Outcomes

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $1,590,760

## Abstract

PROJECT SUMMARY
 Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium that is characterized by
unexplained left ventricular hypertrophy (LVH), myocyte disarray, and fibrosis. It is the most prevalent genetic
heart disorder, affecting ~1 in 500 people. HCM has been the focus of intense clinical and basic science study
for decades. These efforts have provided remarkable insights into the molecular basis and clinical course of
disease-- defining sarcomere mutations as the most common genetic etiology and characterizing the
phenotypic spectrum. Additionally, prior studies have underscored the great heterogeneity of HCM. Although
many patients have serious outcomes, including arrhythmias, advanced heart failure, and sudden cardiac
death, many others experience mild disease with low symptom burden and normal longevity. Moreover, there
is striking diversity in cardiac morphology and function, even amongst patients with identical underlying
sarcomere mutations. The factors that drive such marked heterogeneity are poorly understood, highlighting the
critical need to better characterize determinants of disease expression and clinical outcomes.
 This proposal seeks to identify genotypic and phenotypic features that account for the highly diverse
manifestations of HCM. These goals will be addressed by leveraging the recently established Sarcomeric
Human Cardiomyopathy Registry (SHaRe), containing data on over 9000 HCM patients, and applying state-of-
the-art genetic, imaging, and statistical analyses. Our aims are: (1) To identify common genetic variation that
impacts disease expression in HCM patients both with and without a driving sarcomere mutation (sarcomeric
and non-sarcomeric HCM). These analyses will interrogate background genetic variation to examine how an
individual’s genetic make-up influences their susceptibility or resistance to disease. We will also develop
polygenic risk scores to assess the cumulative effect of common genetic variants on disease expression. (2)
To characterize phenotypic factors that influence disease expression by utilizing machine-learning techniques
to identify novel, quantitative high-dimensional imaging features from routinely-performed cardiac magnetic
resonance (CMR) studies. We will then incorporate these features into rigorous prediction models to improve
clinical risk stratification. This approach will allow us to look more deeply into the structure and function of the
heart by using the full array of digital data available from CMR imaging, thereby drawing new correlations
between phenotype, disease manifestations, and clinical outcomes. Successful completion of these aims will
advance our understanding of why disease experience can be so different from patient to patient, provide new
insights into mechanism and therapeutic targets, and identify novel biomarkers of disease severity. These
results will impact clinical management of patients with HCM by improving the precision and accuracy of
di...

## Key facts

- **NIH application ID:** 10469679
- **Project number:** 5R01HL155568-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Carolyn Y Ho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,590,760
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469679

## Citation

> US National Institutes of Health, RePORTER application 10469679, Hypertrophic Cardiomyopathy: Understanding the Heterogeneity of Disease Expression and Outcomes (5R01HL155568-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10469679. Licensed CC0.

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