# Exercise-induced cardiac adaptation in hypertrophic cardiomyopathy

> **NIH NIH K99** · STANFORD UNIVERSITY · 2023 · $122,578

## Abstract

PROJECT SUMMARY
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and can lead to heart failure and sudden cardiac
death. Mutations in genes encoding sarcomere proteins are responsible for a majority of HCM cases. These
mutations induce a more disordered, energetically inefficient myosin conformation, which increases ATP
utilization, leading to metabolic dysfunction and hypercontractility, and eventually, cardiac hypertrophy and
dysfunction. Moderate endurance training improves cardiovascular function and metabolic health overall,
reducing the risk for cardiovascular morbidity and mortality. However, current guidelines recommend that HCM
patients limit exercise, leading to reduced levels of physical activity in this patient population. Contrary to this,
recent evidence demonstrates that moderate and high-intensity endurance exercise training is safe and
clinically beneficial for patients with HCM. However, the mechanisms behind exercise-induced cardiac
adaptation in HCM are unknown. The hypothesis behind the proposed work is that systemic factors induced by
repeated endurance exercise ameliorate the pathogenic phenotype in sarcomeric HCM by improving the
energetically inefficient myosin structure and associated cardiomyocyte metabolic dysfunction. To address this
hypothesis, the cardioprotective effects of exercise in HCM will be investigated in a well-established mouse
model of HCM, in human HCM patients and in patient-specific iPSC-derived cardiomyocytes. In Aim 1, to
determine if exercise training decelerates disease progression in HCM, deep metabolic and contractile
phenotyping will be performed in cardiac tissue and isolated ventricular myocytes from trained and untrained
mice. In Aim 2, the systemic effects of exercise are evaluated in response to a 30 min bout of exercise, where
HCM patients are compared to healthy individuals. While long-term exercise training promotes health, this is
driven by signalling events from individual exercise bouts. Serum from before and after exercise will be
subjected to untargeted metabolomics, semi-targeted lipidomics and a multiplex cytokine assay analysis to
identify potential mediators of the beneficial effects of exercise and determine the predictive power of
metabolomics for cardiorespiratory fitness in HCM patients. Finally, Aim 3 will determine whether these
exercise-induced systemic factors ameliorate the contractile and metabolic dysfunction of HCM; for this,
iPSC-derived cardiomyocytes from HCM patients will be used as a model system. In addition, in vivo studies
will be conducted in a mouse model of HCM. Altogether, exercise is an accessible intervention to improve
health and overall quality of life, and through these innovative experiments I expect to delineate the
mechanisms by which exercise improves health in HCM. By extension, I expect this work to reveal novel
therapeutic targets for a disease where only symptom-alleviating drugs are available, and the results can be
leveraged to en...

## Key facts

- **NIH application ID:** 10655425
- **Project number:** 5K99HL159233-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Malene Lindholm
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $122,578
- **Award type:** 5
- **Project period:** 2022-07-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10655425

## Citation

> US National Institutes of Health, RePORTER application 10655425, Exercise-induced cardiac adaptation in hypertrophic cardiomyopathy (5K99HL159233-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10655425. Licensed CC0.

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