# Multiscale modeling of inherited cardiomyopathies and therapeutic interventions

> **NIH NIH U01** · UNIVERSITY OF KENTUCKY · 2021 · $576,329

## Abstract

ABSTRACT
The goal of this research is to develop a predictive multiscale model that will improve understanding of familial
cardiomyopathies and that can be used to help screen potential new therapies for cardiac disease. Familial
cardiomyopathies are the most frequently inherited heart defect and affect about 700,000 Americans. Most of
the genetic mutations affect myosin or regulatory proteins that modulate myosin function. The majority of these
mutations also induce abnormal cardiac growth termed hypertrophy. This project will develop, calibrate, and
validate an innovative multiscale model that uses data quantifying myosin-level function to predict how hearts
hypertrophy over time. This is a critical step on the path to developing patient-specific computer models that can
be used to optimize treatments for heart failure and to predict the effects of different types of pharmaceutical
intervention. In the future, one could envision clinicians testing drug treatments in silico and selecting the
intervention that produces the greatest long-term benefit for their patient.
The research team consists of two physiologists/biophysicists (Campbell & Yengo) and two engineers (Wenk &
Lee) who share a common interest in cardiac biology. Together, their research skills span from structure-function
analysis of myosin molecules to computer simulations of hearts that grow and remodel over time. The research
plan integrates state-of-the-art hierarchically-coupled mathematical models with validation experiments that
range from stopped-flow molecular kinetic assays to magnetic resonance imaging of myocardial strain patterns.
The model will be tested using molecular to organ-level experimental data obtained from wild-type mice and from
transgenic animals that develop cardiac hypertrophy because of a K104E mutation in myosin regulatory light
chain. Additional tests will be performed using drugs that enhance (omecamtiv mecarbil) and inhibit (MYK-461)
myosin-level contractile function.
There are three specific aims.
Aim 1: Integrate a multistate kinetic model of myosin into an organ-level finite framework to predict the effects of
genetic and/or pharmaceutical modulation of myosin function.
Aim 2: Develop growth and remodeling algorithms to predict chronic changes in ventricular structure and function
resulting from genetic and/or pharmaceutical modulation of myosin function.
Aim 3: Calibrate and validate the model using experimental data quantifying different spatial and temporal scales.

## Key facts

- **NIH application ID:** 10223922
- **Project number:** 5U01HL133359-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Kenneth S Campbell
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $576,329
- **Award type:** 5
- **Project period:** 2017-08-03 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223922

## Citation

> US National Institutes of Health, RePORTER application 10223922, Multiscale modeling of inherited cardiomyopathies and therapeutic interventions (5U01HL133359-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10223922. Licensed CC0.

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