# Investigating age-dependent differences in cardiac drug response

> **NIH NIH F31** · CHILDREN'S RESEARCH INSTITUTE · 2024 · $35,398

## Abstract

Project Summary: Pediatric patients with congenital heart disease (CHD) frequently require
pharmacological interventions (e.g., inotropic agents) to stabilize and improve cardiac mechanical
function after corrective heart surgery. However, the medications administered to hospitalized
children have not been formally studied in this population - due to underrepresentation of pediatric
patients in clinical trials. Indeed, postnatal development is a dynamic process, as cardiomyocytes
undergo significant adaptations in cell structure, calcium handling, and contractile function. We
hypothesize that cardiomyocyte maturity strongly influences pharmacodynamics, and that
consideration of age-specific differences in inotropic drug response can improve clinical care by
tailoring drug therapies to pediatric patients. This proposal will investigate driving factors of postnatal
cardiomyocyte maturation, the physiological effects on electrophysiology and contractility, and the
impact on myocardial response to inotropic agents. Specifically, Aim 1 will investigate age-specific
differences in drug response on cardiac electrophysiology and excitation- contraction coupling. A
juvenile guinea pig model will be used to measure electrocardiograms, electrophysiology metrics,
optical action potentials and intracellular calcium transients, and left ventricular pressure during
baseline conditions and following treatment with calcium, dopamine, or milrinone. Tissue samples
will be collected for mechanistic analysis of developmental changes in gene and protein expression.
Aim 2 will investigate postnatal development of human cardiomyocytes and the impact of age on
drug response. To aid in the translation of our animal studies, I will collect human cardiac tissue
samples from neonates, infants, and children undergoing corrective heart surgery at my institution.
Age-dependent changes in gene and protein expression will be quantified. Calcium transients will
also be recorded from live, human heart tissue slice preparations under baseline conditions and in
response to inotropes. By providing data on pediatric heart development and drug responsiveness,
the results of this study will have a significant impact on the cardiac research field, cardiac surgery,
and critical care medicine. Further, this 3-year training plan will support my scientific growth, which
builds upon the expertise of my Sponsor (Dr. Posnack: cardiac electrophysiology, pharmacology)
and co- Sponsor (Dr. Ishibashi: pediatric cardiac surgery). I will also benefit from interactions with
collaborators and a mentoring team, who will provide guidance in career development, the goals of
this study, and experimental techniques (e.g., optical mapping, molecular biology). This proposal will
advance my knowledge in cardiac physiology, pharmacology, and clinically relevant approaches –
and support my future goal of independently leading a translational cardiac research laboratory.

## Key facts

- **NIH application ID:** 10996912
- **Project number:** 1F31HL172563-01A1
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Shatha Salameh
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,398
- **Award type:** 1
- **Project period:** 2025-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996912

## Citation

> US National Institutes of Health, RePORTER application 10996912, Investigating age-dependent differences in cardiac drug response (1F31HL172563-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10996912. Licensed CC0.

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