# Genomic Effects on  Right Ventricular Function, Clinical Features and Outcomes in CHD

> **NIH NIH U01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $479,711

## Abstract

ABSTRACT
Dramatic advances in surgical repair and cardiac intervention have improved survival in even the most
complex forms of congenital heart disease (CHD). With this notable success, there has been a shift from
perioperative to chronic cardiac morbidity and accelerated mortality. Right ventricular (RV) dysfunction is an
important determinant of long-term outcomes in children and adults with many forms of CHD. Outcomes such
as RV dysfunction and associated comorbidities are currently thought of primarily in terms of hemodynamic or
physiological factors. However, routine clinical and imaging variables have explained only a small percentage
of the variability in RV function and clinical outcomes in CHD patients, suggesting an important role for as-yet-
unrecognized contributors. We hypothesize that multiple genetic factors contribute to the unexplained
variation in RV performance and patient outcomes. To investigate the relationship of genomic factors and
clinical outcomes, we will study two exemplars of CHD for which right ventricular (RV) dysfunction
especially impacts outcomes: tetralogy of Fallot (TOF) and hypoplastic left heart syndrome (HLHS).
Our proposed study population will leverage a unique clinical and genetic database developed by the PCGC,
as well cohorts within individual PCGC centers and other consortia. In Aim 1, we will study the effects of
rare damaging variants identified in patients with TOF and HLHS on RV function, clinical outcomes,
and anatomical subtypes influencing outcomes. Our primary outcome will be RV ejection fraction by
cardiac MRI (CMR). Secondary outcomes will include other CMR measures of systolic and diastolic function,
as well as clinical outcomes such as transplant-free survival, sustained ventricular and atrial tachycardias, and
heart failure defined as New York Heart Association Class III or IV. In Aim 2, we will study the effects of
common variants identified in patients with TOF and HLHS on RV function, clinical outcomes, and
anatomical subtypes influencing outcomes. Primary and secondary outcomes will be identical to those in
Aim 1. Aim 3 will assess the effects of rare and common variants associated with outcomes on
cardiomyocyte function, metabolism, gene expression, and chromatin accessibility in isogenic
induced pluripotent stem cells differentiated into cardiomyocytes (iPSC-CMs) and CHD tissues. We will
define outcome-associated common variants using bioinformatic and functional assays, and derive iPSC-CMs
with CHD variants, alone or in addition to rare and common outcome-associated variants. We will assess
contraction relaxation, energetic parameters, and transcriptional activities in iPSC-CMs. We will complement
these studies with single cell nuclear sequencing (NucSeq) and ATACseq analyses of CHD tissues to explore
how outcome-associated variants influence in vivo cardiomyocyte biology. By identifying genes affecting
outcomes, our proposal will advance mechanistic insights, improve risk-stratifi...

## Key facts

- **NIH application ID:** 10895435
- **Project number:** 5U01HL098147-16
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Jane W. Newburger
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,711
- **Award type:** 5
- **Project period:** 2009-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895435

## Citation

> US National Institutes of Health, RePORTER application 10895435, Genomic Effects on  Right Ventricular Function, Clinical Features and Outcomes in CHD (5U01HL098147-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10895435. Licensed CC0.

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