# Quantification of the decline of heart muscle cell proliferation and its reversal in pediatric patients

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $411,500

## Abstract

ABSTRACT:
Heart failure continues to be a leading cause of mortality and morbidity. Understanding the basic mechanisms
of heart regeneration in humans and stimulating them would improve the lives of many patients. Proliferation of
heart muscle cells (cardiomyocytes) is essential for heart development and regeneration. After birth, the
proliferative potential of cardiomyocytes declines, but neonatal mammalian hearts are thought to maintain the
ability to regenerate until cardiomyocytes undergo permanent cell cycle arrest, establishing a barrier for
regeneration. Strategies for stimulating cardiomyocyte proliferation are under development and would be most
effective when initiated before cardiomyocytes withdraw permanently from the cell cycle. However, the point at
which cardiomyocyte proliferation ceases in humans is controversial; some studies place this point before birth,
some in the first year after birth, and our data demonstrate cardiomyocyte proliferation extending well into
childhood, i.e., the first 10 – 20 years of life. This picture is further complicated by our published and
unpublished results suggesting that infants with congenital heart disease (CHD) have decreased
cardiomyocyte proliferation. Resolving how age and heart disease alter the temporal pattern of cardiomyocyte
cell cycle withdrawal is an essential problem in cardiac biology. Improved understanding of cardiomyocyte
proliferation will be critical for developing new regenerative strategies to prevent and treat heart failure in
patients with cyanotic CHD, the most common birth defect affecting 0.3% of newborns. We will determine
when cardiomyocyte proliferation decreases in pediatric patients by investigating two leading cardiac diseases:
tetralogy of Fallot (ToF), the most common form of cyanotic congenital heart disease (CHD), which affects
0.3% of newborns, and dilated cardiomyopathy (DCM), the most common cause for heart transplantation in the
pediatric age group. Our central hypothesis is that cardiomyocyte proliferation shows an age- and
disease-dependent decline. We will enroll neonates, infants, and children to quantify cardiomyocyte
proliferation. We have formed a research team consisting of pediatric cardiologists and cardiac surgeons,
pathologists, and basic scientists. The critical element of our approach is the use of a highly innovative method
in which we will label patients with innocuous thymidine carrying stable isotope markers (15N-thymidine and 2H-
thymidine). Cells in S-phase of the cell cycle incorporate thymidine into their DNA, and their offspring retain the
label for at least 6 cell divisions. We will visualize the isotope in post-surgical tissue samples with an innovative
method: Multi-isotope imaging mass spectrometry (MIMS) to quantify cardiomyocyte proliferation and
differentiation. Preliminary data from our first study patient with ToF provide first-in-human results and
validate our approach.

## Key facts

- **NIH application ID:** 10191031
- **Project number:** 5R01HL151386-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Bernhard Kuhn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,500
- **Award type:** 5
- **Project period:** 2020-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191031

## Citation

> US National Institutes of Health, RePORTER application 10191031, Quantification of the decline of heart muscle cell proliferation and its reversal in pediatric patients (5R01HL151386-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10191031. Licensed CC0.

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