New Therapeutic Approach Marks Breakthrough in Pediatric Heart Disease

The condition arises when the left ventricle fails to compact properly during development, leaving the heart unable to contract and relax efficiently. Diagnosis often occurs after symptoms appear, when treatment options are limited, and heart transplantation may be required. Now, new research has identified a molecular cause of LVNC and demonstrates a potential way to prevent the disease before birth.

In the study led by the University of Houston (Houston, TX, USA), researchers focused on epicardial cells, a specialized layer of cells that orchestrates heart development by communicating with the underlying myocardium. They investigated the role of Numb Family Proteins (NFPs), which are known regulators of cell fate and signaling during embryonic development.

Using developmental models, the researchers examined how the loss of NFP function in epicardial cells affects heart formation. They specifically analyzed interactions between epicardial cells, fibroblasts, and myocardial tissue, with a focus on fibroblast growth factor (FGF) signaling pathways that are essential for ventricular maturation.

The researchers found that loss of NFP function disrupted epicardial cell migration into the myocardium, leading to a severe reduction in cardiac fibroblasts. This breakdown in cellular communication impaired FGF signaling within the developing heart muscle, preventing proper ventricular compaction and resulting in LVNC with pediatric-onset heart failure.

Importantly, when exogenous FGF was administered to pregnant models, ventricular development partially recovered. This intervention reduced spongy heart features, demonstrating that restoring fibroblast signaling during development can mitigate the structural defects caused by NFP loss.

The study, published in Cardiovascular Research, reveals a previously unrecognized molecular cause of LVNC rooted in epicardial dysfunction rather than myocardial defects alone. It also highlights fibroblast-mediated signaling as a modifiable pathway, opening the door to prenatal therapeutic strategies for congenital heart disease. Beyond pediatric LVNC, these mechanisms may also be relevant to adult cardiomyopathies linked to epicardial abnormalities.

Future research will aim to refine fetal intervention strategies and determine how epicardial–myocardial crosstalk can be therapeutically modulated. A deeper understanding of these developmental pathways could enable earlier diagnosis and targeted prevention of both congenital and acquired heart disease.

"Our results indicate this loss of NFPs prevented epicardial cells from entering the myocardium, which led to a lack of fibroblasts in the trabeculae, which supports blood flow while the coronary system is still forming,” said Mingfu Wu, professor of pharmacology. “This impairment ultimately resulted in a spongy heart. When Fgf is given from outside the body to the pregnant mother, it can partially fix the problem, preventing a spongy heart.”

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