Haseeb Mohammed

Background:  Hypoplastic left heart syndrome (HLHS) is a rare but severe heart defect present at birth. In babies with HLHS, the left side of the heart—the part responsible for pumping oxygen-rich blood to the rest of the body—is underdeveloped. This includes the left ventricle, mitral valve, aortic valve, and the beginning of the aorta. As a result, the heart can’t effectively circulate blood, and without urgent medical care, infants with HLHS can quickly go into heart failure within the first days of life^1,2.  For a long time, doctors believed HLHS was mainly caused by abnormal blood flow during pregnancy. However, recent research shows that it begins much earlier, during the heart’s development at the cellular level. One key player is NOTCH1, a signaling protein that helps early heart cells develop into the left ventricle. When NOTCH1 is missing or doesn’t work correctly, these cells either stop growing too soon or become the wrong type of heart cell. At the same time, the inner lining of the heart—the endocardium—also doesn’t form properly and can’t communicate with other heart cells^1-3.  These discoveries are changing how we understand HLHS. It’s not just a structural problem—it’s a developmental one, rooted in faulty molecular signals. This new perspective gives hope that in the future, we might be able to detect and even treat HLHS before birth by targeting the underlying biology².

Objective: This review explores how NOTCH1 deficiency contributes to the development of HLHS and examines recent studies that point to potential ways to reverse or treat the condition.

Search Methods: A targeted literature review was conducted using PubMed for articles published between 2018 and 2025. Search terms included “NOTCH1,” “HLHS,” “iPSC,” “ventricular specification,” and “nitric oxide.” Studies using human induced pluripotent stem cells (iPSCs), gene editing tools, and molecular analyses were prioritized^1-5.

Results: When NOTCH1 is lost or reduced, early cardiac cells struggle to become ventricular muscle. Instead, they begin expressing atrial genes like MYH6 and fail to turn on ventricular genes such as MYL2 and HEY2. These cells also stop dividing early on because of increased levels of CDKN1C, a cell cycle inhibitor^1-2. At the same time, the cells that form the inner lining of the heart—the endocardium—also show defects. They can’t properly signal to nearby muscle cells or remodel the heart’s structure, adding to the dysfunction⁴. Interestingly, nitric oxide (NO), a small signaling molecule, can boost NOTCH1 activity by helping it get into the cell’s nucleus. When NO is added to HLHS iPSC models, ventricular genes reactivate, and cell function improves³. In lab studies, combining NOTCH1 ligands like Jagged peptides with NO donors led to even stronger rescue effects^2,3. Gene editing tools like CRISPR have also shown potential to correct these issues directly⁵.

Conclusions: HLHS seems to result from a combination of NOTCH1 signaling loss and endocardial dysfunction, which interfere with the early steps of heart formation. These insights change our thinking about HLHS—from a purely anatomical defect to one rooted in molecular biology. This shift opens the door for early detection through genetic screening and even targeted therapies during fetal development. Approaches like activating NOTCH1, supplementing NO, or using gene editing hold real promise for changing the trajectory of this condition in the future.

Works Cited:

1. Saraf A, Book WM, Nelson TJ, Xu C. Hypoplastic left heart syndrome: From bedside to bench and back. J Mol Cell Cardiol. 2019 Oct;135:109-118. doi: 10.1016/j.yjmcc.2019.08.005. Epub 2019 Aug 13. PMID: 31419439; PMCID: PMC10831616.
2. Bejjani AT, Wary N, Gu M. Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration. Expert Opin Ther Targets. 2021 Aug;25(8):621-632. doi: 10.1080/14728222.2021.1978069. Epub 2021 Sep 15. PMID: 34488532; PMCID: PMC8511342.
3. Datta S, Cao W, Skillman M, Wu M. Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead. Int J Mol Sci. 2023 Oct 17;24(20):15249. doi: 10.3390/ijms242015249. PMID: 37894928; PMCID: PMC10607600.
4. Haas NA, Driscoll DJ, Rickert-Sperling S. Clinical Presentation and Therapy of Hypoplastic Left Heart Syndrome. Adv Exp Med Biol. 2024;1441:931-936. doi:10.1007/978-3-031-44087-8_59
5. Ye S, Wang C, Xu Z, Lin H, Wan X, Yu Y, Adhicary S, Zhang JZ, Zhou Y, Liu C, Alonzo M, Bi J, Ramirez-Navarro A, Deschenes I, Ma Q, Garg V, Wu JC, Zhao MT. Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency. Circ Res. 2023 Jan 20;132(2):187-204. doi: 10.1161/CIRCRESAHA.122.321398. Epub 2022 Dec 30. PMID: 36583388; PMCID: PMC9852089.
6. Yang C, Xu Y, Yu M, et al. Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis. Hum Mol Genet. 2017;26(16):3031-3045. doi:10.1093/hmg/ddx140
7. Hrstka SC, Li X, Nelson TJ; Wanek Program Genetics Pipeline Group. NOTCH1-Dependent Nitric Oxide Signaling Deficiency in Hypoplastic Left Heart Syndrome Revealed Through Patient-Specific Phenotypes Detected in Bioengineered Cardiogenesis. Stem Cells. 2017;35(4):1106-1119. doi:10.1002/stem.2582
8. Miao Y, Tian L, Martin M, et al. Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome. Cell Stem Cell. 2020;27(4):574-589.e8. doi:10.1016/j.stem.2020.07.015
9. Krane M, Dreßen M, Santamaria G, et al. Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome. Circulation. 2021;144(17):1409-1428. doi:10.1161/CIRCULATIONAHA.121.056198