Kristina Montez

Background: Hypoplastic Left Heart Syndrome (HLHS) is characterized by the underdevelopment of the left side of the heart.^1–3 The incidence of HLHS is estimated to be 16-36 cases per 100,000 live births.^1,2. If left untreated, HLHS is 100% fatal within the first week of life.⁴ Patients undergo a three-stage series of palliative surgeries with survivability to the mid-30s; however, patients present with conditions affecting circulation and several organ systems.^1,2,4,5 Despite the limited regenerative capacity of the heart on its own, cell-based therapies have the potential to augment the performance of the HLHS heart, particularly the right ventricle (RV).⁵

Methods: A PubMed database search was performed using the key words “hypoplastic left heart syndrome,” “cell-based therapy,” and “right ventricular function,” with exclusion criteria of studies published more than five years prior to this review.

Results: This review identified five studies utilizing cell-based therapies to increase RV function. The first study successfully reconstructed the RV outflow tract (RVOT) in swine models utilizing a submucosa-derived extracellular matrix scaffold seeded with piglet-derived thymus stem cells (T-MSCs).⁶ Treated groups showed greater areas of host cardiomyocyte regeneration, more organized endothelialization, and less fibrosis.⁶ The second study improved RV function in rat models by implanting cell sheets of human neonatal-derived T-MSCs into the RV free wall.⁷ Treated models possessed higher levels of superoxide dismutase, a known regulator of angiogenesis, greater survivability, increased RV capillary density and less fibrosis.⁷ The third study implanted 3D aggregations of child cardiac progenitor cells in rat models to improve RV function.⁸ Investigators observed upregulation of cardiogenic transcription factors and endothelial markers, increased angiogenesis, and reduced fibrosis.⁸ The fourth study implanted the RVOT with bioactive patches of integrated polyurethane/small intestinal submucosa seeded with urine-derived stem cells.⁹ Investigators reported enhanced vascularization, muscularization, and cell paracrine function due to hypoxic pretreatment, noting decreased fibrosis and inflammatory response.⁹ The fifth study, the ELPIS Phase I Trial, injected the RV of HLHS patients with bone-marrow derived stem cells.¹⁰ Investigators observed positive regulation of cell migration and heart development, describing the treatment as safe and well-tolerated.¹⁰

Conclusions: Cell-based therapies to improve RV function can serve as a safe and feasible addition to current palliative treatment plans for HLHS patients, yet there exist several considerations for the procurement, development, and administration of these therapies. With future investigations, the creation and maintenance of a database containing these combinations will provide tailored care for HLHS patients.

Works Cited:

1. Ramonfaur D, Zhang X, Garza AP, García-Pons JF, Britton-Robles SC. Hypoplastic Left Heart Syndrome: A Review. Cardiology in Review. 2023;31(3):149-154. doi:10.1097/CRD.0000000000000435
2. Javed R, Cetta F, Said SM, Olson TM, O’Leary PW, Qureshi MY. Hypoplastic Left Heart Syndrome: An Overview for Primary Care Providers. Pediatrics In Review. 2019;40(7):344-353. doi:10.1542/pir.2018-0005
3. Anderson RH, Crucean A, Spicer DE. What Is the Hypoplastic Left Heart Syndrome? JCDD. 2023;10(4):133. doi:10.3390/jcdd10040133
4. Rychik J, Atz AM, Celermajer DS, et al. Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association. Circulation. 2019;140(6). doi:10.1161/CIR.0000000000000696
5. Bejjani AT, Wary N, Gu M. Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration. Expert Opinion on Therapeutic Targets. 2021;25(8):621-632. doi:10.1080/14728222.2021.1978069
6. Albertario A, Swim MM, Ahmed EM, et al. Successful Reconstruction of the Right Ventricular Outflow Tract by Implantation of Thymus Stem Cell Engineered Graft in Growing Swine. JACC: Basic to Translational Science. 2019;4(3):364-384. doi:10.1016/j.jacbts.2019.02.001
7. Chery J, Huang S, Gong L, et al. Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload. Bioengineering. 2019;6(1):15. doi:10.3390/bioengineering6010015
8. Trac D, Maxwell JT, Brown ME, Xu C, Davis ME. Aggregation of Child Cardiac Progenitor Cells Into Spheres Activates Notch Signaling and Improves Treatment of Right Ventricular Heart Failure. Circ Res. 2019;124(4):526-538. doi:10.1161/CIRCRESAHA.118.313845
9. Zhao LM, Wang L, Zhang WQ, et al. Promotion of right ventricular outflow tract reconstruction using a novel cardiac patch incorporated with hypoxia-pretreated urine-derived stem cells. Bioactive Materials. 2022;14:206-218. doi:10.1016/j.bioactmat.2021.11.021
10. Kaushal S, Hare JM, Hoffman JR, et al. Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial. Nagy E, ed. European Heart Journal Open. 2023;3(2):oead002. doi:10.1093/ehjopen/oead002