Hypoplastic Left Heart Syndrome: Etiology, Pathogenesis, Management and The Future

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425). This special issue belongs to the section "Pediatric Cardiology and Congenital Heart Disease".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 43865

Special Issue Editor


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Guest Editor
Division of Cardiology, University of California San Diego, Rady’s Hospital MC 5004, San Diego, CA 92123, USA
Interests: congenital heart disease; genetics; cardiac development; hypoplastic left heart syndrome; jacobsen syndrome

Special Issue Information

Dear Colleagues,

Despite the remarkable strides in clinical management over the past half-century, HLHS continues to be one of the most common causes of death in infants born with congenital heart disease.  Although most patients that survive the first year are likely to live into adulthood, long-term survival is still an uncertainty. While, clinically, most patients with HLHS and other variants of an hypoplastic left ventricle undergo surgical palliation entailing the three-stage Norwood–Glenn–Fontan approach, there is a remarkable lack of understanding and consensus on the molecular and cellular mechanisms underlying HLHS. Much of this stems from the phenotypical variation and confusion over what defines HLHS, i.e., distinguishing the hypoplastic left ventricle that occurs in “classic” HLHS from other lesions that are also associated with hypoplasia of the left ventricle. Even within the group of lesions classified as “classic” HLHS, there is tremendous variability in the clinical phenotype, and it is unclear whether these phenotypic subtypes represent distinct disease entities or are variations of a single mechanism. Until recently, there has also been a paucity of animal models that phenocopy the features of the syndrome itself, rather than simply producing hypoplasia of the left ventricle. In this Special Issue, we explore the state-of-the-art in the pathology, etiologies, mechanisms and treatments, as well as areas of future exploration for HLHS. With the advances and vision described in this Special Issue and, hopefully enough monetary support, we are hopeful that a more personalized approach can be created regarding the care of patients with HLHS, and, someday, to prevent this disease. Thank you for agreeing to contribute to this Special Edition of The Journal of Cardiovascular Development and Disease.

Prof. Dr. Paul Grossfeld
Guest Editor

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Keywords

  • hypoplastic left heart syndrome
  • etiology
  • pathogenesis
  • management
  • multi-factorial
  • genetic
  • animal models

Published Papers (16 papers)

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Editorial

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6 pages, 243 KiB  
Editorial
Catalysts for Change: The Role of Nonprofits in Solving Single Ventricle Heart Disease
by Kaitlin A. Davis, Diane M. Pickles and Kirstie E. Keller
J. Cardiovasc. Dev. Dis. 2022, 9(7), 220; https://doi.org/10.3390/jcdd9070220 - 8 Jul 2022
Viewed by 2036
Abstract
Single ventricle (SV) heart disease comprises a spectrum of complex congenital heart defects (CHDs), including hypoplastic left heart syndrome (HLHS), one of the most common causes of death amongst infants with CHD. Despite its incompletely defined etiology and a dearth of curative solutions, [...] Read more.
Single ventricle (SV) heart disease comprises a spectrum of complex congenital heart defects (CHDs), including hypoplastic left heart syndrome (HLHS), one of the most common causes of death amongst infants with CHD. Despite its incompletely defined etiology and a dearth of curative solutions, SV is a solvable problem that can be addressed by unifying a nascent field that is ripe for investment, in part due to its high economic impact and growth potential. Here, we explore the landscape of SV and identify areas of opportunity that will yield an outsized impact through strategic investment that focuses on synchronization across disciplines, community involvement, and infrastructure development, and argue that nonprofits are the appropriate catalyst to spark transformative innovation and impact in the form of functional cures. Full article
3 pages, 156 KiB  
Editorial
Losing a Child with HLHS and Creating Brighter Futures for Children and Families
by Jessica M. Lindberg
J. Cardiovasc. Dev. Dis. 2022, 9(5), 146; https://doi.org/10.3390/jcdd9050146 - 5 May 2022
Viewed by 2539
Abstract
It was a lazy Saturday and my new husband, and I sat on the couch in our Chicago loft to watch TV [...] Full article

Review

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8 pages, 2623 KiB  
Review
What Is the Hypoplastic Left Heart Syndrome?
by Robert H. Anderson, Adrian Crucean and Diane E. Spicer
J. Cardiovasc. Dev. Dis. 2023, 10(4), 133; https://doi.org/10.3390/jcdd10040133 - 23 Mar 2023
Cited by 2 | Viewed by 1387
Abstract
As yet, there is no agreed definition for the so-called “hypoplastic left heart syndrome”. Even its origin remains contentious. Noonan and Nadas, who as far as we can establish first grouped together patients as belonging to a “syndrome” in 1958, suggested that Lev [...] Read more.
As yet, there is no agreed definition for the so-called “hypoplastic left heart syndrome”. Even its origin remains contentious. Noonan and Nadas, who as far as we can establish first grouped together patients as belonging to a “syndrome” in 1958, suggested that Lev had named the entity. Lev, however, when writing in 1952, had described “hypoplasia of the aortic outflow tract complex”. In his initial description, as with Noonan and Nadas, he included cases with ventricular septal defects. In a subsequent account, he suggested that only those with an intact ventricular septum be included within the syndrome. There is much to commend this later approach. When assessed on the basis of the integrity of the ventricular septum, the hearts to be included can be interpreted as showing an acquired disease of fetal life. Recognition of this fact is important to those seeking to establish the genetic background of left ventricular hypoplasia. Flow is also of importance, with septal integrity then influencing its effect on the structure of the hypoplastic ventricle. In our review, we summarise the evidence supporting the notion that an intact ventricular septum should now be part of the definition of the hypoplastic left heart syndrome. Full article
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10 pages, 1161 KiB  
Review
Left-Sided Heart Defects and Laterality Disturbance in Hypoplastic Left Heart Syndrome
by Hisato Yagi and Cecilia W. Lo
J. Cardiovasc. Dev. Dis. 2023, 10(3), 99; https://doi.org/10.3390/jcdd10030099 - 24 Feb 2023
Cited by 1 | Viewed by 1915
Abstract
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by hypoplasia of left-sided heart structures. The developmental basis for restriction of defects to the left side of the heart in HLHS remains unexplained. The observed clinical co-occurrence of rare organ [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by hypoplasia of left-sided heart structures. The developmental basis for restriction of defects to the left side of the heart in HLHS remains unexplained. The observed clinical co-occurrence of rare organ situs defects such as biliary atresia, gut malrotation, or heterotaxy with HLHS would suggest possible laterality disturbance. Consistent with this, pathogenic variants in genes regulating left–right patterning have been observed in HLHS patients. Additionally, Ohia HLHS mutant mice show splenic defects, a phenotype associated with heterotaxy, and HLHS in Ohia mice arises in part from mutation in Sap130, a component of the Sin3A chromatin complex known to regulate Lefty1 and Snai1, genes essential for left–right patterning. Together, these findings point to laterality disturbance mediating the left-sided heart defects associated with HLHS. As laterality disturbance is also observed for other CHD, this suggests that heart development integration with left–right patterning may help to establish the left–right asymmetry of the cardiovascular system essential for efficient blood oxygenation. Full article
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12 pages, 1742 KiB  
Review
The Left Ventricular Myocardium in Hypoplastic Left Heart Syndrome
by Bill Chaudhry, Ahlam Alqahtani, Lorraine Eley, Louise Coats, Corina Moldovan, Srinivas R. Annavarapu and Deborah J. Henderson
J. Cardiovasc. Dev. Dis. 2022, 9(8), 279; https://doi.org/10.3390/jcdd9080279 - 19 Aug 2022
Cited by 4 | Viewed by 2681
Abstract
Hypoplastic left heart syndrome (HLHS) is a collective term applied to severe congenital cardiac malformations, characterised by a combination of abnormalities mainly affecting the left ventricle, associated valves, and ascending aorta. Although in clinical practice HLHS is usually sub-categorised based on the patency [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a collective term applied to severe congenital cardiac malformations, characterised by a combination of abnormalities mainly affecting the left ventricle, associated valves, and ascending aorta. Although in clinical practice HLHS is usually sub-categorised based on the patency of the mitral and aortic (left-sided) valves, it is also possible to comprehensively categorise HLHS into defined sub-groups based on the left ventricular morphology. Here, we discuss the published human-based studies of the ventricular myocardium in HLHS, evaluating whether the available evidence is in keeping with this ventricular morphology concept. Specifically, we highlight results from histological studies, indicating that the appearance of cardiomyocytes can be different based on the sub-group of HLHS. In addition, we discuss the histological appearances of endocardial fibroelastosis (EFE), which is a common feature of one specific sub-group of HLHS. Lastly, we suggest investigations that should ideally be undertaken using HLHS myocardial tissues at early stages of HLHS development to identify biological pathways and aid the understanding of HLHS aetiology. Full article
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8 pages, 275 KiB  
Review
Exercising with a Single Ventricle: Limitations and Therapies
by Jessica Erin Haley and Christopher Davis
J. Cardiovasc. Dev. Dis. 2022, 9(6), 167; https://doi.org/10.3390/jcdd9060167 - 25 May 2022
Cited by 2 | Viewed by 2053
Abstract
Treatment for Hypoplastic Left Heart Syndrome (HLHS) and other single ventricle conditions requires a series of surgical interventions for long-term survival, typically culminating in the Fontan procedure. The result is an abnormal circulatory physiology with an absence of a sub-pulmonary ventricle. Exercise capacity [...] Read more.
Treatment for Hypoplastic Left Heart Syndrome (HLHS) and other single ventricle conditions requires a series of surgical interventions for long-term survival, typically culminating in the Fontan procedure. The result is an abnormal circulatory physiology with an absence of a sub-pulmonary ventricle. Exercise capacity in the Fontan circulation is often limited and is due to multiple factors, both central and peripheral. Multiple interventions, both pharmacologic and nonpharmacologic, have been studied to attempt to overcome these inherent limitations. This review will focus on the physiology of the exercising Fontan patient and on the interventions aimed at the enhancement of exercise capacity studied thus far. Full article
10 pages, 1182 KiB  
Review
Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome
by Anum Rahman, Rajiv R. Chaturvedi and John G. Sled
J. Cardiovasc. Dev. Dis. 2022, 9(5), 154; https://doi.org/10.3390/jcdd9050154 - 12 May 2022
Cited by 4 | Viewed by 3042
Abstract
Hypoplastic left heart syndrome (HLHS) is a life-threatening congenital heart disease that is characterized by severe underdevelopment of left heart structures. Currently, there is no cure, and affected individuals require surgical palliation or cardiac transplantation to survive. Despite these resource-intensive measures, only about [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a life-threatening congenital heart disease that is characterized by severe underdevelopment of left heart structures. Currently, there is no cure, and affected individuals require surgical palliation or cardiac transplantation to survive. Despite these resource-intensive measures, only about half of individuals reach adulthood, often with significant comorbidities such as liver disease and neurodevelopmental disorders. A major barrier in developing effective treatments is that the etiology of HLHS is largely unknown. Here, we discuss how intracardiac blood flow disturbances are an important causal factor in the pathogenesis of impaired left heart growth. Specifically, we highlight results from a recently developed mouse model in which surgically reducing blood flow through the mitral valve after cardiogenesis led to the development of HLHS. In addition, we discuss the role of interventional procedures that are based on improving blood flow through the left heart, such as fetal aortic valvuloplasty. Lastly, using the surgically-induced mouse model, we suggest investigations that can be undertaken to identify the currently unknown biological pathways in left heart growth failure and their associated therapeutic targets. Full article
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7 pages, 1648 KiB  
Review
HLHS: Power of the Chick Model
by David Sedmera
J. Cardiovasc. Dev. Dis. 2022, 9(4), 113; https://doi.org/10.3390/jcdd9040113 - 11 Apr 2022
Cited by 1 | Viewed by 2517
Abstract
Background: Hypoplastic left heart syndrome (HLHS) is a rare but deadly form of human congenital heart disease, most likely of diverse etiologies. Hemodynamic alterations such as those resulting from premature foramen ovale closure or aortic stenosis are among the possible pathways. Methods: The [...] Read more.
Background: Hypoplastic left heart syndrome (HLHS) is a rare but deadly form of human congenital heart disease, most likely of diverse etiologies. Hemodynamic alterations such as those resulting from premature foramen ovale closure or aortic stenosis are among the possible pathways. Methods: The information gained from studies performed in the chick model of HLHS is reviewed. Altered hemodynamics leads to a decrease in myocyte proliferation causing hypoplasia of the left heart structures and their functional changes. Conclusions: Although the chick phenocopy of HLHS caused by left atrial ligation is certainly not representative of all the possible etiologies, it provides many useful hints regarding the plasticity of the genetically normal developing myocardium under altered hemodynamic loading leading to the HLHS phenotype, and even suggestions on some potential strategies for prenatal repair. Full article
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Other

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10 pages, 474 KiB  
Perspective
Use of Frogs as a Model to Study the Etiology of HLHS
by Shuyi Nie
J. Cardiovasc. Dev. Dis. 2023, 10(2), 51; https://doi.org/10.3390/jcdd10020051 - 29 Jan 2023
Cited by 1 | Viewed by 2408
Abstract
A frog is a classical model organism used to uncover processes and regulations of early vertebrate development, including heart development. Recently, we showed that a frog also represents a useful model to study a rare human congenital heart disease, hypoplastic left heart syndrome. [...] Read more.
A frog is a classical model organism used to uncover processes and regulations of early vertebrate development, including heart development. Recently, we showed that a frog also represents a useful model to study a rare human congenital heart disease, hypoplastic left heart syndrome. In this review, we first summarized the cellular events and molecular regulations of vertebrate heart development, and the benefit of using a frog model to study congenital heart diseases. Next, we described the challenges in elucidating the etiology of hypoplastic left heart syndrome and discussed how a frog model may contribute to our understanding of the molecular and cellular bases of the disease. We concluded that a frog model offers its unique advantage in uncovering the cellular mechanisms of hypoplastic left heart syndrome; however, combining multiple model organisms, including frogs, is needed to gain a comprehensive understanding of the disease. Full article
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7 pages, 742 KiB  
Perspective
Endocardium in Hypoplastic Left Heart Syndrome: Implications from In Vitro Study
by Zhiyun Yu, Ziyi Liu, Vidhya Ravichandran, Bonny Lami and Mingxia Gu
J. Cardiovasc. Dev. Dis. 2022, 9(12), 442; https://doi.org/10.3390/jcdd9120442 - 8 Dec 2022
Cited by 1 | Viewed by 2004
Abstract
Endocardium lines the inner layer of the heart ventricle and serves as the source of valve endothelial cells and interstitial cells. Previously, endocardium-associated abnormalities in hypoplastic left heart syndrome (HLHS) have been reported, including endocardial fibroelastosis (EFE) and mitral and aortic valve malformation. [...] Read more.
Endocardium lines the inner layer of the heart ventricle and serves as the source of valve endothelial cells and interstitial cells. Previously, endocardium-associated abnormalities in hypoplastic left heart syndrome (HLHS) have been reported, including endocardial fibroelastosis (EFE) and mitral and aortic valve malformation. However, few mechanistic studies have investigated the molecular pathological changes in endocardial cells. Recently, the emergence of a powerful in vitro system—induced pluripotent stem cells (iPSCs)—was applied to study various genetic diseases, including HLHS. This review summarized current in vitro studies in understanding the endocardial pathology in HLHS, emphasizing new findings of the cellular phenotypes and underlying molecular mechanisms. Lastly, a future perspective is provided regarding the better recapitulation of endocardial phenotypes in a dish. Full article
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11 pages, 1051 KiB  
Perspective
Considering the Genetic Architecture of Hypoplastic Left Heart Syndrome
by John W. Belmont
J. Cardiovasc. Dev. Dis. 2022, 9(10), 315; https://doi.org/10.3390/jcdd9100315 - 21 Sep 2022
Cited by 2 | Viewed by 2826
Abstract
Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant [...] Read more.
Hypoplastic left heart syndrome (HLHS) is among the most severe cardiovascular malformations and understanding its causes is crucial to making progress in prevention and treatment. Genetic analysis is a broadly useful tool for dissecting complex causal mechanisms and it is playing a significant role in HLHS research. However, unlike classical Mendelian disorders where a relatively small number of genes are largely determinative of the occurrence and severity of the disease, the picture in HLHS is complex. De novo single-gene and copy number variant (CNV) disorders make an important contribution, but there is emerging evidence for causal contributions from lower penetrance and common variation. Integrating this emerging knowledge into clinical diagnostics and translating the findings into effective prevention and treatment remain challenges for the future. Full article
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7 pages, 4354 KiB  
Perspective
ETS1 and HLHS: Implications for the Role of the Endocardium
by Paul Grossfeld
J. Cardiovasc. Dev. Dis. 2022, 9(7), 219; https://doi.org/10.3390/jcdd9070219 - 8 Jul 2022
Cited by 2 | Viewed by 1882
Abstract
We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in Ciona intestinalis demonstrated a critical role for ETS1 in heart cell fate determination and cell [...] Read more.
We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in Ciona intestinalis demonstrated a critical role for ETS1 in heart cell fate determination and cell migration, suggesting that the impairment of one or both processes can underlie the pathogenesis of HLHS. Our studies determined that ETS1 is expressed in the cardiac neural crest and endocardium in the developing murine heart, implicating one or both lineages in the development of HLHS. Studies in Drosophila and Xenopus demonstrated a critical role for ETS1 in regulating cardiac cell fate determination, and results in Xenopus provided further evidence for the role of the endocardium in the evolution of the “hypoplastic” HLHS LV. Paradoxically, these studies suggest that the loss of ETS1 may cause a cell fate switch resulting in the loss of endocardial cells and a relative abundance of cardiac myocytes. These studies implicate an “HLHS transcriptional network” of genes conserved across species that are essential for early heart development. Finally, the evidence suggests that in a subset of HLHS patients, the HLHS LV cardiac myocytes are, intrinsically, developmentally and functionally normal, which has important implications for potential future therapies. Full article
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12 pages, 755 KiB  
Perspective
Medical Therapies for Heart Failure in Hypoplastic Left Heart Syndrome
by Angela N. Baybayon-Grandgeorge, Ashley E. Pietra, Shelley D. Miyamoto and Anastacia M. Garcia
J. Cardiovasc. Dev. Dis. 2022, 9(5), 152; https://doi.org/10.3390/jcdd9050152 - 12 May 2022
Cited by 1 | Viewed by 5569
Abstract
Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction [...] Read more.
Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction and ultimately heart failure (HF) remain the most common cause of death and indication for transplantation in this population. Moreover, while early recognition and treatment of single ventricle-related complications are essential to improving outcomes, there are no proven therapeutic strategies for single systemic RV HF in the pediatric population. Importantly, prototypical adult HF therapies have been relatively ineffective in mitigating the need for cardiac transplantation in HLHS, likely due to several unique attributes of the failing HLHS myocardium. Here, we discuss the most commonly used medical therapies for the treatment of HF symptoms in HLHS and other single systemic RV patients. Additionally, we provide an overview of potential novel therapies for systemic ventricular failure in the HLHS and related populations based on fundamental science, pre-clinical, clinical, and observational studies in the current literature. Full article
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16 pages, 899 KiB  
Perspective
Significance of α-Myosin Heavy Chain (MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases
by Melissa Anfinson, Robert H. Fitts, John W. Lough, Jeanne M. James, Pippa M. Simpson, Stephanie S. Handler, Michael E. Mitchell and Aoy Tomita-Mitchell
J. Cardiovasc. Dev. Dis. 2022, 9(5), 144; https://doi.org/10.3390/jcdd9050144 - 3 May 2022
Cited by 9 | Viewed by 3303
Abstract
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants. Specific genes have been implicated in HLHS, including rare, predicted damaging MYH6 variants that are present in >10% of HLHS patients, and which have been shown to be associated with decreased transplant-free survival in our previous studies. MYH6 (α-myosin heavy chain, α-MHC) variants have been reported in HLHS and numerous other CHDs, including LVOT malformations, and may provide a genetic link to these disorders. In this paper, we outline the MYH6 variants that have been identified, discuss how bioinformatic and functional studies can inform clinical decision making, and highlight the importance of genetic testing in HLHS. Full article
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6 pages, 591 KiB  
Perspective
Whole Genome Sequencing in Hypoplastic Left Heart Syndrome
by Jeanne L. Theis and Timothy M. Olson
J. Cardiovasc. Dev. Dis. 2022, 9(4), 117; https://doi.org/10.3390/jcdd9040117 - 15 Apr 2022
Cited by 3 | Viewed by 2713
Abstract
Hypoplastic left heart syndrome (HLHS) is a genetically complex disorder. Whole genome sequencing enables comprehensive scrutiny of single nucleotide variants and small insertions/deletions, within both coding and regulatory regions of the genome, revolutionizing susceptibility-gene discovery research. Because millions of rare variants comprise an [...] Read more.
Hypoplastic left heart syndrome (HLHS) is a genetically complex disorder. Whole genome sequencing enables comprehensive scrutiny of single nucleotide variants and small insertions/deletions, within both coding and regulatory regions of the genome, revolutionizing susceptibility-gene discovery research. Because millions of rare variants comprise an individual genome, identification of alleles linked to HLHS necessitates filtering algorithms based on various parameters, such as inheritance, enrichment, omics data, known genotype–phenotype associations, and predictive or experimental modeling. In this brief review, we highlight family and cohort-based strategies used to analyze whole genome sequencing datasets and identify HLHS candidate genes. Key findings include compound and digenic heterozygosity among several prioritized genes and genetic associations between HLHS and bicuspid aortic valve or cardiomyopathy. Together with findings of independent genomic investigations, MYH6 has emerged as a compelling disease gene for HLHS and other left-sided congenital heart diseases. Full article
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6 pages, 192 KiB  
Perspective
The Potential Role of Regenerative Medicine on the Future Management of Hypoplastic Left Heart Syndrome
by John M. Kelly, Cole Anderson and Christopher K. Breuer
J. Cardiovasc. Dev. Dis. 2022, 9(4), 107; https://doi.org/10.3390/jcdd9040107 - 2 Apr 2022
Cited by 2 | Viewed by 2337
Abstract
The development and translation of regenerative medicine approaches for the treatment of hypoplastic left heart syndrome (HLHS) provides a promising alternative to the current standard of care. We review the strategies that have been pursued to date and those that hold the greatest [...] Read more.
The development and translation of regenerative medicine approaches for the treatment of hypoplastic left heart syndrome (HLHS) provides a promising alternative to the current standard of care. We review the strategies that have been pursued to date and those that hold the greatest promise in moving forward. Significant challenges remain. Continued scientific advances and technological breakthroughs will be required if we are to translate this technology to the clinic and move from palliative to curative treatment. Full article
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