Congenital heart disease in a dish: progress toward understanding patient-specific mutations

Mercer, Emily J.; Evans, Todd

doi:10.21037/jtd.2017.03.178

Cited by 4 publications

(3 citation statements)

References 13 publications

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“…Mice modeling monogenic causes of CHD recapitulate cardiac septation defects, heart valve malformations, and conotruncal heart defects, as well as more complex CHD ( 16 , 17 ). More recently, patient-specific induced pluripotent stem cells (iPSCs) have been employed to study human CHD ( 18 ). In addition, large animal models simulating the corrective treatments employed in children are warranted to determine the positive and negative effects of cardiac surgery on post-natal heart maturation ( 19 – 22 ).…”

Section: Introductionmentioning

confidence: 99%

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Iacobazzi

Alvino

Caputo

et al. 2022

Front. Cardiovasc. Med.

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An increasing number of patients with congenital heart disease (CHD) survive into adulthood but develop long-term complications including heart failure (HF). Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing, and aging. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. While senescence has been mainly considered as a cause of diseases in the adulthood, it may be also implicated in some of the poor outcomes seen in patients with complex CHD. We propose that patients with CHD suffer from multiple repeated stress from an early stage of the life, which wear out homeostatic mechanisms and cause premature cardiac aging, with this term referring to the time-related irreversible deterioration of the organ physiological functions and integrity. In this review article, we gathered evidence from the literature indicating that growing up with CHD leads to abnormal inflammatory response, loss of proteostasis, and precocious age in cardiac cells. Novel research on this topic may inspire new therapies preventing HF in adult CHD patients.

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Section: Introductionmentioning

confidence: 99%

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Iacobazzi

Alvino

Caputo

et al. 2022

Front. Cardiovasc. Med.

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“…Such regulatory-network control applies to many TF interactions that result in tissue-specific gene expression. CHD have strong genetic etiologies, including disruptions of developmentally regulated TFs, whose mutations induce disorders in cardiogenesis [33-35]. Likewise, GATA5 loss-of-function mutations underlying tetralogy of Fallot inform allele-specific therapies [36].…”

Section: Transcription Factor Mutations Impact Cardiogenesismentioning

confidence: 99%

Implementing genome-driven personalized cardiology in clinical practice

Pasipoularides

2018

Journal of Molecular and Cellular Cardiology

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Genomics designates the coordinated investigation of a large number of genes in the context of a biological process or disease. It may be long before we attain comprehensive understanding of the genomics of common complex cardiovascular diseases (CVDs) such as inherited cardiomyopathies, valvular diseases, primary arrhythmogenic conditions, congenital heart syndromes, hypercholesterolemia and atherosclerotic heart disease, hypertensive syndromes, and heart failure with preserved/reduced ejection fraction. Nonetheless, as genomics is evolving rapidly, it is constructive to survey now pertinent concepts and breakthroughs. Today, clinical multimodal electronic medical/health records (EMRs/EHRs) incorporating genomic information establish a continuously-learning, vast knowledge-network with seamless cycling between clinical application and research. It can inform insights into specific pathogenetic pathways, guide biomarker-assisted precise diagnoses and individualized treatments, and stratify prognoses. Complex CVDs blend multiple interacting genomic variants, epigenetics, and environmental risk-factors, engendering progressions of multifaceted disease-manifestations, including clinical symptoms and signs. There is no straight-line linkage between genetic cause(s) or causal gene-variant(s) and disease phenotype(s). Because of interactions involving modifier-gene influences, (micro)-environmental, and epigenetic effects, the same variant may actually produce dissimilar abnormalities in different individuals. Implementing genome-driven personalized cardiology in clinical practice reveals that the study of CVDs at the level of molecules and cells can yield crucial clinical benefits. Complementing evidence-based medicine guidelines from large ("one-size fits all") randomized controlled trials, genomics-based personalized or precision cardiology is a most-creditable paradigm: It provides customizable approaches to prevent, diagnose, and manage CVDs with treatments directly/precisely aimed at causal defects identified by high-throughput genomic technologies. They encompass stem cell and gene therapies exploiting CRISPR-Cas9-gene-editing, and metabolomic-pharmacogenomic therapeutic modalities, precisely fine-tuned for the individual patient. Following the Human Genome Project, many expected genomics technology to provide imminent solutions to intractable medical problems, including CVDs. This eagerness has reaped some disappointment that advances have not yet materialized to the degree anticipated. Undoubtedly, personalized genetic/genomics testing is an emergent technology that should not be applied without supplementary phenotypic/clinical information: Genotype≠Phenotype. However, forthcoming advances in genomics will naturally build on prior attainments and, combined with insights into relevant epigenetics and environmental factors, can plausibly eradicate intractable CVDs, improving human health and well-being.

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“…In vitro noncardiac cellbased models have been used to study potentially pathogenic sequence variants identified in affected individuals with CHD, but have numerous limitations in regard to the biologic relevance of these observations. More recently, patient-specific induced pluripotent stem cells (iPSCs) have begun to be investigated as a model to study human CHD (Mital 2016;Mercer and Evans 2017). Somewhat similar to the weaknesses related to zebrafish and fruit fly in regard to modeling the structural and morphogenetic aspects of CHD, these models are the most genetically similar and may allow for the investigation of the most relevant molecular mechanisms.…”

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confidence: 99%

In Vivo and In Vitro Genetic Models of Congenital Heart Disease

Majumdar

Yasuhara

Garg

2019

Cold Spring Harb Perspect Biol

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Congenital cardiovascular malformations represent the most common type of birth defect and encompass a spectrum of anomalies that range from mild to severe. The etiology of congenital heart disease (CHD) is becoming increasingly defined based on prior epidemiologic studies that supported the importance of genetic contributors and technological advances in human genome analysis. These have led to the discovery of a growing number of disease-contributing genetic abnormalities in individuals affected by CHD. The evergrowing population of adult CHD survivors, which are the result of reductions in mortality from CHD during childhood, and this newfound genetic knowledge have led to important questions regarding recurrence risks, the mechanisms by which these defects occur, the potential for novel approaches for prevention, and the prediction of long-term cardiovascular morbidity in adult CHD survivors. Here, we will review the current status of genetic models that accurately model human CHD as they provide an important tool to answer these questions and test novel therapeutic strategies.

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Congenital heart disease in a dish: progress toward understanding patient-specific mutations

Cited by 4 publications

References 13 publications

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

Implementing genome-driven personalized cardiology in clinical practice

In Vivo and In Vitro Genetic Models of Congenital Heart Disease

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