Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Atrial Septal Defect. Core disease mechanisms, molecular and cellular path...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 18
• Snippets retrieved: 20

Relevant Papers

[1] PITX2c Loss-of-Function Mutations Responsible for Congenital Atrial Septal Defects

• Authors: Fang Yuan, Lan Zhao, Juan Wang, Wei Zhang, Xin Li et al.
• Year: 2013
• Venue: International Journal of Medical Sciences
• URL: https://www.semanticscholar.org/paper/4fa1f0d92b9a07a1f47d54879c4a161b9e7ce55a
• DOI: 10.7150/ijms.6809
• PMID: 23983605
• PMCID: 3753420
• Citations: 24
• Influential citations: 1
• Summary: These findings firstly link PITX2c loss-of-function mutations to atrial septal defects in humans, which provide novel insight into the molecular mechanism responsible for CHD, and suggest potential implications for the early prophylaxis and allele-specific treatment of CHD.
• Evidence snippets:
• Snippet 1 (score: 0.439) > Congenital heart disease (CHD), also known as congenital cardiovascular defect that arises from abnormal formation of the heart or major blood vessels, is the most common form of major developmental anomaly in humans worldwide, with a prevalence of approximately 1% among live births, and is the leading non-infectious cause of infant death, with an estimated 30% of newborns who die of birth defects Ivyspring International Publisher having cardiovascular abnormalities [1]. Congenital cardiovascular malformations are clinically classified into at least 21 different categories with specific anatomic lesions, including ventricular septal defect, atrial septal defect, atrioventricular septal defect, tetraology of Fallot, patent ductus arteriosus, transposition of the great artery, right ventricular outflow tract obstruction, aortic stenosis, coronary artery deformation, tricuspid atresia, and Ebstein's anomaly, of which ventricular septal defect is the most prevalent congenital heart defect at birth, while atrial septal defect is the most common adult congenital heart defect and tetraology of Fallot is the most common type of cyanotic congenital heart disease [1,2]. Various CHDs can occur separately or in combination, resulting in reduced exercise capacity, degraded quality of life, delayed fetal brain development, cardiac dysfunction or congestive heart failure, thromboembolic stroke, pulmonary embolus, subacute bacterial endocarditis, arrhythmias, and even sudden cardiac death [3][4][5][6][7][8][9][10][11][12]. Hence, CHD has imposed a substantial economic burden on patients and health care systems, and the socioeconomic burden is anticipated to increase in the future with increasing CHD adults [13]. Despite the pronounced morbidity and significant mortality throughout life, the molecular mechanism underlying CHD remains poorly understood. > A growing body of studies demonstrates that cardiovascular morphogenesis is a complex and dynamic biological process that requires the orchestration of cardiac cell commitment, differentiation, proliferation, and migration, with both environmental and genetic risk factors being implicated in this heterogeneous process [14][15][16].

[2] From ECG to Imaging: Challenges in the Diagnosis of Adult Congenital Heart Diseases

• Authors: S. Crișan, Ruxandra-Maria Băghină, Silvia-Ana Luca, Oana Pătru, M. Lazăr et al.
• Year: 2024
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/bf13fe1ce4fd24d8fb16f91604368853a69d85b4
• DOI: 10.3390/jcm13164865
• PMID: 39201011
• PMCID: 11355218
• Citations: 4
• Summary: Early diagnosis and adequate treatment are mandatory to avoid possible complications of CHD, and thus, ECG, as well as imaging techniques, are important diagnostic tools, however, patients with CHD need a special healthcare team for the entire monitorization in various life stages.
• Evidence snippets:
• Snippet 1 (score: 0.434) > Congenital heart diseases (CHD) are one of the most common birth defects and the main leading cause of death in children. Many patients with CHD are reaching adulthood due to the success of improved contemporary surgical procedures. Understanding the etiology of CHD remains important for patient clinical management. Both genetic and environmental factors are involved in the development and progression of CHD. Variations in many different genes and chromosomal anomalies can be associated with CHD, by expression of different mechanisms. Sporadic cases are the most frequently encountered in these patients. Atrial septal defect is a common congenital heart disease that refers to direct communication between atrial chambers, found isolated or associated with other syndromes. Imaging techniques, especially transthoracic and transesophageal echocardiography (TOE) represent the key for diagnosis and management of ASD. The disease has a major incidence in adulthood, due to late symptomatology, but assessment and treatment are important to avoid time-related complications. Ebstein’s anomaly is a rare congenital disease, with a dominant genetic participation, characterized by an abnormal displacement of the tricuspid valve and right ventricular myopathy, often requiring surgical intervention. Alongside echocardiography, cardiac magnetic resonance (CMR) imaging is the gold standard tool for the assessment of ventricular volumes. Early diagnosis and adequate treatment are mandatory to avoid possible complications of CHD, and thus, ECG, as well as imaging techniques, are important diagnostic tools. However, patients with CHD need a special healthcare team for the entire monitorization in various life stages.

[3] Pathophysiology and natural history of atrial septal defect.

• Authors: L. Le Gloan, A. Legendre, L. Iserin, M. Ladouceur
• Year: 2018
• Venue: Journal of thoracic disease
• URL: https://www.semanticscholar.org/paper/6fca71b2c70561c37347197a7c2f6107d6970ac0
• DOI: 10.21037/jtd.2018.02.80
• PMID: 30305945
• Citations: 76
• Influential citations: 6
• Summary: Different pathophysiologic mechanisms involved in the direction and magnitude of blood flow through atrial septal defects are described, including the impact of a longstanding shunt on survival.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Pathophysiology and natural history of atrial septal defect.

[4] ANALYSIS OF GENE COPY NUMBER VARIATIONS IN PATIENTS WITH CARDIAC SEPTAL DEFECTS USING MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION

• Authors: Yashvanthi Borkar, K. Nayak, K. RanjanShetty, Rajasekhar Moka
• Year: 2019
• Venue: Asian Journal of Pharmaceutical and Clinical Research
• URL: https://www.semanticscholar.org/paper/3814d49632c999c5b7b46dee641d3318a868c9d0
• DOI: 10.22159/ajpcr.2020.v13i1.36189
• Summary: MLPA could be a useful assay for the detection of CNVs and to be adopted as the first line of screening in patients with congenital heart diseases.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Cardiac septal defects (CSDs) constitute 1% of all congenital heart diseases (CHDs) [1]. The prevalence of CHD worldwide (population based) is between 1 and 150/1000 live births, while in India, it is 8.07/1000 live births [2]. However, septal defects have a reported frequency of 4.1/1000 live births. CHDs can either be isolated (nonsyndromic; septal defects) or in combination with other cardiac lesions (syndromic; Holt-Oram syndrome). The septal defects such as atrial septal defects (ASDs) and ventricular septal defects (VSDs) may be asymptomatic, with the appearance of murmur as the primary symptom. Many small septal defects close on their own as the heart grows; hence, percentage diagnosis that is typically made during childhood is low, except for a few which persist through adulthood. The diagnosis is usually based on echocardiography and transesophageal echocardiography. Congenital septal defects are the most common of all structural malformations of the human heart and are caused by both genetic and environmental factors [3]. Since the year 2000, several genetic epidemiological studies have confirmed its genetic predisposition [4]. Subsequent advancements in the molecular diagnostics helped in identifying genes responsible for cardiogenesis and causative of syndromic and non-syndromic forms of CHDs. Transcriptional factor genes are predominantly articulated in the heart tissue and are documented to have a physical interaction with other regulatory proteins for proper morphogenesis [5]. Despite recent molecular genetic studies, efforts to identify genotype-phenotype correlation in patients with septal defects suggest a more complex pattern of inheritance, where copy number variations (CNVs), as well as single nucleotide polymorphisms, contribute to the disease pathogenesis and tune the spectrum of septal malformations. CNVs contribute majorly toward the genetic diversity in context to evolution and disease susceptibility. Therefore, it is essential to detect the CNVs associated with CHDs.
• Snippet 2 (score: 0.424) > Objective: Cardiac septal defects (CSDs), the most common human congenital heart malformations are complex and heterogeneous. Progress in molecular biology has helped to identify many genes responsible for cardiac morphogenesis. However, etiologic factors in familial as well as isolated syndromes are being identified; the root genetic cause still needs to be resolved and its mechanism is yet to be revealed. The objective of this study is to identify DNA copy number variations (CNVs) and their possible association with septal defects. > Methods: Multiplex ligation-dependent probe amplification (MLPA) was used to detect DNA copy number in non-syndromic CSDs using the P311-A1 Kit consisting of probes for the key genes, namely, NKX2-5 (NK2 transcription factor related, locus 5), GATA4 (GATA binding protein 4), TBX5 (T-box transcription factor), bone morphogenetic protein 4, and CRELD1 (cysteine rich with EGF-like domains 1). > Results: We studied 124 clinically diagnosed CSD subjects, of which 111 (89.5%) had atrial septal defects and 13 (10.5%) had ventricular septal defects. MLPA assay was carried out in all these patients after a thorough clinical and cytogenetic screening. CNVs were identified in 16 (12.9%) cases, of which heterozygous deletions and heterozygous duplications were detected (8 patients each) with apparent phenotypes. > Conclusion: MLPA could be a useful assay for the detection of CNVs and to be adopted as the first line of screening in patients with congenital heart diseases.

[5] Genetic Variants of CITED2 Gene Promoter in Human Atrial Septal Defects: Case-Control Study and Cellular Functional Verification

• Authors: Zhuo Chen, Huan-Xin Chen, Hai‐Tao Hou, Xiu‐Yun Yin, Qin Yang et al.
• Year: 2022
• Venue: Journal of Cardiovascular Development and Disease
• URL: https://www.semanticscholar.org/paper/8cda68e9dc3c473e38c025a7eab890f09b594064
• DOI: 10.3390/jcdd9100321
• PMID: 36286273
• PMCID: 9604052
• Citations: 5
• Summary: It is concluded that the variants of CITED2 promoter in ASD patients affect the transcriptional activity and are likely involved in the occurrence and development of ASD.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Congenital heart disease (CHD) is one of the eight leading causes of infant death, accounting for 30% of fetal deaths, with a prevalence of nearly 1.8 in 100 live births [1]. Atrial septal defect (ASD) is a major subtype of CHD, accounting for 7-10% of CHD in children and 25-30% of CHD in adults [2,3]. The true incidence of ASD is often higher, probably due to early classification and diagnostic problems [4]. Although ASD is considered a simple defect, due to the huge heterogeneity in anatomy and time-related complications (mainly arrhythmias, thromboembolism, right heart failure, and pulmonary arterial hypertension in some patients), optimal diagnosis and treatment of ASD remain challenging [5]. Like other congenital heart diseases, the pathogenesis of ASD is still not clear, and it may be related to genetic and environmental factors [6]. Many epidemiological studies believe that genetic factor is the most important reason [7]. With the breakthrough of molecular genetic technology, point mutation, chromosomal aneuploidy and copy number variant are considered the main genetic causes of congenital heart disease [8]. > CITED2 (OMIM: 602937) is a cAMP response element binding protein (CBP)/p300 interacting transcriptional regulator and a negative regulator of HIF1A, by competing with HIF1A for binding to CBP/p300 [9]. The transcriptional regulator CITED2 is required for normal embryonic development and is involved in the development of multiple organs. CITED2 knockout embryos exhibit cardiac malformations, adrenal hypoplasia, neural crest defects, and anencephaly [10]. > Variants in the coding region of the CITED2 gene lead to a range of cardiac malformations and congenital heart defects, such as ventricular septal defect (VSD), ASD, and tetralogy of Fallot (TOF) [11]. However, the pathogenic mechanism remains unclear. A study [12] has shown that CITED2 affects the development of cardiac neural crest by binding to TFAP2 and p300/CBP.

[6] TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus

• Authors: Ri-tai Huang, Juan Wang, S. Xue, X. Qiu, Hong-Yu Shi et al.
• Year: 2017
• Venue: International Journal of Medical Sciences
• URL: https://www.semanticscholar.org/paper/6e7a4ed81960c6e3402aefa1d7547906a7d7e018
• DOI: 10.7150/ijms.17834
• PMID: 28553164
• PMCID: 5436474
• Citations: 52
• Summary: The TBX20 loss-of-function mutation is linked to familial tetralogy of Fallot or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD.
• Evidence snippets:
• Snippet 1 (score: 0.417) > Congenital heart disease (CHD), which defines a large set of structural defects of the heart and intra-thoracic great vessels that occur during embryogenesis, is the most prevalent form of human birth defect worldwide, affecting approximately 1% of live births, with an estimated prenatal incidence of Ivyspring International Publisher 10 % [1][2][3]. According to specific anatomic lesions, CHD is clinically categorized into more than 20 distinct types, including ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetraology of Fallot (TOF) and double outlet right ventricle, of which ventricular septal defect is the most common CHD; while TOF is the most common type of cyanotic CHD [1]. In addition to degraded quality of life and decreased exercise performance, serious CHD may lead to various complications, including retarded brain development or brain injury, thromboembolism, pulmonary hypertension, chronic heart failure, arrhythmias and sudden cardiac demise [4][5][6][7][8][9][10][11][12][13][14][15][16]. Although enormous advancement in the diagnosis and treatment of pediatric CHD has been made during the past 50 years, which allows more than 75% of CHD children to survive into adulthood, unfortunately, it has brought about a growing population of adults living with CHD, with the prevalence of CHD in adults being approximately 3000 per million, and this unique CHD population is increasing by almost 5% per year [17,18]. Moreover, these survivors have a significantly increased incidence of late complications and sudden cardiac death [18,19]. Obviously, CHD is still associated with substantial morbidity and mortality, and has imposed a heavy socioeconomic burden on patients' families and societies [18,19]. Therefore, reveal of the molecular mechanisms underpinning CHD is of pronounced clinical importance, especially vital to the healthcare of this growing adult CHD community [17]. > Previous studies have demonstrated that CHD are multi-factorial, with both environmental and genetic risk factors involved in the pathogenesis of CHD [17,20,21].

[7] Molecular mechanisms of Ellis-van Creveld gene variations in ventricular septal defect

• Authors: Fadi Liu, Xiao Liu, Zhenyan Xu, P. Yuan, Qiongqiong Zhou et al.
• Year: 2017
• Venue: Molecular Medicine Reports
• URL: https://www.semanticscholar.org/paper/0ea792d0a846909b32703c28504f6fe4184c3a68
• DOI: 10.3892/mmr.2017.8088
• PMID: 29257216
• PMCID: 5780092
• Citations: 7
• Summary: The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti-apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity.
• Evidence snippets:
• Snippet 1 (score: 0.412) > Congenital heart disease (CHD) is a common birth defect in humans and is a leading cause of non-infectious mortalities in infancy (1). Heart development at the embryonic stage is regulated by a developmental network, including signaling pathways, transcription factors and epigenetics (2)(3)(4). Gene mutations in any of these factors may cause the development of CHD (5). Ventricular septal defect (VSD) is the most common type of CHD and accounts for ~30% of diagnoses (6). However, there have been few studies that focused on the underlying molecular pathogenetic mechanism of VSD. Currently, there are several known pathogenetic genes of VSD, including GATA-binding protein 4 (GATA4), GATA6, NK2 homeobox 5, T-box 1 (TBX1) and TBX5 (7). Mutations in the Ellis-van Creveld (EVC) gene may lead to EVC syndrome, and ~60% of patients exhibit the cardiac septal defect phenotype which is comprised of VSD, atrial septal defect and atrioventricular septal defects (8,9). Previous studies on EVC gene mutations have focused on the EVC syndrome lineage and its influence on cartilage development (10,11). There appear to be no studies on EVC gene variations in patients with VSD and the potential underlying pathogenetic mechanism. > The hedgehog (Hh) signaling pathway is a major pathway that is involved in heart development and members of this pathway include the 12-transmembrane receptor patched (Ptc), the 7-transmembrane receptor Smoothened (Smo), and the main effector factors, including members of the cubitus interruptus/glioma-associated oncogene homolog (Gli) family (12). The effector molecules in vertebrates are members of the Gli family. In the absence of Hh ligands, ligand-free Ptc represses the activity of Smo.

[8] Clinical and Genetic Heterogeneity of HCM: The Possible Role of a Deletion Involving MYH6 and MYH7

• Authors: G. Mancuso, Marina Marsan, Paola Neroni, C. Soddu, F. Lai et al.
• Year: 2025
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/fe5eb5262fab2ab82264ca8ad458a22532f47b3d
• DOI: 10.3390/genes16020212
• PMID: 40004541
• PMCID: 11855101
• Citations: 3
• Summary: This case underscores the clinical and genetic heterogeneity of HCM, highlighting the importance of considering genomic deletions involving key sarcomeric genes in the diagnostic evaluation.
• Evidence snippets:
• Snippet 1 (score: 0.403) > Segregation studies on dominant MYH6 and MYH7 mutations linked to congenital heart defects (CHDs) such as atrial septal defects have demonstrated variable penetrance, with several mutation carriers exhibiting no structural heart abnormalities [16,17,46]. Similarly, our study documents variable intra-familial expression, as the proband's father, carrying the same deletion, remains asymptomatic for HCM. According to current guidelines [31], and after excluding RASopathies, no additional molecular tests were performed in the absence of clinical signs suggesting more complex phenotypes. Several scientific works have investigated the clinical relevance of CNVs in HCM, but no cases similar to ours have been reported in these studies [15,47]. Notably, a recent report described a 5-month-old boy with an atrial septal defect and a deletion encompassing MYH6 exons 1-26 and MYH7 exons 28-40. This case highlights the potential pathogenic significance of such deletions, suggesting they may contribute to the development of cardiac phenotypes [48]. Furthermore, three similar deletions were identified on Decipher (available online: https://www.deciphergenomics.org/ (27 January 2025)). One of these, patient 289066, exhibited a comparable deletion and a diagnosis of cardiomyopathy. For the other two patients, no cardiological data was available. These findings emphasize the critical need to investigate the role of combined deletions in MYH6 and MYH7 in the context of HCM and related disorders. A major challenge in the field remains the incomplete understanding of how genetic variations in sarcomeric genes contribute to HCM pathogenesis. Comprehensive genetic testing is essential for the early identification of at-risk individuals, enabling timely intervention before clinical complications occur. Insights into the molecular mechanisms underlying HCM will lead to advances in treatment strategies, facilitate preventive measures, and enhance genetic counseling for affected families. We further highlight the necessity for ongoing research into the functional consequences of MYH6 and MYH7 deletions to improve our understanding of their role in the spectrum of cardiac diseases.

[9] Atrial ERK1/2 activation in the embryo leads to incomplete Septal closure: a novel mouse model of atrial Septal defect

• Authors: C. Yeh, Yanying Fan, Yi-lin Yang, M. Mann
• Year: 2017
• Venue: Journal of Biomedical Science
• URL: https://www.semanticscholar.org/paper/751d34cb7df9a9ac10408c1882a7d035d2b36a10
• DOI: 10.1186/s12929-017-0392-2
• PMID: 29178881
• PMCID: 5702213
• Citations: 4
• Summary: This new model of ASD suggests that enhanced atrial MEK1-ERK1/2 signaling during fetal development disrupts normal atrial septation, possibly regulated by the balance of ERK 1/2 phosphorylation.
• Evidence snippets:
• Snippet 1 (score: 0.403) > Atrial septal defects (ASD) are among the most common types of congenital heart disease (CHD), with an estimated incidence of 56-100 per 100,000 live births [1]. While mutations in GATA4, MYH6, NKX2-5 and TBX5 genes have been linked to the abnormal septation of atrial chambers, most patients with ASD are diagnosed without known etiologic causes [2][3][4][5]. However, the risk of a secundum defect is increased in siblings of ASD patients, suggesting that an inherited molecular mechanism may play a role in abnormal atrial septation. > The function of MEK1 signaling in the adult heart has been associated with "physiologic" hypertrophy [6]. Overexpression of active MEK1 induces hypertrophic changes in adult left ventricular (LV) structure that increase cardiac function and that do not degenerate into cardiomyopathy [6]. Increased MEK1 activity also protects hearts under stress conditions such as ischemiareperfusion and myocardial infarction [7,8]. In contrast to this positive influence of MEK1 activity in adult hearts, recent advances in the study of RASopathies have demonstrated a potentially detrimental role for Ras-Raf-MEK-ERK signaling during embryonic/fetal heart development [9]. RASopathies occur as a cluster of syndromes with germline mutations in genes participating in the Ras-Raf-MEK-ERK kinase signaling pathway. Independent of mutations and other syndromes, CHDincluding ASD -are common in RASopathies patients and are a major source of morbidity and even mortality [9]. Although mutations in human MEK1 genes have been identified in RASopathies, and the early application of a MEK1 inhibitor in animal models has been able to ameliorate associated defects [10][11][12][13], there is no direct evidence indicating how MEK1 may contribute to CHD.

[10] Recurrence of atrial septal defect in three generations.

• Authors: Celso Ferreira, L. Farah, Rui Póvoa, Fº BráulioLuna, A. D. Costa et al.
• Year: 1999
• Venue: Arquivos brasileiros de cardiologia
• URL: https://www.semanticscholar.org/paper/93749cae62f446e4f9aba1de7f87c02202cf6451
• DOI: 10.1590/S0066-782X1999000800009
• PMID: 10752190
• Citations: 3
• Summary: The familial occurrence of ASD by genetic mechanisms of transmission is reported, emphasizing the necessity for genetic-clinical studies in members of the familial nucleus in order to detect new carriers, who usually are asymptomatic, thereby allowing for early and adequate treatment of individuals who may be affected.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Beginning with a patient presenting with an atrial septal defect (ASD) of the secundum type, the genealogy was identified in four affected individuals who belonged to three successive generations of the same family. The defects were visually confirmed in all individuals and were found to be anatomically similar. No other congenital malformations were present in these individuals. The genealogy was identified in 1972, when ASD recurred in two generations, and it was concluded that the mechanism of transmission was autosomal recessive. The fifth individual, identified 21 years later, and having an anomaly identical to that of the others, was the child of a couple who had no consaguinity and whose mother was a member of the previously studied genealogy. Considering the absence of phenotype in the parents and the rarity of the ASD gene in the general population, the occurrence of the uniparental disomy for this family nucleus, and the same autosomal recessive mechanism of transmission by this affected individual is possible. This study reports the familial occurrence of ASD by genetic mechanisms of transmission, emphasizing the necessity for genetic-clinical studies in members of the familial nucleus in order to detect new carriers, who usually are asymptomatic, thereby allowing for early and adequate treatment of individuals who may be affected.
• Snippet 2 (score: 0.378) > Beginning with a patient presenting with an atrial septal defect (ASD) of the secundum type, the genealogy was identified in four affected individuals who belonged to three successive generations of the same family. The defects were visually confirmed in all individuals and were found to be anatomically similar. No other congenital malformations were present in these individuals. The genealogy was identified in 1972, when ASD recurred in two generations, and it was concluded that the mechanism of transmission was autosomal recessive. > The fifth individual, identified 21 years later, and having an anomaly identical to that of the others, was the child of a couple who had no consaguinity and whose mother was a member of the previously studied genealogy. > Considering the absence of phenotype in the parents and the rarity of the ASD gene in the general population, the occurrence of the uniparental disomy for this family nucleus, and the same autosomal recessive mechanism of transmission by this affected individual is possible. > This study reports the familial occurrence of ASD by genetic mechanisms of transmission, emphasizing the necessity for genetic-clinical studies in members of the familial nucleus in order to detect new carriers, who usually are asymptomatic, thereby allowing for early and adequate treatment of individuals who may be affected. > The incidence of congenital heart diseases varies depending on the use of different diagnostic methods by different authors. From 1946 to 1953, 6053 children, including stillborns and newborns weighing >500g, were seen at the Presbyterian Medical Center in New York. Fifty cases of congenital heart disease were present, which represents an overall incidence of 8.3 per 1000, varying from 7.7% in stillborns and those who died in the first month to 6 in 1000 among those living more than a month. 1 At our institution, Saldanha et al 2 found an incidence of 3.4% of malformations in general among children born alive in the Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil. The incidence of cardiac anomalies was 2.37 per 1000. Insley 3 reports an incidence of 6 in 1000 of those born alive.

[11] Right Atrial Myocardial Remodeling in Children With Atrial Septal Defect Involves Inflammation, Growth, Fibrosis, and Apoptosis

• Authors: H. Rouatbi, N. Farhat, R. Heying, A. Gérard, J. Vázquez-Jiménez et al.
• Year: 2020
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/c618d7de2c8e285be610bee6a983c417410e017d
• DOI: 10.3389/fped.2020.00040
• PMID: 32117843
• PMCID: 7033500
• Citations: 12
• Influential citations: 1
• Summary: In children with large ASD, macroscopic right atrial remodeling relates to cellular mechanisms involving the expression of numerous genes that either still act to protect cells and tissues but that also harm as they initiate and/or sustain inflammation, fibrosis, and cell death by apoptosis.
• Evidence snippets:
• Snippet 1 (score: 0.401) > Atrial septal defect (ASD) is a common congenital heart disease responsible for inter-atrial left-to-right shunt and for volume overload of the right cardiac cavities and their dilation. Hemodynamic overload initiates myocardial remodeling that comprises changes in tissue properties secondary to the activation of different signal cascades such as inflammatory-, growth-and death signaling pathways. Consecutive cardiomyocyte loss due to cell death or phenotype transformation in cardio-myofibroblasts ends up in myocardial fibrosis and finally in systolic and/or diastolic myocardial dysfunction. In patients with ASD, right atrial remodeling may elicit late supra-ventricular arrhythmias. > Mechanisms of myocardial remodeling are complex and have principally been studied in models of ischemic myocardial injury or pressure overload, in particular in systemic hypertension (1). In infants, mechanical stress related to pressure overload of the right ventricle leads to myocardial expression of proinflammatory cytokines mainly via the activation of p38MAPK signaling (2). Nevertheless, little information is available about the effect of volume overload on the pathophysiology of myocardial remodeling. > This study was therefore designed to investigate mRNA expression of genes coding for factors involved in mechanical stress (ANF), cell protection [c-Fos, Heat Shock Protein (HSP)-70, HSP-90], inflammation [Tumor necrosis factor (TNF)α, Interleukin (IL)-1β, IL-6, IL-10], growth and angiogenesis [Cardiotrophin (CT)-1, Hypoxia Inducing Factor (HIF)-1α, Vascular Endothelial Growth Factor (VEGF), Insulin-Like Growth Factor (IGF)-1], fibrosis of the extracellular matrix [Tissue Growth Factor (TGF)-β, the amino-terminal peptide of Type III procollagen PIIIP, Collagen III], and regulation of apoptosis (Fas Ligand, Bak, Bcl-xL

[12] Clinical and Echocardiographic Profile of Congenital Heart Diseases in the 0-12-Year Age Group in a Tertiary Care Medical Institute in Eastern India: A Retrospective, Cross-Sectional Study

• Authors: S. Kishore, Manish Kumar, Ajay Kumar, Anand Gupta, C. Chandan et al.
• Year: 2022
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/afd8132067795b3f247ef9dfa5fdf8a31637321a
• DOI: 10.7759/cureus.26114
• PMID: 35747105
• PMCID: 9208535
• Citations: 6
• Influential citations: 1
• Summary: Analyzing the symptoms of different CHDs, of both ACHDs and CCHDs, the common symptoms were fast breathing, which can help know the prevalence of CHDs in this region and will be useful for developing policies by stakeholders.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Congenital heart defect (CHD) is defined as an anatomic malformation of the heart or great vessels that occurs during intrauterine development, irrespective of the age at presentation and represents a major global health problem [1]. It remains the leading cause of death in children with malformations [2]. It is the most common congenital birth defect affecting 28% of all major congenital anomalies [1]. The global prevalence of CHD is eight per 1,000 live births [2]. In India, different studies have reported a prevalence between five and eleven per 1,000 live births [3][4][5]. CHDs are categorized as acyanotic congenital heart disease (ACHD) and cyanotic congenital heart disease (CCHD) according to the pathophysiology and the affected heart structure [6]. The acyanotic lesion consists of septal cardiac defects such as atrial septal defect (ASD), ventricular septal defect (VSD), and atrioventricular canal defects (AVSD). It also includes left ventricular outflow obstructive lesions such as aortic stenosis (AS) and coarctation of the aorta (COA). CCHD includes tetralogy of Fallot (TOF), transposition of great arteries (TGA), total anomalous pulmonary venous returns (TAPVC), hypoplastic left heart syndrome (HLHS), truncus arteriosus, and tricuspid atresia [6]. > Although CHD affects both males and females equally, some lesions such as COA, AS, transposition of great vessels, and TOF show a male preponderance whereas females report more ASD [7]. > The etiology of the majority of CHDs is not known. It is multifactorial and a combination of genetic predisposition and environmental stimulus play a major role [7]. CHD clinically presents according to the type and severity of the defect [8]. Among newborns, the common symptoms of CHD include fast breathing, bluish discoloration of the skin and mucosa, heart failure, and shock.

[13] Genome-wide linkage analysis of congenital heart defects using MOD score analysis identifies two novel loci

• Authors: A. Flaquer, C. Baumbach, Estefanía Piñero, F. García Algas, M. A. de la Fuente Sanchez et al.
• Year: 2013
• Venue: BMC Genetics
• URL: https://www.semanticscholar.org/paper/446839cd0ac91e8f0753152ec458ddd035457775
• DOI: 10.1186/1471-2156-14-44
• PMID: 23705960
• PMCID: 3664624
• Citations: 22
• Influential citations: 4
• Summary: A genome-wide linkage analysis using MOD score analysis in families with diverse CHD identified susceptibility loci for CHD in families affected by distinct defects, finding four candidate genes that have not been described in connection with CHD.
• Evidence snippets:
• Snippet 1 (score: 0.394) > Congenital heart defects (CHD) refer to abnormalities in the heart structure or function that arise at the fetal stages and affect approximately 1% of newborns [1]. Multiple surgeries are almost always required to correct many of the anatomical defects, and quality of life is often greatly compromised. There are many types of CHD. Examples include transposition of the great arteries/vessels (TGA/TGV), tetralogy of Fallot (TOF), double outlet right ventricle (DORV), atrial septal de-fects (ASD), ventricular septal defects (VSD), bicuspid aortic valve (BAV), and Ebstein's anomaly, among many others. > Normal heart development involves many regulatory pathways including receptor-ligand interactions (JAGGED/NOTCH, TGFB-BMP/TGFBR, VEGF/FLT1-FLK1, NODAL/ACVRA-ACVRB and RTK/RAS), signal transduction (kinases or phosphatases such as MAPK, ERK1/2, calcineurin, or GSK), and transcription factors that determine the expression of cardio-specific genes (protein families with a T-box domain TBX1, TBX5, and TBX20, the GATA family GATA4 and FOG2 or homeobox domain NKX2.5 and NKX2.6). Mutations that show a greater penetrance and that therefore approximate a monogenic inheritance are those affecting transcription factors or genes transcribed by them [2]. > Although the major underlying defects that cause CHD are thought to be mutations in regulators of heart development during embryogenesis, epidemiological data also indicate an environmental influence [2][3][4]. However, these epidemiological studies mostly suggest risk factors rather than underlying disease mechanisms. Genetic factors for some of the CHD include Mendelian mutations, copy number variants, translocations, and single nucleotide polymorphisms (SNPs) [5][6][7].

[14] Transcatheter Closure of Atrial Septal Defect: Does Age Matter?

• Authors: N. Kim, Su-Jin Park, J. Choi
• Year: 2011
• Venue: Korean Circulation Journal
• URL: https://www.semanticscholar.org/paper/bca54176f66432fc7ffc51eac45280c12859f58b
• DOI: 10.4070/kcj.2011.41.11.633
• PMID: 22194756
• PMCID: 3242016
• Citations: 27
• Summary: The basis for device closure in small children and elderly patients with ASD is reviewed and an overview of the frequently encountered problems is provided.
• Evidence snippets:
• Snippet 1 (score: 0.393) > Pathophysiology of untreated atrial septal defect in the elderly Elderly patients with hemodynamically significant ASD frequently experience complications with serious long-term adverse consequences such as pulmonary hypertension, atrial arrhythmia, and atrioventricular valve insufficiencies that essentially involve the tricuspid valve as well as right-sided heart failure secondary to chronic volume overload of the right side of the heart. 14) ][16] The pathophysiologic mechanism is summarized in Fig. 2. Longstanding left to right shunt in the atrial level results in progressive right heart dilatation, significant tricuspid insufficiency and subsequent increase in right atrial pressure. > Left heart may also be influenced by chronic volume underload, increased atrial pressure as well as co-morbid diseases such as systemic hypertension or coronary heart disease. Significant numbers of the patients are also affected by more advanced complications inherent to the end stage of this pathophysiologic cascade, including pulmonary hypertension, ventricular dysfunction and atrial arrhythmias which cause significant symptoms. In addition, diastolic compression of left ventricle (LV) by dilated right ventricle reduces LV end-diastolic volume in chronic setting, and this is responsible for so called "masked LV restriction" which may cause serious pulmonary edema secondary to LV dysfunction and left atrium (LA) pressure increase after ASD closure. 17) Because of the chronic nature of the disease, patients are usually adapted to the disabilities they have had and invasive interventions are occasionally refused by patients. Nevertheless, scarce evidence for survival benefit of anatomical closure and higher potential risk of definitive treatment in this group of patients may sometimes affect the decision to a more conservative one.

[15] Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES)

• Authors: Yong Liu, Yu Cao, Yaxiong Li, Dongyun Lei, Lin Li et al.
• Year: 2018
• Venue: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
• URL: https://www.semanticscholar.org/paper/b49c07d7de0f2e8127f3c90f6bb52158c13f125b
• DOI: 10.12659/MSM.908923
• PMID: 29505555
• PMCID: 5849354
• Citations: 10
• Influential citations: 2
• Summary: This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease-associated mutations.
• Evidence snippets:
• Snippet 1 (score: 0.388) > Atrial septal defect (ASD) is the most common subtype of congenital heart disease (CHD), and its prevalence can reach between 8.93-10.6 per 1,000 live births in China [1,2]. ASD can lead to several clinical complications, including infective endocarditis, chronic heart failure, and repeated lung infection, which can severely affect the physical and psychological health of affected patients [3]. The process of cardiac development is regulated by several genes and is precisely controlled; any disruption in cardiac development can cause congenital cardiac defects. Gene mutations have been shown to play important roles in the etiology and pathogenesis of ASD, including mutations in NKX2-5, GATA4, MYH6, and TBX5 [4,5]. However, some genetic variants associated with sporadic ASD remain to be identified. > Whole-exome sequencing (WES) is a powerful and efficient tool to obtain sequencing information on the whole exome with high resolution and low cost [6]. Due to the limitations in current knowledge of the genomic noncoding regions, many recent studies have only focussed on the identification of pathogenic mutations in protein coding regions by using WES [7]. The rapid development in the techniques used in WES has shed light on the complex mechanisms involved in several forms of CHD, including patent ductus arteriosus (PDA), familial ASD, and ventricular septal defect (VSD) [8]. However, few studies have studied the mutations associated with the etiology and pathogenesis of sporadic ASD. Therefore, there is a need to extend studies on the spectrum of ASD-related mutations using WES and to provide a foundation for further functional analysis, which may further clarify the gene associations, the pathogenesis, and possibly lead to new diagnostic markers for sporadic ASD. > The aim of this study was to use WES combined with bioinformatics analysis to identify novel gene variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing and a multiplexed MassARRAY system.

[16] Mechanisms of platypnea-orthodeoxia syndrome

• Authors: J. L. Salas-Pacheco
• Year: 2021
• Venue: Archivos de Cardiología de México
• URL: https://www.semanticscholar.org/paper/9f34dcdecc02c161400054f840725f3c7c6a1683
• DOI: 10.24875/ACM.21000171
• PMID: 34428199
• PMCID: 9005182
• Citations: 16
• Influential citations: 2
• Summary: Understanding the pathophysiology is the key for a rational diagnostic approach and subsequent diagnostic studies, and treatment is possible and effective in the majority of intracardiac mechanisms and some intrapulmonary mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.385) > POS is a complex clinical entity with relatively low prevalence. It is underdiagnosed in some clinical scenarios. At present, clinicians recognize POS more frequently, and the prevalence has risen in the last two decades. The pathophysiology is complex and involves intracardiac and intrapulmonary mechanisms. Multiple diseases with distinct anatomical or physiological alterations participate from common mechanisms and produce this clinical syndrome. Intracardiac POS is given by R-L blood shunt through atrial septal communications; some patients have increased RAP, whereas others with normal RAP have isolated or coexistent aortic, spinal or intracardiac alterations. Intrapulmonary POS is less frequent and is caused by parenchymal or vascular abnormalities. Once POS has been identified, a comprehensive and ordered diagnostic approach allows the correct characterization of the pathophysiological mechanism. Treatment modalities have a high success rate in POS from intracardiac or PAVM origin; however, only supportive treatment is warranted in other diseases. Understanding the mechanisms of this complex syndrome will guide the clinician towards a rational diagnostic approach and offer some patients a curative treatment option.

[17] Atrial Cardiomyopathy in Valvular Heart Disease: From Molecular Biology to Clinical Perspectives

• Authors: A. Molnár, Attila Sánta, D. Pásztor, B. Merkely
• Year: 2023
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/3725c957a487d59f9745c1a368320569f307a656
• DOI: 10.3390/cells12131796
• PMID: 37443830
• PMCID: 10340254
• Citations: 25
• Summary: This review discusses the evolving topic of atrial cardiomyopathy concerning valvular heart disease and reveals that both left atrial volumes and functional parameters are independent predictors of cardiovascular events inValvular disease.
• Evidence snippets:
• Snippet 1 (score: 0.382) > In conclusion, atrial cardiomyopathy has been defined as structural, functional, or electrophysiological atrial changes with potential clinical manifestations [7]. Clinical data, such as serum biomarkers, ECG, and conventional and advanced imaging techniques, can provide information on the diagnosis, and the anatomical and functional features of atria and valves, as well as provide prognostic information for valvular heart disease [6]. These features of atrial cardiomyopathy may vary depending on the type and severity of valvular disease, representing different hemodynamic loads on the atria [2]. Some pathophysiological steps in atrial cardiomyopathy have already been explored, including cellular, molecular, neurohormonal, and biomechanical adaptive responses to valvular disease [5]. Previous histopathological studies have revealed atrial fibrosis in the background of atrial cardiomyopathy. Furthermore, the amount of atrial fibrosis may correlate with atrial function. Increasing evidence suggests that left atrial function, defined by speckle tracking echocardiography-derived strain parameters, can provide important prognostic information in valvular diseases. In addition, atrial dysfunction may precede atrial enlargement and predict the development of atrial fibrillation and the risk of major adverse cardiovascular events. However, questions about atrial cardiomyopathy still remain unanswered in both bedside and bench-side research. Besides the known interactions between atrial cardiomyopathy and valvular heart disease, a more-in-depth cellular and clinical characterization of atrial cardiomyopathy is lacking. There is a paucity of histopathological and molecular biological data on the different stages of atrial cardiomyopathy. Moreover, a deeper pathophysiological understanding and biological approach would help in developing new drug innovations to delay disease progression. From a clinical perspective, the most important question is the usefulness of atrial measurements in clinical decisionmaking. It is essential to select the most appropriate atrial markers to detect the different stages of atrial cardiomyopathy and to define prognostic cut-off points in order to apply them in clinically meaningful management strategies.

[18] Mechanical regulation of cardiac development

• Authors: Stephanie E. Lindsey, J. Butcher, H. Yalcin
• Year: 2014
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/66b19bf607af760ec6f99177594e259cadd4ff59
• DOI: 10.3389/fphys.2014.00318
• PMID: 25191277
• PMCID: 4140306
• Citations: 155
• Influential citations: 5
• Summary: Current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development are summarized in this review.
• Evidence snippets:
• Snippet 1 (score: 0.381) > The heart is the first functional organ to develop in the embryo, convecting nutrients to surrounding tissues to facilitate growth. As the embryo grows, the heart transforms from a linear valveless tube to a multi-chambered structure complete with 4 fibrous valves (Srivastava and Olson, 2000; Bartman and Hove, 2005). Changes in pressure, strain and wall shear stress (WSS) accompany cardiac morphogenesis and orchestrate molecular and cellular responses that help coordinate downstream tissue changes. Congenital heart defects (CHDs) form when cardiac morphogenetic processes are disrupted. CHDs affect 1-2% of newborn children and are the leading cause of death in infants under 1 year of age. CHDs represent the single largest class of birth defects and account for approximately 25% of all human congenital abnormalities (Roger et al., 2011). Despite their prevalence, the etiology of many CHDs remains unknown. While clinical and experimental research has identified multiple genetic mutations that participate in the formation of CHDs, they fail to fully account for the disease phenotype. Extreme locus heterogeneity and lack of a distinct genotype-phenotype correlation have limited causative gene discovery (Yuan et al., 2013). Recent insights into the molecular mechanisms of heart development have shown that a given structural CHD is often linked to multiple loci. A variety of phenotypes is often observed in families with a specific gene mutation (Nemer, 2008). Family members with the same mutation may present with an atrial septal defect, tetralogy of fallot, or ventricular septal defect (Bruneau, 2008). Conversely, mutations in different genes may cause an identical malformation (Fahed et al., 2013). Zaidi and colleagues recently identified new point mutations in hundreds of genes that together may contribute to only approximately 10% of CHDs (Zaidi et al., 2013). Oyen et al. determined the risk of an infant presenting with a CHD in families with prior history of CHDs was only 2-4%, suggesting CHDs largely occur in families without history of disease (Oyen et al., 2009).

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.