Atrial Septal Defect

Congenital Cardiovascular Disorder MONDO:0006664 Pathograph 22 Show in embeddings browser Heart Disorder

Atrial septal defect is a congenital cardiovascular disorder in which a deficiency or interatrial communication permits abnormal flow between the left and right atria. The dominant physiology is usually left-to-right shunting with right-sided volume overload; untreated significant defects can lead to exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction, and pulmonary arterial hypertension.

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4
Pathophys.
11
Phenotypes
4
Gaps
22
Pathograph
4
Genes
4
Medical Actions
4
Subtypes
3
Differentials
1
Datasets
4
Trials
2
References
1
Deep Research
◆

Subtypes

4
Ostium secundum ASD
Defect centered in the oval fossa region; this is the subtype most often considered for transcatheter device closure when rims and size are suitable.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"Secundum atrial septal defect (ASDII) is a common congenital heart defect that causes shunting of blood between the systemic and pulmonary circulations."
The review defines secundum ASD as a common congenital heart defect and supports this subtype as a central ASD classification.
Ostium primum interatrial communication
Inferior interatrial communication associated morphologically with the atrioventricular septal defect spectrum rather than an isolated oval-fossa deficiency.
Show evidence (1 reference)
PMID:22368625 SUPPORT Human Clinical
"Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
The morphologic review names ostium primum as a less frequent interatrial communication included in the ASD clinical spectrum.
Sinus venosus interatrial communication
Superior or inferior caval-region interatrial communication, often discussed separately from true oval-fossa septal defects because the communication is outside the confines of the true atrial septum.
Show evidence (1 reference)
PMID:22368625 SUPPORT Human Clinical
"Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
The morphologic review explicitly names superior and inferior sinus venosus defects among less common interatrial communications.
Coronary sinus interatrial communication
Communication involving the coronary sinus region, clinically grouped with ASD-like interatrial communications but morphologically outside the true oval-fossa septum.
Show evidence (1 reference)
PMID:22368625 SUPPORT Human Clinical
"Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
The morphologic review explicitly lists coronary sinus defect as a less common interatrial communication in this spectrum.
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Discussions and Knowledge Gaps

4
Which patients with ASD and elevated pulmonary vascular resistance benefit from pulmonary-arterial-hypertension therapy followed by closure, and which are harmed by eliminating a pressure-relieving interatrial communication?
KNOWLEDGE GAP OPEN asd-pah-closure-thresholds
Attached to
pathophysiology#Pulmonary Vascular and Ventricular Complications treatments#Transcatheter closure of secundum ASD
This decision separates potentially reversible shunt-associated pulmonary hypertension from severe irreversible disease and Eisenmenger physiology. Existing observational studies use heterogeneous pulmonary-hypertension definitions, so a single pressure estimate is not an adequate closure rule.
Show evidence (2 references)
PMID:33328279 SUPPORT Human Clinical
"Studies applied variable PH definitions."
Heterogeneous definitions limit direct comparison and threshold inference across closure cohorts.
PMID:33328279 SUPPORT Human Clinical
"Larger, prospective studies with consistent PH definitions using the recommended measurement modality are warranted."
The meta-analysis explicitly calls for prospective, consistently measured studies to resolve this management gap.
What surveillance schedule and rhythm strategy best prevent or detect late pulmonary hypertension, atrial arrhythmia, and device-related complications after ASD closure?
KNOWLEDGE GAP OPEN asd-postclosure-surveillance-and-arrhythmia
Attached to
pathophysiology#Atrial Electrical Remodeling treatments#Transcatheter closure of secundum ASD
Closure reduces shunt load but does not erase pre-existing atrial remodeling, and follow-up intensity varies with age at closure, residual lesions, pulmonary pressure, and rhythm history.
Show evidence (2 references)
PMID:30305954 SUPPORT Human Clinical
"Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population."
Persistent excess rhythm risk after closure motivates surveillance and prevention research.
PMID:25884091 SUPPORT Human Clinical
"However, consensus regarding frequency and duration of follow-up after device closure is lacking."
The review explicitly identifies uncertainty about post-device follow-up.
What fraction of apparently isolated ASD is explained by rare Mendelian variants, polygenic susceptibility, or regulatory variation, and how should penetrance and extracardiac risk be incorporated into family counseling?
KNOWLEDGE GAP OPEN asd-genetic-architecture
Attached to
pathophysiology#Abnormal Atrial Septation genetic#NKX2-5 genetic#GATA4 genetic#TBX5 genetic#MYH6
A few stable gene associations explain rare families or syndromic disease, but most secundum ASD is sporadic and a negative current panel cannot exclude a genetic contribution.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"most secundum ASDs occur sporadically"
This directly supports the gap between rare familial genes and the much larger sporadic population.
PMID:38884726 SUPPORT Human Clinical
"Currently, it points to different pathways and gene networks relevant to the dysregulation of cardiomyogenesis and ASD pathogenesis."
The current review supports a heterogeneous network architecture rather than one dominant ASD gene.
For anatomically suitable sinus venosus defects, when does covered-stent correction provide durable efficacy and safety comparable with surgical redirection of anomalous pulmonary venous return?
KNOWLEDGE GAP OPEN asd-sinus-venosus-transcatheter-repair
Attached to
has_subtypes#Sinus venosus
Covered-stent correction is emerging, but dedicated comparative evidence and long-term data remain limited; anatomy also constrains feasibility.
Show evidence (2 references)
clinicaltrials:NCT05865119 SUPPORT Human Clinical
"Preliminary results are limited but promising."
The trial background directly states that existing results remain limited.
clinicaltrials:NCT05865119 SUPPORT Human Clinical
"The objective of this project is to study the feasibility, efficacy and safety of the Optimus stent in this newly developed transcatheter procedure, in comparison with the gold-standard surgical method."
The active comparative study is directly targeted at resolving this gap.
⚙

Pathophysiology

4
Abnormal Atrial Septation
ASD originates from abnormal formation or deficiency of the interatrial septum or from anatomically related interatrial communications. True septal defects are confined to the oval fossa region, while primum, sinus venosus, and coronary sinus communications have distinct morphologic origins but share atrial-level mixing physiology.
endocardial cell CL:0002350 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cell (CL:0002350). CL:0002350 is a cell type from the Cell Ontology.
NKX2-5 hgnc:2488 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NKX2-5 (hgnc:2488). hgnc:2488 is a gene from the HUGO Gene Nomenclature Committee. GATA4 hgnc:4173 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATA4 (hgnc:4173). hgnc:4173 is a gene from the HUGO Gene Nomenclature Committee. TBX5 hgnc:11604 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBX5 (hgnc:11604). hgnc:11604 is a gene from the HUGO Gene Nomenclature Committee. MYH6 hgnc:7576 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH6 (hgnc:7576). hgnc:7576 is a gene from the HUGO Gene Nomenclature Committee.
atrial septum morphogenesis GO:0060413 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal atrial septum morphogenesis (GO:0060413). GO:0060413 is a biological process from the Gene Ontology. ⚠ ABNORMAL heart development GO:0007507 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart development (GO:0007507). GO:0007507 is a biological process from the Gene Ontology. ⚠ ABNORMAL
interatrial septum UBERON:0002085 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interatrial septum (UBERON:0002085). UBERON:0002085 is an anatomical location from the Uberon multi-species anatomy ontology. cardiac atrium UBERON:0002081 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac atrium (UBERON:0002081). UBERON:0002081 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Left-to-Right Shunting and Right Heart Volume Overload The interatrial communication permits shunting between systemic and pulmonary venous circulations, usually from left to right when pulmonary vascular resistance is not elevated.
Paradoxical embolism An interatrial communication can permit venous thrombus to enter the systemic circulation when the pressure gradient transiently or persistently reverses.
Atrial septal defect Abnormal atrial septation produces the structural atrial septal defect phenotype.
Show evidence (3 references)
PMID:22368625 SUPPORT Human Clinical
"True atrial septal defects are limited to deficiencies totally within the confines of the oval fossa and its antero-inferior rim."
This anatomic review grounds true ASD in a deficiency of atrial septal tissue within the oval fossa region.
PMID:22368625 SUPPORT Human Clinical
"The unifying physiological feature of all these variants, whether their morphology is that of a defect within the area of the oval fossa, or an opening elsewhere within the atrium, is that mixing of the systemic and pulmonary blood occurs at atrial level."
The review supports modeling ASD and related interatrial communications as atrial-level mixing lesions.
PMID:15735645 SUPPORT Model Organism
"Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation."
This developmental perturbation links a validated familial ASD gene to atrial-septum formation rather than only to a statistical association.
Left-to-Right Shunting and Right Heart Volume Overload
In most unrepaired ASDs, greater left-sided filling pressure and right ventricular compliance drive left-to-right atrial shunting. The resulting pulmonary overcirculation enlarges right-sided chambers and can produce long-standing volume-overload complications.
cardiac atrium UBERON:0002081 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac atrium (UBERON:0002081). UBERON:0002081 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pulmonary Vascular and Ventricular Complications Persistent volume overload can progress to pulmonary arterial hypertension and ventricular dysfunction, especially when defects are diagnosed late.
Atrial Electrical Remodeling Chronic atrial and right-heart volume load promotes electrical remodeling that predisposes to atrial tachyarrhythmias.
Left-to-right shunt The atrial communication usually permits left-to-right shunting.
Right ventricular dilatation Left-to-right shunting produces right-sided volume overload and dilation of right heart structures.
Right atrial enlargement Chronic atrial-level left-to-right shunting enlarges the right atrium as part of the right-heart volume-overload phenotype.
Fixed splitting of the second heart sound The hemodynamically significant shunt produces the characteristic wide, fixed split second heart sound on examination.
Show evidence (2 references)
PMID:30305948 SUPPORT Human Clinical
"Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
This review directly supports left-to-right shunting and right-heart dilation as the typical pediatric ASD hemodynamic pattern.
PMID:30305954 SUPPORT Human Clinical
"ASDs have left-to-right shunt and primarily right-sided volume overload."
This review concisely states the core hemodynamic mechanism linking ASD to right-sided volume overload.
Pulmonary Vascular and Ventricular Complications
Long-standing unrepaired ASD can produce pulmonary artery hypertension and right or left ventricular dysfunction. These complications are more typical in adults diagnosed late and influence whether closure is safe.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Exercise intolerance Long-standing unrepaired ASD can reduce exercise tolerance as pulmonary and ventricular complications accumulate with age.
Right ventricular dysfunction Chronic right-heart volume overload can progress from dilation to right ventricular dysfunction.
Pulmonary arterial hypertension Persistent pulmonary overcirculation and volume overload can progress to pulmonary arterial hypertension.
Right ventricular failure Advanced right-heart volume and pressure load can culminate in clinical right ventricular failure.
Show evidence (1 reference)
PMID:30305948 SUPPORT Human Clinical
"Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction."
The hemodynamic review links late-diagnosed ASD to pulmonary vascular and ventricular dysfunction complications.
Atrial Electrical Remodeling
Right-sided volume overload and atrial chamber enlargement alter atrial electrophysiology, raising the risk of supraventricular tachyarrhythmias and some conduction disorders, particularly with large shunts or late repair.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Supraventricular arrhythmia ASD-related electrical remodeling predisposes to supraventricular tachyarrhythmias.
Show evidence (2 references)
PMID:30305954 SUPPORT Human Clinical
"This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders."
The arrhythmia review supports the causal link from ASD-related overload to electrical remodeling and atrial tachyarrhythmias.
PMID:30305954 SUPPORT Human Clinical
"Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions."
This supports the clinical modifiers that increase rhythm risk in ASD.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Atrial Septal Defect Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 3
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22368625 SUPPORT Human Clinical
"True atrial septal defects are limited to deficiencies totally within the confines of the oval fossa and its antero-inferior rim."
This supports the core structural phenotype captured by the HPO term.
Right ventricular dilatation HP:0005133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right ventricular dilatation (HP:0005133). HP:0005133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30305948 SUPPORT Human Clinical
"Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
The cited review supports right-heart dilation as a typical hemodynamic finding; the HPO term captures the right ventricular component.
Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
The adult ASD review identifies pulmonary arterial hypertension as an untreated ASD complication.
PMID:30305948 SUPPORT Human Clinical
"Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction."
The hemodynamic review supports pulmonary artery hypertension after long-standing volume overload.
Constitutional 1
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
The adult ASD review lists exercise intolerance as an age-increasing complication of untreated ASD.
Other 7
Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30305948 SUPPORT Human Clinical
"Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
The hemodynamic review directly supports left-to-right shunting in ASD.
Right ventricular dysfunction Abnormal right ventricular function HP:0033118 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal right ventricular function (HP:0033118). HP:0033118 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
The adult ASD review explicitly names right ventricular dysfunction as an age-increasing complication of untreated ASD; HP:0033118 captures abnormal right-ventricular function without conflating it with established failure.
Supraventricular arrhythmia HP:0005115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supraventricular arrhythmia (HP:0005115). HP:0005115 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
The adult ASD review supports supraventricular arrhythmia as an age-related untreated ASD complication.
PMID:30305954 SUPPORT Human Clinical
"This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders."
The arrhythmia review provides a mechanism for atrial tachyarrhythmias in ASD.
Right atrial enlargement HP:0030718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right atrial enlargement (HP:0030718). HP:0030718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30305948 SUPPORT Human Clinical
"Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
The cited review supports dilation of right-heart structures as a typical ASD finding; this term captures the atrial component.
Fixed splitting of the second heart sound HP:0031662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fixed splitting of the second heart sound (HP:0031662). HP:0031662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"Key findings of RV volume overload are RV heave, wide and fixed splitting of the second heart sound and a systolic pulmonary flow murmur."
The review directly identifies fixed S2 splitting as a physical sign of ASD-related right-ventricular volume overload.
Right ventricular failure HP:0001708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right ventricular failure (HP:0001708). HP:0001708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34535989 SUPPORT Human Clinical
"time-related complications primarily arrhythmias, thromboembolism, right heart failure and, in a subset of patients, pulmonary arterial hypertension (PAH)."
The review directly supports right-sided heart failure as an advanced ASD complication.
Paradoxical embolism HP:0033520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paradoxical embolism (HP:0033520). HP:0033520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"a suspected paradoxical systemic thromboembolism initially raises the suspicion of an ASDII being present"
The review directly supports paradoxical embolism as an occasional ASD presentation.
🧬

Genetic Associations

4
NKX2-5 (Rare familial atrial septal defect and conduction disease gene)
Gene: NKX2-5 hgnc:2488 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NKX2-5 (hgnc:2488). hgnc:2488 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:20932824 SUPPORT Human Clinical
"Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
This family study supports NKX2-5 as a rare familial ASD gene with associated conduction and cardiomyopathy phenotypes.
PMID:20932824 SUPPORT In Vitro
"Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5."
Functional cell-assay evidence supports loss of NKX2-5 transcriptional activity as a plausible mechanism for the familial phenotype.
GATA4 (Rare familial atrial septal defect gene)
Gene: GATA4 hgnc:4173 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GATA4 (hgnc:4173). hgnc:4173 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:20659440 SUPPORT Human Clinical
"T280M mutation of GATA4 is suggested to be associated with ASD in this Chinese family."
The family segregation study supports GATA4 as a rare familial ASD gene.
TBX5 (Rare syndromic atrial septal defect gene in Holt-Oram syndrome)
Gene: TBX5 hgnc:11604 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TBX5 (hgnc:11604). hgnc:11604 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:30552424 SUPPORT Human Clinical
"A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%)."
This molecular series supports TBX5 as a rare syndromic ASD-associated gene in Holt-Oram syndrome.
MYH6 (Rare autosomal-dominant familial atrial septal defect gene)
Gene: MYH6 hgnc:7576 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH6 (hgnc:7576). hgnc:7576 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:15735645 SUPPORT Human Clinical
"We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect."
The linkage and segregation evidence supports a rare dominantly inherited MYH6-associated ASD mechanism.
PMID:15735645 SUPPORT Model Organism
"Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation."
The developmental perturbation provides functional support for abnormal atrial septation downstream of MYH6 loss.
💊

Medical Actions

4
Conservative surveillance for a hemodynamically insignificant ASD
Category: Monitoring Action: clinical monitoringNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical monitoring, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Small defects without right-heart enlargement or another accepted closure indication are observed clinically and with periodic echocardiography. Surveillance is individualized rather than treating every anatomical communication as an indication for repair.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"insignificant ASDs do not require closure. Such patients should be followed conservatively"
The review directly supports conservative surveillance when a defect is hemodynamically insignificant.
Transcatheter closure of secundum ASD
Category: Therapeutic Action: transcatheter atrial septal defect closureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is transcatheter atrial septal defect closure, annotated with Septal Defect Repair (NCIT:C148075). NCIT:C148075 is a clinical intervention from the NCI Thesaurus. Ontology label: Septal Defect Repair NCIT:C148075
Device closure is generally preferred for hemodynamically significant secundum ASD when defect size, rims, and pulmonary vascular status are suitable. Severe irreversible pulmonary vascular disease or Eisenmenger physiology is a contraindication; uncertain pulmonary vascular or left ventricular physiology requires specialist invasive assessment before closure.
Mechanism Target:
INHIBITS Left-to-Right Shunting and Right Heart Volume Overload — Device occlusion terminates the atrial-level shunt and unloads the right heart when closure is physiologically appropriate.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"ASDII results in right-sided volume unloading"
The review directly supports right-heart unloading after closure.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"Transcatheter and surgical techniques both provide valid options for ASDII closure, the former being the preferred method."
This review supports transcatheter closure as the preferred closure method for suitable secundum ASD.
PMID:15350172 SUPPORT Human Clinical
"A major reason for this is the lower morbidity of transcatheter closure procedures."
This treatment review explains why transcatheter closure became preferred for many secundum ASDs.
Surgical ASD repair
Category: Therapeutic Action: surgical atrial septal defect repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical atrial septal defect repair, annotated with Septal Defect Repair (NCIT:C148075). NCIT:C148075 is a clinical intervention from the NCI Thesaurus. Ontology label: Septal Defect Repair NCIT:C148075
Surgical repair remains a valid closure strategy, especially when anatomy is unsuitable for device closure or when the defect is primum, sinus venosus, or coronary sinus type.
Mechanism Target:
INHIBITS Left-to-Right Shunting and Right Heart Volume Overload — Surgical closure terminates the interatrial shunt when device closure is anatomically unsuitable or when associated anatomy requires repair.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"Pericardial or synthetic patch closure is preferred over a direct suture, and generally completely terminates the shunt."
The review directly supports surgical patch closure as a means of terminating the interatrial shunt.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"Transcatheter and surgical techniques both provide valid options for ASDII closure, the former being the preferred method."
The review supports surgery as a valid ASDII closure option, while noting that transcatheter closure is preferred when suitable.
PMID:25884091 SUPPORT Human Clinical
"With the exception of those with severe and irreversible PAH, closure is beneficial to, and thus indicated in all patients with significant shunts, regardless of age and symptoms."
This supports closure of significant shunts and the pulmonary vascular contraindication that guides either surgical or transcatheter repair.
Atrial tachyarrhythmia management
Category: Therapeutic Action: cardiac ablationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac ablation (NCIT:C100068). NCIT:C100068 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Ablation NCIT:C100068
Established atrial tachyarrhythmias require rhythm-specific medical or procedural management. In selected patients, ablation before or at closure can be considered because defect closure alone does not reliably eliminate an established arrhythmogenic substrate.
Mechanism Target:
MODULATES Atrial Electrical Remodeling — Ablation interrupts the re-entrant or focal electrical circuits that manifest on the substrate of ASD-related atrial remodeling.
Show evidence (1 reference)
PMID:34535989 SUPPORT Human Clinical
"Atrial septal defects call for tertiary expertise where all options may be considered, namely catheter vs. surgical closure, consideration of pre-closure ablation for patients with atrial tachycardia and suitability for closure or/and targeted therapy for patients with PAH."
The adult ASD review explicitly supports considering pre-closure ablation in patients with atrial tachycardia.
Target Phenotypes: Supraventricular arrhythmia HP:0005115 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Supraventricular arrhythmia (HP:0005115). HP:0005115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30305954 SUPPORT Human Clinical
"Medical and procedural therapy for arrhythmias should consider type and timing of ASD repair."
The arrhythmia review supports individualized medical and procedural rhythm management in relation to ASD anatomy and repair timing.
🔬

Diagnosis

4
Transthoracic echocardiography
Transthoracic echocardiography is the primary diagnostic study for defining an atrial-level communication and assessing shunt direction, right-heart volume load, ventricular function, and estimated pulmonary pressure.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Results: Demonstrates interatrial communication, shunt direction, right-heart dilation, and estimates of pulmonary pressure.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"Transthoracic echocardiography (TTE) is the primary imaging modality for the diagnosis of an ASDII"
The review directly establishes TTE as the primary imaging study for diagnosis and hemodynamic assessment.
PMID:30305948 SUPPORT Human Clinical
"In most cases, hemodynamics can be estimated with echocardiography only."
The hemodynamic review supports echocardiography as the usual method for estimating ASD physiology.
Transesophageal and cross-sectional cardiac imaging
TEE defines defect size and rims for device planning. Cardiac MRI clarifies morphology and quantifies ventricular volumes and function; cardiac CT is an alternative when MRI is contraindicated and is particularly useful for associated pulmonary venous anatomy.
cardiac MRI NCIT:C137915 NCI Thesaurus (NCIT)
Results: Defines the communication, septal rims, relation to valves and veins, associated pulmonary venous connections, and ventricular size and function.
Show evidence (3 references)
PMID:25884091 SUPPORT Human Clinical
"echocardiography (TEE) is required for determining the feasibility of transcatheter closure"
The review supports TEE for detailed device-closure anatomy and feasibility assessment.
PMID:25884091 SUPPORT Human Clinical
"Cardiac magnetic resonance imaging (MRI) can help clarify the morphology of the defect"
This supports CMR for anatomy and quantitative ventricular assessment.
PMID:25884091 SUPPORT Human Clinical
"Cardiac computed tomography (CT) provides an alternative in patients with contraindications to MRI"
The review supports cardiac CT as an alternative cross-sectional modality.
Invasive hemodynamic assessment when pulmonary hypertension is suspected
Cardiac catheterization is not routine for uncomplicated ASD. It is used to measure pulmonary vascular resistance and, when needed, test occlusion or vasoreactivity when pulmonary hypertension, ventricular dysfunction, or closure tolerability is uncertain.
cardiac catheterization NCIT:C38044 NCI Thesaurus (NCIT)
Results: Directly measures pulmonary and systemic pressures, flow ratio, pulmonary vascular resistance, and hemodynamic response to temporary occlusion.
Show evidence (2 references)
PMID:30305948 SUPPORT Human Clinical
"Diagnostic catheterization is usually not indicated unless there is suggestion of pulmonary hypertension on echocardiography."
The review supports selective rather than routine invasive hemodynamic assessment.
PMID:30305948 SUPPORT Human Clinical
"In older patients and/or in those with ventricular dysfunction, measurement of left heart pressures during temporary balloon occlusion is recommended prior to device closure as it may not be tolerated."
This supports temporary occlusion testing in patients at risk of adverse filling-pressure changes after closure.
Selective genetic evaluation
Genetic evaluation is most relevant when ASD is familial, accompanied by conduction disease, or associated with extracardiac or syndromic features. A negative panel does not exclude ASD because most cases are not explained by a single established Mendelian gene.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: May identify a rare familial or syndromic etiology such as NKX2-5-, GATA4-, TBX5-, or MYH6-associated disease and inform counseling and family testing.
Show evidence (1 reference)
PMID:38884726 SUPPORT Human Clinical
"Although atrial septal defects (ASD) can be subdivided based on their anatomical location, an essential aspect of human genetics and genetic counseling is distinguishing between isolated and familiar cases without extracardiac features and syndromic cases with the co-occurrence of extracardiac..."
The current human-genetics review supports selective etiologic evaluation framed around familial, isolated, and syndromic presentations.
📈

Progression

5
Often asymptomatic childhood and adolescence
Age: Childhood through adolescence
An isolated secundum ASD may be clinically silent despite an established left-to-right shunt. This phase is not universal and does not imply that the shunt is hemodynamically insignificant.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"Patients with an isolated ASDII often remain asymptomatic during childhood and adolescence."
The review directly supports an often-asymptomatic pediatric course for isolated secundum ASD.
Adult symptomatic presentation
Age: Commonly from the third or fourth decade
Exercise intolerance, fatigue, or a supraventricular tachyarrhythmia may be the first recognized manifestation. Timing varies with defect size, ventricular compliance, pulmonary vascular disease, and associated lesions.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"However, most will become symptomatic from the third or fourth decade, and life expectancy is reduced overall."
The review directly describes the typical timing of symptomatic adult presentation in untreated isolated secundum ASD.
Right-heart failure in advanced volume overload
Persistent hemodynamically important shunting can progress from right-sided chamber dilation to ventricular dysfunction and right-sided heart failure.
Show evidence (1 reference)
PMID:34535989 SUPPORT Human Clinical
"time-related complications primarily arrhythmias, thromboembolism, right heart failure and, in a subset of patients, pulmonary arterial hypertension (PAH)."
This adult ASD review directly includes right-heart failure among time-related complications.
Pulmonary vascular disease and Eisenmenger physiology
A minority develop severe pulmonary arterial hypertension and eventual right-to-left shunt reversal. This is not an inevitable sequence and must be distinguished from the much more common right-heart volume-overload course.
Show evidence (1 reference)
PMID:25884091 SUPPORT Human Clinical
"Severe PAH, with possible progression to Eisenmenger physiology, ensues in a minority of patients."
The review explicitly limits Eisenmenger progression to a minority of patients.
Post-closure residual risk
Closure unloads the right heart but does not erase established pulmonary vascular disease or atrial electrical remodeling. Risk is greatest with pre-existing pulmonary hypertension, dysrhythmia, or later repair, so surveillance remains individualized.
Show evidence (1 reference)
PMID:30305954 SUPPORT Human Clinical
"Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population."
Persistent excess arrhythmia risk after closure directly supports a post-closure residual-risk phase and ongoing individualized surveillance.
📊

Prevalence

1
Live births
Birth Prevalence 160.0 per 100,000 >1 in 1,000
A commonly cited estimate is 1.6 per 1,000 live births (160 per 100,000). This is an ascertainment-sensitive estimate rather than a universal rate: improved postnatal detection of mild congenital lesions, including ASD, has materially increased reported prevalence over time.
Show evidence (2 references)
PMID:25884091 SUPPORT Human Clinical
"Atrial septal defect (ASD) is a common congenital heart defect, with an estimated birth prevalence of 1.6 per 1000 live births"
The review provides the numeric birth-prevalence estimate, normalized here to a rate per 100,000 live births.
PMID:30783674 SUPPORT Human Clinical
"The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions."
This meta-analysis supports the explicit ascertainment caveat for the reported ASD birth prevalence.
⚖️

Clinical Burden

Variable
Small, hemodynamically insignificant defects may impose little functional burden, whereas persistent significant shunts can require catheter or surgical repair and lifelong congenital-cardiology follow-up and can lead to arrhythmia, thromboembolism, right-heart failure, or pulmonary arterial hypertension. The broad ASD/interatrial-communication umbrella therefore cannot be represented honestly by one low, moderate, or high tier.
Show evidence (1 reference)
PMID:34535989 SUPPORT Human Clinical
"Although considered a simple defect, challenges in optimal diagnostic and treatment options still exist due to great heterogeneity in terms of anatomy and time-related complications primarily arrhythmias, thromboembolism, right heart failure and, in a subset of patients, pulmonary arterial..."
The review directly supports variable burden across anatomy and time and identifies the principal sources of serious morbidity.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Atrial Septal Defect:

Patent foramen ovale
Overlapping Features PFO is persistence of the fetal foramen-ovale flap communication rather than deficiency of atrial septal tissue. Saline contrast with a provocation that transiently raises right-atrial pressure and detailed septal imaging help distinguish its dynamic right-to-left passage from a hemodynamically significant secundum ASD.
Show evidence (3 references)
PMID:35225286 SUPPORT Human Clinical
"The accuracy of PFO detection can be improved by using agitated saline together with maneuvers to transiently increase the right atrial (RA) pressure."
This imaging review supports the provoked contrast-echocardiographic behavior that helps distinguish PFO from a persistent volume-loading ASD.
PMID:35225286 SUPPORT Human Clinical
"Three dimensional TEE identifies further septal fenestrations and describes the dynamic morphology of ASD/PFO and atrial septal aneurysm."
The review supports detailed TEE assessment of the distinct dynamic morphologies of ASD and PFO.
PMID:31424787 SUPPORT Human Clinical
"Higher pressure in the left atrium resulting from increased pulmonary venous flow from the lungs causes the septum primum of the interatrial septum to close the opening."
This embryologic description supports PFO as persistence of the fetal flap-valve communication rather than an oval-fossa tissue deficiency.
Atrioventricular septal defect
Overlapping Features An ostium-primum interatrial communication belongs morphologically to the atrioventricular septal defect spectrum because it occurs with a common atrioventricular junction. It must not be managed as an isolated oval-fossa secundum ASD even though both produce atrial-level shunting.
Show evidence (1 reference)
PMID:22368625 SUPPORT Human Clinical
"The ostium primum defect, for example, has all the characteristics of an atrioventricular septal defect, existing only in the setting of a common atrioventricular junction."
The morphology review directly establishes the primum-to-AVSD boundary.
Congenital partial pulmonary venous return anomaly
Overlapping Features Partial anomalous pulmonary venous return can accompany a superior sinus venosus communication and adds its own right-heart volume load. Pulmonary venous connections therefore must be mapped rather than assuming an isolated oval-fossa ASD.
Show evidence (1 reference)
clinicaltrials:NCT05865119 SUPPORT Human Clinical
"Sinus venosus defect (SVD) accounts for 10% of atrial septal defects and is characterized by an anomalous pulmonary venous return in the superior vena cava associated with a high situated atrial septal defect."
The trial background directly supports the clinically important sinus-venosus/anomalous-pulmonary-venous association.
📊

Related Datasets

1
NGS-based miRNome profile in cardiac muscle tissue of congenital heart disease patients geo:GSE185565
Small-RNA sequencing of human cardiac tissue across atrial septal defect, ventricular septal defect, tetralogy of Fallot, and non-CHD controls. The dataset is useful for exploratory miRNA comparisons but is not an ASD-specific or adequately powered causal cohort.
human BULK RNA SEQ n=10
cardiac muscle tissue UBERON:0001133 Uberon multi-species anatomy ontology (UBERON) Relation: this dataset samples this sample type This dataset samples cardiac muscle tissue (UBERON:0001133). UBERON:0001133 is a sample type from the Uberon multi-species anatomy ontology.
Conditions: atrial septal defect ventricular septal defect tetralogy of Fallot non-congenital-heart-disease control
GEO metadata list two ASD samples, two non-CHD controls, four VSD samples, and two tetralogy-of-Fallot samples; ASD-specific inference is therefore severely sample-limited.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE185565 SUPPORT Other
"The goal of this study was to explore the miRNome profile in three frequently occurring Congenital Heart Disease (CHD) types, namely Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD) and Tetralogy of Fallot (TOF)."
The official GEO series record directly documents ASD among the cardiac tissue miRNA cohorts represented by GSE185565.
🔬

Clinical Trials

4
NCT04591392 NOT_APPLICABLE ACTIVE_NOT_RECRUITING
Prospective multicenter single-arm pivotal study of the reSept occluder in approximately 250 participants with clinically significant secundum ASD. The registry listed the study as active, not recruiting on 2026-07-20, with extended follow-up planned through 2032.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04591392 SUPPORT Human Clinical
"Evaluation of the safety and efficacy of the reSept ASD Occluder to treat patients with clinically significant secundum atrial septal defect"
The registry record directly documents the investigational occluder and clinically significant secundum-ASD population.
NCT05865119 NOT_APPLICABLE RECRUITING
French multicenter comparative study of covered-stent transcatheter correction versus surgical repair for sinus venosus defect, with a planned enrollment of 60 and a primary six-month efficacy-and-safety endpoint. The registry listed the study as recruiting on 2026-07-20.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT05865119 SUPPORT Human Clinical
"The objective of this project is to study the feasibility, efficacy and safety of the Optimus stent in this newly developed transcatheter procedure, in comparison with the gold-standard surgical method."
The registry summary directly documents the active comparison of covered stent correction with surgery for sinus venosus defect.
NCT05887700 NOT_APPLICABLE RECRUITING
Multicenter, single-arm post-market registry of real-world on-label use of the CeraFlex ASD closure system, with planned enrollment of approximately 145 participants and follow-up through 2027. The registry listed the study as recruiting on 2026-07-20.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT05887700 SUPPORT Human Clinical
"The objective of this post-market registry is to assess the clinical use of the Lifetech CeraFlex™ Closure System in a real-world and on-label fashion."
The registry summary directly supports this real-world device-surveillance study.
NCT06849635 NOT_APPLICABLE RECRUITING
Multicenter ambispective post-market follow-up study of the Cera ASD occluder, designed to assess longer-term safety and performance and detect previously unrecognized adverse effects. The registry listed the study as recruiting on 2026-07-20 with planned enrollment of approximately 139.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology. Left-to-right shunt HP:0012382 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Left-to-right shunt (HP:0012382). HP:0012382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06849635 SUPPORT Human Clinical
"collect real-word clinical data and confirm the long-time safety and performance of the Lifetech Cera™ ASD Occluder"
The registry summary directly states the study's long-term post-market safety and performance objective.
{ }

Source YAML

click to show 
name: Atrial Septal Defect
creation_date: "2026-05-06T11:55:36Z"
category: Congenital Cardiovascular Disorder
parents:
- Heart Disorder
disease_term:
  preferred_term: atrial septal defect
  term:
    id: MONDO:0006664
    label: atrial septal defect
description: >-
  Atrial septal defect is a congenital cardiovascular disorder in which a
  deficiency or interatrial communication permits abnormal flow between the left
  and right atria. The dominant physiology is usually left-to-right shunting with
  right-sided volume overload; untreated significant defects can lead to exercise
  intolerance, supraventricular arrhythmias, right ventricular dysfunction, and
  pulmonary arterial hypertension.
references:
- reference: PMID:41411375
  title: "2025 ACC/AHA/HRS/ISACHD/SCAI Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines."
  findings: []
- reference: PMID:32860028
  title: 2020 ESC Guidelines for the management of adult congenital heart disease.
  findings: []
synonyms:
- ASD
- Atrial septal defect
- Interatrial septal defect
- Secundum atrial septal defect
has_subtypes:
- name: Ostium secundum
  display_name: Ostium secundum ASD
  description: >-
    Defect centered in the oval fossa region; this is the subtype most often
    considered for transcatheter device closure when rims and size are suitable.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secundum atrial septal defect (ASDII) is a common congenital heart defect that causes shunting of blood between the systemic and pulmonary circulations."
    explanation: >-
      The review defines secundum ASD as a common congenital heart defect and
      supports this subtype as a central ASD classification.
- name: Ostium primum
  display_name: Ostium primum interatrial communication
  description: >-
    Inferior interatrial communication associated morphologically with the
    atrioventricular septal defect spectrum rather than an isolated oval-fossa
    deficiency.
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
    explanation: >-
      The morphologic review names ostium primum as a less frequent
      interatrial communication included in the ASD clinical spectrum.
- name: Sinus venosus
  display_name: Sinus venosus interatrial communication
  description: >-
    Superior or inferior caval-region interatrial communication, often discussed
    separately from true oval-fossa septal defects because the communication is
    outside the confines of the true atrial septum.
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
    explanation: >-
      The morphologic review explicitly names superior and inferior sinus
      venosus defects among less common interatrial communications.
- name: Coronary sinus
  display_name: Coronary sinus interatrial communication
  description: >-
    Communication involving the coronary sinus region, clinically grouped with
    ASD-like interatrial communications but morphologically outside the true
    oval-fossa septum.
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other communications between the two atriums, such as the superior or inferior sinus venosus defects, coronary sinus defect, and the ostium primum defect, are less frequently seen."
    explanation: >-
      The morphologic review explicitly lists coronary sinus defect as a less
      common interatrial communication in this spectrum.
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 160.0
  notes: >-
    A commonly cited estimate is 1.6 per 1,000 live births (160 per 100,000).
    This is an ascertainment-sensitive estimate rather than a universal rate:
    improved postnatal detection of mild congenital lesions, including ASD,
    has materially increased reported prevalence over time.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atrial septal defect (ASD) is a common congenital heart defect, with an
      estimated birth prevalence of 1.6 per 1000 live births
    explanation: >-
      The review provides the numeric birth-prevalence estimate, normalized here
      to a rate per 100,000 live births.
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The change in prevalence of mild CHD lesions (ventricular septal defect,
      atrial septal defect and patent ductus arteriosus) together explained
      93.4% of the increased overall prevalence, consistent with a major role of
      improved postnatal detection of less severe lesions.
    explanation: >-
      This meta-analysis supports the explicit ascertainment caveat for the
      reported ASD birth prevalence.
progression:
- phase: Often asymptomatic childhood and adolescence
  age_range: Childhood through adolescence
  notes: >-
    An isolated secundum ASD may be clinically silent despite an established
    left-to-right shunt. This phase is not universal and does not imply that the
    shunt is hemodynamically insignificant.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with an isolated ASDII often remain asymptomatic during childhood
      and adolescence.
    explanation: >-
      The review directly supports an often-asymptomatic pediatric course for
      isolated secundum ASD.
- phase: Adult symptomatic presentation
  age_range: Commonly from the third or fourth decade
  notes: >-
    Exercise intolerance, fatigue, or a supraventricular tachyarrhythmia may be
    the first recognized manifestation. Timing varies with defect size,
    ventricular compliance, pulmonary vascular disease, and associated lesions.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, most will become symptomatic from the third or fourth decade, and
      life expectancy is reduced overall.
    explanation: >-
      The review directly describes the typical timing of symptomatic adult
      presentation in untreated isolated secundum ASD.
- phase: Right-heart failure in advanced volume overload
  notes: >-
    Persistent hemodynamically important shunting can progress from right-sided
    chamber dilation to ventricular dysfunction and right-sided heart failure.
  evidence:
  - reference: PMID:34535989
    reference_title: "Atrial septal defect in adulthood: a new paradigm for congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      time-related complications primarily arrhythmias, thromboembolism, right
      heart failure and, in a subset of patients, pulmonary arterial hypertension
      (PAH).
    explanation: >-
      This adult ASD review directly includes right-heart failure among
      time-related complications.
- phase: Pulmonary vascular disease and Eisenmenger physiology
  notes: >-
    A minority develop severe pulmonary arterial hypertension and eventual
    right-to-left shunt reversal. This is not an inevitable sequence and must be
    distinguished from the much more common right-heart volume-overload course.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe PAH, with possible progression to Eisenmenger physiology, ensues in
      a minority of patients.
    explanation: >-
      The review explicitly limits Eisenmenger progression to a minority of
      patients.
- phase: Post-closure residual risk
  notes: >-
    Closure unloads the right heart but does not erase established pulmonary
    vascular disease or atrial electrical remodeling. Risk is greatest with
    pre-existing pulmonary hypertension, dysrhythmia, or later repair, so
    surveillance remains individualized.
  evidence:
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arrhythmia incidence is decreased after ASD closure, but remains elevated
      compared to general population.
    explanation: >-
      Persistent excess arrhythmia risk after closure directly supports a
      post-closure residual-risk phase and ongoing individualized surveillance.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Small, hemodynamically insignificant defects may impose little functional
    burden, whereas persistent significant shunts can require catheter or
    surgical repair and lifelong congenital-cardiology follow-up and can lead to
    arrhythmia, thromboembolism, right-heart failure, or pulmonary arterial
    hypertension. The broad ASD/interatrial-communication umbrella therefore
    cannot be represented honestly by one low, moderate, or high tier.
  evidence:
  - reference: PMID:34535989
    reference_title: "Atrial septal defect in adulthood: a new paradigm for congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although considered a simple defect, challenges in optimal diagnostic and
      treatment options still exist due to great heterogeneity in terms of
      anatomy and time-related complications primarily arrhythmias,
      thromboembolism, right heart failure and, in a subset of patients,
      pulmonary arterial hypertension (PAH).
    explanation: >-
      The review directly supports variable burden across anatomy and time and
      identifies the principal sources of serious morbidity.
pathophysiology:
- name: Abnormal Atrial Septation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    ASD originates from abnormal formation or deficiency of the interatrial
    septum or from anatomically related interatrial communications. True septal
    defects are confined to the oval fossa region, while primum, sinus venosus,
    and coronary sinus communications have distinct morphologic origins but share
    atrial-level mixing physiology.
  genes:
  - preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  - preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  - preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  - preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  locations:
  - preferred_term: interatrial septum
    term:
      id: UBERON:0002085
      label: interatrial septum
  - preferred_term: cardiac atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  biological_processes:
  - preferred_term: atrial septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0060413
      label: atrial septum morphogenesis
  - preferred_term: heart development
    modifier: ABNORMAL
    term:
      id: GO:0007507
      label: heart development
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "True atrial septal defects are limited to deficiencies totally within the confines of the oval fossa and its antero-inferior rim."
    explanation: >-
      This anatomic review grounds true ASD in a deficiency of atrial septal
      tissue within the oval fossa region.
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The unifying physiological feature of all these variants, whether their morphology is that of a defect within the area of the oval fossa, or an opening elsewhere within the atrium, is that mixing of the systemic and pulmonary blood occurs at atrial level."
    explanation: >-
      The review supports modeling ASD and related interatrial communications as
      atrial-level mixing lesions.
  - reference: PMID:15735645
    reference_title: Mutation in myosin heavy chain 6 causes atrial septal defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Morpholino knock-down of expression of the chick MYH6 homolog eliminates
      the formation of the atrial septum without overtly affecting atrial
      chamber formation.
    explanation: >-
      This developmental perturbation links a validated familial ASD gene to
      atrial-septum formation rather than only to a statistical association.
  downstream:
  - target: Left-to-Right Shunting and Right Heart Volume Overload
    causal_link_type: DIRECT
    description: >-
      The interatrial communication permits shunting between systemic and
      pulmonary venous circulations, usually from left to right when pulmonary
      vascular resistance is not elevated.
    evidence:
    - reference: PMID:22368625
      reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The unifying physiological feature of all these variants, whether their
        morphology is that of a defect within the area of the oval fossa, or an
        opening elsewhere within the atrium, is that mixing of the systemic and
        pulmonary blood occurs at atrial level.
      explanation: >-
        The morphology review directly supports atrial-level mixing downstream
        of the structural communication.
  - target: Paradoxical embolism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Transient or sustained right-to-left shunting
    description: >-
      An interatrial communication can permit venous thrombus to enter the
      systemic circulation when the pressure gradient transiently or
      persistently reverses.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a suspected paradoxical systemic thromboembolism initially raises the
        suspicion of an ASDII being present
      explanation: >-
        The review supports paradoxical systemic embolism as an occasional
        clinical consequence that can reveal an interatrial communication.
  - target: Atrial septal defect
    causal_link_type: DIRECT
    description: >-
      Abnormal atrial septation produces the structural atrial septal defect
      phenotype.
    evidence:
    - reference: PMID:22368625
      reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "True atrial septal defects are limited to deficiencies totally within the confines of the oval fossa and its antero-inferior rim."
      explanation: The morphology review directly defines true ASD as atrial septal tissue deficiency.
- name: Left-to-Right Shunting and Right Heart Volume Overload
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    In most unrepaired ASDs, greater left-sided filling pressure and right
    ventricular compliance drive left-to-right atrial shunting. The resulting
    pulmonary overcirculation enlarges right-sided chambers and can produce
    long-standing volume-overload complications.
  locations:
  - preferred_term: cardiac atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
    explanation: >-
      This review directly supports left-to-right shunting and right-heart
      dilation as the typical pediatric ASD hemodynamic pattern.
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ASDs have left-to-right shunt and primarily right-sided volume overload."
    explanation: >-
      This review concisely states the core hemodynamic mechanism linking ASD to
      right-sided volume overload.
  downstream:
  - target: Pulmonary Vascular and Ventricular Complications
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic pulmonary overcirculation
    - Long-standing right-sided volume overload
    description: >-
      Persistent volume overload can progress to pulmonary arterial hypertension
      and ventricular dysfunction, especially when defects are diagnosed late.
    evidence:
    - reference: PMID:30305948
      reference_title: Hemodynamic assessment of atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients diagnosed at adult age often present with complications related
        to long-standing volume overload such as pulmonary artery hypertension
        and right and left ventricular dysfunction.
      explanation: >-
        The hemodynamic review directly links long-standing volume overload to
        pulmonary hypertension and ventricular dysfunction.
  - target: Atrial Electrical Remodeling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Right atrial dilation
    - Chronic chamber stretch
    description: >-
      Chronic atrial and right-heart volume load promotes electrical remodeling
      that predisposes to atrial tachyarrhythmias.
    evidence:
    - reference: PMID:30305954
      reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ASDs have left-to-right shunt and primarily right-sided volume overload.
        This leads to electrical remodeling that may predispose patients to
        atrial tachyarrhythmias and conduction disorders.
      explanation: >-
        The review explicitly connects the hemodynamic load to electrical
        remodeling and atrial tachyarrhythmia risk.
  - target: Left-to-right shunt
    causal_link_type: DIRECT
    description: >-
      The atrial communication usually permits left-to-right shunting.
    evidence:
    - reference: PMID:30305948
      reference_title: Hemodynamic assessment of atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
      explanation: The hemodynamic review directly supports left-to-right shunting in ASD.
  - target: Right ventricular dilatation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - right-sided volume overload
    description: >-
      Left-to-right shunting produces right-sided volume overload and dilation
      of right heart structures.
    evidence:
    - reference: PMID:30305948
      reference_title: Hemodynamic assessment of atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
      explanation: The review pairs left-to-right shunting with dilated right-heart structures.
  - target: Right atrial enlargement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - right-sided volume overload
    description: >-
      Chronic atrial-level left-to-right shunting enlarges the right atrium as
      part of the right-heart volume-overload phenotype.
    evidence:
    - reference: PMID:30305948
      reference_title: Hemodynamic assessment of atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hemodynamics in children is characterized by left-to-right shunting,
        dilated right heart structures and normal pulmonary artery pressures
        (PAP).
      explanation: >-
        Dilated right-heart structures include the right atrial enlargement
        modeled by this phenotype edge.
  - target: Fixed splitting of the second heart sound
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased right ventricular stroke volume
    - Delayed pulmonic valve closure
    description: >-
      The hemodynamically significant shunt produces the characteristic wide,
      fixed split second heart sound on examination.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Key findings of RV volume overload are RV heave, wide and fixed
        splitting of the second heart sound and a systolic pulmonary flow murmur.
      explanation: >-
        The adult ASD review directly identifies fixed splitting as a physical
        sign of right-ventricular volume overload.
- name: Pulmonary Vascular and Ventricular Complications
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Long-standing unrepaired ASD can produce pulmonary artery hypertension and
    right or left ventricular dysfunction. These complications are more typical
    in adults diagnosed late and influence whether closure is safe.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction."
    explanation: >-
      The hemodynamic review links late-diagnosed ASD to pulmonary vascular and
      ventricular dysfunction complications.
  downstream:
  - target: Exercise intolerance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - long-standing volume overload
    - pulmonary vascular disease
    description: >-
      Long-standing unrepaired ASD can reduce exercise tolerance as pulmonary
      and ventricular complications accumulate with age.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
      explanation: The adult ASD review directly lists exercise intolerance as an age-increasing untreated-ASD complication.
  - target: Right ventricular dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - long-standing volume overload
    description: >-
      Chronic right-heart volume overload can progress from dilation to right
      ventricular dysfunction.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
      explanation: The review names right ventricular dysfunction as a complication of untreated ASD.
  - target: Pulmonary arterial hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic pulmonary overcirculation
    - long-standing volume overload
    description: >-
      Persistent pulmonary overcirculation and volume overload can progress to
      pulmonary arterial hypertension.
    evidence:
    - reference: PMID:30305948
      reference_title: Hemodynamic assessment of atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction."
      explanation: The hemodynamic review links long-standing volume overload to pulmonary artery hypertension.
  - target: Right ventricular failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progressive right ventricular dysfunction
    - Elevated pulmonary arterial pressure
    description: >-
      Advanced right-heart volume and pressure load can culminate in clinical
      right ventricular failure.
    evidence:
    - reference: PMID:34535989
      reference_title: "Atrial septal defect in adulthood: a new paradigm for congenital heart disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        time-related complications primarily arrhythmias, thromboembolism, right
        heart failure and, in a subset of patients, pulmonary arterial
        hypertension (PAH).
      explanation: >-
        The review directly includes right-heart failure among time-related ASD
        complications.
- name: Atrial Electrical Remodeling
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Right-sided volume overload and atrial chamber enlargement alter atrial
    electrophysiology, raising the risk of supraventricular tachyarrhythmias and
    some conduction disorders, particularly with large shunts or late repair.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: ABNORMAL
    term:
      id: GO:0061337
      label: cardiac conduction
  evidence:
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders."
    explanation: >-
      The arrhythmia review supports the causal link from ASD-related overload
      to electrical remodeling and atrial tachyarrhythmias.
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions."
    explanation: >-
      This supports the clinical modifiers that increase rhythm risk in ASD.
  downstream:
  - target: Supraventricular arrhythmia
    causal_link_type: DIRECT
    description: >-
      ASD-related electrical remodeling predisposes to supraventricular
      tachyarrhythmias.
    evidence:
    - reference: PMID:30305954
      reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders."
      explanation: The arrhythmia review directly links ASD-related remodeling to atrial tachyarrhythmias.
phenotypes:
- name: Atrial septal defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  description: >-
    A deficiency or ASD-like interatrial communication permits mixing at the
    atrial level.
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "True atrial septal defects are limited to deficiencies totally within the confines of the oval fossa and its antero-inferior rim."
    explanation: >-
      This supports the core structural phenotype captured by the HPO term.
- name: Left-to-right shunt
  category: Cardiovascular
  phenotype_term:
    preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  description: >-
    Flow across the atrial communication is usually from left to right in
    children and in adults without advanced pulmonary vascular disease.
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
    explanation: >-
      The hemodynamic review directly supports left-to-right shunting in ASD.
- name: Right ventricular dilatation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Right ventricular dilatation
    term:
      id: HP:0005133
      label: Right ventricular dilatation
  description: >-
    Chronic left-to-right shunting produces right-sided volume overload with
    enlargement of right heart structures.
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemodynamics in children is characterized by left-to-right shunting, dilated right heart structures and normal pulmonary artery pressures (PAP)."
    explanation: >-
      The cited review supports right-heart dilation as a typical hemodynamic
      finding; the HPO term captures the right ventricular component.
- name: Exercise intolerance
  category: Functional
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  description: >-
    Exercise intolerance can emerge with age when a significant defect remains
    untreated.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
    explanation: >-
      The adult ASD review lists exercise intolerance as an age-increasing
      complication of untreated ASD.
- name: Right ventricular dysfunction
  category: Cardiovascular
  phenotype_term:
    preferred_term: Abnormal right ventricular function
    term:
      id: HP:0033118
      label: Abnormal right ventricular function
  description: >-
    Long-standing untreated ASD can impair right ventricular function in
    adulthood, distinct from right ventricular dilatation.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
    explanation: >-
      The adult ASD review explicitly names right ventricular dysfunction as an
      age-increasing complication of untreated ASD; HP:0033118 captures abnormal
      right-ventricular function without conflating it with established failure.
- name: Supraventricular arrhythmia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Supraventricular arrhythmia
    term:
      id: HP:0005115
      label: Supraventricular arrhythmia
  description: >-
    Atrial tachyarrhythmias and other supraventricular arrhythmias are
    associated with volume overload, pulmonary hypertension, shunt size, and
    later age at repair.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
    explanation: >-
      The adult ASD review supports supraventricular arrhythmia as an
      age-related untreated ASD complication.
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders."
    explanation: >-
      The arrhythmia review provides a mechanism for atrial tachyarrhythmias in
      ASD.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  description: >-
    Pulmonary arterial hypertension can develop after long-standing pulmonary
    overcirculation and is an important determinant of closure risk.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced."
    explanation: >-
      The adult ASD review identifies pulmonary arterial hypertension as an
      untreated ASD complication.
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients diagnosed at adult age often present with complications related to long-standing volume overload such as pulmonary artery hypertension and right and left ventricular dysfunction."
    explanation: >-
      The hemodynamic review supports pulmonary artery hypertension after
      long-standing volume overload.
- name: Right atrial enlargement
  category: Cardiovascular
  phenotype_term:
    preferred_term: Right atrial enlargement
    term:
      id: HP:0030718
      label: Right atrial enlargement
  description: >-
    Right atrial enlargement accompanies chronic right-sided volume overload
    from a hemodynamically significant left-to-right atrial shunt.
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemodynamics in children is characterized by left-to-right shunting,
      dilated right heart structures and normal pulmonary artery pressures
      (PAP).
    explanation: >-
      The cited review supports dilation of right-heart structures as a typical
      ASD finding; this term captures the atrial component.
- name: Fixed splitting of the second heart sound
  category: Cardiovascular
  phenotype_term:
    preferred_term: Fixed splitting of the second heart sound
    term:
      id: HP:0031662
      label: Fixed splitting of the second heart sound
  description: >-
    Wide, fixed splitting of S2 is a characteristic examination sign of
    hemodynamically important right-ventricular volume overload, but it is not
    present in every ASD.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key findings of RV volume overload are RV heave, wide and fixed splitting
      of the second heart sound and a systolic pulmonary flow murmur.
    explanation: >-
      The review directly identifies fixed S2 splitting as a physical sign of
      ASD-related right-ventricular volume overload.
- name: Right ventricular failure
  category: Cardiovascular
  phenotype_term:
    preferred_term: Right ventricular failure
    term:
      id: HP:0001708
      label: Right ventricular failure
  description: >-
    Right ventricular failure is an advanced, non-obligate complication of
    longstanding hemodynamic load, often accompanied by elevated pulmonary
    arterial pressure.
  evidence:
  - reference: PMID:34535989
    reference_title: "Atrial septal defect in adulthood: a new paradigm for congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      time-related complications primarily arrhythmias, thromboembolism, right
      heart failure and, in a subset of patients, pulmonary arterial hypertension
      (PAH).
    explanation: >-
      The review directly supports right-sided heart failure as an advanced ASD
      complication.
- name: Paradoxical embolism
  category: Cardiovascular
  phenotype_term:
    preferred_term: Paradoxical embolism
    term:
      id: HP:0033520
      label: Paradoxical embolism
  description: >-
    A venous embolus may occasionally cross an interatrial communication during
    transient or sustained right-to-left shunting and enter the systemic
    circulation.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a suspected paradoxical systemic thromboembolism initially raises the
      suspicion of an ASDII being present
    explanation: >-
      The review directly supports paradoxical embolism as an occasional ASD
      presentation.
genetic:
- name: NKX2-5
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Rare familial atrial septal defect and conduction disease gene
  gene_term:
    preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  notes: >-
    NKX2-5 variants are a rare cause of familial ASD and can co-occur with
    atrioventricular block, syncope, sudden death, and ventricular noncompaction.
    This association should not be generalized to most sporadic ASD cases.
  evidence:
  - reference: PMID:20932824
    reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
    explanation: >-
      This family study supports NKX2-5 as a rare familial ASD gene with
      associated conduction and cardiomyopathy phenotypes.
  - reference: PMID:20932824
    reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5."
    explanation: >-
      Functional cell-assay evidence supports loss of NKX2-5 transcriptional
      activity as a plausible mechanism for the familial phenotype.
- name: GATA4
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Rare familial atrial septal defect gene
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  notes: >-
    GATA4 is one of several cardiac transcription-factor genes reported in rare
    familial ASD. The cited family study supports association but does not imply
    that GATA4 explains most isolated ASD.
  evidence:
  - reference: PMID:20659440
    reference_title: A novel mutation of GATA4 in a familial atrial septal defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T280M mutation of GATA4 is suggested to be associated with ASD in this Chinese family."
    explanation: >-
      The family segregation study supports GATA4 as a rare familial ASD gene.
- name: TBX5
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Rare syndromic atrial septal defect gene in Holt-Oram syndrome
  gene_term:
    preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  notes: >-
    TBX5 variants cause Holt-Oram syndrome, in which ASD is a frequent cardiac
    phenotype. This is modeled as a rare syndromic ASD association rather than a
    general cause of isolated sporadic ASD.
  evidence:
  - reference: PMID:30552424
    reference_title: "Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%)."
    explanation: >-
      This molecular series supports TBX5 as a rare syndromic ASD-associated
      gene in Holt-Oram syndrome.
- name: MYH6
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Rare autosomal-dominant familial atrial septal defect gene
  gene_term:
    preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  notes: >-
    A segregating MYH6 missense variant was identified in a large family with
    dominantly inherited ASD, and developmental knockdown disrupted atrial
    septum formation. This establishes a rare Mendelian mechanism but does not
    imply that MYH6 explains most sporadic ASD.
  evidence:
  - reference: PMID:15735645
    reference_title: Mutation in myosin heavy chain 6 causes atrial septal defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a new locus linked with atrial septal defect on chromosome
      14q12 in a large family with dominantly inherited atrial septal defect.
    explanation: >-
      The linkage and segregation evidence supports a rare dominantly inherited
      MYH6-associated ASD mechanism.
  - reference: PMID:15735645
    reference_title: Mutation in myosin heavy chain 6 causes atrial septal defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Morpholino knock-down of expression of the chick MYH6 homolog eliminates
      the formation of the atrial septum without overtly affecting atrial
      chamber formation.
    explanation: >-
      The developmental perturbation provides functional support for abnormal
      atrial septation downstream of MYH6 loss.
diagnosis:
- name: Transthoracic echocardiography
  description: >-
    Transthoracic echocardiography is the primary diagnostic study for defining
    an atrial-level communication and assessing shunt direction, right-heart
    volume load, ventricular function, and estimated pulmonary pressure.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  results: >-
    Demonstrates interatrial communication, shunt direction, right-heart
    dilation, and estimates of pulmonary pressure.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transthoracic echocardiography (TTE) is the primary imaging modality for
      the diagnosis of an ASDII
    explanation: >-
      The review directly establishes TTE as the primary imaging study for
      diagnosis and hemodynamic assessment.
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases, hemodynamics can be estimated with echocardiography only."
    explanation: >-
      The hemodynamic review supports echocardiography as the usual method for
      estimating ASD physiology.
- name: Transesophageal and cross-sectional cardiac imaging
  description: >-
    TEE defines defect size and rims for device planning. Cardiac MRI clarifies
    morphology and quantifies ventricular volumes and function; cardiac CT is an
    alternative when MRI is contraindicated and is particularly useful for
    associated pulmonary venous anatomy.
  diagnosis_term:
    preferred_term: cardiac MRI
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  results: >-
    Defines the communication, septal rims, relation to valves and veins,
    associated pulmonary venous connections, and ventricular size and function.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      echocardiography (TEE) is required for determining the feasibility of
      transcatheter closure
    explanation: >-
      The review supports TEE for detailed device-closure anatomy and
      feasibility assessment.
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac magnetic resonance imaging (MRI) can help clarify the morphology
      of the defect
    explanation: >-
      This supports CMR for anatomy and quantitative ventricular assessment.
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac computed tomography (CT) provides an alternative in patients with
      contraindications to MRI
    explanation: >-
      The review supports cardiac CT as an alternative cross-sectional modality.
- name: Invasive hemodynamic assessment when pulmonary hypertension is suspected
  description: >-
    Cardiac catheterization is not routine for uncomplicated ASD. It is used to
    measure pulmonary vascular resistance and, when needed, test occlusion or
    vasoreactivity when pulmonary hypertension, ventricular dysfunction, or
    closure tolerability is uncertain.
  diagnosis_term:
    preferred_term: cardiac catheterization
    term:
      id: NCIT:C38044
      label: Cardiac Catheterization
  results: >-
    Directly measures pulmonary and systemic pressures, flow ratio, pulmonary
    vascular resistance, and hemodynamic response to temporary occlusion.
  evidence:
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic catheterization is usually not indicated unless there is
      suggestion of pulmonary hypertension on echocardiography.
    explanation: >-
      The review supports selective rather than routine invasive hemodynamic
      assessment.
  - reference: PMID:30305948
    reference_title: Hemodynamic assessment of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In older patients and/or in those with ventricular dysfunction,
      measurement of left heart pressures during temporary balloon occlusion is
      recommended prior to device closure as it may not be tolerated.
    explanation: >-
      This supports temporary occlusion testing in patients at risk of adverse
      filling-pressure changes after closure.
- name: Selective genetic evaluation
  description: >-
    Genetic evaluation is most relevant when ASD is familial, accompanied by
    conduction disease, or associated with extracardiac or syndromic features.
    A negative panel does not exclude ASD because most cases are not explained
    by a single established Mendelian gene.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    May identify a rare familial or syndromic etiology such as NKX2-5-, GATA4-,
    TBX5-, or MYH6-associated disease and inform counseling and family testing.
  evidence:
  - reference: PMID:38884726
    reference_title: Human Genetics of Atrial Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although atrial septal defects (ASD) can be subdivided based on their
      anatomical location, an essential aspect of human genetics and genetic
      counseling is distinguishing between isolated and familiar cases without
      extracardiac features and syndromic cases with the co-occurrence of
      extracardiac abnormalities, such as developmental delay.
    explanation: >-
      The current human-genetics review supports selective etiologic evaluation
      framed around familial, isolated, and syndromic presentations.
treatments:
- name: Conservative surveillance for a hemodynamically insignificant ASD
  action_category: MONITORING
  description: >-
    Small defects without right-heart enlargement or another accepted closure
    indication are observed clinically and with periodic echocardiography.
    Surveillance is individualized rather than treating every anatomical
    communication as an indication for repair.
  treatment_term:
    preferred_term: clinical monitoring
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      insignificant ASDs do not require closure. Such patients should be followed
      conservatively
    explanation: >-
      The review directly supports conservative surveillance when a defect is
      hemodynamically insignificant.
- name: Transcatheter closure of secundum ASD
  action_category: THERAPEUTIC
  description: >-
    Device closure is generally preferred for hemodynamically significant
    secundum ASD when defect size, rims, and pulmonary vascular status are
    suitable. Severe irreversible pulmonary vascular disease or Eisenmenger
    physiology is a contraindication; uncertain pulmonary vascular or left
    ventricular physiology requires specialist invasive assessment before
    closure.
  treatment_term:
    preferred_term: transcatheter atrial septal defect closure
    term:
      id: NCIT:C148075
      label: Septal Defect Repair
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  target_mechanisms:
  - target: Left-to-Right Shunting and Right Heart Volume Overload
    treatment_effect: INHIBITS
    description: >-
      Device occlusion terminates the atrial-level shunt and unloads the right
      heart when closure is physiologically appropriate.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ASDII results in right-sided volume unloading
      explanation: >-
        The review directly supports right-heart unloading after closure.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcatheter and surgical techniques both provide valid options for ASDII closure, the former being the preferred method."
    explanation: >-
      This review supports transcatheter closure as the preferred closure method
      for suitable secundum ASD.
  - reference: PMID:15350172
    reference_title: Transcatheter closure of atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A major reason for this is the lower morbidity of transcatheter closure procedures."
    explanation: >-
      This treatment review explains why transcatheter closure became preferred
      for many secundum ASDs.
- name: Surgical ASD repair
  action_category: THERAPEUTIC
  description: >-
    Surgical repair remains a valid closure strategy, especially when anatomy is
    unsuitable for device closure or when the defect is primum, sinus venosus, or
    coronary sinus type.
  treatment_term:
    preferred_term: surgical atrial septal defect repair
    term:
      id: NCIT:C148075
      label: Septal Defect Repair
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  target_mechanisms:
  - target: Left-to-Right Shunting and Right Heart Volume Overload
    treatment_effect: INHIBITS
    description: >-
      Surgical closure terminates the interatrial shunt when device closure is
      anatomically unsuitable or when associated anatomy requires repair.
    evidence:
    - reference: PMID:25884091
      reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pericardial or synthetic patch closure is preferred over a direct suture,
        and generally completely terminates the shunt.
      explanation: >-
        The review directly supports surgical patch closure as a means of
        terminating the interatrial shunt.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcatheter and surgical techniques both provide valid options for ASDII closure, the former being the preferred method."
    explanation: >-
      The review supports surgery as a valid ASDII closure option, while noting
      that transcatheter closure is preferred when suitable.
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the exception of those with severe and irreversible PAH, closure is beneficial to, and thus indicated in all patients with significant shunts, regardless of age and symptoms."
    explanation: >-
      This supports closure of significant shunts and the pulmonary vascular
      contraindication that guides either surgical or transcatheter repair.
- name: Atrial tachyarrhythmia management
  action_category: THERAPEUTIC
  description: >-
    Established atrial tachyarrhythmias require rhythm-specific medical or
    procedural management. In selected patients, ablation before or at closure
    can be considered because defect closure alone does not reliably eliminate
    an established arrhythmogenic substrate.
  treatment_term:
    preferred_term: cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_phenotypes:
  - preferred_term: Supraventricular arrhythmia
    term:
      id: HP:0005115
      label: Supraventricular arrhythmia
  target_mechanisms:
  - target: Atrial Electrical Remodeling
    treatment_effect: MODULATES
    description: >-
      Ablation interrupts the re-entrant or focal electrical circuits that
      manifest on the substrate of ASD-related atrial remodeling.
    evidence:
    - reference: PMID:34535989
      reference_title: "Atrial septal defect in adulthood: a new paradigm for congenital heart disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Atrial septal defects call for tertiary expertise where all options may
        be considered, namely catheter vs. surgical closure, consideration of
        pre-closure ablation for patients with atrial tachycardia and suitability
        for closure or/and targeted therapy for patients with PAH.
      explanation: >-
        The adult ASD review explicitly supports considering pre-closure
        ablation in patients with atrial tachycardia.
  evidence:
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical and procedural therapy for arrhythmias should consider type and
      timing of ASD repair.
    explanation: >-
      The arrhythmia review supports individualized medical and procedural rhythm
      management in relation to ASD anatomy and repair timing.
differential_diagnoses:
- name: Patent foramen ovale
  description: >-
    PFO is persistence of the fetal foramen-ovale flap communication rather than
    deficiency of atrial septal tissue. Saline contrast with a provocation that
    transiently raises right-atrial pressure and detailed septal imaging help
    distinguish its dynamic right-to-left passage from a hemodynamically
    significant secundum ASD.
  evidence:
  - reference: PMID:35225286
    reference_title: Echocardiographic Evaluation of Atrial Communications before Transcatheter Closure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The accuracy of PFO detection can be improved by using agitated saline
      together with maneuvers to transiently increase the right atrial (RA)
      pressure.
    explanation: >-
      This imaging review supports the provoked contrast-echocardiographic
      behavior that helps distinguish PFO from a persistent volume-loading ASD.
  - reference: PMID:35225286
    reference_title: Echocardiographic Evaluation of Atrial Communications before Transcatheter Closure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three dimensional TEE identifies further septal fenestrations and describes
      the dynamic morphology of ASD/PFO and atrial septal aneurysm.
    explanation: >-
      The review supports detailed TEE assessment of the distinct dynamic
      morphologies of ASD and PFO.
  - reference: PMID:31424787
    reference_title: "Anatomy, Thorax, Heart Foramen Ovale."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Higher pressure in the left atrium resulting from increased pulmonary
      venous flow from the lungs causes the septum primum of the interatrial
      septum to close the opening.
    explanation: >-
      This embryologic description supports PFO as persistence of the fetal
      flap-valve communication rather than an oval-fossa tissue deficiency.
- name: Atrioventricular septal defect
  description: >-
    An ostium-primum interatrial communication belongs morphologically to the
    atrioventricular septal defect spectrum because it occurs with a common
    atrioventricular junction. It must not be managed as an isolated oval-fossa
    secundum ASD even though both produce atrial-level shunting.
  evidence:
  - reference: PMID:22368625
    reference_title: Defining the morphologic phenotypes of atrial septal defects and interatrial communications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ostium primum defect, for example, has all the characteristics of an
      atrioventricular septal defect, existing only in the setting of a common
      atrioventricular junction.
    explanation: >-
      The morphology review directly establishes the primum-to-AVSD boundary.
- name: Congenital partial pulmonary venous return anomaly
  description: >-
    Partial anomalous pulmonary venous return can accompany a superior sinus
    venosus communication and adds its own right-heart volume load. Pulmonary
    venous connections therefore must be mapped rather than assuming an isolated
    oval-fossa ASD.
  evidence:
  - reference: clinicaltrials:NCT05865119
    reference_title: OPTImal Treatment of Sinus VENOSUS Defect - Efficacy and Safety of Transcatheter Correction Compared to Surgical Treatment in Patients With Sinus Venosus Defect
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sinus venosus defect (SVD) accounts for 10% of atrial septal defects and is
      characterized by an anomalous pulmonary venous return in the superior vena
      cava associated with a high situated atrial septal defect.
    explanation: >-
      The trial background directly supports the clinically important
      sinus-venosus/anomalous-pulmonary-venous association.
clinical_trials:
- name: NCT04591392
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Prospective multicenter single-arm pivotal study of the reSept occluder in
    approximately 250 participants with clinically significant secundum ASD.
    The registry listed the study as active, not recruiting on 2026-07-20, with
    extended follow-up planned through 2032.
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  evidence:
  - reference: clinicaltrials:NCT04591392
    reference_title: Evaluation of the Safety and Efficacy of the reSept ASD Occluder to Treat Patients With Clinically Significant Secundum Atrial Septal Defect
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evaluation of the safety and efficacy of the reSept ASD Occluder to treat
      patients with clinically significant secundum atrial septal defect
    explanation: >-
      The registry record directly documents the investigational occluder and
      clinically significant secundum-ASD population.
- name: NCT05865119
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    French multicenter comparative study of covered-stent transcatheter
    correction versus surgical repair for sinus venosus defect, with a planned
    enrollment of 60 and a primary six-month efficacy-and-safety endpoint. The
    registry listed the study as recruiting on 2026-07-20.
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  evidence:
  - reference: clinicaltrials:NCT05865119
    reference_title: OPTImal Treatment of Sinus VENOSUS Defect - Efficacy and Safety of Transcatheter Correction Compared to Surgical Treatment in Patients With Sinus Venosus Defect
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective of this project is to study the feasibility, efficacy and
      safety of the Optimus stent in this newly developed transcatheter
      procedure, in comparison with the gold-standard surgical method.
    explanation: >-
      The registry summary directly documents the active comparison of covered
      stent correction with surgery for sinus venosus defect.
- name: NCT05887700
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Multicenter, single-arm post-market registry of real-world on-label use of
    the CeraFlex ASD closure system, with planned enrollment of approximately
    145 participants and follow-up through 2027. The registry listed the study
    as recruiting on 2026-07-20.
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  evidence:
  - reference: clinicaltrials:NCT05887700
    reference_title: "A Multi-center, Single-arm, Real-world Registry Assessing the Clinical Use of the Lifetech CeraFlex™ ASD Closure System"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective of this post-market registry is to assess the clinical use
      of the Lifetech CeraFlex™ Closure System in a real-world and on-label
      fashion.
    explanation: >-
      The registry summary directly supports this real-world device-surveillance
      study.
- name: NCT06849635
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Multicenter ambispective post-market follow-up study of the Cera ASD
    occluder, designed to assess longer-term safety and performance and detect
    previously unrecognized adverse effects. The registry listed the study as
    recruiting on 2026-07-20 with planned enrollment of approximately 139.
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Left-to-right shunt
    term:
      id: HP:0012382
      label: Left-to-right shunt
  evidence:
  - reference: clinicaltrials:NCT06849635
    reference_title: "Cera™ ASD Occluder Post-Market Clinical Follow-Up Study：A Multi-Center, Single-arm, Ambispective Post-Market Follow-Up Study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      collect real-word clinical data and confirm the long-time safety and
      performance of the Lifetech Cera™ ASD Occluder
    explanation: >-
      The registry summary directly states the study's long-term post-market
      safety and performance objective.
datasets:
- accession: geo:GSE185565
  title: NGS-based miRNome profile in cardiac muscle tissue of congenital heart disease patients
  description: >-
    Small-RNA sequencing of human cardiac tissue across atrial septal defect,
    ventricular septal defect, tetralogy of Fallot, and non-CHD controls. The
    dataset is useful for exploratory miRNA comparisons but is not an
    ASD-specific or adequately powered causal cohort.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: cardiac muscle tissue
    term:
      id: UBERON:0001133
      label: cardiac muscle tissue
    tissue_term:
      preferred_term: cardiac muscle tissue
      term:
        id: UBERON:0001133
        label: cardiac muscle tissue
  sample_count: 10
  conditions:
  - atrial septal defect
  - ventricular septal defect
  - tetralogy of Fallot
  - non-congenital-heart-disease control
  notes: >-
    GEO metadata list two ASD samples, two non-CHD controls, four VSD samples,
    and two tetralogy-of-Fallot samples; ASD-specific inference is therefore
    severely sample-limited.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE185565
    reference_title: GEO Accession viewer
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The goal of this study was to explore the miRNome profile in three
      frequently occurring Congenital Heart Disease (CHD) types, namely Atrial
      Septal Defect (ASD), Ventricular Septal Defect (VSD) and Tetralogy of
      Fallot (TOF).
    explanation: >-
      The official GEO series record directly documents ASD among the cardiac
      tissue miRNA cohorts represented by GSE185565.
discussions:
- discussion_id: asd-pah-closure-thresholds
  prompt: >-
    Which patients with ASD and elevated pulmonary vascular resistance benefit
    from pulmonary-arterial-hypertension therapy followed by closure, and which
    are harmed by eliminating a pressure-relieving interatrial communication?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Pulmonary Vascular and Ventricular Complications
  - treatments#Transcatheter closure of secundum ASD
  rationale: >-
    This decision separates potentially reversible shunt-associated pulmonary
    hypertension from severe irreversible disease and Eisenmenger physiology.
    Existing observational studies use heterogeneous pulmonary-hypertension
    definitions, so a single pressure estimate is not an adequate closure rule.
  evidence:
  - reference: PMID:33328279
    reference_title: "Prevalence and outcomes of pulmonary hypertension after percutaneous closure of atrial septal defect: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Studies applied variable PH definitions.
    explanation: >-
      Heterogeneous definitions limit direct comparison and threshold inference
      across closure cohorts.
  - reference: PMID:33328279
    reference_title: "Prevalence and outcomes of pulmonary hypertension after percutaneous closure of atrial septal defect: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Larger, prospective studies with consistent PH definitions using the
      recommended measurement modality are warranted.
    explanation: >-
      The meta-analysis explicitly calls for prospective, consistently measured
      studies to resolve this management gap.
- discussion_id: asd-postclosure-surveillance-and-arrhythmia
  prompt: >-
    What surveillance schedule and rhythm strategy best prevent or detect late
    pulmonary hypertension, atrial arrhythmia, and device-related complications
    after ASD closure?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Atrial Electrical Remodeling
  - treatments#Transcatheter closure of secundum ASD
  rationale: >-
    Closure reduces shunt load but does not erase pre-existing atrial remodeling,
    and follow-up intensity varies with age at closure, residual lesions,
    pulmonary pressure, and rhythm history.
  evidence:
  - reference: PMID:30305954
    reference_title: Arrhythmias and conduction disorders associated with atrial septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arrhythmia incidence is decreased after ASD closure, but remains elevated
      compared to general population.
    explanation: >-
      Persistent excess rhythm risk after closure motivates surveillance and
      prevention research.
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, consensus regarding frequency and duration of follow-up after
      device closure is lacking.
    explanation: >-
      The review explicitly identifies uncertainty about post-device follow-up.
- discussion_id: asd-genetic-architecture
  prompt: >-
    What fraction of apparently isolated ASD is explained by rare Mendelian
    variants, polygenic susceptibility, or regulatory variation, and how should
    penetrance and extracardiac risk be incorporated into family counseling?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Abnormal Atrial Septation
  - genetic#NKX2-5
  - genetic#GATA4
  - genetic#TBX5
  - genetic#MYH6
  rationale: >-
    A few stable gene associations explain rare families or syndromic disease,
    but most secundum ASD is sporadic and a negative current panel cannot exclude
    a genetic contribution.
  evidence:
  - reference: PMID:25884091
    reference_title: "Secundum atrial septal defect in adults: a practical review and recent developments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most secundum ASDs occur sporadically
    explanation: >-
      This directly supports the gap between rare familial genes and the much
      larger sporadic population.
  - reference: PMID:38884726
    reference_title: Human Genetics of Atrial Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, it points to different pathways and gene networks relevant to
      the dysregulation of cardiomyogenesis and ASD pathogenesis.
    explanation: >-
      The current review supports a heterogeneous network architecture rather
      than one dominant ASD gene.
- discussion_id: asd-sinus-venosus-transcatheter-repair
  prompt: >-
    For anatomically suitable sinus venosus defects, when does covered-stent
    correction provide durable efficacy and safety comparable with surgical
    redirection of anomalous pulmonary venous return?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Sinus venosus
  rationale: >-
    Covered-stent correction is emerging, but dedicated comparative evidence and
    long-term data remain limited; anatomy also constrains feasibility.
  evidence:
  - reference: clinicaltrials:NCT05865119
    reference_title: OPTImal Treatment of Sinus VENOSUS Defect - Efficacy and Safety of Transcatheter Correction Compared to Surgical Treatment in Patients With Sinus Venosus Defect
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Preliminary results are limited but promising.
    explanation: >-
      The trial background directly states that existing results remain limited.
  - reference: clinicaltrials:NCT05865119
    reference_title: OPTImal Treatment of Sinus VENOSUS Defect - Efficacy and Safety of Transcatheter Correction Compared to Surgical Treatment in Patients With Sinus Venosus Defect
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective of this project is to study the feasibility, efficacy and
      safety of the Optimus stent in this newly developed transcatheter
      procedure, in comparison with the gold-standard surgical method.
    explanation: >-
      The active comparative study is directly targeted at resolving this gap.
notes: >-
  This entry uses the clinically broad ASD umbrella but preserves morphology:
  true atrial septal tissue deficiency is confined to the oval fossa (secundum
  ASD), whereas primum, sinus venosus, and coronary-sinus lesions are distinct
  interatrial communications. Patent foramen ovale is excluded because it is
  persistence of a fetal flap-valve communication rather than deficiency of
  atrial septal tissue. Management recommendations are not interchangeable
  across these anatomies. Closure decisions require anatomy, right-heart size,
  shunt significance, pulmonary vascular resistance, and ventricular filling
  physiology; Eisenmenger physiology is a do-not-close state.
📚

References & Deep Research

References

2
PMID:41411375
2025 ACC/AHA/HRS/ISACHD/SCAI Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
No top-level findings curated for this source.
PMID:32860028
2020 ESC Guidelines for the management of adult congenital heart disease.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Atrial Septal Defect. Core disease mechanisms, molecular and cellular path...
Asta Scientific Corpus Retrieval 18 citations 2026-05-06T10:41:38.531945

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

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  • No synthesis or second-stage model call is performed.