Left ventricular noncompaction

Cardiovascular Disorder MONDO:0018901 Pathograph 20 Show in embeddings browser Cardiomyopathy Cardiovascular Disorder

Left ventricular noncompaction (LVNC) is a cardiomyopathy marked by excessive trabeculation and deep intertrabecular recesses in a two-layered ventricular wall. Disease biology spans developmental noncompaction, genetic defects in sarcomeric and cytoskeletal programs, and downstream heart failure, arrhythmia, and thromboembolic risk.

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Subtypes

Left ventricular noncompaction 1 (DTNA-related) MONDO:0011403

DTNA hgnc:3057

The locus MONDO and OMIM number LVNC1, attributed to DTNA. It is listed here to make the numbered series navigable and to hold the gene, not because the relationship is settled: the whole primary evidence is one family carrying a single alpha-dystrobrevin missense change, in whom LVNC occurred together with congenital heart disease. See the DTNA genetic record for the full caveat.

Left ventricular noncompaction 7 (MIB1-related) MONDO:0014042

MIB1 hgnc:21086

The MIB1 form, numbered LVNC7. Mechanistically it is the best-resolved arm of this entry and the only one that acts on compaction itself: loss of MIB1 ubiquitin-ligase activity reduces NOTCH1 signalling and arrests chamber myocardium development, so trabeculae never mature and the compact layer never thickens. Autosomal dominant, with the mouse myocardial knockout reproducing the human structural phenotype.

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Pathophysiology

Incomplete ventricular compaction and excessive trabeculation

The core structural lesion of LVNC is failure of the compact myocardial layer to mature normally, leaving a thick noncompacted trabecular layer with deep recesses overlying a thinner compacted wall. This developmental abnormality creates the characteristic spongy ventricular phenotype.

cardiomyocyte CL:0000746

MIB1 hgnc:21086

cardiac ventricle morphogenesis GO:0003208 cardiac muscle tissue morphogenesis GO:0055008

left ventricle myocardium UBERON:0006566

Downstream

Genetic perturbation of cardiomyocyte structural programs Mutations in sarcomeric, cytoskeletal, mitochondrial, and conduction genes predispose to abnormal ventricular wall development.

Impaired ventricular contractile function The abnormal wall architecture increases risk of ventricular dysfunction and heart failure.

Arrhythmogenic myocardial substrate Structural irregularity and persistent trabeculation create an arrhythmogenic substrate.

Show evidence (4 references)

PMID:23314057 SUPPORT Human Clinical

"These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction."

Names the failure of trabecular maturation and compaction that is this node, and places MIB1 loss upstream of it, which is why the gene is bound here rather than on the structural-protein node.

PMID:23314057 SUPPORT Model Organism

"Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1."

The animal evidence that the MIB1 lesion is sufficient for this structural node, and that it acts through the NOTCH ligand-receptor axis rather than through a sarcomeric route.

PMID:40182365 SUPPORT Human Clinical

"Left ventricular noncompaction (LVNC) involves abnormal development of the heart muscle, where the inner layer remains excessively trabeculated instead of compacting properly."

Directly supports abnormal ventricular compaction as the primary structural mechanism of LVNC.

+ 1 more reference

Genetic perturbation of cardiomyocyte structural programs

LVNC is genetically heterogeneous, with recurrent involvement of sarcomeric, mitochondrial, and cytoskeletal genes. These defects can disturb cardiomyocyte organization, contraction, and wall maturation, and they also help explain the overlap between isolated LVNC and broader inherited cardiomyopathy syndromes.

cardiomyocyte CL:0000746

MYH7 hgnc:7577 TAFAZZIN hgnc:11577 NRAP hgnc:7988

muscle contraction GO:0006936 cell adhesion GO:0007155

Downstream

Cytoskeletal and excitation-contraction coupling disruption Structural gene defects disturb cardiomyocyte architecture and calcium handling.

Arrhythmogenic myocardial substrate Genetic defects also increase susceptibility to conduction disease and ventricular arrhythmia.

Show evidence (4 references)

PMID:34918480 SUPPORT Other

"To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion channels, and desmosomal proteins have been identified."

Supports broad genetic heterogeneity across key cardiomyocyte structural pathways in LVNC.

PMID:37565978 SUPPORT Human Clinical

"BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM)."

Provides direct clinical evidence that MYH7 is an established LVNC-associated cardiomyopathy gene.

PMID:30451719 SUPPORT Other

"A 2017 Chinese study, using next generation sequencing to investigate males and females with primary cardiomyopathy in a systematic fashion, showed that 6.5% of males with LVNC ± DCM had pathogenic TAZ mutations."

Supports TAFAZZIN as a recurrent syndromic gene in pediatric LVNC, especially when LVNC overlaps with Barth syndrome biology.

+ 1 more reference

Cytoskeletal and excitation-contraction coupling disruption

Beyond gross wall morphology, LVNC myocardium shows cytoskeletal disorganization with microtubule densification, junctophilin redistribution, T-tubule disruption, and impaired calcium handling. These changes provide a direct bridge from structural disease to heart failure.

cardiomyocyte CL:0000746

microtubule cytoskeleton organization GO:0000226 regulation of cardiac muscle contraction by calcium ion signaling GO:0010882

Downstream

Impaired ventricular contractile function T-tubule and calcium-handling defects reduce effective systolic function.

Show evidence (2 references)

PMID:32143182 SUPPORT Human Clinical

"FINDINGS: LVNC myocardial tissues feature strongly elevated expression of SORBS2, microtubule densification and redistribution of Junctophilin 2 (JP2)."

Supports an LVNC-specific cytoskeletal remodeling state in diseased human myocardium.

PMID:32143182 SUPPORT Model Organism

"In vivo, cardiac dysfunction, β-tubulin densification, JP2 translocation, T-tubule disorganization and Ca2+ handling dysfunction were observed in mice overexpressing SORBS2."

Provides mechanistic evidence that cytoskeletal remodeling can directly produce excitation-contraction coupling defects relevant to LVNC heart failure.

Impaired ventricular contractile function

LVNC commonly progresses to systolic dysfunction and heart failure. Reduced contractility may be both a consequence of abnormal compaction and a driver of later remodeling, symptoms, and device or transplant needs.

cardiomyocyte CL:0000746

Downstream

Congestive heart failure Reduced systolic contraction of a ventricle whose compact layer never thickened is what produces the heart-failure syndrome. In the cited cohort heart failure and arrhythmia were the two presenting syndromes, at 41.7% and 45.8% respectively, so this edge and the arrhythmia edge from the neighbouring node carry comparable weight.

Thromboembolic risk Ventricular dysfunction promotes blood stasis and embolic complications.

Show evidence (2 references)

PMID:35200702 SUPPORT Human Clinical

"We found that 40 patients show valvular regurgitation, 39 manifest reduced systolic contractions, and 46 out of the 46 present different forms of arrhythmias"

Supports the close association of LVNC with impaired ventricular contractility in clinical cohorts.

PMID:40182365 SUPPORT Human Clinical

"Severe left ventricular dysfunction (ejection fraction (EF) <20%) was confirmed,"

Provides direct clinical evidence for severe LV systolic dysfunction as a downstream manifestation of LVNC.

Arrhythmogenic myocardial substrate

LVNC is highly arrhythmogenic, with both supraventricular and ventricular arrhythmias reflecting abnormal myocardial architecture, conduction-system involvement, and gene-specific susceptibility.

cardiomyocyte CL:0000746

regulation of cardiac conduction GO:1903779 cardiac muscle cell action potential GO:0086001

Downstream

Arrhythmia The noncompacted myocardium is itself the arrhythmic substrate, so rhythm disturbance is a consequence of the structural lesion rather than an independent comorbidity.

Atrial fibrillation Atrial fibrillation occurs in noncompaction and is the rhythm that carries the embolic risk downstream of this node, but the route from the ventricular substrate to the atrial rhythm is not established. The largest series to address it concluded that the atria are not part of the noncompaction process, so this edge is not a claim that the same substrate extends into the atrium.

Syncope Syncope in LVNC is a consequence of the rhythm disturbance arising in this substrate rather than of the structural lesion directly.

Ventricular tachycardia The ventricular arm of the same substrate, and the rhythm that carries the sudden-death risk.

Sudden cardiac death Sudden death is the terminal outcome of the arrhythmias arising in this substrate, so the edge runs through the rhythm rather than directly from the structural lesion.

Thromboembolic risk Atrial fibrillation and severe rhythm disease add embolic risk.

Show evidence (2 references)

PMID:25537996 SUPPORT Human Clinical

"While electrocardiographic abnormalities are frequent in isolated ventricular noncompaction, no specific patterns were identified. More large studies are needed for stratification of arrhythmic risk of this highly arrhythmogenic substrate."

Directly supports LVNC as a structurally arrhythmogenic cardiomyopathy.

PMID:25537996 SUPPORT Human Clinical

"RESULTS: The mean age was 42.7±13.1 years. Patients were first presented with heart failure in 41.7% and arrhythmia in 45.8%."

Supports arrhythmia as a common presenting clinical consequence of the LVNC substrate.

Thromboembolic risk

Deep recesses, atrial fibrillation, and systolic dysfunction together increase thromboembolic risk in LVNC. This complication influences both prognosis and treatment strategy.

blood coagulation GO:0007596

Show evidence (2 references)

PMID:34918480 SUPPORT Other

"Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events."

Supports thromboembolic events as a core downstream clinical risk in LVNC.

PMID:34918480 SUPPORT Other

"Left ventricular dysfunction is another risk factor for thromboembolism, as a result of blood stagnation and local myocardial injury."

Directly supports the mechanistic link from LV dysfunction to thromboembolism in LVNC.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Congestive heart failure Cardiovascular HP:0001635

Show evidence (1 reference)

PMID:34918480 SUPPORT Other

"Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events."

Supports heart failure as one of the dominant clinical outcomes of LVNC.

Arrhythmia Cardiovascular HP:0011675

Show evidence (1 reference)

PMID:25537996 SUPPORT Human Clinical

"RESULTS: The mean age was 42.7±13.1 years. Patients were first presented with heart failure in 41.7% and arrhythmia in 45.8%."

Supports arrhythmia as a common presenting phenotype in LVNC.

Ventricular tachycardia Cardiovascular HP:0004756

Show evidence (1 reference)

PMID:25537996 SUPPORT Human Clinical

"RESULTS: The mean age was 42.7±13.1 years. Patients were first presented with heart failure in 41.7% and arrhythmia in 45.8%. Electrocardiogram was abnormal in 91.6% of patients; the most common anomaly was left bundle branch block (LBBB) (41.7%), followed by supraventricular arrhythmias..."

Provides explicit cohort-level support for ventricular tachycardia in LVNC.

Atrial fibrillation Cardiovascular HP:0005110

Show evidence (1 reference)

PMID:40182365 SUPPORT Human Clinical

"We present the case of a 77-year-old male with chronic atrial fibrillation and nonischemic cardiomyopathy who was found to have severe LVNC,"

Supports atrial fibrillation as a clinically important rhythm phenotype in LVNC.

Syncope Neurologic HP:0001279

Show evidence (1 reference)

PMID:25537996 SUPPORT Human Clinical

"The first presentation symptom was dyspnea in 45.8%, followed by palpitation (33.3%), syncope (8.3%), and chest pain (4.2%)."

Supports syncope as a recognized presenting phenotype in LVNC.

Sudden cardiac death Cardiovascular HP:0001645

Show evidence (1 reference)

PMID:34918480 SUPPORT Other

"Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events."

Supports sudden cardiac death as one of the severe adverse outcomes in LVNC.

🧬

Genetic Associations

MIB1 (Causative)

Gene: MIB1 hgnc:21086 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (1 reference)

PMID:23314057 SUPPORT Human Clinical

"We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression..."

The gene-disease assertion, its inheritance mode, and the signalling consequence measured in the affected individuals themselves.

DTNA (Reported in a single pedigree)

Gene: DTNA hgnc:3057 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:11238270 SUPPORT Human Clinical

"In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha-dystrobrevin, changing a proline to leucine (P121L)."

The whole primary human evidence for the DTNA-LVNC relationship: one family, one missense variant, and a phenotype that included congenital heart disease.

PMID:11238270 SUPPORT Human Clinical

"These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD."

The authors' own scoping of the claim, which restricts it to LVNC associated with congenital heart disease rather than isolated LVNC.

MYH7 (Pathogenic Variants)

Gene: MYH7 hgnc:7577 gene page

Show evidence (1 reference)

PMID:37565978 SUPPORT Human Clinical

"BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM)."

Supports MYH7 as a recurrent sarcomeric gene associated with LVNC.

TAFAZZIN (Pathogenic Variants)

Gene: TAFAZZIN hgnc:11577 gene page

Show evidence (1 reference)

PMID:30451719 SUPPORT Other

Supports TAFAZZIN as a recurrent syndromic LVNC-associated gene.

NRAP (Loss-of-function variants)

Gene: NRAP hgnc:7988 gene page

Show evidence (1 reference)

PMID:36815016 SUPPORT Human Clinical

"CONCLUSION: We identified a rare case of LVNC associated with a novel homozygous NRAP frameshift variant."

Supports NRAP as a pathogenic LVNC-associated gene in a rare familial case with functional follow-up.

TTN (Candidate variant reported in a single LVNC cohort)

Gene: TTN hgnc:12403 gene page relationship_type: UNKNOWN

Show evidence (3 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places TTN among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the TTN relationship is recorded as UNKNOWN rather than pathogenic.

PMID:34918480 SUPPORT BACKGROUND Human Clinical

"A strong genotype–phenotype correlation has been reported for Hyperpolarization Activated Cyclic Nucleotide gated potassium channel 4 (HCN4), Titin (TTN), and Lamin A/C (LMNA) mutations, with a high incidence of heart failure (HF) and ventricular arrhythmias."

Peer-reviewed support, independent of the preprint cohort, that TTN is a recurrent noncompaction cardiomyopathy locus with a reported genotype-phenotype correlation.

CTNNA3 (Candidate variant reported in a single LVNC cohort)

Gene: CTNNA3 hgnc:2511 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places CTNNA3 among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the CTNNA3 relationship is recorded as UNKNOWN rather than pathogenic.

DSG2 (Candidate variant reported in a single LVNC cohort)

Gene: DSG2 hgnc:3049 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places DSG2 among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the DSG2 relationship is recorded as UNKNOWN rather than pathogenic.

FLNC (Candidate variant reported in a single LVNC cohort)

Gene: FLNC hgnc:3756 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places FLNC among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the FLNC relationship is recorded as UNKNOWN rather than pathogenic.

JPH2 (Candidate variant reported in a single LVNC cohort)

Gene: JPH2 hgnc:14202 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places JPH2 among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the JPH2 relationship is recorded as UNKNOWN rather than pathogenic.

NKX2-6 (Candidate variant reported in a single LVNC cohort)

Gene: NKX2-6 hgnc:32940 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places NKX2-6 among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the NKX2-6 relationship is recorded as UNKNOWN rather than pathogenic.

TNNC1 (Candidate variant reported in a single LVNC cohort)

Gene: TNNC1 hgnc:11943 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places TNNC1 among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the TNNC1 relationship is recorded as UNKNOWN rather than pathogenic.

JUP (Candidate variant reported in a single LVNC cohort)

Gene: JUP hgnc:6207 gene page relationship_type: UNKNOWN

Show evidence (2 references)

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP)."

Places JUP among the nine genes in which variants were detected in this 25-patient LVNC cohort, which is what this record claims.

PPR:PPR1287587 Preprint · not peer-reviewed SUPPORT Human Clinical

"were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5)."

The cohort's 14 variants span pathogenic, likely pathogenic and uncertain classes, and the abstract gives no per-gene breakdown, so the JUP relationship is recorded as UNKNOWN rather than pathogenic.

💊

Medical Actions

Guideline-directed heart failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

No disease-modifying therapy reverses LVNC, so treatment focuses on heart failure symptom control with standard pharmacologic regimens such as ACE inhibitors and beta blockers when ventricular dysfunction is present.

Mechanism Target:

Impaired ventricular contractile function — Symptomatic therapy is directed at the downstream heart-failure phenotype produced by LV dysfunction.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (2 references)

PMID:37215603 SUPPORT Other

"Currently, no effective treatment strategy exists to reduce its incidence or severity, and symptomatic treatment is the only clinical treatment strategy."

Supports the current treatment paradigm of symptom-directed rather than disease-reversing pharmacotherapy in LVNC.

PMID:40182365 SUPPORT Human Clinical

"Management included pharmacologic rate control for atrial fibrillation, electrical cardioversion, and guideline-directed therapy for heart failure with reduced EF, ultimately leading to implantable cardioverter-defibrillator placement for primary prevention of sudden cardiac death."

This directly supports standard symptom-directed heart-failure pharmacotherapy as part of LVNC management.

Anticoagulation therapy for thromboembolic risk

Action: Pharmacotherapy NCIT:C15986

Anticoagulation is considered when LVNC patients have atrial fibrillation, left ventricular dysfunction, prior embolism, or other high-risk features that increase the probability of intracardiac stasis and embolization.

Mechanism Target:

Thromboembolic risk — Anticoagulation is used to mitigate embolic risk arising from recesses, atrial fibrillation, and ventricular dysfunction.

Target Phenotypes: Thromboembolism HP:0001907

Show evidence (1 reference)

PMID:34918480 SUPPORT Other

"For the clinical management of NCCM patients, an appropriate stratification of the thromboembolic risk is of utmost importance for a timely initiation of anticoagulant therapy."

Directly supports anticoagulation as a mechanism-based management strategy in selected LVNC patients.

Implantable cardioverter-defibrillator placement

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

ICD placement is used for primary or secondary sudden-death prevention in patients with severe systolic dysfunction or malignant ventricular arrhythmia risk.

Mechanism Target:

Arrhythmogenic myocardial substrate — Device therapy interrupts the malignant arrhythmic consequences of the LVNC substrate.

Target Phenotypes: Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:40182365 SUPPORT Human Clinical

Directly supports ICD placement for sudden-death prevention in advanced LVNC.

Heart transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Transplantation is reserved for end-stage disease when heart failure or refractory complications progress despite maximal medical and device therapy.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:38933059 SUPPORT Human Clinical

"At 8 months of age, cardiac transplantation was successfully done and baby has been doing well post-transplantation."

Supports heart transplantation as a salvage therapy in severe LVNC.

🔬

Diagnosis

Echocardiographic diagnosis of trabeculated two-layer myocardium

Echocardiography is a first-line imaging modality for identifying the noncompacted and compacted myocardial layers and for assessing systolic dysfunction.

diagnostic procedure NCIT:C18020

Show evidence (1 reference)

PMID:40182365 SUPPORT Human Clinical

"We present the case of a 77-year-old male with chronic atrial fibrillation and nonischemic cardiomyopathy who was found to have severe LVNC, identified on echocardiography and cardiac MRI using a noncompacted-to-compacted myocardial thickness ratio >2.3 at end-systole."

Directly supports echocardiography as a core diagnostic imaging tool for LVNC.

Cardiac magnetic resonance imaging confirmation

Cardiac MRI provides higher-resolution structural assessment, confirms the trabeculation-to-compaction ratio, and helps characterize myocardial involvement and fibrosis.

diagnostic procedure NCIT:C18020

Show evidence (1 reference)

PMID:25537996 SUPPORT Human Clinical

"Actually, CMR is the technique of choice for the diagnosis of IVNC."

Supports cardiac MRI as the preferred confirmatory imaging modality in LVNC.

Genetic testing for inherited cardiomyopathy

Genetic testing helps define inherited disease, identify overlap syndromes, and support family counseling in a genetically heterogeneous cardiomyopathy.

diagnostic procedure NCIT:C18020

Show evidence (1 reference)

PMID:34918480 SUPPORT Other

"To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion channels, and desmosomal proteins have been identified."

Supports the clinical value of genetic testing in a highly heterogeneous inherited cardiomyopathy.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Left ventricular noncompaction:

Dilated cardiomyopathy MONDO:0005021

Overlapping Features Dilated cardiomyopathy may share ventricular dysfunction and chamber remodeling with LVNC, especially when trabeculation is prominent, but lacks the characteristic diagnostic two-layer noncompaction phenotype.

Distinguishing Features

LV dilation and systolic dysfunction without canonical noncompacted-to-compacted morphology
Trabeculations are not the primary defining feature
Diagnosis depends more on dilation and contractile impairment than on recess architecture

Show evidence (1 reference)

PMID:23361305 SUPPORT Other

"characteristic echocardiographic appearance may help to differentiate LVNC from other forms of cardiomyopathy like apical hypertrophic or dilated cardiomyopathy in patients with impaired left ventricular systolic function."

Directly supports dilated cardiomyopathy as a key structural mimic in the differential diagnosis of LVNC.

Hypertrophic cardiomyopathy MONDO:0005045

Overlapping Features Hypertrophic cardiomyopathy can overlap with LVNC when trabeculations and thickened myocardium coexist, but the dominant phenotype is hypertrophy rather than noncompaction.

Distinguishing Features

Dominant wall thickening and hypertrophy rather than a noncompacted spongy layer
Distinct sarcomeric hypertrophic remodeling pattern
Imaging interpretation depends on whether hypertrophy or noncompaction is primary

Show evidence (1 reference)

PMID:23361305 SUPPORT Other

Directly identifies hypertrophic cardiomyopathy as another important imaging and clinical mimic.

📊

Related Datasets

Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy geo:GSE71912

Public LVNC transcriptomic dataset reused in integrative bioinformatic analyses of myocardial disease mechanisms and candidate biomarkers.

mouse MICROARRAY

Conditions: left ventricular noncompaction cardiomyopathy

PMID:40618167

Show evidence (1 reference)

PMID:40618167 SUPPORT Computational

"The datasets GSE71912 and GSE113251 of left ventricular noncompaction cardiomyopathy were downloaded from the gene expression omnibus (GEO) database generated from GPL13912 and GPL11002 platforms."

Supports GSE71912 as a public LVNC dataset used for disease-mechanism discovery.

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy geo:GSE113251

Public LVNC transcriptomic dataset used alongside GSE71912 for differential expression, co-expression, and hub-gene analysis.

mouse MICROARRAY

Conditions: left ventricular noncompaction cardiomyopathy

PMID:40618167

Show evidence (1 reference)

PMID:40618167 SUPPORT Computational

"The datasets GSE71912 and GSE113251 of left ventricular noncompaction cardiomyopathy were downloaded from the gene expression omnibus (GEO) database generated from GPL13912 and GPL11002 platforms."

Supports GSE113251 as a second public LVNC dataset used in integrated computational analyses.

🔬

Clinical Trials

NCT05281315 NOT_APPLICABLE COMPLETED

Retrospective follow-up study evaluating cardiac MRI features, clinical characteristics, and outcomes in patients with noncompaction cardiomyopathy from Pakistan.

Target Phenotypes: Arrhythmia HP:0011675 Congestive heart failure HP:0001635

Show evidence (1 reference)

clinicaltrials:NCT05281315 SUPPORT Human Clinical

"Objective: To evaluate clinical characteristics, cardiac magnetic resonance imaging features, and outcomes of patients with left ventricle non-compaction."

Supports a disease-specific registered clinical study centered on MRI phenotype and clinical outcomes in LVNC.

{ }

Source YAML

click to show

name: Left ventricular noncompaction
creation_date: "2026-04-21T14:07:20Z"
category: Cardiovascular Disorder
description: >-
  Left ventricular noncompaction (LVNC) is a cardiomyopathy marked by excessive
  trabeculation and deep intertrabecular recesses in a two-layered ventricular
  wall. Disease biology spans developmental noncompaction, genetic defects in
  sarcomeric and cytoskeletal programs, and downstream heart failure,
  arrhythmia, and thromboembolic risk.
disease_term:
  preferred_term: left ventricular noncompaction
  term:
    id: MONDO:0018901
    label: left ventricular noncompaction
synonyms:
- LVNC
- noncompaction cardiomyopathy
- noncompaction of the ventricular myocardium
parents:
- Cardiomyopathy
- Cardiovascular Disorder
has_subtypes:
- name: LVNC1
  display_name: Left ventricular noncompaction 1 (DTNA-related)
  subtype_term:
    preferred_term: left ventricular noncompaction 1
    term:
      id: MONDO:0011403
      label: left ventricular noncompaction 1
  genes:
  - preferred_term: DTNA
    term:
      id: hgnc:3057
      label: DTNA
  description: >-
    The locus MONDO and OMIM number LVNC1, attributed to DTNA. It is listed here to
    make the numbered series navigable and to hold the gene, not because the
    relationship is settled: the whole primary evidence is one family carrying a
    single alpha-dystrobrevin missense change, in whom LVNC occurred together with
    congenital heart disease. See the DTNA genetic record for the full caveat.
- name: LVNC7
  display_name: Left ventricular noncompaction 7 (MIB1-related)
  subtype_term:
    preferred_term: left ventricular noncompaction 7
    term:
      id: MONDO:0014042
      label: left ventricular noncompaction 7
  genes:
  - preferred_term: MIB1
    term:
      id: hgnc:21086
      label: MIB1
  description: >-
    The MIB1 form, numbered LVNC7. Mechanistically it is the best-resolved arm of
    this entry and the only one that acts on compaction itself: loss of MIB1
    ubiquitin-ligase activity reduces NOTCH1 signalling and arrests chamber
    myocardium development, so trabeculae never mature and the compact layer never
    thickens. Autosomal dominant, with the mouse myocardial knockout reproducing the
    human structural phenotype.
pathophysiology:
- name: Incomplete ventricular compaction and excessive trabeculation
  description: >-
    The core structural lesion of LVNC is failure of the compact myocardial
    layer to mature normally, leaving a thick noncompacted trabecular layer with
    deep recesses overlying a thinner compacted wall. This developmental
    abnormality creates the characteristic spongy ventricular phenotype.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac ventricle morphogenesis
    term:
      id: GO:0003208
      label: cardiac ventricle morphogenesis
  - preferred_term: cardiac muscle tissue morphogenesis
    term:
      id: GO:0055008
      label: cardiac muscle tissue morphogenesis
  locations:
  - preferred_term: left ventricle myocardium
    term:
      id: UBERON:0006566
      label: left ventricle myocardium
  genes:
  - preferred_term: MIB1
    term:
      id: hgnc:21086
      label: MIB1
  evidence:
  - reference: PMID:23314057
    reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results implicate NOTCH signaling in LVNC and indicate that MIB1
      mutations arrest chamber myocardium development, preventing trabecular
      maturation and compaction.
    explanation: >-
      Names the failure of trabecular maturation and compaction that is this node,
      and places MIB1 loss upstream of it, which is why the gene is bound here
      rather than on the structural-protein node.
  - reference: PMID:23314057
    reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype
      mimicked by inactivation of myocardial Jagged1 or endocardial Notch1.
    explanation: >-
      The animal evidence that the MIB1 lesion is sufficient for this structural
      node, and that it acts through the NOTCH ligand-receptor axis rather than
      through a sarcomeric route.
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Left ventricular noncompaction (LVNC) involves abnormal development of
      the heart muscle, where the inner layer remains excessively trabeculated
      instead of compacting properly.
    explanation: >-
      Directly supports abnormal ventricular compaction as the primary structural
      mechanism of LVNC.
  - reference: PMID:40618167
    reference_title: "Role of Col1a2 and Postn in left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC) is a
      rare myocardial developmental anomaly characterized by incomplete
      myocardial compact layer development in the left ventricular wall,
      resulting in a multilayered trabeculated myocardium.
    explanation: >-
      Independently supports the developmental noncompaction model from a
      transcriptomic analysis study.
  downstream:
  - target: Genetic perturbation of cardiomyocyte structural programs
    description: >-
      Mutations in sarcomeric, cytoskeletal, mitochondrial, and conduction genes
      predispose to abnormal ventricular wall development.
  - target: Impaired ventricular contractile function
    description: >-
      The abnormal wall architecture increases risk of ventricular dysfunction
      and heart failure.
  - target: Arrhythmogenic myocardial substrate
    description: >-
      Structural irregularity and persistent trabeculation create an
      arrhythmogenic substrate.
- name: Genetic perturbation of cardiomyocyte structural programs
  description: >-
    LVNC is genetically heterogeneous, with recurrent involvement of sarcomeric,
    mitochondrial, and cytoskeletal genes. These defects can disturb
    cardiomyocyte organization, contraction, and wall maturation, and they also
    help explain the overlap between isolated LVNC and broader inherited
    cardiomyopathy syndromes.
  genes:
  - preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  - preferred_term: TAFAZZIN
    term:
      id: hgnc:11577
      label: TAFAZZIN
  - preferred_term: NRAP
    term:
      id: hgnc:7988
      label: NRAP
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
  - preferred_term: cell adhesion
    term:
      id: GO:0007155
      label: cell adhesion
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion
      channels, and desmosomal proteins have been identified.
    explanation: >-
      Supports broad genetic heterogeneity across key cardiomyocyte structural
      pathways in LVNC.
  - reference: PMID:37565978
    reference_title: "Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM),
      noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM).
    explanation: >-
      Provides direct clinical evidence that MYH7 is an established LVNC-associated
      cardiomyopathy gene.
  - reference: PMID:30451719
    reference_title: "Neutropenia in Barth syndrome: characteristics, risks, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A 2017 Chinese study, using next generation sequencing to investigate
      males and females with primary cardiomyopathy in a systematic fashion,
      showed that 6.5% of males with LVNC ± DCM had pathogenic TAZ mutations.
    explanation: >-
      Supports TAFAZZIN as a recurrent syndromic gene in pediatric LVNC,
      especially when LVNC overlaps with Barth syndrome biology.
  - reference: PMID:36815016
    reference_title: "A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA-sequencing (RNA-seq) showed that the expression of genes related to
      heart development decreased significantly, and the NRAP gene mutation
      could participate in biological processes (BPs) such as myocardial
      contraction, cell adhesion, myosin coarse filament assembly of striated
      muscle, myosin complex composition, and muscle α-actin binding.
    explanation: >-
      Provides functional evidence that NRAP-linked LVNC perturbs cardiomyocyte
      structural and contractile programs.
  downstream:
  - target: Cytoskeletal and excitation-contraction coupling disruption
    description: >-
      Structural gene defects disturb cardiomyocyte architecture and calcium
      handling.
  - target: Arrhythmogenic myocardial substrate
    description: >-
      Genetic defects also increase susceptibility to conduction disease and
      ventricular arrhythmia.
- name: Cytoskeletal and excitation-contraction coupling disruption
  description: >-
    Beyond gross wall morphology, LVNC myocardium shows cytoskeletal
    disorganization with microtubule densification, junctophilin
    redistribution, T-tubule disruption, and impaired calcium handling. These
    changes provide a direct bridge from structural disease to heart failure.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
  - preferred_term: regulation of cardiac muscle contraction by calcium ion signaling
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
  evidence:
  - reference: PMID:32143182
    reference_title: "Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FINDINGS: LVNC myocardial tissues feature strongly elevated expression of
      SORBS2, microtubule densification and redistribution of Junctophilin 2
      (JP2).
    explanation: >-
      Supports an LVNC-specific cytoskeletal remodeling state in diseased human
      myocardium.
  - reference: PMID:32143182
    reference_title: "Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In vivo, cardiac dysfunction, β-tubulin densification, JP2 translocation,
      T-tubule disorganization and Ca2+ handling dysfunction were observed in
      mice overexpressing SORBS2.
    explanation: >-
      Provides mechanistic evidence that cytoskeletal remodeling can directly
      produce excitation-contraction coupling defects relevant to LVNC heart
      failure.
  downstream:
  - target: Impaired ventricular contractile function
    description: >-
      T-tubule and calcium-handling defects reduce effective systolic function.
- name: Impaired ventricular contractile function
  description: >-
    LVNC commonly progresses to systolic dysfunction and heart failure. Reduced
    contractility may be both a consequence of abnormal compaction and a driver
    of later remodeling, symptoms, and device or transplant needs.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35200702
    reference_title: "Left Ventricular Noncompaction Is Associated with Valvular Regurgitation and a Variety of Arrhythmias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that 40 patients show valvular regurgitation, 39 manifest
      reduced systolic contractions, and 46 out of the 46 present different
      forms of arrhythmias
    explanation: >-
      Supports the close association of LVNC with impaired ventricular
      contractility in clinical cohorts.
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe left ventricular dysfunction (ejection fraction (EF) <20%) was
      confirmed,
    explanation: >-
      Provides direct clinical evidence for severe LV systolic dysfunction as a
      downstream manifestation of LVNC.
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
    description: >-
      Reduced systolic contraction of a ventricle whose compact layer never
      thickened is what produces the heart-failure syndrome. In the cited cohort
      heart failure and arrhythmia were the two presenting syndromes, at 41.7% and
      45.8% respectively, so this edge and the arrhythmia edge from the neighbouring
      node carry comparable weight.
    evidence:
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RESULTS: The mean age was 42.7±13.1 years. Patients were first presented
        with heart failure in 41.7% and arrhythmia in 45.8%.
      explanation: >-
        Heart failure was one of the two presenting syndromes in an
        isolated-noncompaction cohort, in 41.7% of patients, and is the clinical
        expression of the systolic dysfunction this node describes.
  - target: Thromboembolic risk
    description: >-
      Ventricular dysfunction promotes blood stasis and embolic complications.
- name: Arrhythmogenic myocardial substrate
  description: >-
    LVNC is highly arrhythmogenic, with both supraventricular and ventricular
    arrhythmias reflecting abnormal myocardial architecture, conduction-system
    involvement, and gene-specific susceptibility.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of cardiac conduction
    term:
      id: GO:1903779
      label: regulation of cardiac conduction
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
  evidence:
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While electrocardiographic abnormalities are frequent in isolated
      ventricular noncompaction, no specific patterns were identified. More
      large studies are needed for stratification of arrhythmic risk of this
      highly arrhythmogenic substrate.
    explanation: >-
      Directly supports LVNC as a structurally arrhythmogenic cardiomyopathy.
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RESULTS: The mean age was 42.7±13.1 years. Patients were first presented
      with heart failure in 41.7% and arrhythmia in 45.8%.
    explanation: >-
      Supports arrhythmia as a common presenting clinical consequence of the
      LVNC substrate.
  downstream:
  - target: Arrhythmia
    causal_link_type: DIRECT
    description: >-
      The noncompacted myocardium is itself the arrhythmic substrate, so rhythm
      disturbance is a consequence of the structural lesion rather than an
      independent comorbidity.
    evidence:
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While electrocardiographic abnormalities are frequent in isolated
        ventricular noncompaction, no specific patterns were identified. More
        large studies are needed for stratification of arrhythmic risk of this
        highly arrhythmogenic substrate.
      explanation: >-
        Names the substrate as highly arrhythmogenic while recording that no single
        electrocardiographic pattern characterises it, which is why this edge
        targets arrhythmia generally rather than one rhythm.
  - target: Atrial fibrillation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Atrial fibrillation occurs in noncompaction and is the rhythm that carries the
      embolic risk downstream of this node, but the route from the ventricular
      substrate to the atrial rhythm is not established. The largest series to
      address it concluded that the atria are not part of the noncompaction process,
      so this edge is not a claim that the same substrate extends into the atrium.
    evidence:
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In a large series (21), they identified 9 patients with atrial fibrillation
        among 238 patients affected by noncompaction.
      explanation: >-
        Cohort-level occurrence of atrial fibrillation among patients with
        noncompaction, which is what this edge records. The sentence restates a
        series this paper cites rather than its own patients, and it establishes
        co-occurrence at cohort scale, not the mechanism.
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: REFUTE
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The authors concluded that the atria are not involved in the noncompaction
        process
      explanation: >-
        Refutes the stronger reading of this edge - that the noncompaction substrate
        itself extends into the atrium. Recorded rather than omitted, because it is
        the conclusion of the largest series on the question and it is why this edge
        is typed with unknown intermediates. The source qualifies it, concluding
        this "when the majority of patients has dilated cardiomyopathy", so it
        refutes atrial involvement in that population rather than universally.
  - target: Syncope
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - transient arrhythmia with loss of effective cardiac output
    description: >-
      Syncope in LVNC is a consequence of the rhythm disturbance arising in this
      substrate rather than of the structural lesion directly.
    evidence:
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The first presentation symptom was dyspnea in 45.8%, followed by
        palpitation (33.3%), syncope (8.3%), and chest pain (4.2%).
      explanation: >-
        Records syncope among the presenting symptoms of the same cohort, beside the
        palpitation that marks the rhythm disturbance this edge routes through.
  - target: Ventricular tachycardia
    causal_link_type: DIRECT
    description: >-
      The ventricular arm of the same substrate, and the rhythm that carries the
      sudden-death risk.
    evidence:
    - reference: PMID:25537996
      reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Electrocardiogram was abnormal in 91.6% of patients; the most common anomaly
        was left bundle branch block (LBBB) (41.7%), followed by supraventricular
        arrhythmias (29.1%), repolarization abnormalities (29.1%), and ventricular
        tachycardia (20.8%).
      explanation: >-
        Records ventricular tachycardia in a fifth of an isolated-noncompaction
        cohort, alongside the conduction and repolarization abnormalities that
        describe the same substrate.
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - sustained ventricular arrhythmia degenerating to cardiac arrest
    description: >-
      Sudden death is the terminal outcome of the arrhythmias arising in this
      substrate, so the edge runs through the rhythm rather than directly from the
      structural lesion.
    evidence:
    - reference: PMID:34918480
      reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Clinical presentation is also highly variable, ranging from no symptoms to
        end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or
        thromboembolic events.
      explanation: >-
        Places lethal arrhythmia and sudden cardiac death together at the severe end
        of the LVNC spectrum, which is the ordering this edge's intermediate records.
  - target: Thromboembolic risk
    description: >-
      Atrial fibrillation and severe rhythm disease add embolic risk.
- name: Thromboembolic risk
  description: >-
    Deep recesses, atrial fibrillation, and systolic dysfunction together
    increase thromboembolic risk in LVNC. This complication influences both
    prognosis and treatment strategy.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical presentation is also highly variable, ranging from no symptoms
      to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac
      death, or thromboembolic events.
    explanation: >-
      Supports thromboembolic events as a core downstream clinical risk in LVNC.
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Left ventricular dysfunction is another risk factor for thromboembolism,
      as a result of blood stagnation and local myocardial injury.
    explanation: >-
      Directly supports the mechanistic link from LV dysfunction to
      thromboembolism in LVNC.
phenotypes:
- name: Congestive heart failure
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical presentation is also highly variable, ranging from no symptoms
      to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac
      death, or thromboembolic events.
    explanation: >-
      Supports heart failure as one of the dominant clinical outcomes of LVNC.
- name: Arrhythmia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RESULTS: The mean age was 42.7±13.1 years. Patients were first presented
      with heart failure in 41.7% and arrhythmia in 45.8%.
    explanation: >-
      Supports arrhythmia as a common presenting phenotype in LVNC.
- name: Ventricular tachycardia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RESULTS: The mean age was 42.7±13.1 years. Patients were first presented
      with heart failure in 41.7% and arrhythmia in 45.8%. Electrocardiogram
      was abnormal in 91.6% of patients; the most common anomaly was left
      bundle branch block (LBBB) (41.7%), followed by supraventricular
      arrhythmias (29.1%), repolarization abnormalities (29.1%), and
      ventricular tachycardia (20.8%).
    explanation: >-
      Provides explicit cohort-level support for ventricular tachycardia in
      LVNC.
- name: Atrial fibrillation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the case of a 77-year-old male with chronic atrial
      fibrillation and nonischemic cardiomyopathy who was found to have severe
      LVNC,
    explanation: >-
      Supports atrial fibrillation as a clinically important rhythm phenotype in
      LVNC.
- name: Syncope
  category: Neurologic
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first presentation symptom was dyspnea in 45.8%, followed by
      palpitation (33.3%), syncope (8.3%), and chest pain (4.2%).
    explanation: >-
      Supports syncope as a recognized presenting phenotype in LVNC.
- name: Sudden cardiac death
  category: Cardiovascular
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical presentation is also highly variable, ranging from no symptoms
      to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac
      death, or thromboembolic events.
    explanation: >-
      Supports sudden cardiac death as one of the severe adverse outcomes in
      LVNC.
biochemical: []
genetic:
- name: MIB1
  gene_term:
    preferred_term: MIB1
    term:
      id: hgnc:21086
      label: MIB1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: LVNC7
  inheritance:
  - name: Autosomal dominant
  notes: >-
    MIB1 encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH
    ligands DELTA and JAGGED. Germline MIB1 mutations segregate in
    autosomal-dominant LVNC pedigrees, and the founding report ties them to a
    mechanism rather than to an association alone: affected individuals show
    reduced NOTCH1 activity, the mutations disrupt MIB1 dimerisation, and
    myocardium-specific Mib1 inactivation in mouse reproduces LVNC. This is the one
    gene in this entry whose lesion acts on ventricular compaction itself rather
    than on cardiomyocyte structural proteins, which is why it is bound to the
    compaction node. ClinGen's committed Gene-Disease Validity record for MIB1 is
    for a different disease, dilated cardiomyopathy graded Limited, so it neither
    supports nor weakens the LVNC claim.
  evidence:
  - reference: PMID:23314057
    reference_title: "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that germline mutations in human MIB1 (mindbomb homolog 1), which
      encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands
      DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected
      individuals showing reduced NOTCH1 activity and reduced expression of target
      genes.
    explanation: >-
      The gene-disease assertion, its inheritance mode, and the signalling
      consequence measured in the affected individuals themselves.
- name: DTNA
  gene_term:
    preferred_term: DTNA
    term:
      id: hgnc:3057
      label: DTNA
  association: Reported in a single pedigree
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: LVNC1
  notes: >-
    DTNA encodes alpha-dystrobrevin, a dystrophin-glycoprotein-complex protein.
    MONDO designates the DTNA form LVNC1, but the evidence behind that designation
    is thin and is recorded here as such: the founding report identified a single
    P121L missense change in one family, and that family had LVNC together with
    congenital heart disease rather than isolated LVNC. No ClinGen Gene-Disease
    Validity assertion for DTNA is present in this repository's committed ClinGen
    cache, so the relationship is typed UNKNOWN in line with this entry's other
    single-report genes rather than CAUSATIVE.
  evidence:
  - reference: PMID:11238270
    reference_title: "Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide
      362 of alpha-dystrobrevin, changing a proline to leucine (P121L).
    explanation: >-
      The whole primary human evidence for the DTNA-LVNC relationship: one family,
      one missense variant, and a phenotype that included congenital heart disease.
  - reference: PMID:11238270
    reference_title: "Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel
      gene, alpha-dystrobrevin, identified in LVNC associated with CHD.
    explanation: >-
      The authors' own scoping of the claim, which restricts it to LVNC associated
      with congenital heart disease rather than isolated LVNC.
- name: MYH7
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  association: Pathogenic Variants
  notes: >-
    MYH7 is one of the best-established sarcomeric genes in inherited LVNC and
    overlaps with hypertrophic and dilated cardiomyopathy phenotypes.
  evidence:
  - reference: PMID:37565978
    reference_title: "Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM),
      noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM).
    explanation: >-
      Supports MYH7 as a recurrent sarcomeric gene associated with LVNC.
- name: TAFAZZIN
  gene_term:
    preferred_term: TAFAZZIN
    term:
      id: hgnc:11577
      label: TAFAZZIN
  association: Pathogenic Variants
  notes: >-
    TAFAZZIN-associated Barth syndrome is a clinically important syndromic cause
    of LVNC, particularly in pediatric male patients with overlapping dilated
    cardiomyopathy biology.
  evidence:
  - reference: PMID:30451719
    reference_title: "Neutropenia in Barth syndrome: characteristics, risks, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A 2017 Chinese study, using next generation sequencing to investigate
      males and females with primary cardiomyopathy in a systematic fashion,
      showed that 6.5% of males with LVNC ± DCM had pathogenic TAZ mutations.
    explanation: >-
      Supports TAFAZZIN as a recurrent syndromic LVNC-associated gene.
- name: NRAP
  gene_term:
    preferred_term: NRAP
    term:
      id: hgnc:7988
      label: NRAP
  association: Loss-of-function variants
  notes: >-
    NRAP loss-of-function impairs myocardial development and supports a causal
    cytoskeletal disease mechanism in at least a subset of LVNC.
  evidence:
  - reference: PMID:36815016
    reference_title: "A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSION: We identified a rare case of LVNC associated with a novel
      homozygous NRAP frameshift variant.
    explanation: >-
      Supports NRAP as a pathogenic LVNC-associated gene in a rare familial
      case with functional follow-up.
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    TTN encodes titin, the giant sarcomeric filament protein, and is an established
    locus in inherited cardiomyopathies. In this source TTN is one of nine genes in
    which variants were detected across a 25-patient LVNC cohort; the abstract does
    not report which ACMG class was assigned to the TTN variant, so this record does
    not assert pathogenicity on the strength of this unreplicated preprint. TTN's
    standing as a recurrent LVNC locus rests on the separate peer-reviewed evidence
    cited below, not on this cohort.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places TTN among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the TTN
      relationship is recorded as UNKNOWN rather than pathogenic.
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      A strong genotype–phenotype correlation has been reported for
      Hyperpolarization Activated Cyclic Nucleotide gated potassium channel 4
      (HCN4), Titin (TTN), and Lamin A/C (LMNA) mutations, with a high incidence
      of heart failure (HF) and ventricular arrhythmias.
    explanation: >-
      Peer-reviewed support, independent of the preprint cohort, that TTN is a
      recurrent noncompaction cardiomyopathy locus with a reported
      genotype-phenotype correlation.
- name: CTNNA3
  gene_term:
    preferred_term: CTNNA3
    term:
      id: hgnc:2511
      label: CTNNA3
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    CTNNA3 encodes alpha-T-catenin, an adherens junction protein of the cardiomyocyte
    intercalated disc. Reported here as a candidate: a variant was detected in a
    25-patient LVNC cohort. The source reports a variant, not a functional study, so
    no adhesion mechanism is asserted, and the abstract does not give the per-gene
    ACMG classification.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places CTNNA3 among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the CTNNA3
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: DSG2
  gene_term:
    preferred_term: DSG2
    term:
      id: hgnc:3049
      label: DSG2
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    DSG2 encodes desmoglein-2, a desmosomal cadherin, and is an established
    arrhythmogenic cardiomyopathy gene. Reported here as an LVNC candidate on the
    strength of a variant detected in a 25-patient cohort; the abstract does not
    report which ACMG class that variant received.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places DSG2 among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the DSG2
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: FLNC
  gene_term:
    preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    FLNC encodes filamin C, a Z-disc cytoskeletal protein, and is an established gene
    in inherited myopathy and cardiomyopathy. Reported here as an LVNC candidate on
    the strength of a variant detected in a 25-patient cohort; the abstract does not
    report which ACMG class that variant received.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places FLNC among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the FLNC
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: JPH2
  gene_term:
    preferred_term: JPH2
    term:
      id: hgnc:14202
      label: JPH2
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    JPH2 encodes junctophilin-2, which bridges the sarcolemma and sarcoplasmic
    reticulum at the cardiac dyad. Reported here as an LVNC candidate on the strength
    of a variant detected in a 25-patient cohort. No calcium-handling defect is
    asserted for LVNC from this source, which reports a variant rather than a
    functional assay.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places JPH2 among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the JPH2
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: NKX2-6
  gene_term:
    preferred_term: NKX2-6
    term:
      id: hgnc:32940
      label: NKX2-6
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    NKX2-6 encodes a cardiac homeobox transcription factor whose established human
    disease association is persistent truncus arteriosus and outflow-tract defects.
    Its link to LVNC rests entirely on this single unreplicated 25-patient preprint
    cohort and should be read as a candidate association only.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places NKX2-6 among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the NKX2-6
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: TNNC1
  gene_term:
    preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    TNNC1 encodes cardiac troponin C, the calcium sensor of the thin filament, and is
    an established gene in inherited cardiomyopathy. Reported here as an LVNC
    candidate on the strength of a variant detected in a 25-patient cohort; the
    abstract does not report which ACMG class that variant received.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places TNNC1 among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the TNNC1
      relationship is recorded as UNKNOWN rather than pathogenic.
- name: JUP
  gene_term:
    preferred_term: JUP
    term:
      id: hgnc:6207
      label: JUP
  association: Candidate variant reported in a single LVNC cohort
  relationship_type: UNKNOWN
  notes: >-
    JUP encodes plakoglobin, a component of both desmosomes and adherens junctions,
    and is an established arrhythmogenic cardiomyopathy gene. Reported here as an
    LVNC candidate on the strength of a variant detected in a 25-patient cohort; the
    abstract does not report which ACMG class that variant received.
  evidence:
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic variants were identified in 13 patients, with 14 variants detected in 9 genes (TTN, MYH7, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP).
    explanation: >-
      Places JUP among the nine genes in which variants were detected in this
      25-patient LVNC cohort, which is what this record claims.
  - reference: PPR:PPR1287587
    reference_title: "Genetic Analysis of Patients with Left Ventricular Noncompaction: Identification of Novel Candidate Variants"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were classified as pathogenic (n=1), likely pathogenic (n=7), or variants of uncertain significance (n=5).
    explanation: >-
      The cohort's 14 variants span pathogenic, likely pathogenic and uncertain
      classes, and the abstract gives no per-gene breakdown, so the JUP
      relationship is recorded as UNKNOWN rather than pathogenic.
environmental: []
treatments:
- name: Guideline-directed heart failure pharmacotherapy
  description: >-
    No disease-modifying therapy reverses LVNC, so treatment focuses on heart
    failure symptom control with standard pharmacologic regimens such as ACE
    inhibitors and beta blockers when ventricular dysfunction is present.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  target_mechanisms:
  - target: Impaired ventricular contractile function
    description: >-
      Symptomatic therapy is directed at the downstream heart-failure phenotype
      produced by LV dysfunction.
  evidence:
  - reference: PMID:37215603
    reference_title: "Advances in symptomatic therapy for left ventricular non-compaction in children."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, no effective treatment strategy exists to reduce its incidence
      or severity, and symptomatic treatment is the only clinical treatment
      strategy.
    explanation: >-
      Supports the current treatment paradigm of symptom-directed rather than
      disease-reversing pharmacotherapy in LVNC.
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management included pharmacologic rate control for atrial fibrillation,
      electrical cardioversion, and guideline-directed therapy for heart failure
      with reduced EF, ultimately leading to implantable cardioverter-defibrillator
      placement for primary prevention of sudden cardiac death.
    explanation: >-
      This directly supports standard symptom-directed heart-failure
      pharmacotherapy as part of LVNC management.
- name: Anticoagulation therapy for thromboembolic risk
  description: >-
    Anticoagulation is considered when LVNC patients have atrial fibrillation,
    left ventricular dysfunction, prior embolism, or other high-risk features
    that increase the probability of intracardiac stasis and embolization.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  target_mechanisms:
  - target: Thromboembolic risk
    description: >-
      Anticoagulation is used to mitigate embolic risk arising from recesses,
      atrial fibrillation, and ventricular dysfunction.
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For the clinical management of NCCM patients, an appropriate
      stratification of the thromboembolic risk is of utmost importance for a
      timely initiation of anticoagulant therapy.
    explanation: >-
      Directly supports anticoagulation as a mechanism-based management
      strategy in selected LVNC patients.
- name: Implantable cardioverter-defibrillator placement
  description: >-
    ICD placement is used for primary or secondary sudden-death prevention in
    patients with severe systolic dysfunction or malignant ventricular
    arrhythmia risk.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  target_mechanisms:
  - target: Arrhythmogenic myocardial substrate
    description: >-
      Device therapy interrupts the malignant arrhythmic consequences of the
      LVNC substrate.
  evidence:
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management included pharmacologic rate control for atrial fibrillation,
      electrical cardioversion, and guideline-directed therapy for heart
      failure with reduced EF, ultimately leading to implantable
      cardioverter-defibrillator placement for primary prevention of sudden
      cardiac death.
    explanation: >-
      Directly supports ICD placement for sudden-death prevention in advanced
      LVNC.
- name: Heart transplantation
  description: >-
    Transplantation is reserved for end-stage disease when heart failure or
    refractory complications progress despite maximal medical and device
    therapy.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38933059
    reference_title: "A neonate with a spongy failing heart - What could it be?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 8 months of age, cardiac transplantation was successfully done and
      baby has been doing well post-transplantation.
    explanation: >-
      Supports heart transplantation as a salvage therapy in severe LVNC.
diagnosis:
- name: Echocardiographic diagnosis of trabeculated two-layer myocardium
  description: >-
    Echocardiography is a first-line imaging modality for identifying the
    noncompacted and compacted myocardial layers and for assessing systolic
    dysfunction.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: echocardiography test
        term:
          id: NCIT:C16525
          label: Echocardiography Test
  evidence:
  - reference: PMID:40182365
    reference_title: "Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the case of a 77-year-old male with chronic atrial
      fibrillation and nonischemic cardiomyopathy who was found to have severe
      LVNC, identified on echocardiography and cardiac MRI using a
      noncompacted-to-compacted myocardial thickness ratio >2.3 at end-systole.
    explanation: >-
      Directly supports echocardiography as a core diagnostic imaging tool for
      LVNC.
- name: Cardiac magnetic resonance imaging confirmation
  description: >-
    Cardiac MRI provides higher-resolution structural assessment, confirms the
    trabeculation-to-compaction ratio, and helps characterize myocardial
    involvement and fibrosis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: magnetic resonance imaging of the heart
        term:
          id: NCIT:C137915
          label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:25537996
    reference_title: "Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Actually, CMR is the technique of choice for the diagnosis of IVNC.
    explanation: >-
      Supports cardiac MRI as the preferred confirmatory imaging modality in
      LVNC.
- name: Genetic testing for inherited cardiomyopathy
  description: >-
    Genetic testing helps define inherited disease, identify overlap syndromes,
    and support family counseling in a genetically heterogeneous cardiomyopathy.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: genetic testing
        term:
          id: NCIT:C15709
          label: Genetic Testing
  evidence:
  - reference: PMID:34918480
    reference_title: "A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion
      channels, and desmosomal proteins have been identified.
    explanation: >-
      Supports the clinical value of genetic testing in a highly heterogeneous
      inherited cardiomyopathy.
differential_diagnoses:
- name: Dilated cardiomyopathy
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  description: >-
    Dilated cardiomyopathy may share ventricular dysfunction and chamber
    remodeling with LVNC, especially when trabeculation is prominent, but lacks
    the characteristic diagnostic two-layer noncompaction phenotype.
  distinguishing_features:
  - LV dilation and systolic dysfunction without canonical noncompacted-to-compacted morphology
  - Trabeculations are not the primary defining feature
  - Diagnosis depends more on dilation and contractile impairment than on recess architecture
  evidence:
  - reference: PMID:23361305
    reference_title: "Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      characteristic echocardiographic appearance may help to differentiate LVNC
      from other forms of cardiomyopathy like apical hypertrophic or dilated
      cardiomyopathy in patients with impaired left ventricular systolic
      function.
    explanation: >-
      Directly supports dilated cardiomyopathy as a key structural mimic in the
      differential diagnosis of LVNC.
- name: Hypertrophic cardiomyopathy
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  description: >-
    Hypertrophic cardiomyopathy can overlap with LVNC when trabeculations and
    thickened myocardium coexist, but the dominant phenotype is hypertrophy
    rather than noncompaction.
  distinguishing_features:
  - Dominant wall thickening and hypertrophy rather than a noncompacted spongy layer
  - Distinct sarcomeric hypertrophic remodeling pattern
  - Imaging interpretation depends on whether hypertrophy or noncompaction is primary
  evidence:
  - reference: PMID:23361305
    reference_title: "Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      characteristic echocardiographic appearance may help to differentiate LVNC
      from other forms of cardiomyopathy like apical hypertrophic or dilated
      cardiomyopathy in patients with impaired left ventricular systolic
      function.
    explanation: >-
      Directly identifies hypertrophic cardiomyopathy as another important
      imaging and clinical mimic.
clinical_trials:
- name: NCT05281315
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Retrospective follow-up study evaluating cardiac MRI features, clinical
    characteristics, and outcomes in patients with noncompaction cardiomyopathy
    from Pakistan.
  target_phenotypes:
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: clinicaltrials:NCT05281315
    reference_title: "Cardiac Magnetic Resonance Features and Outcomes of Patients With Non-Compaction Cardiomyopathy - a Retrospective Follow-up From Pakistan"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Objective: To evaluate clinical characteristics, cardiac magnetic
      resonance imaging features, and outcomes of patients with left ventricle
      non-compaction.
    explanation: >-
      Supports a disease-specific registered clinical study centered on MRI
      phenotype and clinical outcomes in LVNC.
datasets:
- accession: geo:GSE71912
  title: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
  description: >-
    Public LVNC transcriptomic dataset reused in integrative bioinformatic
    analyses of myocardial disease mechanisms and candidate biomarkers.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  conditions:
  - left ventricular noncompaction cardiomyopathy
  publication: PMID:40618167
  evidence:
  - reference: PMID:40618167
    reference_title: "Role of Col1a2 and Postn in left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The datasets GSE71912 and GSE113251 of left ventricular noncompaction
      cardiomyopathy were downloaded from the gene expression omnibus (GEO)
      database generated from GPL13912 and GPL11002 platforms.
    explanation: >-
      Supports GSE71912 as a public LVNC dataset used for disease-mechanism
      discovery.
- accession: geo:GSE113251
  title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy
  description: >-
    Public LVNC transcriptomic dataset used alongside GSE71912 for differential
    expression, co-expression, and hub-gene analysis.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  conditions:
  - left ventricular noncompaction cardiomyopathy
  publication: PMID:40618167
  evidence:
  - reference: PMID:40618167
    reference_title: "Role of Col1a2 and Postn in left ventricular noncompaction cardiomyopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The datasets GSE71912 and GSE113251 of left ventricular noncompaction
      cardiomyopathy were downloaded from the gene expression omnibus (GEO)
      database generated from GPL13912 and GPL11002 platforms.
    explanation: >-
      Supports GSE113251 as a second public LVNC dataset used in integrated
      computational analyses.
references: []

📚

References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Add 8 novel LVNC-associated genes from NGS cohort study · 2026-09-21T20:10:03Z · View source

Added genetic entries for TTN, CTNNA3, DSG2, FLNC, JPH2, NKX2-6, TNNC1, and JUP, the eight genes (besides the already-curated MYH7) in which variants were detected in the 25-patient LVNC NGS cohort of Onofri et al. (PPR:PPR1287587). Review round (PR #12465): each entry now carries `evidence:` citing the preprint with exact abstract quotes; previously the source was named only in free-text `notes:`, which nothing validates. `association:` was changed from "Pathogenic and likely pathogenic variants" to "Candidate variant reported in a single LVNC cohort" and `relationship_type: UNKNOWN` was added, because the abstract reports 1 pathogenic, 7 likely pathogenic and 5 uncertain-significance variants across nine genes with no per-gene breakdown -- there is no basis for asserting P/LP for all eight. Notes were rewritten to state candidate/reported status rather than established mechanism; the NKX2-6, CTNNA3 and TTN notes previously read as settled fact. TTN additionally cites PMID:34918480, a peer-reviewed review whose introduction reports the TTN genotype-phenotype correlation, tagged `quote_role: BACKGROUND`. references_cache/PPR_PPR1287587.md was regenerated abstract-only (1,731 -> 33 lines). OpenAlex reports a bogus `full_text_url` for this preprint -- a Promega Maxwell CSC Genomic DNA Kit technical manual (TM677) in Italian, presumably harvested from the paper's own methods section -- so the default fetch cached 1,690 lines of that manual as the paper's body. A snippet quoting the kit manual would have validated silently, since `just validate-kb-references` permits full-text matches. The regeneration used `just fetch-reference`'s underlying command with a config overriding `full_text_providers` to [pmc, epmc_preprint, unpaywall] -- openalex removed. The cache was never hand-edited. Excluding the provider rather than setting `fetch_full_text: false` matters: the full-text chain still runs and records `full_text_attempted: true` in the frontmatter, which is what stops `_maybe_retry_full_text` from re-fetching the Promega PDF on the next `just validate`. A plain abstract-only fetch omits that flag and gets re-inflated immediately; this was confirmed both ways before committing. references_cache/PMID_34918480.md was upgraded from abstract to full text so the TTN snippet resolves. Note the cached text uses an en dash in "genotype-phenotype"; the snippet is copied from the cache, not from the deep-research artifact, which had normalized it to a hyphen. Validation: `just validate` passes (schema + terms + references), 53/53 snippets verified (was 44).

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Left ventricular noncompaction. Core disease mechanisms, molecular and cel...

Asta Scientific Corpus Retrieval 20 citations 2026-04-21T17:03:30.314947

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Left ventricular noncompaction. Core disease mechanisms, molecular and cel...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Advances in symptomatic therapy for left ventricular non-compaction in children

Authors: Dong Li, Ce Wang
Year: 2023
Venue: Frontiers in Pediatrics
URL: https://www.semanticscholar.org/paper/4d1e712606624d4faa7a1a3418fc3579b3c81dbd
DOI: 10.3389/fped.2023.1147362
PMID: 37215603
PMCID: 10192632
Citations: 6
Summary: This review summarized and discussed the coping methods for different left ventricular non-compaction symptoms and suggested strategies to reduce its incidence or severity.
Evidence snippets:
Snippet 1 (score: 0.615) > hmias are also common complications of high clinical concern in patients with LVNC. In addition, these patients often have a neuromuscular disease and may experience fatigue (17, 18), muscle aches and pains, and elevated creatine kinase levels (19). The relevant data are compiled in Table 1. Moreover, even though several children with LVNC have adverse outcomes, to date, no clinically targeted treatment exists, and only symptomatic or prophylactic treatment is available (20-23). > Generally speaking, left ventricular noncompaction is a congenital disease with unknown etiology (26). At present, there is no literature to prove that adult myocardial noncompaction has an acquired trend or mechanism. Some patients with left ventricular noncompaction are asymptomatic from birth to onset, and it is not discovered until they have heart-related symptoms or physical examination. This is called myocardial noncompaction in adults. Therefore, both adults and children with myocardial noncompaction are congenital diseases, but the time of discovery or symptoms is different (27). > In this review, we discuss current advances in the clinical management of the different symptoms of LVNC to further the search for more effective treatments for the various related complications and facilitate the progress of clinical research. The latest treatment strategy, indications and contraindications are compiled in Figures 1-3. Simultaneously, our review provides potential insight for clinical discoveries in the treatment of LVNC.

[2] Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report

Authors: Khaleel Quasem, M. Carrasquel, Jordan Felice, Britni Smith, Dania Baraka et al.
Year: 2025
Venue: Cureus
URL: https://www.semanticscholar.org/paper/6c6befe1e221e91d37a630d1fa265d2e09a8513a
DOI: 10.7759/cureus.80015
PMID: 40182365
PMCID: 11966663
Summary: The case of a 77-year-old male with chronic atrial fibrillation and nonischemic cardiomyopathy who was found to have severe LVNC is presented, highlighting its potential for late onset, the necessity of multimodality imaging to detect coexisting anomalies, and the importance of a comprehensive treatment approach to optimize outcomes in older adults.
Evidence snippets:
Snippet 1 (score: 0.545) > Left ventricular noncompaction (LVNC) is a rare cardiomyopathy characterized by excessive trabeculation of the myocardium, resulting from incomplete compaction of normal myocardial fibers [1]. This process creates a thick, noncompacted endocardial layer over a thinner compacted epicardium. While LVNC was traditionally considered a congenital disorder, emerging evidence suggests it can also be acquired, indicating a multifactorial etiology [2,3]. Myocardial remodeling due to volume overload or progressive changes in other cardiomyopathies has been proposed as a potential mechanism for acquired LVNC. This abnormal myocardial structure can lead to significant ventricular dysfunction, increasing the risk of heart failure, arrhythmias, and thromboembolic events -underscoring the importance of early detection and appropriate management [4]. > LVNC presents along a broad clinical spectrum. Some individuals remain asymptomatic and receive a diagnosis incidentally, while others develop severe cardiac complications [1,2]. In some cases, arrhythmias serve as the initial clinical manifestation, preceding the onset of symptomatic heart failure or thromboembolic complications. These arrhythmias, ranging from atrial fibrillation to potentially lifethreatening ventricular tachyarrhythmias, are thought to arise from structural irregularities that disrupt normal electrical conduction. Diagnosis relies on echocardiography and cardiac MRI [3,5]; however, distinguishing LVNC from other cardiomyopathies, such as dilated or hypertrophic cardiomyopathy with deep trabeculations, remains challenging due to overlapping structural and functional characteristics. Careful imaging interpretation, combined with clinical context, is essential for an accurate diagnosis. > Several factors influence the progression of LVNC to overt heart failure or significant arrhythmias, including the extent of noncompaction, left ventricular systolic dysfunction, underlying comorbidities (e.g., hypertension and coronary artery disease), and early manifestations of arrhythmias.

[3] Expression Signatures of Long Noncoding RNAs in Left Ventricular Noncompaction

Authors: Qingshan Tian, Hanxiao Niu, Dingyang Liu, Na Ta, Qing Yang et al.
Year: 2021
Venue: Frontiers in Cardiovascular Medicine
URL: https://www.semanticscholar.org/paper/44e140f89a1fe15317061c115c86df953959be6e
DOI: 10.3389/fcvm.2021.763858
PMID: 34859074
PMCID: 8631435
Citations: 1
Summary: The use of LncRNA microarray is first reported to understand the pathogenesis of LVNC and to identify several lncRNA and genes and their targets as potential biomarkers.
Evidence snippets:
Snippet 1 (score: 0.520) > Left ventricular noncompaction is a rare disease that is characterized by the failure of densification in the normal embryonic cardiac tissue. It can occur in isolation or association with congenital heart defects (CHDs), neuromuscular disorders, and systemic heart anomalies (1,2). Morphological features of left ventricular noncompaction (LVNC) consist of deep trabecular recesses in the myocardial wall with noncompaction of the loosely interwoven meshwork in the left ventricular cavity (3). The typical clinical result is a triad of heart failure, arrhythmias, and systemic embolism (4). > Left ventricular noncompaction is a genetically heterogeneous disease (5) and is associated with genes and/or proteins that are involved in sarcomere (MYH7, ACTC, MYBPC3, TNNT2), cytoskeletal (ZASP, LMNA), and mitochondrial structure or function (TAZ) (6)(7)(8)(9). However, using exome and mitochondrial DNA sequencing from myocardial tissue samples, Liu Z et al. identified mutations in 16S rRNA 2336T>C mitochondrial mutation but did not detect any pathogenic mutations in TNNT2 and MYBPC3 genes (10). > Long noncoding RNA molecules are >200 nt in length, similar to mRNA, but do not code for structural proteins. Rather, they modulate the expression of protein-coding genes (11). Particularly, relating lncRNA with disease pathogenesis has widespread implications. Long noncoding RNAs (LncRNAs) are easily targetable, and their expression can be controlled from external oligo DNA or RNA that can be administered through blood or tissue specifically (12). A disease development could be delayed or cured by externally manipulating their expressions. Such advantages recently gained specific interest in identifying disease-specific lncRNA (13,14). > Numerous studies show that lncRNAs play a positive and negative role in the differentiation, development, and progression of many diseases such as cancer, neurodegenerative diseases, and heart diseases (13,(15)(16)(17).

[4] Bifid cardiac apex and spongiform cardiomyopathy in fetus with small microdeletion 16p12.2 of paternal origin. Critical points in family communication on 16p12.2 microdeletion

Authors: M. Stabile, Anna F. Rispoli, Maurizio Capuozzo, Umberto Ferbo, G. Stabile
Year: 2023
Venue: Clinical Case Reports
URL: https://www.semanticscholar.org/paper/6a73ad388d154050c68af25faa2ae4ca9d1b7aa4
DOI: 10.1002/ccr3.7602
PMID: 37405046
PMCID: 10315447
Citations: 3
Summary: This is the first case of fetal 16p12.2 microdeletion syndrome inherited from a normal father with autopsy description and evidence of spongious cardiomyopathy and first trimester intake of doxycycline could be a cofactor.
Evidence snippets:
Snippet 1 (score: 0.503) > The UQCRC2 (ubiQuinol-cytochrome c reductase core protein II) gene encodes a subunit of mitochondrial complex III; the homozygous mutations of the gene can give neonatal acidosis with hyperammonemia and hypoglycemia. It is to be considered that the mutations could have a milder effect than the deletion involving complete loss of the gene. > Maternal thrombophilia and the intake of doxycycline during pregnancy may have contributed to the pathological phenotype of the fetus. Doxycycline falls into category D (positive evidence of human fetal risk) according to the US FDA pregnancy category. > Generally, patients with 16p12.2 microdeletion have congenital heart disease (CHD), hypoplastic left heart syndrome (HLHS), and bicuspid aortic valve (BAV). 8 From the literature review, our case with the 16p12.2 microdeletion is the only one documented by autopsy with this particular cardiac phenotype associated with left ventricular noncompaction (LVNC). Left ventricular noncompaction (LVNC) is a very rare congenital cardiomyopathy. It is a disease of endomyocardial trabeculations that increase in number and prominence. This cardiomyopathy carries a high risk of malignant arrhythmias, thromboembolic phenomenon, and left ventricular dysfunction. This disease also has other names like spongy myocardium, spongiform cardiomyopathy, hypertrabeculation, persisting myocardial sinusoids, or zaspopathy. 9 The mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood; the small GTPase Rac1, with cytogenetic location on 7p22.1 (OMIM #602048) acts as a crucial regulator of numerous developmental events. Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart.

[5] A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy

Authors: Zhongman Zhang, Kangkang Xu, Lianfu Ji, Han Zhang, Jie Yin et al.
Year: 2023
Venue: Frontiers in Cardiovascular Medicine
URL: https://www.semanticscholar.org/paper/7aece12fa6728ed05641f00b40606761b3939409
DOI: 10.3389/fcvm.2023.1097957
PMID: 36815016
PMCID: 9940605
Citations: 9
Summary: RNA-sequencing showed that the expression of genes related to heart development decreased significantly, and the NRAP gene mutation could participate in biological processes (BPs) such as myocardial contraction, cell adhesion, myosin coarse filament assembly of striated muscle, myOSin complex composition, and muscle α-actin binding.
Evidence snippets:
Snippet 1 (score: 0.499) > Left ventricular non-compaction (LVNC) was first described in 1990 (1) and was known as a unique type of inherited cardiomyopathy characterized by excessive trabecular meshwork and deep intertrabecular recesses in the LV wall (2,3). The prevalence of LVNC in the pediatric age is around 0.14% (4), and individual differences in clinical manifestations are relatively large from being asymptomatic to heart failure. LVNC is a polygenic heterogenic cardiomyopathy inherited as an autosomal dominant or X-linked recessive disorder, although autosomal recessive and mitochondrial (maternal) inheritance also occur (5). The etiology and specific pathogenesis of LVNC have not been fully elucidated. The molecular genetic analysis uncovered causal mutations for LVNC in many genes, including NKX2-5, TAZ, LMNA, MYH7, ACTC1, LDB3, TNNT2, and MYBPC3, which encode mitochondrial proteins, sarcomere proteins, and cytoskeleton (5,6). However, the types of these pathogenic genes and mutations are complex, and there are interactions between various pathogenic genes, which makes the mechanism study quite complicated. > Therefore, for LVNC, the precise pathogenic mechanism from molecular component and cellular component (CC) to clinical phenotype is still unknown. At present, clinical drug treatment cannot reverse the progression of LVNC, and the treatment is mainly symptomatic. It becomes especially important to discover the causative gene of LVNC and clarify the functional mechanism to define genotype-to-phenotype associations and provide a theoretical basis for gene-targeted therapy. > Nebulin-related-anchoring protein (NRAP) is a multi-domain cytoskeletal protein specifically expressed at the terminal bundles of actin filaments at the myotendinous junction of skeletal muscle and the intercalated disk of cardiac muscles (7). It is located on chromosome 10q25.3

[6] Left Ventricular Noncompaction Is Associated with Valvular Regurgitation and a Variety of Arrhythmias

Authors: Qing Li, Lianjie Miao, L. Xia, Hala Y. Abdelnasser, Fang Zhang et al.
Year: 2022
Venue: Journal of Cardiovascular Development and Disease
URL: https://www.semanticscholar.org/paper/e8986c13856ab763c43317ef2add51d7b3c3424e
DOI: 10.3390/jcdd9020049
PMID: 35200702
PMCID: 8876824
Citations: 10
Summary: Evidence is added to support a congenital origin of LVNC that might benefit the diagnosis and subsequent characterization of LV NC patients and reveal some novel findings.
Evidence snippets:
Snippet 1 (score: 0.497) > Left ventricular noncompaction (LVNC: OMIM No. 604169) is a type of cardiomyopathy anatomically characterized by prominent ventricular trabeculation and deep intertrabecular recesses [1][2][3]. It was reported for the first time in 1969, being addressed as a spongy myocardial condition back then [4]. In the following years, LVNC has gained tremendous attention due to the improvements in cardiac imaging techniques, primarily echocardiography and magnetic resonance imaging, that have enabled more detailed visualization and increased clinical awareness of this syndrome. Subsequently, many LVNC cardiomyopathy cases were reported, and AHA enlisted LVNC as a type of cardiomyopathy in 2006 [3]. LVNC shows highly variable clinical manifestations ranging from asymptomatic to symptomatic, and the major clinical features of LVNC are heart failure, arrhythmias, thromboembolic events, and sudden death [5]. Its symptoms are progressive, considered the 3rd most common cardiomyopathy in the pediatric population, and the mortality of patients with LVNC ranges from 5% to 47% [6][7][8]. Despite its clinical significance, the mechanism of trabecular compaction and the etiology of LVNC are unknown. Moreover, whether LVNC is acquired or congenital cardiomyopathy has been an unraveled controversy [9]. The focus of most clinical investigations on isolated adult LVNC patients failed to trace the anomalies in embryonic developmental stages, and the knowledge gap regarding the molecular level regulation of trabeculation could be the possible reason [10,11]. > As abnormalities in trabecular and ventricular morphogenesis lead to LVNC, the revelation of the biological and physiological development of trabecular formation and ventricular compaction will help elucidate the etiology of LVNC [12,13]. Trabeculae are sheet-like structures extending from the myocardium to the heart lumen and function to increase surface area to support nutrition and oxygen supply when the coronary system is not yet established [14].

[7] Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy

Authors: Chunyan Li, Fan Liu, Shenghua Liu, H. Pan, Haiwei Du et al.
Year: 2020
Venue: EBioMedicine
URL: https://www.semanticscholar.org/paper/de61b3ad5bfa119df19d4d8324bafc2532088bf7
DOI: 10.1016/j.ebiom.2020.102695
PMID: 32143182
PMCID: 7058526
Citations: 22
Influential citations: 1
Summary: A novel mechanism through which SORBS2 interacts with β-tubulin and promotes microtubule densification, eventually effecting JP2 distribution and T-tubule, potentially contributing to heart failure in LVNC disease is identified.
Evidence snippets:
Snippet 1 (score: 0.493) > Left ventricular noncompaction cardiomyopathy (LVNC) is associated with left ventricular diastolic and systolic dysfunction. The myocardial wall is often thickened with a thin, compacted epicardial layer and a thickened endocardial layer. One of LVNC guidelines is to prevent the progression and development of heart failure [29]. > LVNC has gained increasing attention in recent years [30] because of its association with high rates of mortality and morbidity in adults, including heart failure, arrhythmias, and thromboembolic events [31À33]. LVNC may be due to the arrest of the normal compaction process of the myocardial wall during fetal development [34]. Numerous genetic disorders have been reported to be associated with LVNC, including sarcomere and Z-disk gene mutations [35,36]. Regardless of the complicated heterogenous causes of LVNC [37], heart failure is one of the most common clinical consequences in LVNC patients, but the relationship between LVNC and heart failure is not well understood and requires further study [35,36]. All the 8 LVNC patients waiting for heart transplantation, used in our proteomic analyses, suffered from heart failure with severely reduced LV ejection fraction (EF) of 18%À37%. In this study, our primary intention is focused on the identification of the key signaling pathway whose dysfunction has a causal role in the occurrence of heart failure in LVNC patients, but not on the molecular mechanism of LVNC. > The left ventricle (LV) heart samples used in our study were obtained from heart transplantation patients clinically diagnosed with LVNC on the basis of echocardiographic or CMR documentation, and autopsy findings of explanted hearts, with a distinct two-layered appearance of trabeculated and compacted myocardium. Using comparative proteomic analyses, we identified 45 proteins up-regulated in LVNC hearts but not in HCM and ARVC hearts.

[8] A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy

Authors: C. Chimenti, C. Lavalle, M. Magnocavallo, Maria Alfarano, M. Mariani et al.
Year: 2021
Venue: ESC Heart Failure
URL: https://www.semanticscholar.org/paper/d7411ab6be4bb9de52b8f11583d25ac53b9734c4
DOI: 10.1002/ehf2.13694
PMID: 34918480
PMCID: 8788052
Citations: 34
Influential citations: 5
Summary: The aim of the present study is to review the available literature on NCCM with particular attention on thromboembolic risk stratification and prevention and the current evidence for oral anticoagulation therapy.
Evidence snippets:
Snippet 1 (score: 0.485) > Noncompaction cardiomyopathy (NCCM) is a rare condition characterized by prominent left ventricular (LV) trabeculae and deep intertrabecular recesses, first described in 1969 by Feldt et al., 1 who reported a biventricular spongy myocardium in a female patient who died at the age of 3 months. NCCM is characterized by a two-layered myocardial structure, characterized by a spongy endocardial layer and a thinner and compacted epicardial one. Apical and lateral segments of the LV are the most commonly involved, but both ventricles can be affected. > The prevalence of NCCM is unknown, but it has been estimated to be approximately 0.05-0.27% among adults referred to echocardiography lab, 2 with males more affected than females. 3 Age at the time of diagnosis is variable from early infancy to late adulthood. 3 Noncompaction cardiomyopathy is a genetic cardiomyopathy, because it has been described in association with mutations in more than 40 genes coding for sarcomeric, cytoskeletal, Z-line, and mitochondrial proteins 4 and even in chromosomal defects. 3 A strong genotype-phenotype correlation has been reported for Hyperpolarization Activated Cyclic Nucleotide gated potassium channel 4 (HCN4), Titin (TTN), and Lamin A/C (LMNA) mutations, with a high incidence of heart failure (HF) and ventricular arrhythmias. 5 Furthermore, NCCM can be associated to genetic syndromes, including congenital heart disease, neuromuscular disorders, and facial dysmorphisms. 5 From a pathogenetic point of view, NCCM may be due to an abnormal myocardial compaction during intrauterine cardiac development. 6 However, some authors have suggested that NCCM could be the result of abnormal persistence of the trabecular layer rather than the effect of noncompaction of the ventricular wall. 6 Clinical presentation of NCCM is highly variable, ranging from no symptoms to end-stage HF, lethal arrhythmias, sudden cardiac death, or thromboembolic events (stroke, transient ischaemic attack, me

[9] Role of Col1a2 and Postn in left ventricular noncompaction cardiomyopathy

Authors: Huibing Liu, Ling-bing Meng, Qian Liu
Year: 2025
Venue: Journal of Cardiothoracic Surgery
URL: https://www.semanticscholar.org/paper/2f2a34464fc3d8a4ea7b1120afbaf573846ce247
DOI: 10.1186/s13019-025-03509-4
PMID: 40618167
PMCID: 12229011
Citations: 2
Summary: Left ventricular noncompaction cardiomyopathy (LVNC) is a rare myocardial developmental anomaly characterized by incomplete myocardial compact layer development in the left ventricular wall, resulting in a multilayered trabeculated myocardium. The datasets GSE71912 and GSE113251 of left ventricular noncompaction cardiomyopathy were downloaded from the gene expression omnibus (GEO) database generated from GPL13912 and GPL11002 platforms. Batch normalization was performed, followed by different...
Evidence snippets:
Snippet 1 (score: 0.481) > Left ventricular noncompaction cardiomyopathy (LVNC) is a relatively rare type of cardiomyopathy, primarily characterized by incomplete development of the compact layer of the left ventricular myocardium. This results in a thickened noncompacted layer of the ventricular wall, giving the heart a distinct "spongy" appearance with deep trabeculated recesses [1]. LVNC may occur as an isolated condition or in conjunction with other cardiac abnormalities. Its prevalence among cardiomyopathies is relatively low, affecting approximately 1 to 3 adults per 10,000 people [2]. LVNC can develop at any age, including infancy, childhood, and adulthood. The condition is more common in males than females, and in adults, it usually manifests in middle age or later [3]. The clinical presentation and prognosis vary significantly. Some patients may be asymptomatic, while others may develop severe complications such as heart failure, arrhythmias, or sudden cardiac death. Echocardiography and magnetic resonance imaging typically reveal uneven wall thickness in the left ventricle, displaying the characteristic "spongy" structure [4]. > Treatment options for LVNC include medication (such as ACE inhibitors and β-adrenergic blockers), management of arrhythmias, and heart failure treatment. In severe cases, implantable cardioverter defibrillators or heart transplants may be required [5,6]. The etiology of LVNC is unclear, but it is likely associated with genetic factors, chromosomal abnormalities, and gene fusions. Therefore, it is crucial to study the molecular mechanisms underlying LVNC. > In recent years, bioinformatics has made significant advances in life sciences and medicine, becoming a vital tool for understanding complex biological systems, disease mechanisms, and personalized medicine [7]. Bioinformatics excels in its efficiency and comprehensiveness. By integrating various data types, bioinformatics provides a more holistic and systematic view of biological information, enabling researchers to extract valuable knowledge from vast datasets.

[10] Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction

Authors: Salwa Akhbour, I. Fellat, Nada Fennich, S. Abdelali, N. Doghmi et al.
Year: 2014
Venue: Anatolian Journal of Cardiology
URL: https://www.semanticscholar.org/paper/2830fcf849c534626293c56be914752e522da369
DOI: 10.5152/akd.2014.5577
PMID: 25537996
PMCID: 5337034
Citations: 12
Influential citations: 1
Summary: While electrocardiographic abnormalities are frequent in isolated ventricular noncompactison, no specific patterns were identified and more large studies are needed for stratification of arrhythmic risk of this highly arrhythmogenic substrate.
Evidence snippets:
Snippet 1 (score: 0.464) > Mutations in the human cardiac sodium channel alpha-subunit gene (SCN5A), a well-known gene involved in multiple cardiac arrhythmias, were highly associated with arrhythmias in patients with left ventricular noncompaction than in those without them (50% vs. 7%: p=0.0003). The most frequent arrhythmias were VT and premature ventricular beats (20). This report suggests that the mechanism underlying VT in IVNC could be a gene mutation and may explain the lack of correlation between VT and ventricular dysfunction or fibrosis. Accordingly, we need more studies to clarify risk factors for VT in IVNC. > Patients with IVNC may develop supraventricular arrhythmias (4%-29%) (6,8). Supraventricular tachycardia revealed IVNC in 12.5% patients in the present study. In a large series (21), they identified 9 patients with atrial fibrillation among 238 patients affected by noncompaction. No case of supraventricular tachycardia was noted. The authors concluded that the atria are not involved in the noncompaction process when the majority of patients has dilated cardiomyopathy. In our study, supraventricular arrhythmias are not a consequence of atrial dilatation or systolic dysfunction but may be due to cardiac involvement in the context of ventricular noncompaction. > Only one patient in our series presented with WPW syndrome. It is more frequently reported in children (12%-15%) than in adults (0%-2.7%) (3, 6-8, 15, 22, 23). Failed regression of developmental embryologic atrioventricular anatomical and electrical continuity during embryonic development in the noncompacted myocardium can explain this association. In our patient, the accessory pathway was type B. This finding is consistent with other reports, because defects in the annulus fibrosis lead to the formation of accessory pathways on the right side of the heart around the tricuspid valve (24).

[11] The Role of Ventricular Assist Devices in Patients With Heart Failure Due to Dilated Cardiomyopathy: A Systematic Review

Authors: Billy McBenedict, W. Hauwanga, Emmanuel S Amadi, Melvin Chun Yang Yau, C. R. Amuzie et al.
Year: 2024
Venue: Cureus
URL: https://www.semanticscholar.org/paper/209c45dbd836722b8376b65f34c4b7ae1187a259
DOI: 10.7759/cureus.66259
PMID: 39238676
PMCID: 11377123
Citations: 1
Summary: It is concluded that VADs play a crucial role in managing advanced HF due to DCM by providing mechanical circulatory support, improving cardiac function, and enhancing patient survival and quality of life.
Evidence snippets:
Snippet 1 (score: 0.464) > Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by left ventricular (LV) or biventricular dilation and systolic dysfunction in the absence of either pressure or volume overload or coronary artery disease (CAD) sufficient enough to explain the dysfunction [1]. DCM is marked by the dilation and impaired contraction of the ventricles, primarily affecting the left ventricle and resulting in systolic dysfunction. This condition increases ventricular volumes to maintain cardiac output, leading to the thin-walled, dilated appearance of the left ventricle. Genetic mutations are significant contributors to DCM, impacting various intracellular structures and pathways. Key mechanisms include deficits in force generation due to mutations in sarcomeric proteins like titin and myosin, defects in the nuclear envelope involving Lamin-A/C mutations, and issues with force transmission linked to cytoskeletal protein mutations such as filamins and dystrophin. Additionally, abnormalities in cell-to-cell adhesion from desmosomal protein mutations, mitochondrial energy production defects, calcium-cycling issues from phospholamban gene mutations, ion channel mutations, epigenetic perturbations, and protein misfolding diseases all contribute to the pathophysiology of DCM [1]. > Cardiac remodeling in DCM involves significant alterations in function, particularly in the LV pressurevolume relationship. Increased end-diastolic volumes and pressures, along with diastolic dysfunction due to incomplete relaxation and increased stiffness, complicate the clinical scenario [1]. The law of Laplace explains that wall tension is directly proportional to ventricular dilation and inversely proportional to wall thickness, highlighting the increased afterload and energetic consequences of heart failure (HF) [1]. Understanding these genetic and molecular mechanisms is crucial for developing targeted therapies and improving outcomes for DCM patients [2]. > Histological examination of the myocardium typically shows nonspecific changes of fibrosis and hypertrophy, along with myocardial injury marked by an inflammatory cell infiltrate [2]. It is the most common form of cardiomyopathy and the most frequent indication for cardiac transplantation.

[12] Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

Authors: M. Hoes, N. Bomer, P. van der Meer
Year: 2018
Venue: Stem Cells Translational Medicine
URL: https://www.semanticscholar.org/paper/51dc8ec48dc758584279d54d6072d8fa15f7b8f6
DOI: 10.1002/sctm.18-0052
PMID: 30302938
PMCID: 6312446
Citations: 38
Summary: Limits in the field of human in vitro cardiomyopathy modeling are emphasized, including residual somatic epigenetic signatures induced pluripotent stem cells, and modeling diseases with unknown genetic causes.
Evidence snippets:
Snippet 1 (score: 0.454) > A plethora of genetic mutations have been associated with the pathogenesis of genetic heart diseases, including the main inherited cardiomyopathies (i.e., HCM, DCM, ACM, and LVNC). Investigating how genetic mutations explain causality in the pathophysiology of cardiomyopathies and how they interact with secondary genetic and environmental factors is imperative to improving diagnosis and decision-making regarding treatment strategies. The introduction of patient-specific hiPSC-CM provides a versatile new tool that may tremendously improve our understanding of the disease mechanisms. Consequently, these cells have been widely applied to study the complexity of cardiac disease. However, cardiomyopathies are divided into four classes, each with a distinct pathophysiology, resulting in various types of heart failure. The most common cardiomyopathy, HCM, is characterized by increased cardiac mass due to left ventricular wall thickening (hypertrophy) that most often is asymmetric, with particular involvement of the interventricular septum, myocytes disarray, and cardiac fibrosis [30]. DCM is characterized by left ventricular chamber enlargement and systolic dysfunction, which often leads to heart failure, arrhythmia, and sudden death. ACM predominantly affects right ventricular cardiomyocytes and occurs due to defects in the cardiac desmosome as a consequence of mutations in key desmosomal components, but also because of ion channel defects. Consequently, ACM hallmarks include right ventricular dilation, scarring, exaggerated lipogenesis and lipid infiltration, and arrhythmias. Finally, LVNC is characterized by cardiac noncompaction, primarily resulting in trabeculation and deep recesses in the left ventricle. Many studies performed in patient-derived hiPSC-CM have often recapitulated these respective hallmarks of inherited cardiomyopathies and thereby markedly increased our understanding of underlying molecular mechanisms, as summarized in Table 1. In addition to cardiomyopathies, inherited arrhythmias are generally caused by a pathological mutation in a gene encoding an ion channel or an associated protein. However, this review focusses on cardiomyopathies, whereas arrhythmias are

[13] Hypertrophic and noncompacted cardiomyopathy of left ventricle: different manifestations of the same disease

Authors: V. P. Pejčinović, V. Peršić, M. Boban, M. Rakić, Helena Antić Kauzlarić et al.
Year: 2017
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/c3ad9915af15ba9e02ea0c3aa49ec0a70d0229b5
DOI: 10.15836/CCAR2017.135
Citations: 1
Summary: A patient is presented with clear overlapping pheenotyp for LVNC and HCM, using the imaging method cardiac MRI, and it is speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiopathy may be associated with left ventricular noncompaction.
Evidence snippets:
Snippet 1 (score: 0.449) > B3, which codes the protein Cypher/ZASP, genes of the internal nuclear membrane proteins (LMNA, which encodes lamin A/C) and even genes that code sarcomeric proteins like cardiac alpha-actin and the beta-myosin heavy chain and cardiac troponin T. The clinical picture of both diseases, HCM and LVNC, varies from mild forms until severe forms with heart failure and complex ventricular arrhythmias. LVNC and HCM may appear as overlapping entities. Cases of patients sharing both the LVNC and HCM phenotypes have been already published, and it is speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction.1-5 In our case report, we are presenting patient with clear overlapping pheenotyp for LVNC and HCM, using the imaging method cardiac MRI. Vesna Pehar Pejčinović*, Viktor Peršić, Marko Boban, Marijana Rakić, Helena Antić Kauzlarić, Vladimir Peša

[14] 2017 Riley Heart Center Symposium on Cardiac Development: Development and Repair of the Ventricular Wall

Authors: L. Field, W. Shou, L. Markham
Year: 2018
Venue: Pediatric Cardiology
URL: https://www.semanticscholar.org/paper/230fb86b1eda43dc80b4fe54e8e4b801d389dfc2
DOI: 10.1007/s00246-018-1942-4
PMID: 30066104
PMCID: 6096844
Citations: 1
Summary: The 5th Riley Heart Center Symposium was held in Indianapolis, Indiana, on November 20, 2017, and sessions focused on the genetic regulation of cardiac development, the role of cell polarity in ventricular wall morphogenesis, the cell and molecular basis for arrhythmic cardiomyopathies, and cell cycle-based interventions to promote myocardial regeneration.
Evidence snippets:
Snippet 1 (score: 0.448) > Abnormal heart morphogenesis can result in congenital heart defects (CHDs) or inherited cardiomyopathies. Inappropriate gene expression [1, 2], expression of mutant gene products [3, 4], and exposure to cardiotoxic chemicals [5] or drugs [6] are all known to promote CHDs. The resulting structural defects (exemplified by heterotaxy, atrial and ventricular septal defects, noncompaction, etc.) render heart pump function inadequate. Nearly 1% of all newborns will have a structural heart defect [7], and the majority of these are severe enough to cause death in the absence of surgical and/or other palliative intervention. Inherited cardiomyopathies (that is, abnormalities of the sarcomere) [8, 9] constitute another important class of CHDs. While much is known about the clinical sequelae of CHDs, in many cases, the underlying molecular etiology remains undefined. For example, visceral heterotaxy results from the loss of left–right patterning during early embryogenesis, when the cell and molecular signaling cascades, which normally regulate sidedness pattern formation, are well-established. However, the spectrum of cardiac defects in many heterotaxy models and within patients with heterotaxy is more severe than what would be anticipated from a simple breakdown of sidedness patterning. The molecular basis for this is not understood. Similarly, the anatomical and clinical sequelae resulting from anomalies in ventricular septation and papillary muscle morphogenesis are well characterized. Moreover, multiple genes have been identified, which when dysregulated impact the development of these structures. How dysregulated gene expression mechanistically gives rise to these morphogenic defects is at best poorly understood. A similar case can be made for events that regulate maturation of the ventricular wall. Left ventricular noncompaction (LVNC) is recognized as a distinct form of cardiomyopathy, which results from a morphogenic defect. However, the molecular processes that underlie this defect are not well understood; understanding the underlying molecular mechanisms which give rise to LVNC is critical to effect improvements in diagnosis and care [10]. To promote interactions between clinical and basic

[15] Inherited cardiomyopathies.

Authors: J. Towbin
Year: 2014
Venue: Circulation journal : official journal of the Japanese Circulation Society
URL: https://www.semanticscholar.org/paper/6936a7dda78e293648fd18864be60e9a468e2516
DOI: 10.1253/circj.cj-14-0893
PMID: 25186923
Citations: 50
Influential citations: 1
Summary: Left ventricular noncompaction cardiomyopathy (LVNC) is an overlap disorder and it appears that any of these "final common pathways" can be involved depending on the specific form of LVNC.
Evidence snippets:
Snippet 1 (score: 0.448) > Cardiomyopathies (ie, diseases of the heart muscle) are major causes of morbidity and mortality. A significant percentage of patients with cardiomyopathies have genetic-based, inheritable disease and, over the past 2 decades the genetic causes of these disorders have been increasingly discovered. The genes causing these disorders when they are mutated appear to encode proteins that frame a "final common pathway" for that specific disorder, but the specifics of the phenotype, including age of onset, severity, and outcome is variable for reasons not yet understood. The "final common pathways" for the classified forms of cardiomyopathy include the sarcomere in the primarily diastolic dysfunction disorders hypertrophic cardiomyopathy and restrictive cardiomyopathy, the linkage of the sarcomere and sarcolemma in the systolic dysfunction disorder dilated cardiomyopathy, and the desmosome in arrhythmogenic cardiomyopathy. Left ventricular noncompaction cardiomyopathy (LVNC) is an overlap disorder and it appears that any of these "final common pathways" can be involved depending on the specific form of LVNC. The genetics and mechanisms responsible for these clinical phenotypes will be described.

[16] Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy

Authors: Jason Laird, Gayani Perera, R. Batorsky, Hongjie Wang, K. Arkun et al.
Year: 2023
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/25eb86bd5813dca0914c125c2c6a06c78999df82
DOI: 10.3390/ijms241612625
PMID: 37628806
PMCID: 10454036
Citations: 8
Influential citations: 1
Summary: A spatial transcriptomic analysis of the areas of focal myocyte disarray compared to areas of normal tissue using a commercially available platform identifies novel and potential disease-modifying targets for therapy in HCM.
Evidence snippets:
Snippet 1 (score: 0.438) > Hypertrophic Cardiomyopathy (HCM) is an inherited disorder affecting between 1 in 500 and 1 in 200 people (OMIM 192600, 115195, 115196, 115197 and others). The disease is characterized by unexplained left ventricular hypertrophy that is often asymmetric, involves the interventricular septum, and is associated with left ventricular outflow tract (LVOT) obstruction, fibrosis, microvascular occlusion, and sudden cardiac death. Histologically, it is characterized by focal areas of myocyte hypertrophy, myocyte disarray, fibrosis and medial hyperplasia. Anatomically, it is characterized by mitral valve abnormalities and left ventricular outflow tract obstruction. Physiologically, it is characterized by enhanced contractile function, reduced diastolic function and increased risk of sudden cardiac death [1]. Traditionally, HCM is considered a disease that ensues from sarcomere gene dysfunction, but in most patients, pathogenic sarcomere gene mutations cannot be identified. In those patients where pathogenic gene mutations are found, most are located in the sarcomere genes MYBPC3 and MYH7. The genetic landscape of HCM is well-summarized [2]. The activation of signaling pathways that promote cardiac myocyte hypertrophy and fibrosis of the heart have been implicated in many studies [3], but additional mechanisms are likely contributing. Comprehensive studies to understand how sarcomere gene mutations can lead to phenotypes not related to sarcomere function or those seen in cells that do not express sarcomere genes are lacking in the field. Since sarcomere gene mutation-negative patients have similar phenotypes to sarcomere gene mutation-positive patients, it is likely that there are final common pathological pathways independent of sarcomere gene mutations that are involved, but these final common pathways are incompletely understood. Recent reports using single-nucleus RNA sequencing of human HCM tissue have identified potential alterations in cell-to-cell communication involving extracellular matrix proteins, integrin receptors and the activation of immune cells as potential contributors to the HCM phenotype [4][5][6].

[17] Screening for dilated cardiomyopathy in immediate family members: to whom, how, when (and where)

Authors: M. Pieroni, M. Ciabatti, C. Zocchi
Year: 2024
Venue: European Heart Journal Supplements : Journal of the European Society of Cardiology
URL: https://www.semanticscholar.org/paper/9d12e21d05e5bdad6ea72e27cfe86abc1abfe06f
DOI: 10.1093/eurheartjsupp/suae024
PMID: 38784151
PMCID: 11110450
Summary: Screening of family members of patients affected by DCM represents an important tool for early diagnosis, treatment, and prognostic stratification and it is important that family screening and follow-up of identified patients are carried out in units dedicated to the treatment and study of cardiomyopathies.
Evidence snippets:
Snippet 1 (score: 0.438) > Abstract Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular dilation and systolic dysfunction in the absence of coronary artery disease, valvular disease, congenital heart disease, or altered haemodynamic conditions. Dilated cardiomyopathy can recognize multiple aetiologies, including infectious processes, effect of toxic substances, immunological mechanisms, and genetic causes. In recent years, many genes coding for proteins involved in the structure and function of the cardiomyocytes have been associated with the development of DCM, making the identification of familial forms increasingly frequent. At the same time, an ever-increasing use of cardiac magnetic resonance imaging has made it possible to identify early morpho-functional alterations in subjects with initial forms of the disease, or carriers of pathogenic genetic variants. The increasingly in-depth understanding of the genetic and molecular mechanisms operating in DCM has also favoured the development of new therapeutic strategies including drugs with molecular targets and gene therapies. In this panorama, screening of family members of patients affected by DCM represents an important tool for early diagnosis, treatment, and prognostic stratification. In relation to its clinical relevance and its complexity, it is important that family screening and follow-up of identified patients are carried out in units dedicated to the treatment and study of cardiomyopathies.

[18] Left Ventricular Noncompaction Associated with Hypertrophic Cardiomyopathy: Morphologic and Functional Evaluation with Multidetector CT

Authors: H. Lee, Jae-Wook Lee, F. Meinel, U. Schoepf
Year: 2019
Venue: Cardiovascular Imaging Asia
URL: https://www.semanticscholar.org/paper/d871ca8c8ad851d43d59e03a33fdfbcc452181df
DOI: 10.22468/CVIA.2018.00255
Summary: With these cases showing a combination of two rare cardiac diseases, the utility of cardiac CT for the anatomical assessment of coronary arteries and the evaluation of ventricular morphology and function is emphasized.
Evidence snippets:
Snippet 1 (score: 0.437) > namic chamber and no other cardiac or systemic disease [1,3]. HCM is one of the most common genetic cardiac diseases, with a reported prevalence of around 0.2%. The imaging diagnosis of HCM is based on a maximal LV wall thickness ≥15 mm in the end-diastolic phase [1,5]. HCM is associated with a wide variety of phenotypes and a diverse clinical course, including sudden cardiac death in young adults [1,3]. HCM follows as a Mendelian autosomal dominant inheritance pattern and is caused by a missense mutation in one of the sarcomeric genes that encode cardiac sarcomeric protein [1,2,4]. The pathologic hallmark of HCM is myocyte disorganization/disarray, which is widespread throughout the LV and, to a lesser extent, in the right ventricle. > LV noncompaction is a rare cardiomyopathy, with a prevalence of less than 0.02%, characterized by excessive trabeculations of the LV with two distinct layers of NC and C myocardium. It is diagnosed and also differentiated from hypertrabeculation by a ratio of NC/C myocardium >2.0 at end-systole on echocardiography, and >2.3 at end-diastole on MR [6]. The natural history of LV noncompaction is unclear. Patients may be asymptomatic or suffer from dyspnea, arrhythmia, and systolic heart failure, thromboembolic events secondary to atrial fibrillation, or sudden cardiac death. Although not much is known about its inheritance pattern, LV noncompaction is a genetically heterogeneous entity with a sporadic and familial form [2]. > Recently, different mutations in sarcomeric genes, which previously have been found to be involved in the pathogenesis of HCM, have been also identified in patients with isolated LV noncompaction without myocardial hypertrophy. Thus, there seems to be a shared genetic origin of these two different cardiomyopathic phenotypes [1][2][3][4]6].

[19] Extracellular vesicles in cardiomyopathies: A narrative review

Authors: A. Rizzuto, A. Faggiano, C. Macchi, S. Carugo, C. Perrino et al.
Year: 2023
Venue: Heliyon
URL: https://www.semanticscholar.org/paper/d9f9d3f5e11a4f42af7d1ead3cff3c874fff64a4
DOI: 10.1016/j.heliyon.2023.e23765
PMID: 38192847
PMCID: 10772622
Citations: 5
Influential citations: 1
Summary: The aims of this narrative review are to elucidate the potential role of EVs in the paracrine cell-to-cell communication among cardiac tissue compartments, in aiding the diagnosis of the diverse subtypes of cardiomyopathies in a minimally invasive manner, and to address whether certain molecular and phenotypical characteristics of EVs may correlate with cardiomyopathy disease phenotype and severity.
Evidence snippets:
Snippet 1 (score: 0.437) > Cardiomyopathies refer to myocardial disorders affecting the heart muscle, in which structural and functional abnormalities are observed, in the absence of diseases such as coronary artery disease, hypertension, valvular disease, or congenital heart disease that could account for the observed abnormalities. According to the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies, morphological traits (ventricular hypertrophy: left and/or right; ventricular dilation: left and/or right; non-ischemic ventricular scar) and functional characteristics (global and/or regional ventricular systolic and/or diastolic dysfunction) are clinically employed to categorize five distinct cardiomyopathy phenotypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). Furthermore, the guidelines also specify the existence of syndromic and metabolic cardiomyopathies, including Anderson-Fabry disease, RASopathies, Friedreich ataxia, and Glycogen storage disorders [4]. > Whilst this phenotypic description is essential in paving the diagnostic and therapeutic pathway, the exact evolving nature of cardiomyopathies, along with their underlying aetiological complexities, are yet to be fully elucidated [5]. Within this context, biomarkers represent putative tools for identifying high-risk patients in a prompt manner, unveiling potential risk associations with disease progression and outcomes, and may also provide insights on unexplored molecular mechanisms at the basis of the pathophysiology of these disorders. > Thus, the aim of the present narrative review is to summarize the current knowledge on EVs in the setting of cardiomyopathies and to elucidate whether certain molecular and phenotypical characteristics of EVs (e.g., miRNA content) may correlate with cardiomyopathy phenotypes and severity.

[20] Left Ventricular Noncompaction

Authors: A. Almeida
Year: 2017
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/68fc2309bef159675fd75eb39dda0a58d7a29dfd
DOI: 10.5772/66291
Citations: 1
Summary: Left ventricular noncompaction (LVNC) is accepted as an unclassified (the American Heart Association) or a genetic cardiomyopathy (the European Society of Cardiology), but some argue that this phenotype may be a morphologic trait shared by different cardiomyopathies. This chapter covers the state of the art on the pathology, underly ing mechanisms, its clinical manifestations, and diagnosis and treatment modalities of LVNC. LVNC may be defined as follows: an inner non‐compacted layer with pro...
Evidence snippets:
Snippet 1 (score: 0.435) > Left ventricular noncompaction (LVNC) is accepted as an unclassified (the American Heart Association) or a genetic cardiomyopathy (the European Society of Cardiology), but some argue that this phenotype may be a morphologic trait shared by different cardiomyopathies. This chapter covers the state of the art on the pathology, underly ing mechanisms, its clinical manifestations, and diagnosis and treatment modalities of LVNC. LVNC may be defined as follows: an inner non‐compacted layer with prominent left ventricular trabeculae and deep intertrabecular recesses and a thin outer compacted layer. Mechanisms are still debatable, with the hypothesis of compaction arrest during embryogenesis as the most accepted theory. Genetic data support LVNC as a distinct cardiomyopathy, although evidence for LVNC as a shared morphological trait is not ruled out, since LVNC may be associated with other cardiomyopathies, congenital heart diseases and in some cases may be acquired. Diagnosis is based on imaging and may be confirmed by the use of genetics. Clinical picture and prognosis and the management options are discussed.

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Relevant Papers

[1] Advances in symptomatic therapy for left ventricular non-compaction in children

[2] Left Ventricular Noncompaction in Advanced Heart Failure With an Anomalous Coronary Artery: A Case Report

[3] Expression Signatures of Long Noncoding RNAs in Left Ventricular Noncompaction

[4] Bifid cardiac apex and spongiform cardiomyopathy in fetus with small microdeletion 16p12.2 of paternal origin. Critical points in family communication on 16p12.2 microdeletion

[5] A novel loss-of-function mutation in NRAP is associated with left ventricular non-compaction cardiomyopathy

[6] Left Ventricular Noncompaction Is Associated with Valvular Regurgitation and a Variety of Arrhythmias

[7] Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy

[8] A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy

[9] Role of Col1a2 and Postn in left ventricular noncompaction cardiomyopathy

[10] Electrocardiographic findings in correlation to magnetic resonance imaging patterns in African patients with isolated ventricular noncompaction

[11] The Role of Ventricular Assist Devices in Patients With Heart Failure Due to Dilated Cardiomyopathy: A Systematic Review

[12] Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering

[13] Hypertrophic and noncompacted cardiomyopathy of left ventricle: different manifestations of the same disease

[14] 2017 Riley Heart Center Symposium on Cardiac Development: Development and Repair of the Ventricular Wall

[15] Inherited cardiomyopathies.

[16] Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy

[17] Screening for dilated cardiomyopathy in immediate family members: to whom, how, when (and where)

[18] Left Ventricular Noncompaction Associated with Hypertrophic Cardiomyopathy: Morphologic and Functional Evaluation with Multidetector CT

[19] Extracellular vesicles in cardiomyopathies: A narrative review

[20] Left Ventricular Noncompaction

Notes