Are NONO variants linked to congenital heart disease? Patient reports and review.

Pediatric Left Ventricular Non-compaction: A Single-center Experience from Anatolia

The current diagnostic criteria for noncompaction of the ventricular myocardium (NVM) remain inconsistent, and comprehensive cardiac magnetic resonance (CMR) imaging data on the disease are limited. Therefore, the purpose of this study is to evaluate the clinical utility of CMR imaging in the diagnosis and functional assessment of patients with NVM. Twenty patients with NVM and twenty age- and sex-matched healthy controls (HC) underwent comprehensive CMR imaging. Postprocessing software was used to quantify left ventricular longitudinal strain, both global longitudinal strain (GLS) and strain in the basal, middle, and apical segments (BLS, MLS, and ALS, respectively). Statistical analyses were performed to assess group differences. Compared with the HC group, patients with NVM presented significantly increased left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and myocardial mass index (LVMI) and a significantly reduced left ventricular ejection fraction (LVEF) (all P < 0.001). All NVM patients presented prominent trabeculations and deep intertrabecular recesses in the left ventricle during diastole. Cine imaging revealed direct blood flow communication between the recesses and the ventricular cavity. The myocardium exhibited a thin compacted outer layer (C) and a thickened noncompacted inner layer (NC), with an average NC/C ratio of 2.8 ± 0.5. For these patients, NVM primarily involved the apical and adjacent mid-ventricular free wall segments; in five patients, it also involved the basal segment. Right ventricular noncompaction was observed in five patients, and apical ventricular aneurysms were identified in two patients. Compared with the HC group, the NVM group presented a significantly lower ALS (P < 0.05); however, the BLS, MLS, and GLS values were not significantly different between the groups (P > 0.05). Our study demonstrated the feasibility of using CMR imaging to quantitatively assess left ventricular systolic function in NVM patients. The choice of longitudinal strain as a primary parameter was driven by the fact that NVM predominantly affects the endocardial myocardium, particularly the subendocardial fibers, which are primarily longitudinal. As such, longitudinal strain is particularly sensitive for detecting myocardial contractile dysfunction in NVM. Our results indicated that ALS apical longitudinal strain is a more significant marker of contractile dysfunction in NVM than MLS, which was not significantly altered in NVM patients relative to HCs. CMR imaging offers robust diagnostic capabilities for patients with NVM and, when combined with feature tracking, allows the quantitative assessment of left ventricular systolic function. The ALS may serve as a sensitive marker of early myocardial dysfunction and may be clinically important in guiding timely diagnosis and intervention.

Left ventricular noncompaction (LVNC) is a form of cardiomyopathy characterized by excessive trabeculation and a thin compacted myocardial layer. Variants in MYH7, which encodes the β-myosin heavy chain, are among the most commonly identified genetic causes of LVNC. Despite its clinical relevance, the metabolic disturbances associated with LVNC remain poorly understood, and the pathophysiological mechanisms have not been investigated in an animal model of MYH7-related LVNC. To address this gap, we generated a mouse model carrying the human MYH7 Gln315Arg (Q315R) variant, a representative mutation linked to LVNC. Mice with the MYH7 Q315R variant exhibited key features of LVNC, including impaired diastolic function, reduced contractility, and excessive trabeculations extending across the ventricular walls. Metabolomic analysis revealed significant metabolic remodeling, characterized by suppressed glycolysis, lipid oxidation, and tricarboxylic acid (TCA) cycle activity. Levels of key intermediates, including glucose-6-phosphate, pyruvate, and acetyl-CoA, were reduced, along with downregulated expression of glycolytic and mitochondrial genes. Additionally, alterations in the pentose phosphate pathway indicated impaired nucleic acid synthesis, while an increased lactate-to-pyruvate ratio suggested a metabolic shift toward anaerobic glycolysis. This study underscores the critical role of metabolic inflexibility—marked by suppression of glycolysis, lipid metabolism, and TCA cycle activity—in the pathophysiology of LVNC. Targeting these dysregulated metabolic pathways, particularly by enhancing mitochondrial function and restoring metabolic adaptability, presents a potential therapeutic strategy for LVNC treatment.

Ebstein anomaly (EA) is a rare congenital heart defect characterized by an abnormal development of the tricuspid valve (TV) and ventricular myocardium. The TV is displaced downward into the right ventricle (RV), leading to an atrialized basal portion of the RV above the closure plane of the TV and an often hypoplastic functional RV. Common consequences include cyanosis, TV regurgitation, arrhythmias, and heart failure. Although primarily a valve defect, EA can be regarded as a cardiomyopathy as well. Coexistence of EA with other cardiomyopathies, including left ventricular non-compaction (LVNC), suggests a shared genetic or developmental basis. Diagnostic advancements such as echocardiography, cardiac magnetic resonance, and electrophysiological studies have greatly improved early identification, risk stratification, and management of EA. However, challenges persist, particularly in prenatal detection and differentiation of EA from other congenital TV malformations. Autopsy is fundamental in fatal EA cases to ascertain the diagnosis, understand the cause of death, and guide family counseling. Significant knowledge gaps remain concerning the exact etiology of EA. Future research should focus on unveiling the genetic/epigenetic pathways and environmental factors involved in the pathogenesis of this heart malformation. Filling these gaps will be essential for developing targeted and effective treatments and improving patient outcomes.

A 16-year-old-male presented in 2016 after a fall with a concussion due to dizziness. Chest X-ray showed a prominent cardiac silhouette. Further workup showed an echocardiogram with no left ventricular hypertrophy and mild left ventricular dilation. A Holter monitor recorded 1259 single PACs and 87 aberrantly conducted PACs. The patient was diagnosed with anxiety in 2017 and started on sertraline and later changed to fluoxetine. These medications were stopped at the end of 2022. In early 2023, he presented with symptomatic sinus bradycardia. A coronary angiogram revealed no obstructive CAD. MRI showed LV noncompaction towards the ventricular apex. Genetic testing showed a heterozygous HCN4 gene mutation. The HCN4 gene mutation variants affect the cyclic nucleotide-gated cardiac ion channels, potentially leading to arrhythmias. It is most associated with patients with sinus node dysfunction. Specific mutations have been known to also present with left ventricular noncompaction (like in our patient), sick sinus syndrome, and susceptibility to ventricular fibrillation. Emerging evidence suggests that HCN4 gene may have potential expression in the brain. It is known that the HCN1 and HCN2 genes are common in the brain, but they are finding that the HCN4 gene is used as an “on-off” button that can control the way neurons respond to synaptic input. This gene mutation, Gln375Ter, is associated with LV noncompaction or sinus node dysfunction. However, very few cases show an association of arrhythmias with mood disorders. There is evidence that the HCN4 gene may be associated with anxiety and depression because of its presence in the brain and specifically its location in the frontal cortex, and thalamocortical network. Our case illustrates how symptoms related to the mutation gradually emerged in the interval of presentation and diagnosis of the HCN4 gene mutation. For patients presenting with symptomatic bradycardia, screening for anxiety and depression using DSM-V criteria could be crucial in identifying a genetic basis for their condition. Given that the HCN4 gene mutation can manifest in diverse ways due to its expression in both the heart and brain, awareness of these potential symptoms can aid the care team in accurately diagnosing this mutation.

Background: Pathogenic/likely pathogenic (P/LP) variants in the RBM20-encoded RNA-binding protein motif 20 splicing factor result in a penetrant form of arrhythmogenic/dilated cardiomyopathy (ACM/DCM) characterized by ventricular arrhythmias (VA) and early-onset heart failure. The role of cardiac magnetic resonance (CMR) imaging in characterizing RBM20 cardiomyopathy and guiding risk stratification remains inadequately defined. Objectives: To characterize CMR phenotypes in patients with RBM20 cardiomyopathy and explore associations between variant type, CMR phenotype, and VA risk. Methods: Retrospective analysis of 1,061 genotype-positive ACM/DCM patients was used to identify individuals with P/LP arginine/serine-rich domain-localizing missense (RBM20msv) or truncating (RBM20tv) variants in RBM20. Clinical outcomes, including major VA (MVA; sudden cardiac arrest, sustained ventricular arrhythmia, or appropriate ICD therapy) events, were compared between RBM20msv and RBM20tv-positive patients. When available, CMR findings were also analyzed by variant type and correlated with MVA events. Results: Overall, 64 of 1,061 (6%) ACM/DCM patients possessed an RBM20msv or RBM20tv. Of those, 35 (mean age 38±16 years, 54% female, 94% Caucasian) underwent CMR. Late gadolinium enhancement (LGE) was present in 9/35 (26%), typically in a mid-myocardial septal or inferolateral pattern. Left ventricular (LV) noncompaction was noted in 9/35 (26%). Within the CMR subgroup, RBM20msv accounted for 29/35 (83%) of cases, while RBM20tv was observed in 6/35 (17%). No significant difference in LV ejection fraction (36±7% vs. 42±13%, p=0.358), LV end-diastolic volume index (100±32 mL/m2 vs. 118±44 mL/m2, p=0.342), or LGE prevalence (1/6 [17%] vs. 8/29 [28%], p=1.000) was observed between RBM20tv- and RBM20msv-positive patients. However, MVA events were more frequent among RBM20tv-positive patients in the CMR subset (3/6 [50%] vs. 2/29 [7%], p=0.026) and the overall cohort (7/15 [47%] vs. 6/49 [12%], p=0.008). Conclusions: RBM20tv-positive patients experienced a higher rate of MVA events despite similar rates of LGE and structural remodeling compared to those with RBM20msv. Future studies are needed to determine whether mechanisms independent of fibrosis/re-entry drive arrhythmogenesis in RBM20tv-positive patients and to establish if RBM20tv represents an independent risk factor for MVA events that merits incorporation into genotype-specific risk stratification strategies.

Introduction: Congenital heart disease (CHD) is the most common birth defect and a major cause of neonatal mortality. Over half of CHD cases remain genetically unexplained. The lipid mediator sphingosine-1-phosphate (S1P) acts through the endothelial receptor S1PR1 to regulate cardiovascular development. While S1P–S1PR1 signaling has been studied in early cardiac morphogenesis, its role in later trabecular angiogenesis (E15.5–P7) is unknown. Hypothesis: Low S1PR1 levels in the left ventricular (LV) endocardium, achieved via spatially restricted internalization and degradation, are essential for proper coronary vessel development and trabecular compaction. Dysregulation of this pathway leads to structural heart defects. Methods: Reporter mice expressing GFP-tagged S1PR1 were used to track internalization. Immunohistochemistry and scRNA-seq were employed to analyze expression of S1PR1 and its degradation mediators (GRK2, ARRB2, WWP2) across ventricular regions. Functional studies in S1PR1 internalization-defective mice (S1PR1 S5A ), S1PR1 endothelial overexpression (ECOE) mice, and S1PR1 pharmacological inhibition models were conducted. Markers of angiogenesis (VEGFR2/3), EndoMT (SNAI2, TGFB2), and proliferation (Ki67, EdU) were used to evaluate ventricular development. Results: S1PR1 internalization was enriched in the LV and interventricular septum, aligning with coronary vessel formation. CHD patient data revealed elevated S1PR1 expression in endocardial cells, especially in LVNC and Tetralogy of Fallot cases. ECOE mice showed LV noncompaction, septal defects, and reduced trabecular angiogenesis. S1PR1 S5A mice exhibited similar phenotypes, confirming the importance of internalization. Pharmacological inhibition using AUY954 and W146 partially rescued these defects. Conclusions: Spatial suppression of S1PR1 via internalization is a crucial developmental mechanism in late-stage heart formation. Excess S1PR1 signaling disrupts endocardial-to-endothelial transition and coronary vessel development. These findings reveal a novel pathophysiological pathway for CHD and suggest therapeutic potential for S1PR1-targeting drugs in preventing structural heart defects.

Double-chambered left ventricle (DCLV) is a rare congenital anomaly in which a muscular band divides the left ventricular cavity into 2 chambers. It may mimic other conditions such as left ventricular noncompaction (LVNC), thrombus, or aneurysm. This case highlights the diagnostic role of multimodality cardiac magnetic resonance (CMR) imaging. We report a 12-year-old girl undergoing anthracycline chemotherapy for pre-B acute lymphoblastic leukemia who presented with non-radiating chest pain for 1 week. Her medical history included patent ductus arteriosus closure at age 2 and ongoing growth hormone therapy for short stature. Diagnosis of DCLV was established based on CMR findings of a bifid apex separated by a synchronously contracting muscular band with myocardial-like signal intensity and absence of late gadolinium enhancement. A trabecular-to-compact ratio of 1.84 further excluded LVNC, and imaging features were inconsistent with diverticulum, thrombus or aneurysm. The patient received no medical or surgical intervention. Given her stable condition and absence of concerning findings on follow-up, she remained under routine clinical observation without the need for further treatment. The patient remained asymptomatic during 1 year of follow-up, with no recurrence of chest pain or development of cardiac complications. When DCLV presents with an ambiguous apical mass and abnormal cavity with complex comorbidities, it can mimic serious conditions such as LVNC, thrombus, aneurysm, or diverticulum, making accurate diagnosis challenging using echocardiography alone. In situations where echocardiographic findings are inconclusive, CMR with tissue characterization is essential to avoid misdiagnosis and unnecessary treatment. Early use of multimodality CMR in such cases helps to clarify morphology and guide clinical management.

Right atrial (RA) strain is increasingly recognized as a significant predictor of adverse events in patients with various cardiovascular conditions. However, the prognostic value of RA strain in patients with left ventricular noncompaction (LVNC) is unclear. The objective of this study was to evaluate the prognostic significance of RA strain derived from cardiac magnetic resonance feature tracking (CMR-FT) in patients with LVNC. 394 LVNC patients who underwent CMR at 4 Chinese medical facilities from September 2014 to July 2023 were retrospectively and consecutively included in total. RA strain parameters were obtained using CMR-FT. Major adverse cardiac events (MACEs) were assessed, and all patients were followed up. 156 patients (39.6%) experienced MACEs during a median follow-up of 34 months. At univariable analysis, RA conduit strain was associated with MACE (hazard ratio [HR] 0.88 [95% CI 0.85-0.91]; P < 0.001). RA conduit strain maintained an independent predictor of MACE in a multivariate model that included left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) (HR 0.89 [95% CI 0.85-0.93]; p < 0.001). Furthermore, adding RA conduit strain to the multivariate model greatly enhanced the prognostic role of endpoint events (C-statistic improvement: 0.766-0.871, Delong test: p < 0.001). Net reclassification index (NRI) (0.201, p < 0.05) and integrated discrimination improvement (IDI) (0.038, p < 0.05) also showed the same trend. CMR-FT derived RA conduit strain is a potent independent indicator of major adverse cardiac events in left ventricular noncompaction patients. In addition, RA conduit strain can provide additional prognostic value over the multivariable baseline clinical model.

Left Ventricular Noncompaction (LVNC) is a congenital cardiomyopathy characterized by excessively prominent trabeculations and deep intertrabecular recesses within the ventricular cavity. Modern medical management primarily focuses on symptomatic treatment, lacking specific therapeutic agents. In contrast, Traditional Chinese Medicine (TCM), based on the therapeutic principle of “Supplementing Qi and Warming Yang, Activating Blood and Promoting Diuresis, “ demonstrates distinct advantages. It employs multi-component, multi-target interventions to regulate myocardial energy metabolism, suppress inflammatory responses, and ameliorate myocardial fibrosis. The integrated approach of TCM and Western medicine offers a more comprehensive therapeutic strategy for patients with LVNC. Future research should prioritize high-quality clinical studies and in-depth mechanistic exploration.

Left ventricular non-compaction (LVNC) cardiomyopathy is a rare congenital cardiomyopathy which is characterized by prominent and extensive trabeculation and deep intertrabecular recesses communicating with left ventricular cavity. Here we present a rare case report of patient with severe secondary Mitral regurgitation (MR) and severe tricuspid regurgitation (TR) in LVNC cardiomyopathy who underwent MV Repair using ring annuloplasty with #28 CG future ring and kay's suture annuloplasty for severe TR and its postoperative management. Patient recovered well after surgery and was discharged with improved hemodynamics. The valve surgery in patients with such cardiomyopathy is very rare. This case will add to the small growing literature of surgery in severe secondary Mitral regurgitation in LVNC and the problems we faced while coming off bypass and its postoperative management.

Cardiac CT fractal analysis of LV noncompaction and common cardiomyopathies.

Early Detection of Left Ventricular Noncompaction in a Newborn

Prognostic Value of Compact Myocardial Thinning in Patients With Left Ventricular Noncompaction.

CMR imaging at the left ventricular outflow tract level reveals left ventricular dilatation, reduced systolic function, and left ventricular myocardial non-compaction.

Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease characterized by abnormal prenatal development of the left ventricle that has an aberrantly thick trabecular layer and a thinner compacted myocardial layer. However, the underlying molecular mechanisms of LVNC regulated by mitochondrial phosphatase genes remain largely unresolved. Methods: We generated a mouse model with cardiac-specific deletion (CKO) of Ptpmt1, a type of mitochondrial phosphatase gene, using the αMHC-Cre, and investigated the effects of cardiac-specific Ptpmt1 deficiency on cardiac development. Morphological, histological, and immunofluorescent analyses were conducted in Ptpmt1 CKO and littermate controls. A transcriptional atlas was identified by RNA sequencing (RNA-seq) analysis. Results: We found that CKO mice were born at the Mendelian ratio with normal body weights. However, most of the CKO mice died within 24 h after birth, developing spontaneous ventricular tachycardia. Morphological and histological analysis further revealed that newborn CKO mice developed an LVNC phenotype, evidenced by a thicker trabecular layer and a thinner myocardium layer, when compared with the littermate control. We then examined the embryonic hearts and found that such an LVNC phenotype could also be observed in CKO hearts at E15.5 but not at E13.5. We also performed the EdU incorporation assay and demonstrated that cardiac cell proliferation in both myocardium and trabecular layers was significantly reduced in CKO hearts at E15.5, which is also consistent with the dysregulation of genes associated with heart development and cardiomyocyte proliferation in CKO hearts at the same stage, as revealed by both the transcriptome analysis and the quantitative real-time PCR. Deletion of Ptpmt1 in mouse cardiomyocytes also induced an increase in phosphorylated eIF2α and ATF4 levels, indicating a mitochondrial stress response in CKO hearts. Conclusions: Our results demonstrated that Ptpmt1 may play an essential role in regulating left ventricular compaction during mouse heart development.

LVNC (Left Ventricular Non-Compaction), which is a type of cardiomyopathy characterized by an abnormal heart muscle structure. Retinoic acid (RA) is crucial for normal heart development, including the regulation of myocardial differentiation and chamber formation. Cyp26b1 plays a key role in regulating RA signaling by degrading RA. However, more targeted research is needed to directly link Cyp26b1 with LVNC pathology. To explore the effect of Cyp26b1 on heart development, we collected heart tissues from wild type (WT) and Cyp26b1 knockout (KO) mice at four time points (E10.5-E13.5) and performed single-cell RNA sequencing. We obtained 134,499 high-quality cells (57,923 WT and 62,488 KO) after filtering. The data quality was confirmed through various evaluation index and analytical methods mapping rates. Our initial analysis identified 10 major cell types in hearts, and differential expression analysis revealed the transcriptional change after deletion of Cyp26b1, particularly in cardiomyocytes. Collectively, these data offer a valuable resource for researchers investigating the role of Cyp26b1 in heart development.

Coronary Ct Angiography Fractal Analysis Differentiates Lv Noncompaction From Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy, And Controls

Left ventricular noncompaction (LVNC) is characterized by excessive trabeculation, which may impair left ventricular function over time. While cardiac magnetic resonance imaging (CMR) is considered the gold standard for evaluating LV morphology, the optimal modality for follow-up remains uncertain. This study aimed to assess the correlation and agreement among two-dimensional transthoracic echocardiography (2D_TTE), three-dimensional transthoracic echocardiography (3D_TTE), and CMR by comparing volumetric and strain parameters in LVNC patients and healthy individuals. Thirty-eight LVNC subjects with preserved ejection fraction and thirty-four healthy controls underwent all three imaging modalities. Indexed end-diastolic, end-systolic, and stroke volumes, ejection fraction, and global longitudinal and circumferential strains were evaluated using Pearson correlation and Bland–Altman analysis. In the healthy group, volumetric parameters showed strong correlation and good agreement across modalities, particularly between 3D_TTE and CMR. In contrast, agreement in the LVNC group was moderate, with lower correlation and higher percentage errors, especially for strain parameters. Functional data exhibited weak or no correlation, regardless of group. These findings suggest that while echocardiography may be suitable for volumetric follow-up in LVNC after baseline CMR, deformation parameters are not interchangeable between modalities, likely due to trabecular interference. Further studies are warranted to validate modality-specific strain assessment in hypertrabeculated hearts.