Left Ventricular Myocardial Noncompaction with Advanced Atrioventricular Conduction Disorder and Ventricular Arrhythmias in a Young Patient: Role of MIB1 Gene.
Ontology highlight
ABSTRACT:
SUBMITTER: Balla C
PROVIDER: S-EPMC8468736 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Left ventricular noncompaction (LVNC) Causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. 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. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction. RNA was isolated from the ventricles of 16 WT and 16 Mib1flox; CTnT-cre hearts at E14.5 and then pooled into four replicates.
2015-08-10 | E-GEOD-71912 | biostudies-arrayexpress
Project description:Left ventricular noncompaction (LVNC) Causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. 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. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.
2015-08-10 | GSE71912 | GEO
Project description:The NKX2-5 gene encodes a transcription factor and is actively involved in heart formation and development. A pediatric case with its variant and left ventricular noncompaction (LVNC) has not been reported. A 12-year-old girl with a history of a surgery for atrial septal detect was referred because of syncope during exercise. The electrocardiogram showed atrioventricular block, and the echocardiogram revealed prominent trabeculations in the left ventricular wall, suggesting LVNC. A novel heterozygous variant in the NKX2-5 gene (NM_004387.1: c.255_256delCT, p.Phe86fs) was identified. NKX2-5 variants should be considered in cases with LVNC, congenital heart disease, arrhythmia, and syncope to prevent sudden cardiac death.
| S-EPMC9181799 | biostudies-literature
Project description:Left ventricular noncompaction (LVNC) is a type of cardiomyopathy characterized anatomically by prominent ventricular trabeculation and deep intertrabecular recesses. The mortality associated with LVNC ranges from 5% to 47%. The etiology of LVNC is yet to be fully understood, although decades have passed since its recognition as a clinical entity globally. Furthermore, critical questions, i.e., whether LVNC represents an acquired pathology or has a congenital origin and whether the reduced contractile function in LVNC patients is a cause or consequence of noncompaction, remain to be addressed. In this study, to answer some of these questions, we analyzed the clinical features of LVNC patients. Out of 9582 subjects screened for abnormal cardiac functions, 45 exhibit the characteristics of LVNC, and 1 presents right ventricular noncompaction (RVNC). We found that 40 patients show valvular regurgitation, 39 manifest reduced systolic contractions, and 46 out of the 46 present different forms of arrhythmias that are not restricted to be caused by the noncompact myocardium. This retrospective examination of LVNC patients reveals some novel findings: LVNC is associated with regurgitation in most patients and arrhythmias in all patients. The thickness ratio of the trabecular layer to compact layer negatively correlates with fractional shortening, and reduced contractility might result from LVNC. This study adds evidence to support a congenital origin of LVNC that might benefit the diagnosis and subsequent characterization of LVNC patients.
| S-EPMC8876824 | biostudies-literature
Project description:Isolated left ventricular noncompaction (LVNC) was described for the first time in 1984. It is a rare congenital disease, characterized by prominent trabecular meshwork pattern and deep intertrabecular recesses, communicated with the left ventricular chamber. Clinical presentation varies from asymptomatic patients, to those developing supraventricular and ventricular arrhythmias, thromboembolism, heart failure and sudden cardiac death. We present an unusual case, where the patient with Neurofibromatosis type 1 presented with a wide complex orthodromic atrioventricular reentrant tachycardia (AVRT) and a diagnosis of left posterior paraseptal accessory pathway in association with LVNC.
| S-EPMC6440266 | biostudies-literature
Project description:BackgroundLeft ventricular noncompaction cardiomyopathy (LVNC) is a hereditary heart disease characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. The guidelines for management of LVNC patients aim to improve quality of life by preventing cardiac heart failure. However, the mechanism underlying LVNC-associated heart failure remains poorly understood.MethodsUsing protein mass spectrometry analysis, we established that Sorbin And SH3 Domain Containing 2 (SORBS2) is up-regulated in LVNC hearts without changes to structure proteins. We conducted in vivo experiments wherein the heart tissues of wild-type mice were injected with an AAV9 vector to overexpress SORBS2, followed by analysis using echocardiography, T-tubule analysis and Ca2+ imaging to identify functional and morphological changes. In addition, we analyzed the function and structure of SORBS2 overexpressing human embryonic stem cell (hESC) derived cardiomyocytes (hESC-CM) via immunoblotting, immunohistochemistry, immunofluorescence, and confocal Ca2+ imaging.FindingsLVNC myocardial tissues feature strongly elevated expression of SORBS2, microtubule densification and redistribution of Junctophilin 2 (JP2). SORBS2 interacts with β-tubulin, promoting its polymerization in 293T cells and hESC-derived CMs. In vivo, cardiac dysfunction, β-tubulin densification, JP2 translocation, T-tubule disorganization and Ca2+ handling dysfunction were observed in mice overexpressing SORBS2.InterpretationWe identified 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. FUND: This work was supported by a CAMS Initiative for Innovative Medicine grant (CAMS-I2M, 2016-I2M-1-015 to Y.J.Wei).
| S-EPMC7058526 | biostudies-literature
Project description:BackgroundLeft ventricular noncompaction is a rare cardiomyopathy characterized by a thin, compacted epicardial layer and a noncompacted endocardial layer, with trabeculations and recesses that communicate with the left ventricular cavity. In the advanced stage of the disease, the classical triad of heart failure, ventricular arrhythmia, and systemic embolization is common. Segments involved are the apex and mid inferior and lateral walls. The right ventricular apex may be affected as well.Case presentationA 29-year-old Caucasian male was hospitalized with dyspnea and fatigue at minimal exertion during the last months before admission. He also described a history of edema of the legs and abdominal pain in the last weeks. Physical examination revealed dyspnea, pulmonary rales, cardiomegaly, hepatomegaly, and splenomegaly. Electrocardiography showed sinus rhythm with nonspecific repolarization changes. Twenty-four-hour Holter monitoring identified ventricular tachycardia episodes with right bundle branch block morphology. Transthoracic echocardiography at admission revealed dilated left ventricle with trabeculations located predominantly at the apex but also in the apical and mid portion of lateral and inferior wall; end-systolic ratio of noncompacted to compacted layers > 2; moderate mitral regurgitation; and reduced left ventricular ejection fraction. Between apical trabeculations, multiple thrombi were found. The right ventricle had normal morphology and function. Speckle-tracking echocardiography also revealed systolic left ventricle dysfunction and solid body rotation. Abdominal echocardiography showed hepatomegaly and splenomegaly. Abdominal computed tomography was suggestive for hepatic and renal infarctions. Laboratory tests revealed high levels of N-terminal pro-brain natriuretic peptide and liver enzymes. Cardiac magnetic resonance evaluation at 1 month after discharge confirmed the diagnosis. The patient received anticoagulants, antiarrhythmics, and heart failure treatment. After 2 months, before device implantation, he presented clinical improvement, and echocardiographic evaluation did not detect thrombi in the left ventricle. Coronary angiography was within normal range. A cardioverter defibrillator was implanted for prevention of sudden cardiac death.ConclusionsLeft ventricular noncompaction is rare cardiomyopathy, but it should always be considered as a possible diagnosis in a patient hospitalized with heart failure, ventricular arrhythmias, and systemic embolic events. Echocardiography and cardiac magnetic resonance are essential imaging tools for diagnosis and follow-up.
| S-EPMC8186052 | biostudies-literature
Project description:The major clinical features of myocardial noncompaction are heart failure, arrhythmias, and thromboembolic events. Prominent myocardial trabeculae and deep recesses characteristic of myocardial noncompaction can cause stagnant blood flow and the formation of left ventricular clots. We describe the case of a 62-year-old woman who presented with symptoms of heart failure secondary to left ventricular noncompaction. Transthoracic and transesophageal echocardiography revealed multiple left ventricular thrombi, which had formed despite the patient's long-term therapy with aspirin. Anticoagulative therapy should be considered for patients with myocardial noncompaction who also have risk factors for thromboembolism, such as atrial fibrillation, a history of systemic embolism, or severe left ventricular systolic dysfunction. However, chronic antiplatelet therapy may not sufficiently prevent clot formation in patients who have myocardial noncompaction and severe left ventricular systolic dysfunction.
| S-EPMC3423290 | biostudies-literature
Project description:BackgroundCoronary venous ethanol ablation (VEA) can be used as a strategy to treat ventricular arrhythmias arising from the left ventricular summit, but collateral flow and technical challenges cannulating intramural veins in complex venous anatomies can limit its use. Advanced techniques for VEA can capitalize on collateral vessels between target and nontarget sites to improve success.MethodsOf 55 patients with left ventricular summit ventricular arrhythmia, advanced techniques were used in 15 after initial left ventricular summit intramural vein mapping failed to show suitable targets for single vein, single-balloon VEA. All patients had previous radiofrequency ablation attempts. Techniques included: double-balloon for distal protection to block distal flow and target the proximal portion of a large intramural vein where best signal was proximal (n=6); balloons in 2 different left ventricular summit veins for a cross-fire multivein VEA (n=4); intramural collateral vein-to-vein cannulation to reach of targeted vein via collateral with antegrade ethanol and proximal balloon block (n=2); prolonged ethanol dwell time for vein sclerosis of large intramural vein and subsequent VEA (n=3); and intramural collateral VEA (n=1).ResultsFifteen (8 females) patients (age 60.6±17.6 years) required advanced techniques. Procedure time was 210±49.9 minutes, fluoroscopy time was 25.3±14.1 minutes, and 113±17.9 cc of contrast was utilized. A median of 7 cc of ethanol was delivered (range, 4-15 cc). Intraprocedural radiofrequency ablation was delivered before ethanol in 9 out of 15 patients but failed. Ethanol achieved acute success in all 15 patients. Ethanol was used as the sole treatment in two patients. At a median follow-up of 194 days, one patient experienced recurrence.ConclusionsAdvanced techniques capitalizing on venous anatomy can enable successful VEA and selective targeting of arrhythmogenic sites, by blocking distal flow, utilization of collaterals between nontarget and target veins and multivein VEA. Understanding individual anatomy is critical for VEA success.
| S-EPMC9388546 | biostudies-literature
Project description:Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. The cardiac conduction system is implicated in arrhythmias, but how it is altered following MI is poorly understood. We demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganised bundling of conduction fibres after MI, global His/Purkinje disruption and regional loss of connexin-40. Single-cell RNA-sequencing revealed that Purkinje cells undergo specific molecular changes to regenerate the network, versus sustained aberrant electrical alterations during fibrotic repair. This manifested functionally as transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modelling the non-regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and ventricular dyssynchrony, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration versus repair and reveal the consequences of MI-induced damage for clinical arrhythmogenesis.
2024-10-31 | GSE245872 | GEO