Noncompaction Of The Ventricular Myocardium Research Articles

RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium

Noncompaction of the ventricular myocardium (NVM), the third most diagnosed cardiomyopathy, is characterized by prominent trabeculae and intratrabecular recesses. However, the genetic etiology of 40%–60% of NVM cases remains unknown. Here, we identify two infants with NVM, in a nonconsanguineous family, with a typical clinical presentation of persistent bradycardia since the prenatal period. A homozygous missense variant (R223L) of RCAN family member 3 (RCAN3) is detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction is detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan−/− embryos. Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNAs rescue these phenotypes. RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency results in reduced proliferation and increased apoptosis, together with an abnormal mitochondrial ultrastructure. Thus, we suggest that RCAN3 is a susceptibility gene for cardiomyopathies, especially NVM and that the R223L mutation is a potential loss-of-function variant.

Non-compaction of the ventricular myocardium and multimodality imaging: diagnostic work-up and outcome

Non-compaction of the ventricular myocardium and multimodality imaging: diagnostic work-up and outcome

BIVENTRICULAR NON-COMPACTION CARDIOMYOPATHY WITH LEFT VENTRICULAR DYSFUNCTION

Non-compaction of the ventricular myocardium involving both ventricles is a rare condition and characterized by deeply increased trabeculations in one or more segments of the ventricle. Non-compaction is thought to be due to intrauterine arrest of compaction of the loosely interwoven meshwork present in fetal myocardial primordium. More recent studies suggest that non-compaction of the ventricular myocardium can be acquired later on in life sporadically.The apical segment of the left ventricle is most commonly affected, but biventricular involvement is also described. Herein, we describe an unusual case of biventricular non-compaction cardiomyopathy with left ventricular systolic and diastolic dysfunction. A 54-year-old man presented with clinical heart failure as well as arrhythmia. Transthoracic echocardiography revealed left ventricular non-compaction with depressed ejection fraction. Cardiac magnetic resonance imaging (MRI) further revealed right ventricular noncompaction.

Splicing factor Srsf5 deletion disrupts alternative splicing and causes noncompaction of ventricular myocardium

SummaryThe serine/arginine-rich (SR) family of splicing factors plays important roles in mRNA splicing activation, repression, export, stabilization, and translation. SR-splicing factor 5 (SRSF5) is a glucose-inducible protein that promotes tumor cell growth. However, the functional role of SRSF5 in tissue development and disease remains unknown. Here, Srsf5 knockout (Srsf5−/−) mice were generated using CRISPR-Cas9. Mutant mice were perinatally lethal and exhibited cardiac dysfunction with noncompaction of the ventricular myocardium. The left ventricular internal diameter and volume were increased in Srsf5−/− mice during systole. Null mice had abnormal electrocardiogram patterns, indicative of a light atrioventricular block. Mechanistically, Srsf5 promoted the alternative splicing of Myom1 (myomesin-1), a protein that crosslinks myosin filaments to the sarcomeric M-line. The switch between embryonic and adult isoforms of Myom1 could not be completed in Srsf5-deficient heart. These findings indicate that Srsf5-regulated alternative splicing plays a critical role during heart development.

Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects.

Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.

Clinical manifestations and gene mutation analysis of children with noncompaction of the ventricular myocardium: an analysis of 6 cases

This article summarizes and analyzes the clinical features and gene mutation characteristics of children with noncompaction of the ventricular myocardium (NVM). For the 6 children with NVM (4 boys and 2 girls), the age of onset ranged from 3 months to 12 years. Of the 6 children, 5 had arrhythmia, 3 had cardiac insufficiency, 1 had poor mental state, and 1 had chest distress and sighing. NVM-related gene mutations were detected in 4 children, among whom 2 had MYH7 gene mutation, 1 had PRDM16 gene mutation, and 1 had mutations in the ACTN2 and TNNT2 genes. Four children had improvement in cardiac function. The two children with no significant improvement in cardiac function had a younger age of onset, a greater reduction in systolic function on echocardiography, and greater increases in myocardial enzyme and N-terminal pro-brain natriuretic peptide. It is concluded that for children with the initial symptoms of chest distress, sighing, arrhythmia, enlarged heart shadow, and increased myocardial enzyme, echocardiography and cardiac magnetic resonance are recommended for the diagnosis of NVM. NVM can have various genetic mutations.

Isolated Right Ventricular Non-compaction as a Cause of Death in Cornelia de Lange Syndrome

Abstract Introduction/Objective We report the case of a 32-year-old white male with a past medical history of bipolar disorder, autistic spectrum disorder, and Cornelia de Lange Syndrome (CdLS), who was admitted to the ED with cardiac arrest. Resuscitative efforts were unsuccessful. The autopsy revealed an isolated right ventricular non-compaction. Methods The non-compaction of the ventricular myocardium is a type of cardiomyopathy caused by aberrant embryogenesis, often presenting with other congenital cardiac defects, especially in syndromic patients. Such is the case with Cornelia de Lange Syndrome, in which multiple cardiac anomalies are commonly seen. However, only a few cases of ventricular non-compaction were reported for patients with CdLS. To our knowledge, this is the first case of CdLS with death attributed to the isolated right ventricular non-compaction cardiomyopathy. Results CdLS is characterized by intellectual disability, distinctive facial features, growth retardation, hirsutism, and malformation of multiple organ systems. In general, ventricular non-compaction is defined by the persistence of deep intertrabecular recesses that communicate with both the ventricular cavity and the coronary circulation. The two main diagnostic criteria include the absence of well-formed papillary muscles and more than 50% penetration of invaginated endocardial recesses toward the epicardial surface. Additional features include the presence of staghorn shaped endocardial recesses, endomyocardial thickening, and endocardial fibrosis. Clinical diagnosis is based on ECG, echocardiography, and ventricular angiography. Magnetic resonance imaging is also helpful in providing a good correlation with echocardiogram for localization and the extent of non-compaction. Conclusion In the general population, the non-compaction involves the left ventricle predominantly. The prevalence of iRVNC remains underestimated, and although echocardiography can aid in the diagnosis, the morphological assessment of RV continues to be difficult and challenging. Pathologists should be aware of non-compaction as a cause of sudden cardiac death in syndromic and non-syndromic patients when performing autopsies.

Abstract 432: Loss of Primary Cilia PertErbBs Ventricular Maturation in the Developing Heart

The embryonic heart requires cardiac neural crest cells (CNCC), which elaborate the sensory organelle called the primary cilium and assist in the development of the cardiac valves, the interventricular septum, and the outflow tract. Our laboratory has modeled congenital heart defects (CHD) resulting from CNCC-specific ciliary loss, using a Wnt1:Cre-2, Ift88 -targeted conditional elimination of primary cilia. Ift88 -homozygous mutants (MUT) displayed a variety of predicted CNCC-associated CHDs, but also revealed a novel disorganization of the ventricular endocardium, pronounced noncompaction of the ventricular myocardium, and perinatal lethality. Neuregulin-1 / ErbB signaling is a well-known key modulator of myocardial development as well as the compaction process of the ventricular myocardium. Flow cytometric analysis of embryonic day 12.5 (E12.5) whole hearts revealed that loss of cilia in CNCC of MUT hearts led to a 43% reduction in cardiomyocytes (CM), defined as VCAM-1-positive/CD31-negative cells (p<0.01), and a trend towards increased CD31-positive endocardial cell (EC) populations (34% increase; p = 0.09) when compared to control (CON) hearts. Analysis of cell surface expression of ErbB receptors revealed a slight decrease in ErbB2 and ErbB4 expression in VCAM-1-positive CM of MUT with no change in ErbB3 expression, and decreased ErbB4 expression in MUT EC. Immunofluorescence analysis of proliferation was quantified in various cardiac subpopulations, including cardiac Troponin-T-positive (cTnT+/CM) cells in the ventricular myocardium. While overall cell density at E12.5 did not differ between the MUT and CON (p=0.43), CM proliferation increased significantly in MUT (5.50%) when compared to CON (2.70%; p<0.01). Taken together, decreased ErbB4 expression in the expanding MUT EC population, combined with decreased CM numbers, could serve as a novel mechanistic explanation for the pronounced hypertrabeculation and noncompaction of the MUT phenotype seen at E14.5. Our results indicate that loss of CNCC primary cilia leads to ventricular noncompaction, with a shift in the relative proportion and dynamics of both CM and EC subpopulations, which is potentially attributable to impaired ErbB signaling of the developing endocardium.

Prenatal ultrasound diagnosis of fetal isolated right ventricular noncompaction with pulmonary artery sling: A rare case report

Noncompaction of the ventricular myocardium (NVM), also known as spongy myocardium, is a rare type of cardiomyopathy that has a serious impact on fetuses, children, and adults. NVM mainly affects the left ventricle, as isolated right ventricular noncompaction (IRVNC) is rare. Pulmonary artery sling (PAS) is a rare condition in which the left pulmonary artery anomalously originates from a normal positioned right pulmonary artery, and only a few studies have reported PAS in fetuses. Fetal IRVNC complicated with PAS has not been reported yet. Here, we report a case of IRVNC complicated with PAS that was diagnosed prenatally at 30weeks gestation and confirmed by postpartum anatomy and pathology.

Abstract 627: Primary Cilia of the Cardiac Neural Crest Orchestrate Critical Aspects of Ventricular Maturation and Postnatal Cardiac Function: A Role for Hedgehog Signaling

Primary cilia are tiny, plasma-membrane bound organelles that function to modulate intra- and extracellular signaling, in particular Hedgehog signaling, implicated in both normal development as well as in various disease pathologies, including congenital heart disease (CHD). Cardiac neural crest cells (CNCC) display primary cilia and function as a major progenitor cell population contributing to the developing heart. We hypothesized that damage to or loss of primary cilia in CNCC would impair normal heart development, leading to CHD. We present 1) a precise description of CHD’s resulting from loss of primary cilia of CNCC in vivo ; 2) characterization of the functional, electrophysiological aspects of the perinatal phenotype; and 3) a preliminary investigation of the molecular mechanisms leading to this phenotype. Using a Wnt1:Cre-2, Ift88-targeted conditional elimination of primary cilia, and a Td-tomato reporter to track CNCC, we observed loss of cilia in CNCC at embryonic day E9.5, with notable CNCC contribution to the ventricular myocardium and pronounced disorganization of the endocardium by E10.5.The phenotype resulting from cilia loss in CNCC was characterized by a variety predicted CHDs in addition to disorganization of the ventricular endocardium, pronounced noncompaction of the ventricular myocardium, and perinatal lethality. To investigate potential changes in Hedgehog signaling resulting from cilia loss, we implemented an in vivo conditional knockout in which Wnt1:Cre-2 drives expression of a mutant, constitutively-active Hedgehog receptor. Noncompaction observed in all Wnt1:Cre-2/Ift88 mutants became exacerbated in a primary-cilia dependent fashion with the introduction of forced Hedgehog signaling in CNCC. These results support a critical role for both primary cilia and Hedgehog signaling in the development of the ventricular myocardium. Further electrophysiological assessments of Wnt1:Cre-2/Ift88 newborn mutant mice revealed bradycardia, conduction defects, and ECG tracings consistent with ventricular hypertrophy. These data collectively support a role for Hedgehog signaling via primary cilia of CNCC in the pathogenesis of outflow tract defects, VSD, and most notably, ventricular maturation CHDs.

PROGNOSTIC INDICATORS IN PATIENTS WITH ISOLATED NONCOMPACTION OF THE VENTRICULAR MYOCARDIUM

Isolated noncompaction of the ventricular myocardium (INVM) is a rare cardiomyopathy characterized by an excessive number of abnormally prominent trabeculations in the left ventricular (LV) apex. Complications include LV dysfunction, ventricular arrhythmias and systemic emboli, but these

Differentiation of patients with two-dimensional echocardiography false positive non-compaction of ventricular myocardium by contrast echocardiography.

Although echocardiography can be used to detect patients with non-compaction of the ventricular myocardium, it is often difficult to diagnose. In this study, the endocardium may be clearly visualized by contrast echocardiography to improve the diagnostic accuracy of patients with noncompaction of the ventricular myocardium. Twenty-four patients (n = 24) suspected with non-compaction of the ventricular myocardium Underwent transthoracic echocardiography including an intracardiac contrast echocardiography. The clinical data, Left ventricular opacification, and contrast echocardiography results were analyzed retrospectively. Twenty-four patients (n = 24) suspected with non-compaction of the ventricular myocardium were classified with transthoracic echocardiography and contrast echocardiography results into two groups: false positive and true positive. There were no significant differences in age, predisposing segments, Left Ventricular End-Diastolic Diameter, Left Ventricular End-Diastolic Volume, Left Ventricular End-Systolic Diameter, Left Ventricular End-Systolic Volume and ejection fraction between the two groups (P>0.05). The thickness ratio of noncompacted to compacted myocardium (N/C) in the true positive group was significantly higher than that in the false positive group (3.47 ± 1.31 vs. 4.96 ± 1.28; P<0.05). The range of noncompact myocardium in non-compaction of the ventricular myocardium patients can be observed clearly by Left ventricular opacification. Contrast medium in trabecular space and crypt is plentiful and ultrasonic contrast is more objective in measuring the thickness of dense myocardium. Two-dimensional echocardiography plays a characteristic role in the diagnosis of non-compaction of the ventricular myocardium; however, some suspected patients were observed to be false positive. Left ventricular opacification can greatly improve the clarity and accuracy of the endocardial margin by enhancing left ventricular imaging, displaying the true dense and non-dense layers, and improve the accuracy of ultrasonic diagnosis of non-compaction of the ventricular myocardium. The purpose of this paper was to explore the applied value of contrast echocardiography for heart diagnosis.

Abstract 16756: Coxsackievirus Infection During Early Pregnancy Leads to Congenital Heart Defects

Introduction: Coxsackievirus B (CVB), the most common cause of myocarditis, targets cardiomyocytes through the Coxsackie and Adenovirus Receptor which is highly expressed in the fetal heart. Association between maternal CVB infection and fetal cardiac malformations has not been studied. Hypothesis: CVB infection during early pregnancy may play a role in the pathogenesis of congenital heart disease (CHD). Methods: Pregnant C57Bl/6J mice were infected between embryonic days (E) 5-11 with CVB3 (Nancy strain) at doses 1x10 6 , 2.5x10 6 , and 5x10 6 TCID50. Presence of the virus was confirmed by RT-PCR and infectivity assay and quantified by qPCR. Fetal heart phenotype was assessed by histology and to determine changes at the molecular level after infection, RNA was collected from fetal hearts using laser microdissection and analyzed by RNA-Seq. The results were confirmed by immunohistochemistry and qPCR. To assess the potential clinical relevance of our observations in mice, we analyzed the sera from pregnant women for presence of antibody titers against of CVB. Results: Offspring of pregnant mice infected with CVB3 at different time points developed a spectrum of CHD (38.2%, n=78/204): ventricular septal defect, double outlet right ventricle, and non-compaction of the ventricular myocardium, along with fetal death. Infection at E9 led to the highest incidence of VSD compared to infection earlier (E5, E7 or E8) or later (E11) in gestation. Transcripts found to be differentially expressed between infected fetal hearts with VSDs compared with controls were mediators of the Transforming growth factor β and Extracellular matrix signaling pathways. Consistent with the former, expression levels of BMP2 and Smad1/5/9 mRNA were elevated. Simultaneously suppressed proliferation of cardiomyocytes in these fetuses was observed. Serum analysis from 66 pregnant women who had babies with heart defects showed elevated titers of antibodies against CVB underlining the clinical significance of CVB infection during pregnancy. Conclusions: In mice, there is a critical window during pregnancy where CVB infection leads to abnormal cardiac development, likely through reduction of cardiomyocyte proliferation mediated by elevated levels of BMP2 and Smad1/5/9. Collectively, the data confirm a link between CVB infection and CHD development in mouse and human.

The Value of Echocardiography in the Diagnosis of Non-compaction of the Ventricular Myocardium

To analyze the echocardiographic features of non-compaction of the ventricular myocardium (NVM) and evaluate the diagnostic value of echocardiography in NVM. 34 patients with clinically diagnosed cardiac insufficiency and cardiac arrhythmia were examined by multi-slice scan with GE vivid 7 and Philips IE33 color Doppler sonography. The echocardiographic findings were NVM. Echocardiographic features of NVM were summarized and the distribution characteristics of the lesion area were analyzed. It was found that echocardiography in all 34 patients had obvious characteristics. The myocardium at the lesion site was divided into 2 distinct layers. The outer layer was thin and dense, and the inner layer was thicker, consisting of rich trabeculae and deep recesses with different sizes, which tended to occur in the apical and lateral walls. Color Doppler ultrasound can detect blood flow in the recess and interconnect with the heart cavity. 34 patients were involved in varying degrees of valvular regurgitation of mitral, tricuspid and aortic valves. 29 patients had left ventricular dysfunction, 17 patients with complete left bundle branch block, 12 patients with premature ventricular contractions, and 7 patients with atrial fibrillation. To be concluded, NVM has typical echocardiographic features. Echocardiography can be diagnosed without noticeable symptoms, and it is the most convenient method for diagnosis of NVM.

LEFT VENTRICULAR NONCOMPACTION AND PRE-EXCITATION: AN UNUSUAL FINDING IN ADULTS

Left ventricular noncompaction (LVNC) is a rare form of cardiomyopathy characterized by prominent left ventricular (LV) trabeculae, deep intertrabecular recesses, and the thin compacted layer. The disease is potentially associated with sudden cardiac death due to LV dysfunction and ventricular arrhythmias. The presence of accessory pathway and Wolff-Parkinson-White syndrome is particularly rare in adults. Here we describe the rare association of LVNC and ventricular pre-excitation in an 18-year-old female with neonatal hypoxic brain injury. Keywords: Wolff-Parkinson-White syndrome; pre-excitation syndromes; isolated noncompaction of the ventricular myocardium

Left Ventricle Non-Compaction Myocardium and Thrombophilia in a Pregnant Woman

Non-compaction of the ventricular myocardium (NCM) is a genetic cardiomyopathy usually due to mutationof the G4.5 gene located in the Xq28 chromosomal region. This congenital disorder is characterized by pronounced trabeculations and intertrabecular recesses resulting from abnormal embryogenesis between the fifth and eighth fetal weeks. The reported prevalence in the general population is between 0.014% and 1.3%. The classic triad of complications includes heart failure, ventricular arrhythmias and systemic embolic events, although some patients have an asymptomatic form. NCM is commonly diagnosed by echocardiography, but contrast ventriculography, CT and MRI can also be used. Here we present a case of left ventricle NCM, manifested after respiratory infection, in a pregnant patient with congenital thrombophilia and a history of myocardial infarction.LEARNING POINTSNon-compaction myocardium (NCM) in pregnant women has been associated with a poor prognosis.We should avoid routinely recommending young women with NCM to refuse pregnancy.A decision to continue pregnancy should be made by the patient in discussion with specialists.

Noncompaction of the Ventricular Myocardium and Polycystic Kidney Disease: A Case Report

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders, characterized by the formation of multiple cysts in the kidneys and other organs, as well as noncystic manifestations such as cerebral aneurysm. The most common cardiovascular disorders associated with ADPKD include valvular abnormalities and aortic aneurysm. An association between ADPKD and impaired left ventricular function has occasionally been reported. We describe a 74-year-old woman with ADPKD and exertional dyspnea. Impaired left ventricular function resulting from noncompaction of the ventricular myocardium (NVM) and secondary left ventricular aneurysm were diagnosed. Cardiac sarcoidosis and ischemic heart disease were ruled out. Myocardial ischemia resulting from NVM was the presumptive cause of the ventricular aneurysm. To our knowledge, this is the first report of concurrent isolated NVM and left ventricular aneurysm in a patient with ADPKD. ADPKD and various cardiomyopathies, including NVM, are all reported to involve mutations of sarcomere genes, suggesting a possible link between the conditions.

Isolated Left Ventricular Noncompaction Mimicking Cystic Mass

Noncompaction of the ventricular myocardium is a recently recognized genetic cardiomyopathy thought to be caused by arrest of normal embryogenesis of the endocardium and myocardium. The diagnosis is usually made by echocardiography. Herein we report the case of a 29-year-old male with isolated left ventricular noncompaction mimicking cystic mass.

GW26-e2283 Incremental Value of Contrast Echocardiography in the Diagnosis of Left Ventricular Noncompaction

Contrast echocardiography with left ventricular opacification (LVO) can improve endocardium definition and potentially becomes supplement of conventional two-dimensional echo (2DE) in the diagnosis of noncompaction of the ventricular myocardium (NCVM). This study aimed to access the feasibility,

Isolated Right Ventricular Noncompaction Accompanied by Right Ventricular Failure

Noncompaction of the ventricular myocardium is a rare congenital cardiomyopathy caused by arrest of normal endomyocardial embryogenesis. Isolated right ventricular noncompaction (IRNC) is an even rarer form of this disease. We report herein on a 68 year-old male diagnosed with IRNC who presented with right-sided heart failure, without involvement of the left ventricle. Diagnosis was achieved with the aid of echocardiography and ventriculography. Medical treatment including prescription of diuretics, a calcium channel blocker, and digitalis, improved both the symptoms and right ventricular function. (Korean J Med 2015; 88:69-73)