Sox7-positive endothelial progenitors establish coronary arteries and govern ventricular compaction.

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.

Genetic and phenotypic spectrum in the NONO-associated syndromic disorder.

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.

The outcome of peripartum cardiomyopathy patients-single center experience.

OBJECTIVE: Peripartum cardiomyopathy (PPCM) diagnosis made by excluding identifiable causes of heart failure (HF) and occurs end of the pregnancy or during the postpartum period of five months. It presents a clinical HF spectrum with left ventricular systolic dysfunction. BACKGROUND: The purpose of this study is to retrospectively evaluate the clinical characteristics, cardiac magnetic resonance (CMR) imaging features, and end-points consisting of left ventricle recovery, left ventricular assist device implantation, heart transplantation, and all-cause mortality. METHOD: Outpatient HF records between 2008 to 2021 were screened. Thirty-seven patients were defined as PPCM. Twenty-five patients had CMR evaluation at the time of diagnosis, and six patients were re-evaluated with CMR. RESULTS: The mean age was 30.5 ± 5.6 years, and the mean LVEF was 28.2% ± 6.7%. In 13(35.7%) patients, LVEF recovered during the follow-up course. The median recovery time was 281(IQR [78-358]) days. LVEF on CMR was 35.3 ± 10.5, and three patients exhibited late gadolinium enhancement(LGE) patterns. Sub-endocardial and mid-wall uptake pattern types were detected. 18(75%) patients met the Petersen left ventricle non-compaction cardiomyopathy(LVNC) criteria. Patients with NC/C ratio lower than 2.3 had lower LVEDVi and LVESVi (124.9 ± 35.4, 86.4 ± 7.5, p = .003; 86.8 ± 34.6, 52.6 ± 7.6, p = .006), respectively. The median follow-up time was 2129 (IQR [911-2634]) days. The primary endpoint-free 1-year survival was 88.9% (event rate 11.1%), and 5-year survival was 75.7% (event rate 24.3%). CONCLUSION: In a retrospective cohort of PPCM patients, 35.7% of patients' LVEF recovered, and the primary end-point of free-5-year survival was 75%. Twenty-five patients were assessed with CMR; three of four met the Petersen CMR-derived LVNC at initial evaluation.

Association of Myocardial Muscle Non-Compaction and Multiple Ventricular Septal Defects by Echocardiography.

The aim of this study is to examine the possible high association between multiple ventricular septal defect (mVSDs) and noncompaction cardiomyopathy (NCM) as same embryological origin, and the effect of depressed ventricular function in NCM cases during the follow-up, using echocardiography. A total of 150 patients with mVSDs were diagnosed in a single center in Saudi Arabia; 40 cases with isolated or associated with minor congenital heart disease were recruited. Three specialist echocardiography consultants confirmed the NCM diagnosis separately using Jenni, Chin and Patrick criteria, and myocardial function was estimated by ejection fraction at admission and at follow-up after surgery. Stata-14 to analyze the data was used. In our cohort of 40 cases with mVSD (median age at diagnosis = 0.5 years; mean follow-up = 4.84 years), 13(33%) had criteria of non-compaction confirmed by the three specialist consultants. All were operated by surgery and 11 hybrid approach (interventional & surgery). A significant relationship between abnormal trabeculations and mVSD with or without non-compaction was observed, 34% vs 66% respectively (p < 0.03, Fisher's exact test). A repeated-measures t-test found the difference between follow-up and preoperative ejection-fractions to be statistically significant (t (39) = 2.07, p < 0.04). Further, the myocardial function in the mVSD non-compaction group normalized substantially postoperatively compared with preoperative assessment (mean difference (MD) 11.77, 95% CI: 4.40-19.14), whilst the mVSD group with normal myocardium had no significant change in the myocardium function (MD 0.74, 95% CI: -4.10-5.58). Thus, treatment outcome appears better in the mVSD non-compaction group than their peers with normal myocardium. Acknowledging the lack of genetic data, it is evident the high incidence of non-compaction in this cohort of patients with mVSD and supports our hypothesis of embryonic/genetic link, unlikely to be explained by acquired cardiomyopathy.

Biventricular non-compaction cardiomyopathy and tricuspid hypoplasia in a novel non-POU domain-containing octamer-binding gene variant.

A maternally inherited novel pathogenic non-POU domain-containing octamer-binding gene variant c.767G>T, p.R256I [NM_001145408], manifested in a male infant as dilated cardiomyopathy with severe left ventricular dysfunction and dilation, biventricular non-compaction, tricuspid hypoplasia, and hydrocephaly. To the best of our knowledge, no previous non-POU domain-containing octamer-binding gene variants with biventricular non-compaction have been associated with tricuspid valve hypoplasia. Hence, this case introduces a new pathogenic variant observed in the non-POU domain-containing octamer-binding gene and adds to the range of cardiac phenotypes identified in non-POU domain-containing octamer-binding gene variants.

The clinical utility of pediatric cardiomyopathy genetic testing: From diagnosis to a precision medicine-based approach to care.

BACKGROUND: Pediatric-onset cardiomyopathies are rare yet cause significant morbidity and mortality in affected children. Genetic testing has a major role in the clinical evaluation of pediatric-onset cardiomyopathies, and identification of a variant in an associated gene can be used to confirm the clinical diagnosis and exclude syndromic causes that may warrant different treatment strategies. Further, risk-predictive testing of first-degree relatives can assess who is at-risk of disease and requires continued clinical follow-up. AIM OF REVIEW: In this review, we seek to describe the current role of genetic testing in the clinical diagnosis and management of patients and families with the five major cardiomyopathies. Further, we highlight the ongoing development of precision-based approaches to diagnosis, prognosis, and treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW: Emerging application of genotype-phenotype correlations opens the door for genetics to guide a precision medicine-based approach to prognosis and potentially for therapies. Despite advances in our understanding of the genetic etiology of cardiomyopathy and increased accessibility of clinical genetic testing, not all pediatric cardiomyopathy patients have a clear genetic explanation for their disease. Expanded genomic studies are needed to understand the cause of disease in these patients, improve variant classification and genotype-driven prognostic predictions, and ultimately develop truly disease preventing treatment.

The Double Mutation DSG2-p.S363X and TBX20-p.D278X Is Associated with Left Ventricular Non-Compaction Cardiomyopathy: Case Report.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein-2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.

Advanced Heart Failure in Special Population: Cardiomyopathies and Myocarditis.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF) in young populations. The variety of causes, multiple underlying pathophysiological mechanisms, and different phenotypic expressions influence their presentation and response to treatment. Dilated cardiomyopathy is the most prevalent cause of HF. Advanced HF in hypertrophic, restrictive, and arrhythmogenic cardiomyopathies is rare, but its development portends a poor prognosis. The active phase of fulminant myocarditis may result in acute HF requiring advanced strategies to support the systemic circulation or may determine an irreversible persisting left ventricular failure with end-stage HF.

The pivotal role of cardiovascular imaging in the identification and risk stratification of non-compaction cardiomyopathy patients.

Non-compaction cardiomyopathy (NCM) is a heterogeneous myocardial disease that can finally lead to heart failure, arrhythmias, and/or embolic events. Therefore, early diagnosis and treatment is of paramount importance. Furthermore, genetic assessment and counseling are crucial for individual risk assessment and family planning. Echocardiography is the first-line imaging modality. However, it is hampered by interobserver variability, depends among others on the quality of the acoustic window, cannot assess reliably the right ventricle and the apex, and cannot provide tissue characterization. Cardiovascular magnetic resonance (CMR) provides a 3D approach allowing imaging of the entire heart, including both left and right ventricle, with low operator variability or limitations due to patient's body structure. Furthermore, tissue characterization, using late gadolinium enhancement (LGE), allows the detection of fibrotic areas possibly representing the substrate for potentially lethal arrhythmias, predicts the severity of LV systolic dysfunction, and differentiates apical thrombus from fibrosis. Conversely, besides being associated with high costs, CMR has long acquisition/processing times, lack of expertise among cardiologists/radiologists, and limited availability. Additionally, in cases of respiratory and/or cardiac motion artifacts or arrhythmias, the cine images may be blurred. However, CMR cannot be applied to patients with not CMR-compatible implanted devices and LGE may be not available in patients with severely reduced GFR. Nevertheless, native T1 mapping can provide detailed tissue characterization in such cases. This tremendous potential of CMR makes this modality the ideal tool for better risk stratification of NCM patient, based not only on functional but also on tissue characterization information.

Fetal Echocardiography is Useful for Screening Fetuses with a Family History of Cardiomyopathy.

We screened all fetal echocardiograms performed at our institution for the past 5 years for the indication of family history of cardiomyopathy. Twenty-six patients were identified who had fetal echocardiograms performed due to a family history of cardiomyopathy. Three out of 26 patients (11.5%) had findings of decreased ventricular function and dilation consistent with cardiomyopathy. All who had cardiomyopathy on fetal echocardiography had parents with genetic mutations (2 maternal, 1 paternal), including one mother who had a cardiac transplant at age 8 for dilated cardiomyopathy. All 3 affected infants had prenatal planning for high level care and were transferred to our facility immediately after birth for cardiology evaluation and management. 2 patients required inotropic support in the newborn period. One patient was transplanted at age 2 months. One patient required ECMO support for one week and initially recovered, but subsequently required mechanical support and listing for heart transplant. We recommend patients with a strong family history of cardiomyopathy in either parent, especially those with known genetic mutations associated with cardiomyopathy, have fetal echocardiograms performed.

Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies.

Cardiomyopathies are diseases of heart muscle, a significant percentage of which are genetic in origin. Cardiomyopathies can be classified as dilated, hypertrophic, restrictive, arrhythmogenic right ventricular or left ventricular non-compaction, although mixed morphologies are possible. A subset of neuromuscular disorders, notably Duchenne and Becker muscular dystrophies, are also characterized by cardiomyopathy aside from skeletal myopathy. The global burden of cardiomyopathies is certainly high, necessitating further research and novel therapies. Genome editing tools, which include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) systems have emerged as increasingly important technologies in studying this group of cardiovascular disorders. In this review, we discuss the applications of genome editing in the understanding and treatment of cardiomyopathy. We also describe recent advances in genome editing that may help improve these applications, and some future prospects for genome editing in cardiomyopathy treatment.

Therapy of ventricular arrhythmias in patients suffering from isolated left ventricular non-compaction cardiomyopathy.

AIMS: Non-compaction cardiomyopathy (NCCM) is associated with high rates of mortality and morbidity. Knowledge regarding risk stratification, arrhythmogenesis, therapy, and prognosis is limited. The aim of this study was to analyse the outcome of patients suffering from NCCM and ventricular arrhythmias (VAs) focusing on a treatment with implantable cardioverter-defibrillator (ICD) therapy and catheter ablation. METHODS AND RESULTS: We conducted a multicentre observational study on 18 patients with NCCM, who underwent ICD implantation for secondary (n = 12) and primary (n = 6) prevention. In patients with multiple symptomatic episodes of VAs catheter ablation was performed. During a follow-up of 62 ± 42 months, 12 patients (67%) presented with appropriate ICD therapies [ventricular tachycardia (VT): n = 8; ventricular fibrillation (VF): n = 4; VT/VF: n = 3]. Ten patients underwent catheter ablation for VT/VF. Solely endocardial ablation was conducted in eight patients, and in two patients endo- and epicardial ablation was performed within the same procedure. Acute procedural success was achieved in 9/10 patients. Ventricular tachycardia recurrence was observed in two patients and the median arrhythmia free interval was 9.5 months (interquartile range 5.3-21 months). One patient underwent reablation, four patients died due to the underlying NCCM, and one patient received a left ventricular assist device. CONCLUSION: Ventricular arrhythmias are common in patients suffering from NCCM and ICD therapy may be effective for primary and secondary prevention. In our cohort, consisting of patients with multiple VA episodes and recurrent ICD therapy, catheter ablation offered a safe and effective therapeutically option.

Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.

AIMS: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. INTRODUCTION: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. METHODS AND RESULTS: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. CONCLUSION: Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.

Novel findings of left ventricular non-compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A-associated Cornelia de Lange syndrome.

Relatively few patients with Cornelia de Lange syndrome (CdLS) due to SMC1A mutation have been reported, limiting understanding of the full extent of the phenotype. Compared to children with classic NIPBL-associated CdLS, patients with SMC1A-associated CdLS have a milder physical phenotype with prominent intellectual disability, high rate of cleft palate and absence of limb reductions. We present a patient with SMC1A-associated CdLS who had typical features including developmental delay, seizure disorder, feeding difficulties, hirsutism, and cleft palate. She also was found to have three novel features: (i) left ventricular non-compaction (LVNC) cardiomyopathy; (ii) microform cleft lip; and (iii) severe hyperopia and astigmatism. These features have implications regarding potential insight into the pathogenesis of the disorder, screening, and medical management. Hypertrophic cardiomyopathy has previously been reported in SMC1A-associated CdLS, but to our knowledge this is the first reported child with LVNC. Previous reports have included children with isolated clefts of the palate without involvement of the lip. When cleft palate alone is associated with a disorder, the underlying pathophysiology for clefting is sometimes secondary due to mechanical blocking of the fusion of the palatal shelves with the developing tongue. The presence of microform cleft lip in this patient suggests that the pathophysiology of clefting in SMC1A is primary rather than secondary. Few studies report ophthalmologic findings specific to SMC1A. Based on these findings, LVNC cardiomyopathy and cleft lip should be considered features of SMC1A-associated CdLS. All patients should receive echocardiogram and undergo thorough ophthalmologic evaluation as part of routine CdLS care. © 2016 Wiley Periodicals, Inc.

Left ventricular non-compaction cardiomyopathy with coronary artery anomaly complicated by ventricular tachycardia.

BACKGROUND: Non-compaction cardiomyopathy (NCCM) is characterized by prominent trabeculations, deep intertrabecular recesses, and a thick non-compacted endocardial myocardium. Prevalence in the general population remains unclear, but echocardiography series report 0.05%. During fetal development muscle fibers and trabeculae should compact into a solid myocardium and when this fails, NCCM occurs. The condition is genetic, even though acquired forms have been described. Worsening myocardial dysfunction may lead to heart failure and/or arrhythmias. CASE PRESENTATION: A 52-year-old man presented with heart failure. The diagnosis of NCCM was confirmed after echocardiography and cardiac magnetic resonance tomography. Interestingly, the angiogram revealed a coronary anomaly, in which the circumflex artery rose aberrantly from the right coronary artery. Due to left ventricular ejection fraction being less than 35% despite optimal pharmacological therapy, an implantable cardioverter defibrillator (ICD) was implanted and four years later a ventricular tachycardia was terminated by antitachycardia pacing. CONCLUSION: We describe a case of NCCM with a concomitant coronary anomaly, in which systolic myocardial dysfunction developed. The ICD subsequently terminated a life-threatening ventricular arrhythmia, which supports risk stratification based on low ejection fraction and possibly coronary anomaly.

Fetal left ventricular non-compaction cardiomyopathy with ascites: A case report.

Here we report a case of fetal left ventricular non-compaction cardiomyopathy with ascites and cardiac dysfunction at a gestational age of 34+5  weeks. Laboratory tests did not reveal any sign of viral infection in utero. A female neonate weighing 2436 g was delivered by emergency cesarean section due to non-reassuring fetal status. Postnatal echocardiography confirmed left ventricular non-compaction cardiomyopathy with severe cardiac failure. Although she was treated effectively during the acute period by continuous flow peritoneal dialysis, surgical ligation of a patent ductus arteriosus, and inhaled nitric oxide, she died on day 41 of life. Symptoms of severe cardiac dysfunction appeared antenatally in this patient and the outcome was poor.

Morphogenesis of myocardial trabeculae in the mouse embryo.

Formation of trabeculae in the embryonic heart and the remodelling that occurs prior to birth is a conspicuous, but poorly understood, feature of vertebrate cardiogenesis. Mutations disrupting trabecular development in the mouse are frequently embryonic lethal, testifying to the importance of the trabeculae, and aberrant trabecular structure is associated with several human cardiac pathologies. Here, trabecular architecture in the developing mouse embryo has been analysed using high-resolution episcopic microscopy (HREM) and three-dimensional (3D) modelling. This study shows that at all stages from mid-gestation to birth, the ventricular trabeculae comprise a complex meshwork of myocardial strands. Such an arrangement defies conventional methods of measurement, and an approach based upon fractal algorithms has been used to provide an objective measure of trabecular complexity. The extent of trabeculation as it changes along the length of left and right ventricles has been quantified, and the changes that occur from formation of the four-chambered heart until shortly before birth have been mapped. This approach not only measures qualitative features evident from visual inspection of 3D models, but also detects subtle, consistent and regionally localised differences that distinguish each ventricle and its developmental stage. Finally, the combination of HREM imaging and fractal analysis has been applied to analyse changes in embryonic heart structure in a genetic mouse model in which trabeculation is deranged. It is shown that myocardial deletion of the Notch pathway component Mib1 (Mib1(flox/flox) ; cTnT-cre) results in a complex array of abnormalities affecting trabeculae and other parts of the heart.

Health Status and Psychological Distress in Patients with Non-compaction Cardiomyopathy: The Role of Burden Related to Symptoms and Genetic Vulnerability.

BACKGROUND: Non-compaction cardiomyopathy (NCCM) is a cardiomyopathy characterized by left ventricular tribeculae and deep intertrabecular recesses. Because of its genetic underpinnings and physical disease burden, noncompaction cardiomyopathy is expected to be associated with a lower health status and increase in pscyhological distress. PURPOSE: This study determined the health status and psychological distress in NCCM patients. We also examined the potential contribution of genetic predisposition and cardiac symptoms to health status and distress in NCCM, by comparing NCCM patients with (1) patients with familial hypercholesterolemia (FH) and (2) patients with acquired dilated cardiomyopathy (DCM). METHODS: Patients were recruited from the Erasmus Medical Center, Rotterdam, The Netherlands. Using a case-control design, NCCM patients (N = 45, mean age 46.7 ± 15.1 years, 38 % male) were compared with 43 FH patients and 42 DCM patients. Outcome measures were health status (Short Form Health Survey-12), anxiety (Generalized Anxiety Disorder 7-item scale) and depression (Patient Health Questionnaire 9-item scale). RESULTS: NCCM patients showed significantly worse health status (Physical Component Score F(1,84) = 9.58, P = .003; Mental Component Score F(1,84) = 16.65, P < .001), anxiety (F(1,85) = 9.63, P = .003) and depression scores (F(1,82) = 5.4, P = .023) compared to FH patients, also after adjusting age, sex, comorbidity, educational level and time since diagnosis. However, NCCM patients did not differ from DCM patients (Physical Component Score F(1,82) = 2,61, P = .11; Mental Component Score F(1,82) = .55, P = .46), anxiety (F(1,82) = 1.16, P = .28) and depression scores (F(1,82) = 1,95, P = .17). CONCLUSION: Cardiac symptoms are likely to play a role in the observed poor health status and elevated levels of anxiety and depressive symptoms in NCCM, whereas the burden of having a genetic condition may contribute less to these health status and psychological measures.