Primary Endocardial Fibroelastosis Research Articles

Analysis on missed diagnosis or misdiagnosis of anomalous origin of left coronary artery from pulmonary artery by echocardiography from one single medical center

Objectives: To analyze the reasons of missed diagnosis or misdiagnosis on anomalous origin of left coronary artery from pulmonary artery (ALCAPA) by echocardiography. Methods: This is a retrospective study. Patients with ALCAPA who underwent surgical treatment in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from August 2008 to December 2021 were included. According to the results of preoperative echocardiography and surgical diagnosis, the patients were divided into confirmed group or missed diagnosis/misdiagnosis group. The results of preoperative echocardiography were collected, and the specific echocardiographic signs were analyzed. According to the experience of the doctors, the echocardiographic signs were divided into four types, namely clear displayed, vague/doubtful displayed, no display and no notice, and the display rate of each sign was calculated (display rate=number of clearly displayed cases/total number of cases×100%). By referring the surgical data, we analyzed and recorded the pathological anatomy and pathophysiological characteristics of the patients, and the rate of missed diagnosis/misdiagnosis of echocardiography in patients with different characteristics was compared. Results: A total of 21 patients were enrolled, including 11 males, aged 1.8 (0.8, 12.3) years (range 1 month to 47 years). Except for one patient with anomalous origin of left anterior descending artery, the others were all originated from the main left coronary artery (LCA). There were 13 cases of ALCAPA in infant and children, and 8 cases of adult ALCAPA. There were 15 cases in the confirmed group (diagnostic accuracy was 71.4% (15/21)), and 6 cases in the missed diagnosis/misdiagnosis group (three cases were misdiagnosed as primary endocardial fibroelastosis, two cases were misdiagnosed as coronary-pulmonary artery fistula; and one case was missed diagnosis). The working years of the physicians in the confirmed group were longer than those in the missed diagnosis/misdiagnosed group ((12.8±5.6) years vs. (8.3±4.7) years, P=0.045). In infants with ALCAPA, the detection rate of LCA-pulmonary shunt (8/10 vs. 0, P=0.035) and coronary collateral circulation (7/10 vs. 0, P=0.042) in confirmed group was higher than that in missed diagnosis/misdiagnosed group. In adult ALCAPA patients, the detection rate of LCA-pulmonary artery shunt was higher in confirmed group than that in missed diagnosis/misdiagnosed group (4/5 vs. 0, P=0.021). The missed diagnosis/misdiagnosis rate of adult type was higher than that of infant type (3/8 vs. 3/13, P=0.410). The rate of missed diagnosis/misdiagnosis was higher in patients with abnormal origin of branches than that of abnormal origin of main trunk (1/1 vs. 5/21, P=0.028). The rate of missed diagnosis/misdiagnosis in patients with LCA running between the main and pulmonary arteries was higher than that distant from the main pulmonary artery septum (4/7 vs. 2/14, P=0.064). The rate of missed diagnosis/misdiagnosis in patients with severe pulmonary hypertension was higher than that in patients without severe pulmonary hypertension (2/3 vs. 4/18, P=0.184). The reasons with an echocardiography missed diagnosis/misdiagnosis rate of≥50% included that (1) the proximal segment of LCA ran between the main and pulmonary arteries; (2) abnormal opening of LCA at the right posterior part of the pulmonary artery; (3) abnormal origin of LCA branches; (4) complicated with severe pulmonary hypertension. Conclusions: Echocardiography physicians' knowledge of ALCAPA and diagnostic vigilance are critical to the accuracy of diagnosis. Attention should be paid to the pediatric cases with no obvious precipitating factors of left ventricular enlargement, regardless of whether the left ventricular function is normal or not, the origin of coronary artery should be routinely explored.

Abstract MP212: Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations In Primary Endocardial Fibroelastosis: A Rare Neonatal Cardiomyopathy

Background: Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) population with a devastating course and grave prognosis. Objective: We aimed to investigate potential genetic contributions to pEFE etiology. Methods: We performed integrative genomic analysis in 8 infants with confirmed pathological diagnosis of pEFE using whole exome sequencing (WES), RNA-seq and functional genomics studies. Patient-derived fibroblasts, neonatal rat ventricular myocytes and neonatal rat cardiac fibroblasts were used for cellular assays. Real-time cell migration and proliferation analyses were performed using xCELLigence technology. Results: Whole exome sequencing detected novel and deleterious de novo single nucleotide variants, or inherited homozygous rare variants in 11 cilia-related genes in seven out of the eight affected probands. In particular, a novel homozygous variant [c.1938delA] in ALMS1 was identified in a female proband, pEFE4. This variant resulted in a frameshift introducing a premature stop codon and complete absence of the ALMS1 protein in the proband fibroblasts and explanted heart. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome [OMIM 203800], a rare recessive ciliopathy. RNA-sequencing of the proband’s dermal fibroblasts revealed significantly dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT), potentially mediated by TGFβ signaling activation. The proband fibroblasts exhibited enhanced migration activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated WES with RNA-seq analysis to elucidate the molecular mechanisms by which the novel causal ALMS1 variant contributes to the unique pathology of pEFE in a female infant with Alstrom syndrome. Conclusions: Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.

Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome

Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.Key messagePrimary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology.Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology.In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology.Infants with pEFE should be examined for syndromic features of Alstrom syndrome.Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.

Endocardial fibroelastosis and dilated cardiomyopathy - the past and future of the interface between histology and genetics.

Endocardial fibroelastosis (EFE) signifies the pathological process by which collagen and elastin are focally or diffuse deposited in the endocardium of the left ventricle. The new layer causes left ventricular dysfunction sometimes with fulminant progression to heart failure. EFE is a major component in many congenital heart abnormalities but can also occur in the absence of heart malformations, either as a primary process or in response to cardiac injury. The endothelial–mesenchymal transition (EndMT) abnormalities seem to be main pathogenic factor in fibroelastosis development. The “gold standard” for diagnosis of primary EFE (pEFE) is the histological examination. Additionally, genetic studies may help to establish the natural course of the disease and to communicate prophylactic measures to family members of the affected child. Moreover, in the newborn, EFE takes the form of dilated cardiomyopathy (DCM) with unfavorable evolution. The proper management should be established considering negative prognostic factors, involving early transplantation, drug therapy and long-term follow-up.

A Case of Pediatric Heart Failure Caused by Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery: Case Report and Literature Review

A female patient aged 3 months and 10 days was admitted to the cardiology department because of symptoms of heart failure. According to the echocardiography results, the patient received a diagnosis of primary endocardial fibroelastosis and was treated with γ-globulin, prednisone, digoxin, and diuretics. Coronary computed tomographic angiography and coronary angiography were performed as there was no improvement after 2 months of treatment. Finally, the patient received a diagnosis of anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). ALCAPA is a rare congenital heart defect that can cause severe heart failure during infancy, and is easily misdiagnosed clinically. In this report, we show the process of misdiagnosis of the case and consult the relevant literature, hoping to improve the understanding and early diagnosis of ALCAPA.

Progress in etiology of primary endocardial fibroelastosis

Endocardial fibroelastosis(EFE), associated with diffuse endocardial thickening due to proliferation of fibrous and elastic tissue, is a rare cardiac disorder that mainly occurs in infants.Its etiology is unknown, viral infection, immunology and genetics have been reported having effects on the pathogenesis of EFE.However, its pathogenesis is not yet fully understood.Recently, with the improvement of genetic testing techniques, many studies have shown that a variety of genetic factors involved in the occurrence of EFE.The TAZ gene on the X chromosome, the Nexn gene on the autosome, the Nebulette gene, the CSRP3 gene, the Sarcomere protein gene, and endothelial to mesenchymal transition(EndMT)are confirmed to be involved in the pathogenesis.This provides a new basis for the early diagnosis and accurate treatment of primary endocardial fibroelastosis and helps to improve the prognosis of the disease.This article discussess the etiology of EFE, including viral infection, immunology and genetics, aiming at raising awareness of the pathogenesis of this disease. Key words: Endocardial fibroelastosis; Etiology; Genetics

Niewyjaśniona niewydolność serca u 14-miesięcznego dziecka

Endocardial fibroelastosis is a cardiomyopathy rarely seen in the present age. Here, we report a case of 14-months-old baby who presented with failure to thrive, sweating while feeding, a dilated left ventricle, and left ventricular dysfunction. Chest x-ray revealed cardiomegaly with pulmonary venous hypertension. Electrocardiogram showed left ventricular hypertrophy with strain pattern. Echocardiogram revealed dilated left ventricle with severe systolic dysfunction which was labelled as endocardial fibroelastosis. As there were no associated lesions, it was labelled as primary endocardial fibroelastosis (pEFE). The baby was managed conservatively. Here, we would like to highlight the fact that primary endocardial fibroelastosis (pEFE) can masquerade as idiopathic dilated cardiomyopathy. Progressive ventricular dilation and ventricular dysfunction portends poor prognosis, though few of them may be managed with conservative treatment.

SEVERE MITRAL AND LEFT VENTRICULAR CALCIFICATION AS A LATE COMPLICATION OF ANOMALOUS LEFT MAIN CORONARY ARTERY FROM THE PULMONARY ARTERY

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital condition that has historically been misdiagnosed as primary endocardial fibroelastosis (EFE). Due to symptoms of heart failure (HF) and failure to thrive, ALCAPA is often corrected in the 1st year of life. A 2-

Primary Endocardial Fibroelastosis and Nonimmune Hydrops Fetalis: Case Report with Autopsy

Endocardial fibroelastosis is an important cause of congestive heart failure and death in infancy and early childhood. When present, it is commonly associated with non immune hydrops fetalis. The aim of this study is to draw attention for possible cardiac abnormalities in cases of fetal hydrops, and report a case of premature death by primary endocardial fibroelastosis with autopsy.

Primary endocardial fibroelastosis: an underappreciated cause of cardiomyopathy in children

Endocardial fibroelastosis (EFE) is a thickening of the endocardium by collagen and elastic fibers. Primary EFE is characterized by a dilated left ventricle (LV) that typically has a high takeoff of the papillary muscles and thickening of the free edge of the mitral valve leaflets, in addition to diffuse thickening of the endocardium by aortic-like thick and parallel elastic fibers. In the past, EFE was considered a rare cardiomyopathy, but in the latest American Heart Association classification (2006) of cardiomyopathies, EFE is not mentioned. The existence of the entity of "primary" EFE has been questioned. We reviewed medical records, echocardiograms, explanted hearts, and microscopic slides from 52 pediatric heart transplant cases at our institution with a diagnosis of dilated cardiomyopathy (DCM). Fourteen hearts showed both gross and microscopic findings of primary EFE, with no apparent cause of the diffuse endocardial thickening. Patients with EFE were significantly younger than patients with DCM (median age: 10.1 vs. 142.0 months). No case of EFE was diagnosed clinically. LV wall and endocardial thickness were significantly greater in EFE, with the mitral valve and papillary muscles showing characteristic findings. Clinically and pathologically, EFE is different from DCM. EFE is not rare and found in 25% of pediatric cases transplanted for "DCM." EFE should be recognized to promote understanding of the natural history and etiology of EFE.

P34.05: Prenatal ultrasound detection of primary endocardial fibroelastosis in 12–13 weeks of gestation: a case report

P34.05: Prenatal ultrasound detection of primary endocardial fibroelastosis in 12–13 weeks of gestation: a case report

Assessment of endocardial fibroelastosis by cardiac MRI

A 17-year-old patient was referred to the Unit of Cardiovascular Medicine at the Leeds General Infirmary (Leeds, United Kingdom) for a cardiac magnetic resonance imaging (MRI) scan. At the age of two months, she had developed dyspnea and was found to have unexplained left atrial enlargement. By the age of six years, she had developed significant tricuspid regurgitation and pulmonary hypertension. Cardiac catheterization at that time confirmed a mean pulmonary artery pressure of 50 mmHg, with no evidence of pulmonary artery stenosis or shunt. A diagnosis of restrictive cardiomyopathy secondary to primary endocardial fibroelastosis was established after right ventricular endomyocardial biopsy. Cardiac MRI using steady-state free precession cine imaging revealed the typical features of a restrictive cardiomyopathy (Figure 1A). The left ventricular cavity was small and showed normal systolic function. There was marked left atrial and right atrial dilation, global pericardial effusion, right ventricular hypertrophy and severe tricuspid regurgitation. The pulmonary arteries were dilated and the interventricular septum appeared flattened, consistent with right ventricular pressure overload (mean pulmonary artery pressure measured 80 mmHg at repeat cardiac catheterization at 17 years of age). In addition, the inferior vena cava was grossly dilated (Figure 1B) and a thrombus extended from the left atrial appendage into the left atrium (Figure 1C). Late gadolinium hyperenhancement imaging revealed a characteristic pattern of high-signal intensity confined to the endocardial surface of both ventricles and both atria (Figure 1D), representing fibrosis in these areas. Figure 1) A Four-chamber cine image demonstrating biatrial dilation, right ventricular hypertrophy, a small left ventricular cavity and pericardial effusion. B Cine image demonstrating dilation of the inferior vena cava (arrow). C Short-axis cine image demonstrating ... Cardiac MRI clearly demonstrates the pathognemonic features of endocardial fibroelastosis and can identify additional complications such as intracardiac thrombus.

Sudden infant death from dilated cardiomyopathy with endocardial fibroelastosis

A four-month-old female with no previous medical history suddenly collapsed and failed to recover despite 2 h of resuscitation. An autopsy showed marked cardiomegaly (88 g) with prominent dilatation of the left ventricle and a whitish opacity on the endocardial surface. The ductus arteriosus was patent, but both orifices were severely stenosed. Microscopically, the endocardium showed pronounced thickening with laminar deposition of elastic and collagen fibers. Additionally, there was a mixture of myocardial fibers with a marked “wavy” appearance and a scattering of mild interstitial lymphocytic infiltration. We believe that endocardial thickening in this infant met the diagnostic criteria for endocardial fibroelastosis (EFE). Although it is controversial whether primary EFE is a distinct pathologic entity or an epiphenomenon, we speculated that “dilated cardiomyopathy with EFE” had caused the decedent’s death based on the appearance of the myocardial fibers.

Primary endocardial fibroelastosis with dilated cardiomyopathy: report of one case.

We report a case of dilated cardiomyopathy presented in a premature infant of 27 weeks' gestational age. A prenatal sonography revealed left ventricular enlargement. The infant presented with respiratory distress and heart failure soon after birth. Echocardiograms performed after birth showed dilated cardiomyopathy, and endocardial fibroelastosis was suspected. Heart failure progressed despite administration of inotropic agents. The infant died after fifteen days from circulatory failure. Postmortem examination confirmed the diagnosis of endocardial fibroelastosis.

Estudo de 11 casos de fibroelastose endocárdica primária

INTRODUCAO: A fibroelastose endocardica (FEE) e definida como espessamento difuso do endocardio ventricular em funcao da proliferacao de fibras colagenas e elasticas. Pode ser classificada como primaria ou secundaria. A FEE primaria apresenta-se na forma dilatada, mais comum, ou na forma restritiva. Geralmente manifesta-se como insuficiencia cardiaca inexplicada, em criancas com menos de 12 meses de idade. OBJEIVOS: Avaliar aspectos epidemiologicos, clinicos e anatomopatologicos da FEE primaria. MATERIAL E METODO: Foram pesquisadas, entre 1960 e 2000, 6.211 necropsias perinatais e pediatricas do Hospital de Clinicas da Universidade Federal do Parana (UFPR), tendo sido verificados 11 casos de FEE. RESULTADOS: Em nove casos (81,8%), o surgimento dos sintomas ocorreu antes de 1 ano de idade. Em oito (72,7%), o obito ocorreu antes de 1 ano de idade. Dentre os sinais clinicos, destacaram-se taquipneia (54,5%), hepatomegalia (45,5%), tosse (36,4%), cianose (36,4%) e febre (36,4%). Todas as radiografias (n = 6) apresentavam cardiomegalia. O espessamento endocardico predominou no coracao esquerdo (90,9%). A causa de obito foi insuficiencia respiratoria aguda em cinco casos (45,5%) e choque cardiogenico em quatro (36,4%). DISCUSSAO E CONCLUSOES: Os resultados mostram acometimento predominante de criancas com menos de 1 ano de idade e rapida progressao para obito. Sinais clinicos frequentes, como taquipneia, tosse e febre, sugeriram infeccao respiratoria, que foi confirmada por necropsia em tres casos (27,3%). Os exames complementares mostraram apenas achados sugestivos de insuficiencia cardiaca. Os dados analisados neste estudo mostram que, em nosso meio, a FEE primaria nao difere significativamente do que e apresentado na literatura internacional em relacao a caracteristicas epidemiologicas, clinicas e anatomopatologicas.

Three neonates of primary endocardial fibroelastosis associated with hydrops fetalis

Three neonates of primary endocardial fibroelastosis associated with hydrops fetalis

CLINICAL EVALUATION OF PRIMARY ENDOCARDIAL FIBROELASTOSIS

Primary endocardial fibroelastosis (EFE) is a cardiomyopathy of unknown origin that affects infants and young children.We treated 6 cases of EFE. 4 cases are alive and 2 cases died. The important prognostic factors are : duration of untreated period, low voltage and extremely high voltage in the left chest leads of the electrocardiogram and a high degree of fibroelastosis histologically.The LV functions of the 3 living cases have not improved on echocardiography despite intensive treatment, so careful follow up is necessary.

Primary endocardial fibroelastosis associated with hydrops fetalis in a premature infant

Primary endocardial fibroelastosis associated with hydrops fetalis in a premature infant

Dilated and contracted forms of primary endocardial fibroelastosis: a single fetal disease with two stages of development.

Left ventricular endocardial fibroelastosis was diagnosed by echocardiographic scanning in a fetus at 20 weeks' gestation. Repeated prenatal examination over the next 20 weeks' gestation showed the development of the left ventricle from a chamber with a dilated cavity to a small cavity with a very thick wall. These findings were confirmed at necropsy and by the absence of other morphological anomalies. The contracted form of primary fibroelastosis in the fetus must have followed an insult that prevented any further increase in the size of the left ventricular cavity.

A case of primary endocardial fibroelastosis in the left and right side of the heart with associated secondary mitral and tricuspid regurgitation

A case of primary endocardial fibroelastosis in the left and right side of the heart with associated secondary mitral and tricuspid regurgitation