Clinical and necropsy evaluation of endocardial fibroelastosis in a mixed-breed cat with left side heart failure

A two-month-old, male intact, mixed-breed cat weighing 0.6 kg was presented with respiratory distress and anorexia. From the transthoracic echocardiographic, reduced fractional shortening (FS) and increased endocardial echogenicity were recognised with severe congestive heart failure (CHF). The kitten was administered an antibiotic and pimobendane under oxygen supplementation in an ICU cage. However, the respiratory condition worsened and the cat died the next day, and the subsequent necropsy and histopathology examinations confirmed endocardial fibroelastosis (EFE). There is a lack of information regarding the antemortem cardiac function evaluated by tissue Doppler imaging (TDI) in EFE cases. We report on the echocardiographic findings including the TDI in the EFE cat with a concomitant necropsy and histopathology confirmation in this paper. The echocardiographic findings showed presence of a ventricular false tendon within the left ventricle, a decrease in the left ventricular contractility (FS 11.1%, and a marked CHF). In this case, the echocardiographic findings were consistent with the human counterpart. However, these findings were like those of dilated cardiomyopathy and, hence, non-specific to EFE. As a result, veterinarians should keep in mind that endocardial fibroelastosis might be a possible reason for respiratory distress resulting from CHF with a low fractional shortening in young cats.

Outcome of Antibody‐Mediated Fetal Heart Disease With Standardized Anti‐Inflammatory Transplacental Treatment

Background Transplacental fetal treatment of immune‐mediated fetal heart disease, including third‐degree atrioventricular block (AVB III) and endocardial fibroelastosis, is controversial. Methods and Results To study the impact of routine transplacental fetal treatment, we reviewed 130 consecutive cases, including 108 with AVB III and 22 with other diagnoses (first‐degree/second‐degree atrioventricular block [n=10]; isolated endocardial fibroelastosis [n=9]; atrial bradycardia [n=3]). Dexamethasone was started at a median of 22.4 gestational weeks. Additional treatment for AVB III included the use of a β‐agonist (n=47) and intravenous immune globulin (n=34). Fetal, neonatal, and 1‐year survival rates with AVB III were 95%, 93%, and 89%, respectively. Variables present at diagnosis that were associated with perinatal death included an atrial rate <90 beats per minute (odds ratio [OR], 258.4; 95% CI, 11.5–5798.9; P <0.001), endocardial fibroelastosis (OR, 28.9; 95% CI, 1.6–521.7; P <0.001), fetal hydrops (OR, 25.5; 95% CI, 4.4–145.3; P <0.001), ventricular dysfunction (OR, 7.6; 95% CI, 1.5–39.4; P =0.03), and a ventricular rate <45 beats per minute (OR, 12.9; 95% CI, 1.75–95.8; P =0.034). At a median follow‐up of 5.9 years, 85 of 100 neonatal survivors were paced, and 1 required a heart transplant for dilated cardiomyopathy. Cotreatment with intravenous immune globulin was used in 16 of 22 fetuses with diagnoses other than AVB III. Neonatal and 1‐year survival rates of this cohort were 100% and 95%, respectively. At a median age of 3.1 years, 5 of 21 children were paced, and all had normal ventricular function. Conclusions Our findings reveal a low risk of perinatal mortality and postnatal cardiomyopathy in fetuses that received transplacental dexamethasone±other treatment from the time of a new diagnosis of immune‐mediated heart disease.

Infant Ross-Konno, Endocardial Fibroelastosis Resection and Mitral Valve Repair

Optimal management of critical aortic stenosis (AS) in infants depends on the left ventricle's (LV's) ability to maintain adequate output. Determining feasibility of biventricular repair may be difficult, particularly in those with mitral disease, endocardial fibroelastosis (EFE), multi-level obstruction, and uncertain physiologic capacity. We report a case of a three-month-old with critical AS, severely reduced LV function, EFE, and moderate mitral regurgitation (MR), who underwent a Ross-Konno procedure with concomitant EFE resection and mitral valve repair. Although the technical sequence is challenging, definitive surgery completely relieved multi-level obstruction and MR with markedly improved LV function.

Paediatric dilated cardiomyopathy with and without endocardial fibroelastosis – a pathological analysis of 89 explants

Heart failure due to dilated cardiomyopathy is a major indication for paediatric cardiac transplantation. Endocardial fibroelastosis is a recognised pathological finding of unknown prognostic significance in paediatric dilated cardiomyopathy. To evaluate the nature of the association between left ventricular endocardial fibroelastosis and paediatric dilated cardiomyopathy, we reviewed surgical pathology reports of dilated cardiomyopathy explants (1986–2016) in order to characterise the pathological findings and to compare and contrast their frequency among four age groups: less than 1 year; 1–5 years; 6–10 years; and greater than 11 years. The 89 explants (47 males and 42 females) were all characterised by increased weight and left ventricular chamber dilatation without increased wall thickness. Ninety-five per cent of the specimens in the two youngest subsets had left ventricular endocardial fibroelastosis. Compared to the oldest age group, recipients aged 1–5 years had a 6-fold increase and those younger than 1 year a 19-fold increase in the odds of observing left ventricular endocardial fibroelastosis. Explants with and without endocardial fibroelastosis were otherwise phenotypically similar. In paediatric dilated cardiomyopathy endocardial fibroelastosis is a very common pathological finding, especially in infants and young children. We propose that the descriptive, clinico-pathological designation “Dilated Cardiomyopathy with Endocardial Fibroelastosis” should be adopted to facilitate future investigation into the potential prognostic/therapeutic significance of left ventricular endocardial fibroelastosis.

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 message Primary 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.

Aortic Valve Surgery After Neonatal Balloon Aortic Valvuloplasty in Congenital Aortic Stenosis

Background: We sought to identify predictive factors for aortic valve (AoV) surgery after neonatal balloon aortic valvuloplasty (BAV) and characterize clinical outcomes of AoV surgery after neonatal BAV. Methods: Time-to-event analysis identified predictors for AoV surgery after neonatal BAV. Clinical outcomes of AoV surgery following neonatal BAV were examined. Results: This study included 96 consecutive patients who underwent neonatal BAV for congenital aortic stenosis between 1998 and 2018, in 26 of whom a fetal BAV had been performed. Fifty-six patients underwent AoV surgery at a median age of 2.0 years. Significant risk factors for AoV surgery in univariate Cox regression (result presented as hazard ratio [HR], [95% CI]; P value) were a history of fetal BAV (HR, 4.05 [95% CI, 2.19–7.40]; P <0.001), AoV annulus diameter Z score (HR, 0.56 [95% CI, 0.43–0.75]; P =0.001), the presence of endocardial fibroelastosis (HR, 2.61 [95% CI, 1.48–4.51]; P =0.001), severe left ventricular dysfunction before neonatal BAV (HR, 1.75 [95% CI, 1.03–2.97]; P =0.04), and recent era (HR, 3.08 [95% CI, 1.68–5.91]; P =0.0002) in the entire cohort. Area under the receiver operating characteristic curve and Youden J index analysis identified a cutoff value for AoV annulus diameter Z score of −2.6 in patients without fetal BAV. In 24 patients with midterm cardiac catheterization data, univariate linear regression analysis (result presented as B coefficient [95% CI]; P ) showed that the presence of greater-than-moderate aortic regurgitation immediately after BAV (B coefficient, 4.8 [95% CI, 1.0–8.6]; P =0.018) and before AoV surgery (B coefficient, 6.1 [95% CI, 2.2–10.0]; P =0.004) were significant risk factors for elevated left ventricular end-diastolic pressure after AoV surgery, while concomitant endocardial fibroelastosis resection at AoV surgery had a protective effect (B coefficient, −3.8 [95% CI, −7.6 to −0.06]; P =0.05). Conclusions: A small AoV annulus diameter Z score with a cutoff value of −2.6 and a history of fetal BAV were significantly associated with AoV surgery after neonatal BAV. Concomitant endocardial fibroelastosis resection is recommended at AoV surgery following neonatal BAV to improve left ventricular diastolic function.