Ventricular Noncompaction Research Articles

Left Ventricular Noncompaction in Children: The Role of Genetics, Morphology, and Function for Outcome.

Left ventricular noncompaction (LVNC) is a ventricular wall anomaly morphologically characterized by numerous, excessively prominent trabeculations and deep intertrabecular recesses. Accumulating data now suggest that LVNC is a distinct phenotype but must not constitute a pathological phenotype. Some individuals fulfill the morphologic criteria of LVNC and are without clinical manifestations. Most importantly, morphologic criteria for LVNC are insufficient to diagnose patients with an associated cardiomyopathy (CMP). Genetic testing has become relevant to establish a diagnosis associated with CMP, congenital heart disease, neuromuscular disease, inborn error of metabolism, or syndromic disorder. Genetic factors play a more decisive role in children than in adults and severe courses of LVNC tend to occur in childhood. We reviewed the current literature and highlight the difficulties in establishing the correct diagnosis for children with LVNC. Novel insights show that the interplay of genetics, morphology, and function determine the outcome in pediatric LVNC.

Co-occurrence of Myocardial Sarcoidosis and Left Ventricular Non-compaction in a Patient with Advanced Heart Failure.

A 46-year-old man with systolic heart failure, end-stage renal disease on dialysis, ventricular tachycardia and pulmonary sarcoidosis presented with decompensated heart failure and cardiogenic shock of unknown aetiology. The hospital course was complicated by worsening shock requiring inotropic and mechanical circulatory support, as well as eventual dual heart and kidney transplantation. Cardiac imaging was used to assess the aetiology of the patient's non-ischaemic cardiomyopathy, including a PET scan and cardiac MRI. Imaging demonstrated findings consistent with left ventricular non-compaction, but was inconclusive for cardiac sarcoidosis. After eventual heart transplantation, histopathology of the patient's explanted heart showed evidence of both non-compaction and cardiac sarcoidosis. In this case report, the authors review the pathophysiology of both cardiac sarcoidosis and left ventricular non-compaction, and highlight a multimodality approach to the diagnosis of non-ischaemic cardiomyopathy.

Prognostic Value of Left Atrial Reservoir Strain in Left Ventricular Myocardial Noncompaction: A 3.0 T Cardiac Magnetic Resonance Feature Tracking Study.

The relationship of left atrial (LA) strain to high-risk heart failure (HF) events in patients with left ventricular myocardial noncompaction (LVNC) remains to be thoroughly investigated. To evaluate the LA performance in patients with LVNC, and to investigate the prognostic value of LA phasic strain on high-risk HF events, and its influencing factors. Retrospective. A total of 95 LVNC patients (74 with LA enlargement [LAE] and 21 without LAE) and 50 healthy controls. A 3.0 T, balanced steady-state free-precession cine imaging. LA longitudinal strains were measured by cardiac MRI feature tracking technique. LA volume index (LAVI) and LA ejection fraction (LAEF) were calculated. Their intraobserver and interobserver reproducibility were evaluated. The primary outcome was high-risk HF events, a composite of first HF hospitalization, hospitalization for worsening HF and death from HF. Student's t/Mann-Whitney U, one-way analysis of variance/Kruskal-Wallis, Chi-squared, receiver operating characteristic, Kaplan-Meier, log-rank, Cox regression, Pearson and Spearman correlation and linear regression analyses were performed. The significance threshold was set at P < 0 .05. LAEF and LA longitudinal strains decreased in LVNC patients irrespective of the presence of LAE. During a median follow-up of 32.17months, high-risk HF occurred in 13 (13.68%) patients. Patients with increased LAVI, decreased LAEF and decreased LA longitudinal strain had significantly higher risks of high-risk HF events. In patients with LVNC, LA reservoir strain (εs) was independently associated with high-risk HF (hazard ratio=23.208 [95% CI: 2.993-179.967]). LV global longitudinal strain (LV GLS) (β=-1.783 [95% CI: -2.493 to -1.073]) was significantly and independently associated with εs. Intraobserver and interobserver reproducibility was excellent for LAVI, LAEF, and LA strain. In patients with LVNC, εs was an independent predictor for high-risk HF events. LV GLS was an independent determinant of εs in LVNC. 4 TECHNICAL EFFICACY: Stage 4.

Left Ventricular Noncompaction Cardiomyopathy: Left Ventricular Dilation and Dysfunction at Baseline Portend the Risk of Death or Heart Transplantation.

Left ventricular noncompaction (LVNC) is associated with genetic and phenotypic variability that influences outcomes. We aimed to identify risk factors for death or heart transplantation (HTx) in a paediatric LVNC cohort. We reviewed patients < 18 years of age (2001-2018) with LVNC, either isolated (I-LVNC) or with dilated phenotype (D-LVNC), and at least mildly reduced left ventricular ejection fraction (EF). Patients with dilated cardiomyopathy (DCM) were included as control subjects. Descriptive statistics, multivariate analysis, and time-to-event analysis were used. We included 188 patients, 34 (18%) with I-LVNC, 37 (20%) with D-LVNC, and 117 (62%) with DCM. Overall median age at diagnosis was 1.08 years (interquartile range [IQR] 0.22-10.65) and median follow-up was 1.4 years (IQR 0.2-5.2) years. I-LVNC patients' median baseline LVEF was 47%, compared with 33% for D-LVNC, and 21% for DCM (P < 0.0001); 62% of I-LVNC patients developed moderate to severe LV dysfunction during follow-up. The incidence of death or transplantation was 43.6% in the overall cohort. Freedom from death or HTx at 10 years after diagnosis was 88.6% (95% CI 76%-100%) for I-LVNC, 47% (95% CI 29%-65%) for D-LVNC, and 42.3% (95% CI 33%-52%) for DCM. On multivariable analysis, baseline LVEF and LV end-diastolic diameter (LVEDD) z-score were associated with death or transplantation. Patients with a baseline LVEDD z-score > 4 and moderate to severe LV dysfunction had a transplantation-free survival of 38%. Baseline LV dilation and systolic dysfunction were independently associated with progression to death or HTx in LVNC patients.

Left ventricular noncompaction cardiomyopathy: Recent advances.

From its initial description to the present day, left ventricular noncompaction cardiomyopathy has been the subject of numerous studies and publications. In question as a real cardiomyopathy, left ventricular noncompaction can appear in isolation or in association with other cardiac malformations, genetic syndromes, and neuromuscular disorders. As a genetically heterogeneous disorder, it can be sporadic or familial, with an autosomal dominant pattern with variable penetrance most frequently observed. Different diagnostic criteria have been described through the years, first by using echocardiogram and later on by cardiac magnetic resonance. The lack of universally accepted diagnostic criteria has led to the condition being over-diagnosed in the general population. Differential diagnosis between real cardiomyopathy, epiphenomenon (phenocopy in the setting of loading conditions or even other cardiomyopathies), and physiological hypertrabeculation, like in the athlete's heart must be considered. Clinically it can present as heart failure, ventricular arrhythmias, and even sudden death, but it can also be asymptomatic during familial screening. The main prognosis factors are left ventricular dilatation, dysfunction, and fibrosis. There is no specific treatment. Familial screening is recommended and special recommendations in the case of athletes must be taken into account. In the present article, we review the myth and reality concerning main and more recent aspects of left ventricular noncompaction.

Tricuspid Annular Abnormalities in Isolated Left Ventricular Non-compaction-Insights From the Three-dimensional Speckle-Tracking Echocardiographic MAGYAR-Path Study.

IntroductionProminent trabecular left ventricular (LV) meshwork and deep intertrabecular LV recesses are featuring LV non-compaction (LVNC). The aim of this study was to evaluate tricuspid annular (TA) morphological and functional abnormalities by three-dimensional speckle-tracking echocardiography (3DSTE) in patients with LVNC without right ventricular (RV) involvement.Materials and MethodsThis study consisted of 21 patients with isolated LVNC, from which 6 cases were excluded due to inferior image quality. The remaining patient group consisted of 15 subjects with a mean age of 52.1 ± 11.4 years (9 males). LVNC was defined according to the Jenni's criteria. Their results were compared to 21 age- and gender-matched healthy controls (mean age: 52.4 ± 3.9 years, 14 males). Complete routine 2-dimensional Doppler echocardiographic examination was performed in all the patients with isolated LVNC and healthy controls. End-systolic and end-diastolic TA dimensions were assessed on selected planes derived from full-volume 3D echocardiographic datasets during 3DSTE.ResultsPatients with isolated LVNC showed significantly dilated end-systolic and end-diastolic TA diameter and area, which were accompanied with preserved TA functional properties and associated with right atrial (RA) volumes. TA plane systolic excursion (TAPSE) showed mild correlations with TA fractional area change (TAFAC) and TA fractional shortening (TAFS). No correlations could be demonstrated between TAPSE and TA morphological features. Extent of LVNC did not correlate with any echocardiographic parameters.ConclusionTA is dilated with preserved sphincter-like function in patients with isolated LVNC. Longitudinal (TAPSE) and sphincter-like (TAFAC and TAFS) TA movements correlate with each other. TA dilation is associated with an increased RA volumes respecting cardiac cycle.

Genetic Basis of Left Ventricular Noncompaction.

Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated. Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC. We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.

Dilated-Left Ventricular Non-Compaction Cardiomyopathy in a Pediatric Case with SPEG Compound Heterozygous Variants

Left Ventricular Non-Compaction (LVNC) is defined by the triad prominent myocardial trabecular meshwork, thin compacted layer, and deep intertrabecular recesses. LVNC associated with dilation is characterized by the coexistence of left ventricular dilation and systolic dysfunction. Pediatric cases with dilated-LVNC have worse outcomes than those with isolated dilated cardiomyopathy and adult patients. Herein, we report a clinical and genetic investigation using trio-based whole-exome sequencing of a pediatric case with early-onset dilated-LVNC. Compound heterozygous mutations were identified in the Striated Muscle Enriched Protein Kinase (SPEG) gene, a key regulator of cardiac calcium homeostasis. A paternally inherited mutation: SPEG; p.(Arg2470Ser) and the second variant, SPEG; p.(Pro2687Thr), is common and occurred de novo. Subsequently, Sanger sequencing was performed for the family in order to segregate the variants. Thus, the index case, his father, and both sisters carried the SPEG: p.(Arg2470Ser) variant. Only the index patient carried both SPEG variants. Both sisters, as well as the patient’s father, showed LVNC without cardiac dysfunction. The unaffected mother did not harbor any of the variants. The in silico analysis of the identified variants (rare and common) showed a decrease in protein stability with alterations of the physical properties as well as high conservation scores for the mutated residues. Interestingly, using the Project HOPE tool, the SPEG; p.(Pro2687Thr) variant is predicted to disturb the second fibronectin type III domain of the protein and may abolish its function. To our knowledge, the present case is the first description of compound heterozygous SPEG mutations involving a de novo variant and causing dilated-LVNC without neuropathy or centronuclear myopathy.

Prognosis of Adults With Isolated Left Ventricular Non-Compaction: Results of a Prospective Multicentric Study.

BackgroundWhether left ventricular non-compaction (LVNC) bears a different prognosis than dilated cardiomyopathy (DCM) is still a matter of debate.MethodsFrom a multicenter French prospective registry, we compared the outcomes of 98 patients with LVNC and 65 with DCM. The primary endpoint combined cardiovascular death, heart transplantation, and hospitalization for cardiovascular events. The two groups presented similar outcomes but different left ventricular ejection fractions (LVEF) (43.3% in LVNC vs. 35.95% in DCM, p = 0.001). For this reason, a subgroup analysis was performed comparing only patients with LVEF ≤ 45%, including 56 with LVNC and 49 with DCM.ResultsAmong patients with LVEF≤ 45%, at 5-year follow-up, the primary endpoint occurred in 33 (58.9%) among 56 patients with LVNC and 18 (36.7%) among 49 patients with DCM (p = 0.02). Hospitalization for heart failure (18 [32.14%] vs. 5 [10.20%], p = 0.035) and heart transplantation were more frequent in the LVNC than in the DCM group. The incidences of rhythmic complications (24 [42.85%] vs. 12 [24.48%], p = 0.17), embolic events, and cardiovascular death were similar between LVNC and DCM cases. Among the 42 patients with LVNC and LVEF > 45%, the primary endpoints occurred in only 4 (9.52%) patients, including 2 hospitalizations for heart failure and 3 rhythmic complications, but no embolic events.ConclusionIn this prospective cohort, patients with LVNC who have left ventricular dysfunction present a poorer prognosis than DCM patients. Heart failure events were especially more frequent, but embolic events were not. Patients with LVNC and preserved ejection fraction present very few events in 5 years.

Screening for new causative genes and their expression profiles in patients with left ventricular noncompaction

Screening for new causative genes and their expression profiles in patients with left ventricular noncompaction

Decreased Contraction Rate, Altered Calcium Transients, and Increased Proliferation seen in Patient‐specific iPSC‐CMs Modeling Ebstein’s Anomaly and Left Ventricular Noncompaction

IntroductionPatients presenting with Ebstein’s anomaly (EA) have right heart dysfunction, mainly tricuspid valve insufficiency, and often manifest with left ventricular noncompaction (LVNC). Apart from a few sarcomeric variant associations, the genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. In a familial case where 10 of 17 members, including four fetal deaths, inherited EA/LVNC in an autosomal dominant pattern, we discovered a novel and damaging missense variant in the gene KLHL26 that segregates with disease. The KLHL26 (p.R237C) variant comprises an altered electrostatic surface profile, likely decoupling the CUL3‐interactome and altering protein turnover.ObjectiveOur in vitro patient‐specific studies enable the discovery of EA/LVNC developmental pathways and possibly related forms of heart failure and cardiomyopathy that may inform early clinical interventions and improve long‐term patient outcomes.HypothesisWe hypothesize that the KLHL26 variant is etiologic for this familial EA/LVNC case.MethodsWe differentiated a family trio (a heart‐healthy daughter and EA/LVNC‐affected mother and daughter) of induced pluripotent stem cells into cardiomyocytes (iPSC‐CMs) in a blinded manner on three iPSC clones per subject. Using flow cytometry, immunofluorescence, and biomechanical, electrophysiological, and automated contraction methods, we investigated iPSC‐CM differentiation efficiency between D10‐20, contractile properties and cell cycle regulation at D20, and sarcomere organization at D60. We further conducted differential analyses following label‐free protein and RNA‐Seq quantification at D20. Via CRISPR‐Cas9 gene editing, we plan to characterize KLHL26 variant‐specific iPSC‐CM alterations and connect findings to discoveries from patient‐specific studies.ResultsAll iPSC lines differentiated into CMs with an increased percentage of cTnT+ cells in the affected daughter line. In comparison to the unaffected, affected iPSC‐CMs had fewer contractions per minute and altered calcium transients, mainly a higher amount of total calcium release, faster rate of rise and faster rate of fall. The affected daughter line further had shorter shortening and relaxation times, higher proliferation, lower apoptosis, and a smaller cell surface area per nucleus. The affected mother line trended in a similar direction to the affected daughter line. There were no gross differences in sarcomere organization between the lines. We also discovered differential expression of candidate proteins such as kinase VRK1 and collagen COL5A1 from proteomic profiling.DiscussionThese discoveries suggest that EA/LVNC characteristics or pathogenesis may result from decreased contractile ability, altered calcium transients, and cell cycle dysregulation. Through CRISPR‐Cas9 correction and introduction of the KLHL26 variant in the daughter lines, we will build upon this understanding to inform exploration of critical clinical targets for EA/LVNC and related forms of cardiomyopathy and heart failure.

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.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction.

BACKGROUNDMutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODSThe whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTSA novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONSThe TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

MR -specific characteristics of left ventricular noncompaction and dilated cardiomyopathy

BackgroundThe differentiation of dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC) is a recurring issue during cardiac imaging processes; thus, we aimed to compare the left ventricular (LV) cardiac MRI characteristics of these patients. MethodsThirty-one nonischemic DCM patients, 42 LVNC patients with reduced ejection fraction and 42 healthy controls were included in this retrospective study. LV volumetric, functional and myocardial mass parameters were measured with a threshold-based technique, while global and segmental strain values and rotational patterns were analyzed with feature-tracking strain analysis. ResultsOf the LV volumetric and myocardial mass parameters, only the trabeculated and papillary muscle mass (TPMi) values differed significantly between the patient groups and were higher in the LVNC group (DCM vs LVNC: 43.2 ± 8.9 vs 51.6 ± 13.6 g/m2, p < 0.002). The global longitudinal and circumferential strains were similar between the patient groups and significantly worse than those of the controls. In comparing the segmental strains between the patient groups, only the circumferential apical strain was significantly lower in the LVNC group (DCM vs LVNC: −30.5 ± 13.5 vs −24.5 ± 12.0%, p < 0.05). There was no difference in the rotational pattern between the patient groups, and both healthy and patient populations showed heterogeneous rotational patterns. ConclusionsDespite the similarities between DCM and LVNC in volumetric, global strain parameters, and rotational patterns, we found some differences between the patient groups, as the TPMi was higher and the apical circumferential strains were significantly lower in LVNC. These minor alterations might be due to the morphological characteristics of LVNC with a trabeculated apical region.

A Systematic Review of Ebstein’s Anomaly with Left Ventricular Noncompaction

Traditional definitions of Ebstein’s anomaly (EA) and left ventricular noncompaction (LVNC), two rare congenital heart defects (CHDs), confine disease to either the right or left heart, respectively. Around 15–29% of patients with EA, which has a prevalence of 1 in 20,000 live births, commonly manifest with LVNC. While individual EA or LVNC literature is extensive, relatively little discussion is devoted to the joint appearance of EA and LVNC (EA/LVNC), which poses a higher risk of poor clinical outcomes. We queried PubMed, Medline, and Web of Science for all peer-reviewed publications from inception to February 2022 that discuss EA/LVNC and found 58 unique articles written in English. Here, we summarize and extrapolate commonalities in clinical and genetic understanding of EA/LVNC to date. We additionally postulate involvement of shared developmental pathways that may lead to this combined disease. Anatomical variation in EA/LVNC encompasses characteristics of both CHDs, including tricuspid valve displacement, right heart dilatation, and left ventricular trabeculation, and dictates clinical presentation in both age and severity. Disease treatment is non-specific, ranging from symptomatic management to invasive surgery. Apart from a few variant associations, mainly in sarcomeric genes MYH7 and TPM1, the genetic etiology and pathogenesis of EA/LVNC remain largely unknown.

Saw-Tooth Cardiomyopathy: the Evidence in the First Decade.

Saw-tooth cardiomyopathy (STC), a rare form of left ventricular cardiomyopathy characterized by saw-tooth like myocardial projections extending from the lateral walls towards the ventricular cavity, is a newly discovered cardiomyopathy first described in 2009. Detailed cardiac magnetic resonance can demonstrate multiple dense myocardial protrusions originating from the inferior wall, interventricular septum and lateral ventricular walls, which differ from typical left ventricular noncompaction. STC case reports are increasing since the first discovery. A total of ten cases have been reported. This review focuses on the clinical presentation and imaging features of this disease and analyzes the latest evidence regarding STC. Furthermore, we summarize the clinical evidence from the current decade, which may enhance detection and diagnosis of this disease in the future.

A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction.

Cardiomyopathies are a group of common heart disorders that affect numerous people worldwide. Left ventricular non-compaction (LVNC) is a structural disorder of the ventricular wall, categorized as a type of cardiomyopathy that mostly caused by genetic disorders. Genetic variations are underlying causes of developmental deformation of the heart wall and the resultant contractile insufficiency. Here, we investigated a family with several affected members exhibiting LVNC phenotype. By whole-exome sequencing (WES) of three affected members, we identified a novel heterozygous missense variant (c.1963C>A:p.Leu655Met) in the gene encoding myosin heavy chain 7 (MYH7). This gene is evolutionary conserved among different organisms. We identified MYH7 as a highly enriched myosin, compared to other types of myosin heavy chains, in skeletal and cardiac muscles. Furthermore, MYH7 was among a few classes of MYH in mouse heart that highly expresses from early embryonic to adult stages. In silico predictions showed an altered actin-myosin binding, resulting in weaker binding energy that can cause LVNC. Moreover, CRISPR/Cas9 mediated MYH7 knockout in zebrafish caused impaired cardiovascular development. Altogether, these findings provide the first evidence for involvement of p.Leu655Met missense variant in the incidence of LVNC, most probably through actin-myosin binding defects during ventricular wall morphogenesis.

371 Decreased Contraction Rate, Altered Calcium Transients, and Increased Proliferation seen in Patient-specific iPSC-CMs Modeling Ebsteins Anomaly and Left Ventricular Noncompaction

OBJECTIVES/GOALS: In a familial case where 10 of 17 members inherited EA/LVNC in an autosomal dominant pattern, we discovered a novel, damaging missense variant in the gene KLHL26 that segregates with disease and comprises an altered electrostatic surface profile, likely decoupling the CUL3-interactome. We hypothesize that this KLHL26 variant is etiologic of EA/LVNC. METHODS/STUDY POPULATION: We differentiated a family trio (a heart-healthy daughter and EA/LVNC-affected mother and daughter) of induced pluripotent stem cells into cardiomyocytes (iPSC-CMs) in a blinded manner on three iPSC clones per subject. Using flow cytometry, immunofluorescence, and biomechanical, electrophysiological, and automated contraction methods, we investigated iPSC-CM differentiation efficiency between D10-20, contractility analysis and cell cycle regulation at D20, and sarcomere organization at D60. We further conducted differential analyses following label-free protein and RNA-Seq quantification at D20. Via CRISPR-Cas9 gene editing, we plan to characterize KLHL26 variant-specific iPSC-CM alterations and connect findings to discoveries from patient-specific studies. RESULTS/ANTICIPATED RESULTS: All iPSC lines differentiated into CMs with an increased percentage of cTnT+ cells in the affected daughter line. In comparison to the unaffected, affected iPSC-CMs had fewer contractions per minute and altered calcium transients, mainly a higher amount of total calcium release, faster rate of rise and faster rate of fall. The affected daughter line further had shorter shortening and relaxation times, higher proliferation, lower apoptosis, and a smaller cell surface area per cardiac nucleus. The affected mother line trended in a similar direction to the affected daughter line. There were no gross differences in sarcomere organization between the lines. We also discovered differential expression of candidate proteins such as kinase VRK1 and collagen COL5A1 from proteomic profiling. DISCUSSION/SIGNIFICANCE: These discoveries suggest that EA/LVNC characteristics or pathogenesis may result from decreased contractile ability, altered calcium transients, and cell cycle dysregulation. Through the KLHL26 variant correction and introduction in the daughter lines, we will build upon this understanding to inform exploration of critical clinical targets.

Orthotopic Heart Transplant in Toddler with Histiocytoid Cardiomyopathy and Left Ventricular Non-Compaction

<h3>Introduction</h3> Histiocytoid cardiomyopathy (HC) is a rare form of cardiomyopathy associated with ventricular arrhythmias and sudden death in infancy. Most cases are diagnosed at autopsy or, occasionally, after heart explant at heart transplantation (HT). We report the case of a toddler with recalcitrant arrhythmias despite multiple medications for whom HC was not suspected. The patient underwent HT, after which biopsy of the explanted heart revealed HC. This case highlights the potential value of a pre-transplant diagnosis of this rare disease, especially in age groups with anticipated long waitlist times. <h3>Case Report</h3> A 16-month old female patient was admitted to the cardiac intensive care unit for Wolf-Parkinson White syndrome (WPW) and recalcitrant ventricular tachycardia (VT) with left ventricular noncompaction (LVNC). She underwent ICD placement, bilateral sympathectomies, and transitioned to oral antiarrhythmic agents with adequate rhythm control. She required readmission for multiple AICD discharges for VT and VF. Despite maximizing antiarrhythmic therapy, she had increasing episodes of VT and was ultimately listed for HT (status 1A by exception). She remained on the waitlist for 37 days prior undergoing HT. Biopsy of her explanted heart showed subendocardial fibrosis, a diffuse nodular thickening of the subendocardium with a proliferation of clear cuboidal/polygonal cells that have granular cytoplasm and bland round nuclei, and stained positive for MYOD1, findings diagnostic for HC in addition to LVNC (Figure 1). <h3>Summary</h3> HC, particularly alongside LVNC, is a rare condition that requires endomyocardial tissue for diagnosis. Pre-HT diagnosis is not described. In this case, pre-transplant listing likely would have prompted earlier listing for HT. Despite the risks associated with catheterization and biopsy in patients with cardiomyopathy and arrhythmia, the pursuit of a pre-HT diagnosis may be warranted to affect patient management and justify status 1A exception requests.

Left Ventricular Non-Compaction Spectrum in Adults and Children: From a Morphological Trait to a Structural Muscular Disease

Left ventricular non-compaction (LVNC) is an extremely heterogeneous disorder with a highly variable clinical presentation, morphologic appearance at imaging testing, and prognosis. It is still unclear whether LVNC should be classified as a separate cardiomyopathy or if it is a mere morphological trait shared by many phenotypically distinct cardiomyopathies. Moreover, the hypertrabeculated phenotype may be reversible in some cases, possibly reflecting the left ventricular physiological response of the cardiac muscle to chronic overload. The current diagnostic criteria have several limitations, leaving many patients in a grey area. Here, we review the available literature on LVNC in order to provide an overview of the current knowledge on this complex disorder.