KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.

In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a KrasFSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras+/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras+/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.

8p23.1 deletion: Look out for left ventricular hypertrabeculation and not only congenital heart diseases. Single-center experience and literature revision.

Deletions involving the distal portion of the short arm of chromosome 8(8p23.1) show a high phenotypic variability. Congenital heart diseases (CHD) are often described. GATA4 when mutated or deleted is reported to be involved in cardiac morphogenesis. Only twice, left ventricular non compaction (LVNC) was reported in literature in association with 8p23.1 deletion. The present cohort includes five new patients with 8p23.1 deletions including GATA4. The spectrum of CHD is variable. Moreover, in four patients, LV hypertrabeculation was detected and in the fifth LVNC was recognized. Literature revision identified 45 patients with 8p23.1 deletions (encompassing GATA4) and heart involvement. It included wide spectrum of CHD including: heterotaxy spectrum 7/45 (15, 6%), atrioventricular canal 14/45 (balanced 3/45 including two of them with hypoplastic aortic arch; unbalanced 4/45, Fallot-AVC 1/45, partial AVC 3/45, unspecified 3/45), predominant major left heart lesions included 2/45 (4, 4%): interrupted aortic arch and hypoplastic left heart syndrome. Left ventricular hypertrabeculation might be potentially underestimated in patients with 8p23.1 deletion. These might suggest the importance of including microarray analysis in this group of patients. Moreover, 8p23.1 microdeletion or GATA4 variants can be considered in heterotaxy genetic panels.

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.

Left Ventricular Noncompaction Syndrome: Genetic Insights and Therapeutic Perspectives.

PURPOSE OF REVIEW: To discuss the association of left ventricular hypertrabeculation/noncompaction (LVHT/LVNC/NCCM) with genetic disease and to outline the therapeutic options for non-symptomatic and symptomatic LVHT. RECENT FINDINGS: A number of new mutated genes have been recently detected being associated with LVHT. There are indications that microtubules changing cell polarity, the transcription factor Nkx2-5, and NOTCH-1 signaling are involved in the pathogenesis of LVHT. There are also indications that the PKC signaling pathway, which is involved in the regulation of gap junction intercellular communication, is disturbed in LVHT. LVHT is the same as LVNC and is associated with pathogenic variants in > 110 mtDNA or nDNA genes. LVHT has been also reported in > 15 chromosomal defects. However, a causal relation between any of these variants and LVHT has not been proven. There is no general agreement on the treatment of LVHT. According to expert opinions, LVHT patients require anticoagulation if they meet the criteria for anticoagulation or an ICD if they meet the appropriate criteria. Heart failure therapy is equal to patients with other causes of heart failure.

Deficiency in the mouse mitochondrial adenine nucleotide translocator isoform 2 gene is associated with cardiac noncompaction.

The mouse fetal and adult hearts express two adenine nucleotide translocator (ANT) isoform genes. The predominant isoform is the heart-muscle-brain ANT-isoform gene 1 (Ant1) while the other is the systemic Ant2 gene. Genetic inactivation of the Ant1 gene does not impair fetal development but results in hypertrophic cardiomyopathy in postnatal mice. Using a knockin X-linked Ant2 allele in which exons 3 and 4 are flanked by loxP sites combined in males with a protamine 1 promoter driven Cre recombinase we created females heterozygous for a null Ant2 allele. Crossing the heterozygous females with the Ant2(fl), PrmCre(+) males resulted in male and female ANT2-null embryos. These fetuses proved to be embryonic lethal by day E14.5 in association with cardiac developmental failure, immature cardiomyocytes having swollen mitochondria, cardiomyocyte hyperproliferation, and cardiac failure due to hypertrabeculation/noncompaction. ANTs have two main functions, mitochondrial-cytosol ATP/ADP exchange and modulation of the mitochondrial permeability transition pore (mtPTP). Previous studies imply that ANT2 biases the mtPTP toward closed while ANT1 biases the mtPTP toward open. It has been reported that immature cardiomyocytes have a constitutively opened mtPTP, the closure of which signals the maturation of cardiomyocytes. Therefore, we hypothesize that the developmental toxicity of the Ant2 null mutation may be the result of biasing the cardiomyocyte mtPTP to remain open thus impairing cardiomyocyte maturation and resulting in cardiomyocyte hyperproliferation and failure of trabecular maturation. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Neuromuscular comorbidity, heart failure, and atrial fibrillation as prognostic factors in left ventricular hypertrabeculation/noncompaction.

BACKGROUND: There is some controversy concerning the prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT). LVHT is frequently associated with neuromuscular disorders (NMDs). The aim of this study was to assess cardiac and neurological findings as predictors of mortality in patients with LVHT. PATIENTS AND METHODS: The study included patients with LVHT diagnosed between June 1995 and January 2014 in one echocardiographic laboratory. They underwent a baseline cardiologic examination and were invited for a neurological examination. Between January and February 2014, their survival status was assessed. RESULTS: LVHT was diagnosed in 220 patients (68 female, aged 52 ± 17 years) with a prevalence of 0.35 %/year. During a follow-up of 72 ± 61 months, 65 patients died. The mortality was 5 %/year. A neurological investigation was performed on 173 patients (79 %) and revealed specific NMDs in 31 (14 %), NMD of unknown etiology in 103 (47 %), and normal findings in 39 (18 %) patients. In multivariate analysis, the predictors of mortality were increased age (p = 0.0001), presence of a specific NMD (p = 0.0062) or NMD of unknown etiology (p = 0.0062), heart failure NYHA III (p = 0.0396), atrial fibrillation (p = 0.0022), and sinus tachycardia (p = 0.0395). CONCLUSIONS: LVHT patients should undergo systematic neurological examinations. Whether an optimal therapy of heart failure and atrial fibrillation will improve the prognosis of LVHT patients needs to be addressed in further studies.

Assessment of tenascin-C levels in ventricular noncompaction/hypertrabeculation patients: a cross-sectional study.

PURPOSE: Ventricular noncompaction/hypertrabeculation (NC/HT) is a rare form of congenital cardiomyopathy. We aimed to investigate the presence of serum tenascin-C (TN-C) in adult patients with NC/HT and evaluate its value. METHODS AND RESULTS: Serum TN-C levels were measured by ELISA in 50 NC/HT patients both with/without systolic dysfunction and in 23 normal controls. Systolic dysfunction was defined as ejection fraction (EF) ≤ 40. Mann-Whitney U-test and ROC curve analysis were done. Of 49 NC/HT patients, 24 (49%) patients had systolic dysfunction (mean age 36 ± 15) and 25 patients (51%) had normal systolic function (mean age 36 ± 17). The ages between groups were not different. The mean levels of serum TN-C in patients with or without systolic dysfunction were 26 ± 10 ng/mL and 26 ± 8 ng/mL respectively, compared to normal controls, 7 ± 2 ng/mL (P < 0.001). No significance was observed between 2 groups of NC/HT patients regarding TN-C levels (P = 0.8). The ROC curve analysis revealed that a TN-C value of 11.7 ng/mL identified patients with NC/HT with 100% sensitivity and specifity. CONCLUSION: High serum TN-C levels are present in adult NC/HT cardiomyopathy even when left ventricular systolic function remains normal. Also, serum TN-C levels could be regarded as a candidate biomarker in the diagnosis of NC/HT which needs to be tested in larger prospective studies.

Characterization and Long-Term Prognosis of Patients with Different Phenotypes of Dilated Cardiomyopathy.

BACKGROUND: Long-term prognosis of dilated cardiomyopathy (DCM) in the Chinese population is lacking, and the left ventricular (LV) hypertrabeculation phenotype usually overlaps with DCM. OBJECTIVES: The study aims to investigate whether the presence of the LV hypertrabeculation phenotype confers additional adverse prognostic information for DCM patients. METHODS: We retrospectively reviewed all DCM patients (≥18 years of age at diagnosis) hospitalized in the Peking Union Medical College Hospital between September 2002 and September 2022. The eligible patients were divided into two groups based on echocardiography at diagnosis: the isolated DCM (n = 353), and DCM with the LV hypertrabeculation phenotype (n = 97). The primary endpoint was major adverse cardiac events (MACEs), and multivariate Cox hazards regression models were used to compare the endpoints between the two groups. RESULTS: During a mean follow-up time of 4.6 years, there was no significant difference in the primary endpoint between the isolated DCM and DCM with the LV hypertrabeculation phenotype (p = 0.19). The risk of MACEs in the first 5 years was significantly higher in DCM with the LV hypertrabeculation phenotype than isolated DCM (adjusted HR [95%CI]: 1.83 [1.21-2.77]) and after 5 years the effect of the LV hypertrabeculation phenotype as a prognostic attenuated. Subgroup analysis found a significant interaction for the incidence of MACEs between sex and DCM subtypes (p for interaction = 0.01). CONCLUSIONS: DCM with LV hypertrabeculation phenotypes had a higher early (first 5 years) risk of MACEs. For males, the presence of LV hypertrabeculation phenotypes might be an important clue for identifying high-risk DCM patients.

Genetic, clinical and imaging implications of a noncompaction phenotype population with preserved ejection fraction.

Introduction: The genotype of symptomatic left ventricular noncompaction phenotype (LVNC) subjects with preserved left ventricular ejection fraction (LVEF) and its effect on clinical presentation are less well studied. We aimed to characterize the genetic, cardiac magnetic resonance (CMR) and clinical background, and genotype-phenotype relationship in LVNC with preserved LVEF. Methods: We included 54 symptomatic LVNC individuals (LVEF: 65 ± 5%) whose samples were analyzed with a 174-gene next-generation sequencing panel and 54 control (C) subjects. The results were evaluated using the criteria of the American College of Medical Genetics and Genomics. Medical data suggesting a higher risk of cardiovascular complications were considered "red flags". Results: Of the LVNC population, 24% carried pathogenic or likely pathogenic (P) mutations; 56% carried variants of uncertain significance (VUS); and 20% were free from cardiomyopathy-related mutations. Regarding the CMR parameters, the LVNC and C groups differed significantly, while the three genetic subgroups were comparable. We found a significant relationship between red flags and genotype; furthermore, the number of red flags in a single subject differed significantly among the genetic subgroups (p = 0.002) and correlated with the genotype (r = 0.457, p = 0.01). In 6 out of 7 LVNC subjects diagnosed in childhood, P or VUS mutations were found. Discussion: The large number of P mutations and the association between red flags and genotype underline the importance of genetic-assisted risk stratification in symptomatic LVNC with preserved LVEF.

What happened to the left ventricular non-compaction cardiomyopathy? to be or not to be: This is the question.

For several years, left ventricular non-compaction (LVNC) was considered as a true cardiomyopathy and several definitions have followed one another. Particularly, LVNC was characterized by prominent left ventricular trabeculae separated from deep intertrabecular recesses. Several echocardiographic criteria and cardiac magnetic resonance imaging (CMR) criteria have been used to diagnose LVNC, leading to overestimate the diagnosis of LVNC in patients with other diseases and/or physiological conditions. Left ventricular hypertrabeculation (LVH) can be present in several cardiac diseases and physiological conditions: heart failure with reduced ejection fraction, thalassemia and other hematological diseases, pregnancy, athlete's heart. Thus, the presence of LVH does not necessarily indicate the presence of an LVNC. In addition, the great heterogeneity of clinical manifestations has raised concerns regarding the existence of a true LVNC as a cardiomyopathy. In fact, LVNC ranges from genetic to acquired and even transient conditions, isolated forms or forms associated with other cardiomyopathies, congenital heart diseases or syndromes with a very different prognosis. Thus, considering LVH as a manifestation of various diseases and physiological conditions, the recent 2023 ESC guidelines on cardiomyopathies did not include LVNC among cardiomyopathies, but they suggested using the term "LVH" rather than LVNC, to describe this phenotype especially when it is transient or of adult-onset. In this review, we aimed to make an excursion on LVNC, from its initial description to the present day, to understand why current guidelines decided to consider LVH as a phenotypic trait rather than a distinct cardiomyopathy.

Electrophysiological phenotyping of left ventricular noncompaction cardiomyopathy in pediatric populations: A systematic review.

Left ventricular noncompaction cardiomyopathy (LVNC) is a structural heart defect that has been associated with generation of arrhythmias in the population and is a cause of sudden cardiac death with severe systolic dysfunction and fatal arrhythmias. LVNC has gained increasing acknowledgment with increased prevalence. We conducted a systematic review of reported electrocardiogram (ECG) results for pediatric LVNC patients. EMBASE database query was performed, yielding 4531 articles related to LVNC between 1990 and December 2023. Patient age ranged from prenatal to 18 years of age. Qualitative analyses were performed to characterize individual arrhythmias, and summative interpretation of ECG evaluations was gathered for the entire cohort. Systematic review of 57 LVNC cases and ECG presentation revealed many waveform consistencies, including abnormal left ventricular, atrioventricular node, and interventricular septal patterns, and specifically a high incidence of Mobitz type II and Wolff-Parkinson-White waveforms. This review of ECG analysis reinforces the clinical and etiologic significance of pediatric LVNC. While LVNC in pediatric populations may not always present as acute clinical cases, further investigation into the electrophysiology of the disease supports the need for further evaluation and risk stratification for patients with suspected LVNC and/or ventricular arrhythmia.

Familial ebstein anomaly, left ventricular hypertrabeculation, and ventricular septal defect associated with a MYH7 mutation.

Ebstein anomaly is a rare congenital heart defect that most often occurs sporadically within a kindred. Familial cases, although reported, are uncommon. At this time, the genetic etiology of Ebstein anomaly is not fully elucidated. Here, we describe clinical and molecular investigations of a rare case of familial Ebstein anomaly in association with a likely pathogenic mutation of the MYH7 gene. The severity of presentation varies, and Ebstein anomaly can be observed in association with such other heart defects as ventricular septal defect and left ventricular (LV) hypertrabeculation, as seen in our family of study. In our family of study, the 31-year-old father and four of his children have been diagnosed with Ebstein anomaly. Genetic testing revealed that the father was heterozygous for the Glu1220del variant detected in exon 27 of the MYH7 gene. The MYH7 gene encodes the ß-myosin heavy chain and is expressed in cardiac muscle. DNA sequencing of three of his affected children confirmed that they carried the same variant while the fourth affected child was not available for testing. This is the first report of familial Ebstein anomaly associated with the Glu1220del mutation of the MYH7 gene. The mutation segregates with disease in a family with autosomal dominant transmission of congenital heart defects including Ebstein anomaly and other associated cardiovascular defects including LV hypertrabeculation and ventricular septal defect.

The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype.

Excessive trabeculation of the cardiac left ventricular wall is a complex phenotypic substrate associated with various physiological and pathological processes. There has been considerable conjecture as to whether hypertrabeculation contributes to disease and whether left ventricular non-compaction (LVNC) cardiomyopathy is a distinct pathology. Building on recent insights into the genetic basis of LVNC cardiomyopathy, in particular three meta-analysis studies exploring genotype-phenotype associations using different methodologies, this review examines how genetic research can advance our understanding of trabeculation. Three groups of genes implicated in LVNC are described-those associated with other cardiomyopathies, other cardiac/syndromic conditions and putatively with isolated LVNC cardiomyopathy-demonstrating how these findings can inform the underlying pathologies in LVNC patients and aid differential diagnosis and management in clinical practice despite the limited utility suggested for LVNC genetic testing in recent guidelines. The outstanding questions and future research priorities for exploring the genetics of hypertrabeculation are discussed.

Different methods, different results? Threshold-based versus conventional contouring techniques in clinical practice.

BACKGROUND: The quantitative differences of left and right ventricular (LV, RV) parameters of using different cardiac MRI (CMR) post-processing techniques and their clinical impact are less studied. We aimed to assess the differences and their clinical impact between the conventional contouring (CC) and the threshold-based (TB) methods using 70% and 50% thresholds in different hypertrabeculated conditions. METHODS: This retrospective study included 30 dilated cardiomyopathy, 30 left ventricular non-compaction (LVNC), 30 arrhythmogenic cardiomyopathy patients, 30 healthy athletes and 30 healthy volunteers. All participants underwent CMR imaging on 1.5 T. Cine sequences were used to derive measures of the cardiac volumes, function, total muscle mass (TMi) and trabeculae and papillary muscle mass (TPMi) using CC and TB segmentation methods. RESULTS: Comparing the CC and the 70% and 50% threshold TB methods, the LV and RV volumes were significantly lower, the ejection fraction (EF) and the TMi were significantly higher with the TB methods. Between the two threshold setups, only TPMi was significantly higher with the 70% threshold. Regarding the clinical benefits, the LVNC was the only group in whom all the diagnostic and therapeutic decisions and risk stratification were influenced using the TB method. Diagnostic changes occurred in three-quarters of the population, and all the cardiomyopathy groups were affected regarding the decision-making about pharmaco- and device therapy. CONCLUSIONS: Using the TB method, only TPMi was significantly higher with the 70% threshold than the 50% setup, and both of them differed significantly from the CC technique, with relevant clinical impacts in all patient groups.

The use of 2-D speckle tracking echocardiography in assessing adolescent athletes with left ventricular hypertrabeculation meeting the criteria for left ventricular non-compaction cardiomyopathy.

BACKGROUND: Current echocardiographic criteria cannot accurately differentiate exercise induced left ventricular (LV) hypertrabeculation in athletes from LV non-compaction cardiomyopathy (LVNC). This study aims to evaluate the role of speckle tracking echocardiography (STE) in characterising LV myocardial mechanics in healthy adolescent athletes with and without LVNC echocardiographic criteria. METHODS: Adolescent athletes evaluated at three sports academies between 2014 and 2019 were considered for this observational study. Those meeting the Jenni criteria for LVNC (end-systolic non-compacted/compacted myocardium ratio > 2 in any short axis segment) were considered LVNC+ and the rest LVNC-. Peak systolic LV longitudinal strain (Sl), circumferential strain (Sc), rotation (Rot), corresponding strain rates (SRl/c) and segmental values were calculated and compared using a non-inferiority approach. RESULTS: A total of 417 participants were included, mean age 14.5 ± 1.7 years, of which 6.5% were LVNC+ (n = 27). None of the athletes showed any additional LVNC clinical criteria. All average Sl, SRl Sc, SRc and Rot values were no worse in the LVNC+ group compared to LVNC- (p values range 0.0003-0.06), apart from apical SRc (p = 0.2). All 54 segmental measurements (Sl/Sc SRl/SRc and Rot) had numerically comparable means in both LVNC+ and LVNC-, of which 69% were also statistically non-inferior. CONCLUSIONS: Among healthy adolescent athletes, 6.5% met the echocardiographic criteria for LVNC, but showed normal LV STE parameters, in contrast to available data on paediatric LVNC describing abnormal myocardial function. STE could better characterise the myocardial mechanics of athletes with LV hypertrabeculation, thus allowing the transition from structural to functional LVNC diagnosis, especially in suspected physiological remodelling.

Peripartum anesthetic management in patients with left ventricular noncompaction: a case series and review of the literature.

BACKGROUND: This retrospective review focuses on peripartum anesthetic management and outcome of a series of five pregnant women with left ventricular noncompaction (LVNC). METHODS: The Mayo Clinic Advanced Cohort Explorer medical database was utilized to identify women diagnosed with LVNC who had been admitted for delivery at the Mayo Clinic in Rochester, Minnesota, between January 2001 and September 2021. Echocardiograms were independently reviewed by two board-certified echocardiographers, and those determined by both to meet the Jenni criteria and/or having compatible findings on magnetic resonance imaging (MRI) were included. Electronic medical records were reviewed for information pertaining to cardiac function, labor, delivery, and postpartum management. RESULTS: We identified 44 patients whose medical record included the term "noncompaction" or "hypertrabeculation" and who had delivered at our institution during the study period. Upon detailed review of the medical records, 36 did not meet criteria for LVNC, and three additional patients did not receive the diagnosis until after delivery, leaving five patients with confirmed LVNC who had undergone six deliveries during the study interval. All five patients had a history of arrhythmias or had developed arrhythmias during pregnancy. One patient underwent emergency cesarean delivery due to sustained ventricular tachycardia requiring three intra-operative cardioversions. CONCLUSIONS: This case series adds new evidence to that already available about pregnancies among women with LVNC. Favorable obstetrical outcomes were achievable when multidisciplinary teams were prepared to manage the maternal and fetal consequences of intrapartum cardiac arrhythmias and hemodynamic instability.

RBPMS is an RNA-binding protein that mediates cardiomyocyte binucleation and cardiovascular development.

Noncompaction cardiomyopathy is a common congenital cardiac disorder associated with abnormal ventricular cardiomyocyte trabeculation and impaired pump function. The genetic basis and underlying mechanisms of this disorder remain elusive. We show that the genetic deletion of RNA-binding protein with multiple splicing (Rbpms), an uncharacterized RNA-binding factor, causes perinatal lethality in mice due to congenital cardiovascular defects. The loss of Rbpms causes premature onset of cardiomyocyte binucleation and cell cycle arrest during development. Human iPSC-derived cardiomyocytes with RBPMS gene deletion have a similar blockade to cytokinesis. Sequencing analysis revealed that RBPMS plays a role in RNA splicing and influences RNAs involved in cytoskeletal signaling pathways. We found that RBPMS mediates the isoform switching of the heart-enriched LIM domain protein Pdlim5. The loss of Rbpms leads to an abnormal accumulation of Pdlim5-short isoforms, disrupting cardiomyocyte cytokinesis. Our findings connect premature cardiomyocyte binucleation to noncompaction cardiomyopathy and highlight the role of RBPMS in this process.

Prognostic Value of Late Gadolinium Enhancement in Left Ventricular Noncompaction: A Multicenter Study.

Current diagnostic criteria for left ventricular noncompaction (LVNC) may be poorly related to adverse prognosis. Late gadolinium enhancement (LGE) is a predictor of major adverse cardiovascular events (MACE), but risk stratification of LGE in patients with LVNC remains unclear. We retrospectively analyzed the clinical and cardiovascular magnetic resonance (CMR) data of 75 patients from three institutes and examined the correlation between different LGE types and MACE based on the extent, pattern (including a specific ring-like pattern), and locations of LGE in LVNC. A total of 51 patients (68%) presented LGE. A specific ring-like pattern was observed in 9 (12%). MACE occurred in 29 (38.7%) at 4.3 years of follow-up (interquartile range: 2.1−5.7 years). The adjusted hazard ratio (HR) for patients with ring-like LGE were 6.10 (95% CI, 1.39−26.75, p < 0.05). Free-wall or mid-wall LGE was associated with an increased risk of MACE after adjustment (HR 2.85, 95% CI, 1.31−6.21; HR 4.35, 95% CI, 1.23−15.37, respectively, p < 0.05). The risk of MACE in LVNC significantly increased when the LGE extent was greater than 7.5% and ring-like, multiple segments, and free-wall LGE were associated with MACE. These results suggest the value of LGE risk stratification in patients with LVNC.

Left ventricular non-compaction cardiomyopathy automatic diagnosis using a deep learning approach.

BACKGROUND AND OBJECTIVE: Left ventricular non-compaction (LVNC) is an uncommon cardiomyopathy characterised by a thick and spongy left ventricle wall caused by the high presence of trabeculae (hyper-trabeculation). Recently, the percentage of the trabecular volume to the total volume of the external wall of the left ventricle (VT%) has been proposed to diagnose this illness. METHODS: This paper presents the use of a deep learning-based method to measure the (VT%) value and diagnose this rare cardiomyopathy. The population used in this research was composed of 277 patients suffering from hypertrophic cardiomyopathy. 134 patients only suffered hypertrophic cardiomyopathy, and 143 also suffered left ventricular non-compaction. Our deep learning solution is based on a 2D U-Net. This artificial neural network (ANN) was trained on short-axis magnetic resonance imaging to segment the left ventricle's internal cavity, external wall, and trabecular tissue. 5-fold cross-validation was performed to ensure the robustness of the results. The Dice coefficient of the three classes was computed as a measure of the precision of the segmentation. Based on this segmentation, the percentage of the trabecular volume (VT%) was computed. Two specialist cardiologists rated the segmentation produced by the neural network for 25 patients to evaluate the clinical validity of the outputs. The computed VT% was used to automatically diagnose the 277 patients depending on whether or not a given threshold was exceeded. A receiver operating characteristic analysis was also performed. RESULTS: According to the cross-validation results, the average and standard deviation of the Dice coefficient for the internal cavity, external wall, and trabeculae were 0.96±0.00, 0.89±0.00, and 0.84±0.00, respectively. The cardiologists rated 99.5% of the evaluated segmentations as clinically valid for diagnosis, outperforming existing automatic traditional tools. The area under the ROC curve was 0.94 (95% confidence interval, 0.91-0.96). The accuracy, sensitivity, and specificity values of diagnosis using a threshold of 25% were 0.87, 0.93, and 0.80, respectively. CONCLUSIONS: The U-Net neural network can achieve excellent results in the delineation of different cardiac structures of short-axis cardiac MRI. The high-quality segmentation allows for the correct measurement of left ventricular hyper-trabeculation and a definitive diagnosis of LVNC illness. Using this kind of solution could lead to more objective and faster analysis, reducing human error and time spent by cardiologists.