Features Of Left Ventricular Noncompaction Research Articles

Loss of Rearranged L-Myc Fusion (RLF) results in defects in heart development in the mouse

Recently we reported that Rearranged L-Myc Fusion, RLF, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island shores and enhancers across the genome. Here we focus on the phenotype of Rlf null mutant mice generated via an ENU mutagenesis screen, to identify genes required for epigenetic regulation.RLF is expressed in a range of fetal mouse tissues, including the fetal heart. Comprehensive timed-mating studies are consistent with our previously reported findings that Rlf homozygous mutant mice rarely survive to adulthood, with the majority dying shortly after birth. Histological analysis of two independent Rlf ENU mutant lines at E11.5–E14.5 showed heart defects resembling those present in humans with Left Ventricular Non-Compaction (LVNC). In situ hybridisation analysis localized expression of Rlf to the endocardium and epicardium of embryonic and postnatal hearts, and transiently to cardiomyocytes during heart looping and early chamber formation stages. RNA-seq analysis of Rlf mutant hearts highlighted defective NOTCH pathway signalling, recently describe as one cause of LVNC.This study provides the first evidence that RLF is required for normal heart development in the mouse. The heart morphological defects present at high penetrance in Rlf mutants are consistent with features of LVNC in humans, and molecular analysis identified attenuated JAGGED 1 expression and NOTCH signalling as likely contributors to these defects. Our study highlights the importance of RLF-dependent epigenetic modifications to DNA for maintaining correct gene regulatory network and intercellular signalling interactions during heart chamber and septal development. Further investigations are needed to define the biochemical role of RLF in the developing heart, and whether RLF mutations are a cause of heart defects in humans.

Letter by Finsterer and Zarrouk-Mahjoub Regarding Article, “Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction”

With interest, we read the article by Hastings et al1 about a 3-generation family in whom 7 members carried the titin mutation p.A178D , and 5 (3 on echocardiography and 2 on cardiac magnetic resonance imaging [MRI]) had left ventricular hypertrabeculation/noncompaction (LVHT). We have the following comments and concerns. To date, a causal relation between mutations in any of the >40 genes and many chromosomal defects associated with LVHT and LVHT has never been proven. Arguments against a causal relation are that only a small number of patients with a certain mutation in any of these genes regarded as causative truly develop LVHT; …

Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.

High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterized in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small-angle x ray scattering, and circular dichroism spectroscopy suggest partial unfolding and domain destabilization in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left ventricular noncompaction. This expands the spectrum of titin's roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here.

When it rains, it pours: Peripartum cardiomyopathy with features of left‐ventricular noncompaction in a hemodialysis patient

Pregnancy and associated pre-eclampsia carry a high maternal risk in hemodialysis patients, yet no guidelines on how to monitor these patients' cardiovascular function exist. A 34-year-old hemodialysis patient presented with peripartum cardiomyopathy after a late second trimester miscarriage. On cardiac magnetic resonance imaging, diagnostic features of left ventricular noncompaction were apparent. Yet, histological and gene panel analyses remained negative. Upon stringent dry weight control and pharmacological heart failure therapy, the pathological changes showed complete regression. As pregnant hemodialysis patients have an excessively increased risk for pre-eclampsia-related cardiac disease, thorough screening appears valuable in these patients.

A case of cardiac amyloidosis who showed the resolution of echocardiographic features of left ventricular noncompaction

A case of cardiac amyloidosis who showed the resolution of echocardiographic features of left ventricular noncompaction

Effects of β-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic β-blocker treatment. Study patients (n=20; 42.5 [36.3; 52.5]years; 12 men) exhibited reduced LV ejection fraction (median LVEF=32%) and an increased LV mass of 210g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving β-blocker therapy (n=17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p=0.007) at 13±6months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-β-adrenergic agent showed LV mass increase from 180 [169; 197]g to 199 [185; 213]g (p=0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic β-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during β-blocker therapy. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies.

Biventricular non-compaction demonstrated on multi-slice computed tomography with echocardiographic correlation

Left ventricular non-compaction (LVNC) is a myocardial disorder characterized by prominent trabeculations and deep intertrabecular recesses within the left ventricular wall. Multi-slice computed tomography (CT) might represent a valid non-invasive imaging technique for the diagnostic work-up of these patients, being able to visualize the compacted and non-compacted layers and to simultaneously rule out the presence of associated coronary artery disease and congenital heart disease. In the present report, the CT features of LVNC are described.

Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome

Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients’ fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-013-9584-4) contains supplementary material, which is available to authorised users.

Features of left ventricular noncompaction in peripartum cardiomyopathy: A case series

Features of left ventricular noncompaction in peripartum cardiomyopathy: A case series