Formation of trabeculae in the embryonic heart and the remodelling that occurs prior to birth is a conspicuous, but poorly understood, feature of vertebrate cardiogenesis. Mutations disrupting ...trabecular development in the mouse are frequently embryonic lethal, testifying to the importance of the trabeculae, and aberrant trabecular structure is associated with several human cardiac pathologies. Here, trabecular architecture in the developing mouse embryo has been analysed using high‐resolution episcopic microscopy (HREM) and three‐dimensional (3D) modelling. This study shows that at all stages from mid‐gestation to birth, the ventricular trabeculae comprise a complex meshwork of myocardial strands. Such an arrangement defies conventional methods of measurement, and an approach based upon fractal algorithms has been used to provide an objective measure of trabecular complexity. The extent of trabeculation as it changes along the length of left and right ventricles has been quantified, and the changes that occur from formation of the four‐chambered heart until shortly before birth have been mapped. This approach not only measures qualitative features evident from visual inspection of 3D models, but also detects subtle, consistent and regionally localised differences that distinguish each ventricle and its developmental stage. Finally, the combination of HREM imaging and fractal analysis has been applied to analyse changes in embryonic heart structure in a genetic mouse model in which trabeculation is deranged. It is shown that myocardial deletion of the Notch pathway component Mib1 (Mib1flox/flox; cTnT‐cre) results in a complex array of abnormalities affecting trabeculae and other parts of the heart.
In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes.
Left ventricular non-compaction ...cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome.
In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays.
Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.
The non‐POU domain‐containing octamer‐binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene ...were confirmed to cause a rare X‐linked syndromic disorder. Through our in‐house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO‐associated disorder. The combined cohort consists of 16 live‐born males showing developmental delay, corpus callosum anomalies, non‐compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in‐frame splice deletion, we reinforce loss‐of‐function as the pathomechanism for the NONO‐associated syndromic disorder.
Aim
. To study and compare genotypic and phenotypic signs in patients with non-compaction cardiomyopathy (NCM) and dilated cardiomyopathy (DCM), to conduct a comparative analysis of clinical outcomes ...and 5-year cumulative survival of patients with NCM and DCM.
Material and methods
. The study included 144 unrelated patients with cardiomyopathy: NCM (n=74) and DCM (n=70). Mean age was 39 30; 49 years (men, 96 (66,7%); left ventricular ejection fraction (LVEF) was 30,5 24; 46%. A comprehensive clinical examination included electrocardiography, Holter monitoring, echocardiography, cardiac magnetic resonance imaging, coronary angiography, DNA diagnostics (NGS+Sanger), cascade screening, and cosegregation analysis. To assess clinical outcomes, the NCM group was divided into 2 subtypes according to baseline LV systolic function (NCM/DCM phenotype — 50 individuals with LVEF ≤49%; and isolated NCM — 24 patients with LVEF ≥50%). The following adverse events were assessed as the composite endpoint: cardiovascular death, heart transplantation (HT), sustained ventricular tachycardia, ventricular fibrillation, successful cardiopulmonary resuscitation, cerebral thromboembolism. The follow-up period was 62 months.
Results
. Among patients with LVEF ≤49% at a 5-year follow-up, 37 (74,0%) of 50 patients with the NCM/DCM phenotype and 41 (58,6%) of 70 patients with DCM achieved composite endpoint. Out of 24 patients with NCM with LVEF ≥50% (median LVEF, 56 51; 61%), 2 (8,3%) patients achieved composite endpoint (χ
2
=28,8; p=0,001). In the NCM/DCM group with LVEF ≤49%, a higher level of pathogenic genetic variants (64% vs 41,4%/DCM vs 29,2%/NCM; χ
2
=11,4; p=0,003), cerebral thromboembolism (χ
2
=11,8; p=0,003) and HT (χ
2
=10,6; p=0,005). The results of the 5-year survival analysis (Kaplan-Meier) showed a worse prognosis for NCM with LVEF ≤49% compared with DCM (log rang: χ
2
=11,5; p=0,001) and isolated NCM (log rang: χ
2
=17,02; p=0,0001). In the overall cohort (n=144), gene-positivity was also associated with worse prognosis (log rang: χ
2
=5,38; p=0,02).
Conclusion
. In the present study, patients with dilated subtype of NCM showed a worse prognosis compared with DCM and isolated NCM. Heart failure progression and cerebral thromboembolism were the most common complications in patients with NCM/DCM.
Non-compaction cardiomyopathy (NCC) is a rare pathology, but the exact rates of its prevalence are not known due to the lack of a diagnostic gold standard. The purpose of this article is to analyse ...the available cardiovascular magnetic resonance (CMR) diagnostic criteria of non-compaction described in the literature and to compare their sensitivity and specificity in the diagnosis of NCC. A search of available literature related to the CMR diagnostic criteria of myocardial non-compaction was conducted in the medical database PubMed in February of 2022. The period of publication of scientific articles covered the years from 1996 to 2022. A total of 7 full-text scientific articles were included in the final literature review. The main diagnostic criteria were used: the maximum non-compact (NCM) to compact myocardial layers (CM) ratio (NCM:CM), the percentage of trabeculated left ventricular (LV) myocardial mass, the percentage of trabeculated LV myocardial volume, the non-compact myocardial mass index of the total LV, and the determination of the total LV and the maximal fractal dimension (FD) of the apex with the use of fractal analysis. The lack of accurate diagnostic criteria results in an overdiagnosis of NCC. The highest sensitivity and specificity are associated with the maximum FD > 1.30 of the apex established by applying the fractal analysis method. Fractal analysis requires dedicated software, and this method is difficult to apply in routine clinical practice. Thus, the diagnostic criteria for the NCC using magnetic resonance imaging with higher diagnostic value remain to be sought.
Left ventricular non compaction (LVNC) is a relatively rare variety of cardiomyopathy of genetic origin.
We report three cases of LVNC diagnosed on cardiac magnetic resonance imaging (MRI) in Abidjan ...in patients aged 42, 46 and 60 years, referred for suspected LVNC on echocardiography.
We used a 1.5 T MRI and performed the following sequences: black blood and white blood, LV minor axis, LV major axis, 4 cavities, and T1 SPIR Gadolinium (early and late enhancement at 10 minutes).
MRI made the diagnosis of LVNC based on a double-layered myocardium, the inner (endocardium) non compacted, fibrillar thickened and the outer (epicardium) compacted thin with a non compacted to compacted myocardium ratio greater than 2.3, making the formal diagnosis.
Cardiac MRI is an excellent diagnostic tool for LVNC. Its recent use in Africa should be common in the management of this cardiomyopathy.
Mitochondrial Cardiomyopathies El-Hattab, Ayman W; Scaglia, Fernando
Frontiers in cardiovascular medicine,
07/2016, Letnik:
3
Journal Article
Recenzirano
Odprti dostop
Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small ...fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia.
Abstract
Background:
Left ventricular (LV) twist originates from the interaction between myocardial fibre helices that are formed during the formation of compact myocardium in the final stages of the ...development of myocardial architecture. Since non-compaction cardiomyopathy (NCCM) is probably caused by intrauterine arrest of this final stage, it may be anticipated that LV twist characteristics are altered in NCCM patients, beyond that seen in patients with impaired LV function and normal compaction.
Aims:
The purpose of this study was to assess LV twist characteristics in NCCM patients compared to patients with non-ischaemic dilated cardiomyopathy (DCM) and normal subjects.
Methods and results:
The study population consisted of 10 patients with NCCM, 10 patients with DCM, and 10 healthy controls. LV twist was determined by speckle tracking echocardiography. In all controls and DCM patients, rotation was clockwise at the basal level and counterclockwise at the apical level. In contrast, in all NCCM patients the LV base and apex rotated in the same direction.
Conclusions:
These findings suggest that 'LV solid body rotation', with near absent LV twist, may be a new sensitive and specific, objective and quantitative, functional diagnostic criterion for NCCM.
The
gene encodes a nuclear protein involved in transcriptional regulation, RNA synthesis and DNA repair. Hemizygous loss-of function,
or maternally inherited variants in
have been associated with an ...X-linked syndromic intellectual developmental disorder-34 (OMIM # 300967), characterized by developmental delay, intellectual disability, hypotonia, macrocephaly, elongated face, structural abnormalities of corpus callosum and/or cerebellum, congenital heart defect and left ventricular non-compaction cardiomyopathy. Few patients have been described in the literature and the phenotype data are limited. We report a 17-year-old boy with dolihocephaly, elongated face, strabismus, speech and motor delay, intellectual disability, congenital heart defect (ASD, VSD and Ebstein's anomaly), left ventricular non-compaction cardiomyopathy, bilateral inguinal hernia and cryptorchidism. Additional features included recurrent fractures due to multiple non-ossifying fibromas, thrombocytopenia, and renal anomalies. Exome sequencing revealed a
pathogenic variant (NM_001145408.2: c.348+2_ 348+15del) in intron 5 of the
gene. Renal anomalies and thrombocytopenia have been rarely reported in patients with
-X-linked intellectual disability syndrome, while recurrent fractures due to multiple non-ossifying fibromas have not previously been associated with this syndrome. The phenotypic spectrum of
-X-linked intellectual disability syndrome may be broader than currently known.
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