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1.
J Genet Genomics ; 51(5): 543-553, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38181896

RESUMEN

Noncompaction of the ventricular myocardium (NVM), the third most diagnosed cardiomyopathy, is characterized by prominent trabeculae and intratrabecular recesses. However, the genetic etiology of 40%-60% of NVM cases remains unknown. Here, we identify two infants with NVM, in a nonconsanguineous family, with a typical clinical presentation of persistent bradycardia since the prenatal period. A homozygous missense variant (R223L) of RCAN family member 3 (RCAN3) is detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction is detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan-/- embryos. Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNAs rescue these phenotypes. RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency results in reduced proliferation and increased apoptosis, together with an abnormal mitochondrial ultrastructure. Thus, we suggest that RCAN3 is a susceptibility gene for cardiomyopathies, especially NVM and that the R223L mutation is a potential loss-of-function variant.


Asunto(s)
Pez Cebra , Animales , Humanos , Pez Cebra/genética , Masculino , Femenino , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Mutación Missense/genética , Linaje , Lactante , Cardiomiopatías/genética , Cardiomiopatías/patología , Miocardio/patología , Miocardio/metabolismo , Miocardio/ultraestructura , Ventrículos Cardíacos/patología , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Secuenciación del Exoma
2.
BMC Cardiovasc Disord ; 23(1): 352, 2023 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-37460987

RESUMEN

BACKGROUND: Left ventricular noncompaction (LVNC) is a specific type of cardiomyopathy characterized by coarse trabeculae and interspersed trabecular crypts within the ventricles. Clinical presentation varies widely and may be nonsignificant or may present with progressive heart failure, malignant arrhythmias, and multiorgan embolism. The mode of inheritance is highly heterogeneous but is most commonly autosomal dominant. The TTN gene encodes titin, which is not only an elastic component of muscle contraction but also mediates multiple signalling pathways in striated muscle cells. In recent years, mutations in the TTN gene have been found to be associated with LVNC, but the exact pathogenesis is still not fully clarified. CASE PRESENTATION: In this article, we report a case of an adult LVNC patient with a TTN gene variant, c.87857G > A (p. Trp29286*), that has not been reported previously. This 43-year-old adult male was hospitalized repeatedly for heart failure. Echocardiography showed reduced myocardial contractility, dilated left ventricle with many prominent trabeculae, and a loose texture of the left ventricular layer of myocardium with crypt-like changes. During the out-of-hospital follow-up, the patient had no significant signs or symptoms of discomfort. CONCLUSION: This case report enriches the mutational spectrum of the TTN gene in LVNC and provides a basis for genetic counselling and treatment of this patient. Clinicians should improve their understanding of LVNC, focusing on exploring its pathogenesis and genetic characteristics to provide new directions for future diagnosis and treatment.


Asunto(s)
Cardiopatías Congénitas , Insuficiencia Cardíaca , No Compactación Aislada del Miocardio Ventricular , Adulto , Humanos , Masculino , Ventrículos Cardíacos/patología , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Conectina/genética
3.
Circ Res ; 133(1): 48-67, 2023 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-37254794

RESUMEN

BACKGROUND: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. METHODS: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I, with congenital heart defects. We engineered a humanized mouse model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. RESULTS: CHD4M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. CONCLUSIONS: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.


Asunto(s)
No Compactación Aislada del Miocardio Ventricular , Mutación Missense , Humanos , Animales , Niño , Ratones , Ventrículos Cardíacos , Causalidad , Mutación , Miocitos Cardíacos , Cromatina , No Compactación Aislada del Miocardio Ventricular/genética , Proteína ADAMTS1/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética
4.
Genes (Basel) ; 13(10)2022 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-36292635

RESUMEN

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.


Asunto(s)
Cardiomiopatías , No Compactación Aislada del Miocardio Ventricular , Humanos , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Corazón , Mutación Missense , Cadenas Pesadas de Miosina/genética , Miosinas Cardíacas/genética
5.
Circ Genom Precis Med ; 15(3): e003517, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35549379

RESUMEN

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.


Asunto(s)
Cardiomiopatías , Cardiomiopatía Dilatada , No Compactación Aislada del Miocardio Ventricular , Animales , Cardiomiopatías/genética , Niño , Humanos , No Compactación Aislada del Miocardio Ventricular/genética , Fenotipo , Sarcómeros
6.
Genes (Basel) ; 13(2)2022 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-35205353

RESUMEN

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype-phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations.


Asunto(s)
Cardiomiopatías , Cardiomiopatía Hipertrófica , Cardiopatías Congénitas , No Compactación Aislada del Miocardio Ventricular , Cardiomiopatías/genética , Cardiomiopatía Hipertrófica/complicaciones , Forminas , Cardiopatías Congénitas/patología , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/genética , Miocardio
8.
Int Heart J ; 62(6): 1420-1429, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34853230

RESUMEN

Left ventricular noncompaction cardiomyopathy (LVNC) is a heart muscle disorder morphologically characterized by reticulated trabeculations and intertrabecular recesses in the left ventricular (LV) cavity. LVNC is a genetically and phenotypically heterogeneous condition, which has been increasingly recognized with the accumulation of evidence provided by genotype-phenotype correlation analyses. Here, we report 2 sporadic adult cases of LVNC; both developed acute heart failure as an initial clinical manifestation and harbored causal sarcomere gene mutations. One case was a 57-year-old male with digenic heterozygote mutations, p.R1344Q in myosin heavy chain 7 (MYH7) and p.R144W in troponin T2, cardiac type (TNNT2), who showed morphological characteristics of LVNC in the lateral to apical regions of the LV together with a comorbidity of non-transmural myocardial infarction, resulting from a coronary artery stenosis. After the removal of ischemic insult and standard heart failure treatment, LVNC became less clear, and LV function gradually improved. The other case was a 36-year-old male with a heterozygote mutation, p.E334K in myosin binding protein C3 (MYBPC3), who exhibited cardiogenic shock on admission with morphological characteristics of LVNC being most prominent in the apical segment of the LV. The dosage of beta-blocker was deliberately increased in an outpatient clinic over 6 months following hospitalization, which remarkably improved the LV ejection fraction from 21% to 54.3%. Via a combination of imaging and histopathological and genetic tests, we have found that these cases are not compatible with a persistent phenotype of primary cardiomyopathy, but their morphological features are changeable in response to treatment. Thus, we point out phenotypic plasticity or undulation as a noticeable element of LVNC in this case report.


Asunto(s)
No Compactación Aislada del Miocardio Ventricular/diagnóstico , Enfermedad Aguda , Adulto , Miosinas Cardíacas/genética , Proteínas Portadoras/genética , Insuficiencia Cardíaca/etiología , Heterocigoto , Humanos , No Compactación Aislada del Miocardio Ventricular/genética , Masculino , Persona de Mediana Edad , Mutación , Cadenas Pesadas de Miosina/genética , Fenotipo , Choque Cardiogénico/etiología , Troponina T/genética
9.
J Am Coll Cardiol ; 78(7): 643-662, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-34384546

RESUMEN

BACKGROUND: Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. OBJECTIVES: This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. METHODS: This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. RESULTS: A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. CONCLUSIONS: LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.


Asunto(s)
Arritmias Cardíacas/epidemiología , Embolia/epidemiología , Insuficiencia Cardíaca/epidemiología , No Compactación Aislada del Miocardio Ventricular/mortalidad , Modelación Específica para el Paciente , Adulto , Anciano , Arritmias Cardíacas/etiología , Embolia/etiología , Femenino , Insuficiencia Cardíaca/etiología , Humanos , No Compactación Aislada del Miocardio Ventricular/complicaciones , No Compactación Aislada del Miocardio Ventricular/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , España/epidemiología , Adulto Joven
10.
J Card Fail ; 27(6): 677-681, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34088380

RESUMEN

BACKGROUND: Few data exist concerning genotype-phenotype relationships in left ventricular noncompaction (LVNC). METHODS AND RESULTS: From a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients with LVNC, and their genotype-phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate. CONCLUSIONS: Ion channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.


Asunto(s)
Insuficiencia Cardíaca , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , No Compactación Aislada del Miocardio Ventricular , Proteínas Musculares/genética , Canales de Potasio/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Genotipo , Humanos , Canales Iónicos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Fenotipo , Función Ventricular Izquierda
13.
Can J Cardiol ; 37(11): 1864-1866, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33984427

RESUMEN

Two siblings presented with early lethal noncompaction cardiomyopathy (NCCM). Both carry compound heterozygous variants in the ryanodine receptor gene (RYR2). Evolving animal and human data have begun to implicate a role for RYR2 dysfunction in the development of NCCM. The identified RYR2 variants are therefore likely causative for this early lethal NCCM phenotype. Further research is needed to understand the role of RYR2 in the heart compaction process.


Asunto(s)
ADN/genética , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Canal Liberador de Calcio Receptor de Rianodina/genética , Hermanos , Adulto , Análisis Mutacional de ADN , Ecocardiografía , Electrocardiografía , Resultado Fatal , Femenino , Humanos , Recién Nacido , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/metabolismo , Masculino , Linaje , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo
15.
Curr Opin Cardiol ; 36(3): 301-308, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33605617

RESUMEN

PURPOSE OF REVIEW: This article summarises current understanding of the genetic architecture underpinning left ventricular noncompaction (LVNC) and highlights the difficulty in differentiating LVNC from hypertrabeculation seen in normal, healthy individuals, that caused by physiological adaptation or that seen in association with cardiomyopathy phenotypes. RECENT FINDINGS: Progress has been made in better defining the LVNC phenotype and those patients who may benefit from genetic testing. Yield of diagnostic genetic testing may be low in the absence of syndromic features, systolic dysfunction and a family history of cardiomyopathy. Sarcomeric gene variants are most commonly identified but a wide-range of genes are implicated, emphasising the high degree of heterogeneity of studied cohorts. SUMMARY: More accurate phenotyping and genotype-phenotype correlation are required to better characterise the genetic architecture of LVNC.


Asunto(s)
Cardiomiopatías , No Compactación Aislada del Miocardio Ventricular , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Estudios de Asociación Genética , Pruebas Genéticas , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/genética , Fenotipo
16.
Genes (Basel) ; 12(1)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33478057

RESUMEN

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.


Asunto(s)
Cardiomiopatía Dilatada/genética , Desmina/genética , No Compactación Aislada del Miocardio Ventricular/genética , Adolescente , Adulto , Cardiomiopatía Dilatada/diagnóstico , Línea Celular , Análisis Mutacional de ADN , Desmina/metabolismo , Desmoplaquinas/genética , Femenino , Pruebas Genéticas , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , Imagen por Resonancia Magnética , Masculino , Mutagénesis Sitio-Dirigida , Mutación , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Federación de Rusia
17.
Int J Cardiovasc Imaging ; 37(2): 429-438, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32897524

RESUMEN

In non-compaction cardiomyopathy (NCCM), there are several echocardiographic and cardiac magnetic resonance (CMR)-based quantitative diagnostic indices, current criteria mainly placed on morphological features, and none of the diagnostic indices includes left ventricular (LV) function. LV function and hemodynamics could be normal in NCCM patients. Evaluation of left ventricular function at the subclinical stage, strain echocardiographic parameters could be used alternative to standard echocardiographic examinations. The aim of this study to evaluate; NCCM patients, their first-degree relatives, ventricular motion patterns, strain characteristics, and the predictive capabilities of these features for early diagnosis of cardiomyopathy. This cross-sectional, case-control study included 32 NCCM patients, 30 first-degree relatives (father, mother, siblings and children) and 31 healthy volunteers. All patients evaluated with baseline echocardiography, strain measurements, and ventricular wall motion pattern. There were no differences between the groups in terms of age, weight, and body surface area. We observed a statistically significant decrease in ejection fraction (EF), fractional shortening (FS), E/E' and global strain values in patients' relatives compared to healthy volunteers (Patients' relatives: LVEF:60.9 ± 7.2%, FS:0.34 ± 0.07, E/E':7.51 ± 1.83, GLS: - 18.6 ± 3.6, GLSr: - 1.1 ± 0.1, GCS: - 17.1 ± 3.1, GCSr: - 1.2 ± 0.1, GRS:37.1 ± 6.2, GRSr:1.7 ± 0.1; all p values< 0.05). 'Rigid Body Rotation (RBR)' movement pattern was also observed in some of the patient's relative's like in the patients. RBR movement pattern determined patients; EF, longitudinal strain-strain rate, and basal layer rotation values were significantly lower, but radial strain values were higher with the RBR movement pattern (for all values p < 0.05). RBR movement pattern, deterioration of strain parameters, and accompanying echocardiographic features like LVEF, fractional shortening (FS), E/E' in patients' relative groups may contribute to reveal the subclinical status of disease and could be predictive for early diagnosis of cardiomyopathy.


Asunto(s)
Cardiomiopatías/diagnóstico por imagen , Ecocardiografía Doppler , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Volumen Sistólico , Función Ventricular Izquierda , Adulto , Fenómenos Biomecánicos , Cardiomiopatías/genética , Cardiomiopatías/fisiopatología , Estudios de Casos y Controles , Estudios Transversales , Diagnóstico Precoz , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Torsión Mecánica , Adulto Joven
18.
Andes Pediatr ; 92(5): 667-676, 2021 Oct.
Artículo en Español | MEDLINE | ID: mdl-35319572

RESUMEN

Left ventricular non-compaction (LVNC) and restrictive cardiomyopathies (RCM) are rare diseases with high morbidity and mortality in the pediatric age group, particularly the restrictive. They can be diagnosed at any age even in fetal life, in isolation or association with other cardiomyopathies or congenital heart disease. The causes may be genetic, neuromuscular, metabolic, storage, or idiopathic disorders. The main morphological characteristic of LVNC is the presence of a non-compact myocar dium with numerous prominent trabeculations and deep recesses, which may results in myocardial dysfunction, malignant arrhythmias and thromboembolism. On the other hand, in RCM there is an abnormal myocardial stiffness, which generates a restrictive ventricular filling and atrial dilatation secondary. Clinically it manifested by severe diastolic dysfunction, pulmonary hypertension, arrhyth mias and sudden death. For both cardiomyopathies, the Doppler color echocardiography, electro cardiography and Holter monitoring of arrhythmias are the gold standard for diagnosis and follow up. Cardiac resonance adds information on functional assessment and quantification of myocardial fibrosis. The therapy is oriented to improve symptoms and quality of life. Patients with severe forms of LVNC and RCM may require extracorporeal ventricular support and cardiac transplantation, even in early stages of the disease. The pediatrician plays an important role in the early recognition of these pathologies for timing to referral as well as in the follow-up and screening for complications. The objective of this review is to update the clinical, genetic, diagnostic, therapeutic issues and prognostic of the LVNC and RCM.


Asunto(s)
Cardiomiopatías , Cardiomiopatía Restrictiva , No Compactación Aislada del Miocardio Ventricular , Pediatría , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Cardiomiopatía Restrictiva/complicaciones , Cardiomiopatía Restrictiva/diagnóstico , Cardiomiopatía Restrictiva/terapia , Niño , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/terapia , Calidad de Vida
19.
Int J Cardiol ; 328: 122-129, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33309763

RESUMEN

BACKGROUND: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy, associated with high morbidity and mortality, but the role of genetics in cases of fetal-onset has not been fully evaluated. The goal of this study was to identify the genetic background in LVNC fetal-onset patients using next-generation sequencing (NGS). METHODS: Thirty-three fetal-onset Japanese probands with LVNC (20 males and 13 females) were enrolled. In the enrolled patients, 81 genes associated with cardiomyopathy were screened using next-generation sequencing (NGS) retrospectively. RESULTS: Twenty-three patients had congestive heart failure (CHF), and six patients had arrhythmias. Prominent trabeculations were mostly observed in lateral LV, posterior LV, and apex of LV in patients with LVNC. Twelve died; three patients experienced intrauterine death or termination of pregnancy. Overall, 15 variants were found among eight genes in 16 patients. Seven variants were detected in MYH7 and two in TPM1. Sarcomere gene variants accounted for 75.0%. A multivariable proportional hazards model revealed that CHF at diagnosis and a higher ratio of the noncompacted layer/compacted layer in the LV posterior wall were independent risk factors for death in LVNC fetal-onset patients (odds ratio = 4.26 × 106 and 1.36 × 108, p = 0.0075 and 0.0005, respectively). CONCLUSIONS: The present study is the first report focusing on genetic background combined with clinical features in LVNC fetal-onset patients using NGS. Sarcomere variants were most commonly identified in fetal-onset patients, and greater attention should be paid to fetal-onset patients with LVNC having prominent trabeculations in the LV because they are more likely to develop CHF.


Asunto(s)
Cardiopatías Congénitas , No Compactación Aislada del Miocardio Ventricular , Femenino , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/genética , Masculino , Embarazo , Estudios Retrospectivos , Sarcómeros/genética , Función Ventricular Izquierda
20.
Circ Arrhythm Electrophysiol ; 13(10): e008712, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32755394

RESUMEN

BACKGROUND: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. METHODS: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). RESULTS: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. CONCLUSIONS: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.


Asunto(s)
Cardiomiopatías/genética , Enfermedades Genéticas Congénitas/genética , Atrios Cardíacos/anomalías , Bloqueo Cardíaco/genética , No Compactación Aislada del Miocardio Ventricular/genética , Proteínas de la Membrana/genética , Mutación , Proteínas Nucleares/genética , Accidente Cerebrovascular/etiología , Tromboembolia/etiología , Distrofia Muscular de Emery-Dreifuss Ligada a X/genética , Adolescente , Adulto , Anciano , Trastorno del Sistema de Conducción Cardíaco/complicaciones , Trastorno del Sistema de Conducción Cardíaco/diagnóstico , Trastorno del Sistema de Conducción Cardíaco/genética , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Niño , Femenino , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades Genéticas Congénitas/diagnóstico , Predisposición Genética a la Enfermedad , Bloqueo Cardíaco/complicaciones , Bloqueo Cardíaco/diagnóstico , Humanos , No Compactación Aislada del Miocardio Ventricular/complicaciones , No Compactación Aislada del Miocardio Ventricular/diagnóstico , Masculino , Persona de Mediana Edad , Fenotipo , Síndrome del Seno Enfermo/complicaciones , Síndrome del Seno Enfermo/genética , Accidente Cerebrovascular/diagnóstico por imagen , Tromboembolia/diagnóstico por imagen , Distrofia Muscular de Emery-Dreifuss Ligada a X/complicaciones , Distrofia Muscular de Emery-Dreifuss Ligada a X/diagnóstico , Adulto Joven
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