RESUMEN
Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle presented areas of fetal dispersion and resorptive degeneration; islands of conduction tissue were detected in the central fibrous body. Arcuate nucleus of the brainstem showed bilateral severe hypoplasia. The right bundle branch was hypoplastic. The final cause of death was an electrical conduction disfunction in an LVNC involving mainly the right ventricle. To the best of our knowledge, the herein described case is the first reported observation of sudden intrapartum death from LVNC involving mainly the right ventricle well documented post-mortem with cardiac conduction and brainstem studies. Our findings confirm the need of an accurate post-mortem examination including the study of the cardiac conduction system on serial section in every case of sudden unexpected fetal death, although there are no universally recognized guidelines.
Asunto(s)
Ventrículos Cardíacos , Mortinato , Humanos , Femenino , Embarazo , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/patología , Adulto , Autopsia , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/patología , Edad Gestacional , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Muerte FetalRESUMEN
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 , Femenino , Humanos , Lactante , Masculino , Cardiomiopatías/genética , Cardiomiopatías/patología , Secuenciación del Exoma , Ventrículos Cardíacos/patología , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Mutación Missense/genética , Miocardio/patología , Miocardio/metabolismo , Miocardio/ultraestructura , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Linaje , Pez Cebra/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin and SH3 domain-containing protein 2 (SORBS2) converges on the actin and microtubule cytoskeleton. Here, we investigated the proteins interacting with SORBS2 to elucidate the pathogenic mechanism of LVNC. As reported in previous studies, SORBS2 enhances the occurrence of LVNC by potentiating heart failure, but the specific mechanism remains unclear. METHODS: Building from our previous finding of elevated SORBS2 levels in LVNC hearts, we screened for proteins interacting with SORBS2 by proteomics and conducting IP experiments. Co-IP and immunofluorescence were used to verify the effects. RESULTS: We selected several proteins with high scores and high coverage that could be closely related to SORBS2 according to earlier reports showing a correlation with LVNC for verification. We finally obtained several proteins that were related to the pathogenesis of LVNC and also interacted with SORBS2, such as α-actinin, ß-tubulin, MYH7, FLNA, MYBPC3, YWHAQ and DES, and YWHAQ was the most associated. CONCLUSIONS: We focused on the YWHAQ protein, and we identified a novel mechanism through which SORBS2 interacts with YWHAQ, having a negative effect on the cell cycle, potentially leading to LVNC.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cardiomiopatías , Insuficiencia Cardíaca , No Compactación Aislada del Miocardio Ventricular , Proteínas de Unión al ARN/metabolismo , Animales , Cardiomiopatías/metabolismo , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/patología , Humanos , No Compactación Aislada del Miocardio Ventricular/complicaciones , No Compactación Aislada del Miocardio Ventricular/metabolismo , No Compactación Aislada del Miocardio Ventricular/patología , Ratones , Miocardio/patologíaRESUMEN
The ventricular walls of the human heart comprise an outer compact layer and an inner trabecular layer. In the context of an increased pre-test probability, diagnosis left ventricular noncompaction cardiomyopathy is given when the left ventricle is excessively trabeculated in volume (trabecular vol >25% of total LV wall volume) or thickness (trabecular/compact (T/C) >2.3). Here, we investigated whether higher spatial resolution affects the detection of trabeculation and thus the assessment of normal and excessively trabeculated wall morphology. First, we screened left ventricles in 1112 post-natal autopsy hearts. We identified five excessively trabeculated hearts and this low prevalence of excessive trabeculation is in agreement with pathology reports but contrasts the prevalence of approximately 10% of the population found by in vivo non-invasive imaging. Using macroscopy, histology and low- and high-resolution MRI, the five excessively trabeculated hearts were compared with six normal hearts and seven abnormally trabeculated and excessive trabeculation-negative hearts. Some abnormally trabeculated hearts could be considered excessively trabeculated macroscopically because of a trabecular outflow or an excessive number of trabeculations, but they were excessive trabeculation-negative when assessed with MRI-based measurements (T/C <2.3 and vol <25%). The number of detected trabeculations and T/C ratio were positively correlated with higher spatial resolution. Using measurements on high resolution MRI and with histological validation, we could not replicate the correlation between trabeculations of the left and right ventricle that has been previously reported. In conclusion, higher spatial resolution may affect the sensitivity of diagnostic measurements and in addition could allow for novel measurements such as counting of trabeculations.
Asunto(s)
Cardiomiopatías , No Compactación Aislada del Miocardio Ventricular , Corazón , Ventrículos Cardíacos/anatomía & histología , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Syndromic microphthalmia-9 (MCOPS9) is a rare autosomal recessive disorder caused by mutations in STRA6, an important regulator of vitamin A and retinoic acid metabolism. This disorder is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The clinical characteristics of this disorder have not been fully determined because of the rarity of clinical reports. METHODS: A comprehensive genotyping examination including copy number variation sequencing (CNV-Seq) and whole-exome sequencing (WES) was applied to a fetus of Han Chinese with bilateral anophthalmia, bilateral pulmonary agenesis, interrupted aortic arch type A, and left ventricular non-compaction (LVNC). RESULTS: No aneuploidy or pathogenic CNV were identified by CNV-seq. WES analysis revealed a previously reported homozygous splice site (NM_022369.4:c.113+3_113+4del) in the STRA6 gene. This variant was confirmed by Sanger sequencing. The diagnosis of MCOPS9 was confirmed given the identification of the STRA6 mutation and the association of bilateral anophthalmia, pulmonary agenesis, and cardiac malformations. CONCLUSION: This case adds to the phenotypic spectrum of MCOPS9, supporting the association with LVNC, and the presence of interruption of aortic arch further demonstrates the variability of the cardiac malformations.
Asunto(s)
Anoftalmos/genética , Enfermedades Fetales/genética , No Compactación Aislada del Miocardio Ventricular/genética , Enfermedades Pulmonares/genética , Proteínas de la Membrana/genética , Microftalmía/genética , Fenotipo , Adulto , Anoftalmos/diagnóstico por imagen , Anoftalmos/patología , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/patología , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/patología , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/patología , Microftalmía/diagnóstico por imagen , Microftalmía/patología , Embarazo , SíndromeRESUMEN
Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy characterised by excessive trabeculation and deep intertrabecular recesses in direct communication with the left ventricular cavity. In LVNC, hypertrabeculation has been associated with heart failure, ventricular arrhythmia, and systemic thromboembolism. However, hypertrabeculation alone is not sufficient to define a subject as at risk for such complications and thus should not be sufficient to diagnose LVNC. Despite several studies having investigated parameters to predict adverse cardiovascular events, physicians have no effective tools to differentiate between clinically silent hypertrabeculation and LVNC. The aim of this paper was to review literature on LVNC diagnostic criteria and to provide an easy and accessible diagnostic algorithm to distinguish between hypertrabeculation phenotype, non-compaction phenotype and LVNC cardiomyopathy.
Asunto(s)
No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Miocardio/patología , Función Ventricular Izquierda , Algoritmos , Diagnóstico Diferencial , Humanos , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , No Compactación Aislada del Miocardio Ventricular/terapia , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVE: Left ventricular non-compaction is an architectural abnormality of the myocardium, associated with heart failure, systemic thromboembolism, and arrhythmia. We sought to assess the prevalence of left ventricular non-compaction in patients with single ventricle heart disease and its effects on ventricular function. METHODS: Cardiac MRI of 93 patients with single ventricle heart disease (mean age 24 ± 8 years; 55% male) from three tertiary congenital centres was retrospectively reviewed; 65 of these had left ventricular morphology and are the subject of this report. The presence of left ventricular non-compaction was defined as having a non-compacted:compacted (NC:C) myocardial thickness ratio >2.3:1. The distribution of left ventricular non-compaction, ventricular volumes, and function was correlated with clinical data. RESULTS: The prevalence of left ventricular non-compaction was 37% (24 of 65 patients) with a mean of 4 ± 2 affected segments. The distribution was apical in 100%, mid-ventricular in 29%, and basal in 17% of patients. Patients with left ventricular non-compaction had significantly higher end-diastolic (128 ± 44 versus 104 ± 46 mL/m2, p = 0.047) and end-systolic left ventricular volumes (74 ± 35 versus 56 ± 35 mL/m2, p = 0.039) with lower left ventricular ejection fraction (44 ± 11 versus 50 ± 9%, p = 0.039) compared to those with normal compaction. The number of segments involved did not correlate with ventricular function (p = 0.71). CONCLUSIONS: Left ventricular non-compaction is frequently observed in patients with left ventricle-type univentricular hearts, with predominantly apical and mid-ventricular involvement. The presence of non-compaction is associated with increased indexed end-diastolic volumes and impaired systolic function.
Asunto(s)
No Compactación Aislada del Miocardio Ventricular/diagnóstico , Corazón Univentricular/diagnóstico , Adolescente , Adulto , Femenino , Humanos , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Imagen por Resonancia Cinemagnética , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Volumen Sistólico , Sístole , Corazón Univentricular/patología , Corazón Univentricular/fisiopatología , Función Ventricular Izquierda , Adulto JovenRESUMEN
Left ventricular non-compaction (LVNC) is defined by an increase of trabeculations in left ventricular endo-myocardium. Although LVNC can be in isolation, an increase in hypertrabeculation often accompanies genetic cardiomyopthies. Several enhancements are proposed and implemented to improve a software tool for the automatic quantification of the exact hyper-trabeculation degree in the left ventricular myocardium for a population of patients with LVNC cardiomyopathy (QLVTHC-NC). The software tool is developed and evaluated for a population of 18 patients (133 cardiac images). An end-diastolic cardiac magnetic resonance images of the patients are the input of the software, whereas the left ventricular mass, volumes and proportion of trabeculation produced by the compacted zone and the trabeculated zone are the outputs. Significant improvements are obtained with respect to the manual process, so saving valuable diagnosis time. Comparing the method proposed with the fractal proposal to differentiate LVNC and non-LVNC patients in subjects with previously diagnosed LVNC cardiomyophaty, QLVTHC-NC presents higher diagnostic accuracy and lower complexity and cost than the fractal criterio.
Asunto(s)
Cardiomiopatías/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Corazón/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Ventrículos Cardíacos/fisiopatología , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las PruebasRESUMEN
Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Pulmonary capillary hemangiomatosis (PCH) is a rare disease that causes uncontrollable proliferation of pulmonary capillaries. We experienced a 52-year-old man who was diagnosed with LVNC about 8â¯years previously who subsequently died of heart failure. The major autopsy findings were enlargement of the heart with prominent trabeculations and deep intertrabecular recesses in the apical and middle regions of the left ventricular wall. The mean ratio of noncompacted to compacted layers was 2.4. In the lung, thickened alveolar walls with numerous pulmonary capillaries were evident, findings very similar to PCH. PCH-like lesions and LVNC may have coexisted coincidentally, and both, or either of them, may have contributed to the development of his pulmonary hypertension.
Asunto(s)
Capilares/patología , Hemangioma Capilar/patología , No Compactación Aislada del Miocardio Ventricular/patología , Neoplasias Pulmonares/patología , Pulmón/irrigación sanguínea , Causas de Muerte , Resultado Fatal , Hemangioma Capilar/complicaciones , Humanos , Hipertensión Pulmonar/etiología , No Compactación Aislada del Miocardio Ventricular/complicaciones , Neoplasias Pulmonares/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
Although echocardiography can be used to detect patients with non-compaction of the ventricular myocardium, it is often difficult to diagnose. In this study, the endocardium may be clearly visualized by contrast echocardiography to improve the diagnostic accuracy of patients with noncompaction of the ventricular myocardium. Twenty-four patients (n = 24) suspected with non-compaction of the ventricular myocardium Underwent transthoracic echocardiography including an intracardiac contrast echocardiography. The clinical data, Left ventricular opacification, and contrast echocardiography results were analyzed retrospectively. Twenty-four patients (n = 24) suspected with non-compaction of the ventricular myocardium were classified with transthoracic echocardiography and contrast echocardiography results into two groups: false positive and true positive. There were no significant differences in age, predisposing segments, Left Ventricular End-Diastolic Diameter, Left Ventricular End-Diastolic Volume, Left Ventricular End-Systolic Diameter, Left Ventricular End-Systolic Volume and ejection fraction between the two groups (P>0.05). The thickness ratio of noncompacted to compacted myocardium (N/C) in the true positive group was significantly higher than that in the false positive group (3.47 ± 1.31 vs. 4.96 ± 1.28; P<0.05). The range of noncompact myocardium in non-compaction of the ventricular myocardium patients can be observed clearly by Left ventricular opacification. Contrast medium in trabecular space and crypt is plentiful and ultrasonic contrast is more objective in measuring the thickness of dense myocardium. Two-dimensional echocardiography plays a characteristic role in the diagnosis of non-compaction of the ventricular myocardium; however, some suspected patients were observed to be false positive. Left ventricular opacification can greatly improve the clarity and accuracy of the endocardial margin by enhancing left ventricular imaging, displaying the true dense and non-dense layers, and improve the accuracy of ultrasonic diagnosis of non-compaction of the ventricular myocardium. The purpose of this paper was to explore the applied value of contrast echocardiography for heart diagnosis.
Asunto(s)
Medios de Contraste/administración & dosificación , Errores Diagnósticos , Ecocardiografía , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Adulto , Diagnóstico Diferencial , Reacciones Falso Positivas , Femenino , Humanos , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las Pruebas , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Left ventricular non-compaction (LVNC) is a heritable cardiomyopathy characterized by hypertrabeculation, inter-trabecular recesses and thin compact myocardium, but the genetic basis and mechanisms remain unclear. This study identified novel LVNC-associated mutations inNOTCH-dependent genes and investigated their mutational effects.MethodsâandâResults:High-resolution melting screening was performed in 230 individuals with LVNC, followed by whole exome and Sanger sequencing of available family members. Dimerization of bone morphogenetic protein 10 (BMP10) and its binding to BMP receptors (BMPRs) were evaluated. Cellular differentiation, proliferation and tolerance to mechanical stretch were assessed in H9C2 cardiomyoblasts, expressing wild-type (WT) or mutant BMP10 delivered by adenoviral vectors. Rare variants, p.W143*-NRG1and p.V407I-BMP10, were identified in 2 unrelated probands and their affected family members. Although dimerization of mutant V407I-BMP10 was preserved like WT-BMP10, V407I-BMP10 pulled BMPR1a and BMPR2 receptors more weakly compared with WT-BMP10. On comparative gene expression and siRNA analysis, expressed BMPR1a and BMPR2 receptors were responsive to BMP10 treatment in H9C2 cardiomyoblasts. Expression of V407I-BMP10 resulted in a significantly lower rate of proliferation in H9C2 cells compared with WT-BMP10. Cyclic stretch resulted in destruction and death of V407I-BMP10 cells. CONCLUSIONS: The W143*-NRG1and V470I-BMP10variants are associated with LVNC. Impaired BMPR-binding ability, perturbed proliferation and differentiation processes and intolerance to stretch in V407I-BMP10 mutant cardiomyoblasts may underlie myocardial non-compaction.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Miocitos Cardíacos/metabolismo , Polimorfismo de Nucleótido Simple , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Estudios de Casos y Controles , Diferenciación Celular , Proliferación Celular , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , No Compactación Aislada del Miocardio Ventricular/metabolismo , No Compactación Aislada del Miocardio Ventricular/patología , Masculino , Mecanotransducción Celular , Ratones , Miocitos Cardíacos/patología , Fenotipo , Unión Proteica , RatasRESUMEN
BACKGROUND: The definition of left ventricular (LV) non-compaction is controversial, and discriminating between normal and excessive LV trabeculation remains challenging. Our goal was to quantify LV trabeculation on cardiovascular magnetic resonance (CMR) images in a genetic mouse model of non-compaction using a dedicated semi-automatic software package and to compare our results to the histology used as a gold standard. METHODS: Adult mice with ventricular non-compaction were generated by conditional trabecular deletion of Nkx2-5. Thirteen mice (5 controls, 8 Nkx2-5 mutants) were included in the study. Cine CMR series were acquired in the mid LV short axis plane (resolution 0.086 × 0.086x1mm3) (11.75 T). In a sub set of 6 mice, 5 to 7 cine CMR were acquired in LV short axis to cover the whole LV with a lower resolution (0.172 × 0.172x1mm3). We used semi-automatic software to quantify the compacted mass (Mc), the trabeculated mass (Mt) and the percentage of trabeculation (Mt/Mc) on all cine acquisitions. After CMR all hearts were sliced along the short axis and stained with eosin, and histological LV contouring was performed manually, blinded from the CMR results, and Mt, Mc and Mt/Mc were quantified. Intra and interobserver reproducibility was evaluated by computing the intra class correlation coefficient (ICC). RESULTS: Whole heart acquisition showed no statistical significant difference between trabeculation measured at the basal, midventricular and apical parts of the LV. On the mid-LV cine CMR slice, the median Mt was 0.92 mg (range 0.07-2.56 mg), Mc was 12.24 mg (9.58-17.51 mg), Mt/Mc was 6.74% (0.66-17.33%). There was a strong correlation between CMR and the histology for Mt, Mc and Mt/ Mc with respectively: r2 = 0.94 (p < 0.001), r2 = 0.91 (p < 0.001), r2 = 0.83 (p < 0.001). Intra- and interobserver reproducibility was 0.97 and 0.8 for Mt; 0.98 and 0.97 for Mc; 0.96 and 0.72 for Mt/Mc, respectively and significantly more trabeculation was observed in the Mc Mutant mice than the controls. CONCLUSION: The proposed semi-automatic quantification software is accurate in comparison to the histology and reproducible in evaluating Mc, Mt and Mt/ Mc on cine CMR.
Asunto(s)
Ventrículos Cardíacos/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos , Miocardio/patología , Animales , Automatización , Biopsia , Modelos Animales de Enfermedad , Ventrículos Cardíacos/patología , Proteína Homeótica Nkx-2.5/deficiencia , Proteína Homeótica Nkx-2.5/genética , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Ratones Noqueados , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosAsunto(s)
Anomalías Cardiovasculares/diagnóstico , Predisposición Genética a la Enfermedad/genética , Adulto , Miosinas Cardíacas/genética , Anomalías Cardiovasculares/genética , Anomalías Cardiovasculares/patología , Proteínas Portadoras/genética , Pruebas Genéticas , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Uso Excesivo de los Servicios de Salud , Cadenas Pesadas de Miosina/genéticaRESUMEN
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Insuficiencia Cardíaca/genética , Ventrículos Cardíacos/embriología , Proteína Homeótica Nkx-2.5/metabolismo , No Compactación Aislada del Miocardio Ventricular/genética , Morfogénesis/genética , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Perfilación de la Expresión Génica , Ventrículos Cardíacos/patología , Proteína Homeótica Nkx-2.5/genética , Proteínas de Homeodominio/metabolismo , Humanos , No Compactación Aislada del Miocardio Ventricular/complicaciones , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/patología , Ratones , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Ramos Subendocárdicos/patología , Eliminación de Secuencia , Índice de Severidad de la Enfermedad , Regulación hacia ArribaAsunto(s)
No Compactación Aislada del Miocardio Ventricular/diagnóstico , Miocardio/patología , Enfermedades Neuromusculares/diagnóstico , Errores Diagnósticos , Predisposición Genética a la Enfermedad , Humanos , No Compactación Aislada del Miocardio Ventricular/epidemiología , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Enfermedades Neuromusculares/epidemiología , Enfermedades Neuromusculares/genética , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Derivación y ConsultaRESUMEN
Ehlers-Danlos Syndrome comprises a heterogeneous group of heritable connective tissue disorders resulting from various gene mutations. We present an unusual case of vascular Ehlers-Danlos Syndrome with distinctive physical characteristics and a cardiomyopathy with features suggesting isolated left ventricular non-compaction. The cardiac features represent the first report of a cardiomyopathy associated with a mutation in the COL3A1 gene. This case also illustrates the multi-system nature of Ehlers-Danlos Syndrome and the complexity of managing patients with the vascular subtype.
Asunto(s)
Síndrome de Ehlers-Danlos/patología , No Compactación Aislada del Miocardio Ventricular/patología , Miocardio/patología , Adulto , Colágeno Tipo III/genética , Análisis Mutacional de ADN , Ecocardiografía , Síndrome de Ehlers-Danlos/tratamiento farmacológico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , No Compactación Aislada del Miocardio Ventricular/tratamiento farmacológico , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Imagen por Resonancia Magnética , Masculino , Mutación , Fenotipo , Resultado del TratamientoRESUMEN
BACKGROUND: Mutations of α-actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts. METHODS AND RESULTS: In an Italian family of 7 subjects, 4 aged 10 (II-1), 14 (II-2), 43 (I-4) and 46 years (I-5), presenting abnormal ECG changes, dyspnea and palpitation (II-2, I-4, and I-5), and recurrent cerebral ischemic attack (I-5), underwent 2-dimensional echo, cardiac magnetic resonance, Holter monitoring, and next-generation sequencing gene analysis. Patients II-2 and I-5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age-related prolongation of QRS duration. Two-dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I-4, I-5, and II-2 a progressive LV hypertrophy up to 22-mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next-generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC. CONCLUSIONS: Novel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.
Asunto(s)
Actinas/genética , Cardiomiopatía Hipertrófica Familiar/genética , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Miocardio/patología , Adolescente , Adulto , Biopsia , Isquemia Encefálica/genética , Isquemia Encefálica/patología , Cardiomiopatía Hipertrófica Familiar/diagnóstico por imagen , Cardiomiopatía Hipertrófica Familiar/patología , Cardiomiopatía Hipertrófica Familiar/terapia , Niño , Angiografía Coronaria , Análisis Mutacional de ADN , Ecocardiografía , Electrocardiografía Ambulatoria , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Herencia , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/terapia , Italia , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Miocardio/ultraestructura , Linaje , Fenotipo , Pronóstico , Recurrencia , Taquicardia Ventricular/genética , Taquicardia Ventricular/patologíaAsunto(s)
Medios de Contraste/administración & dosificación , Ecocardiografía , Fluorocarburos/administración & dosificación , Ventrículos Cardíacos/diagnóstico por imagen , No Compactación Aislada del Miocardio Ventricular/diagnóstico por imagen , Miocardio/patología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , No Compactación Aislada del Miocardio Ventricular/patología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Imagen por Resonancia Magnética , Masculino , Microburbujas , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Función Ventricular IzquierdaRESUMEN
A definitively diagnosed case of left ventricular noncompaction (LVNC) has not been previously reported in a non-human species. We describe a Maine Coon cross cat with echocardiographically and pathologically documented LVNC. The cat was from a research colony and was heterozygous for the cardiac myosin binding protein C mutation associated with hypertrophic cardiomyopathy (HCM) in Maine Coon cats (A31P). The cat had had echocardiographic examinations performed every 6 months until 6 years of age at which time the cat died of an unrelated cause. Echocardiographic findings consistent with LVNC (moth-eaten appearance to the inner wall of the mid- to apical region of the left ventricle (LV) in cross section and trabeculations of the inner LV wall that communicated with the LV chamber) first were identified at 2 years of age. At necropsy, pathologic findings of LVNC were verified and included the presence of noncompacted myocardium that consisted of endothelial-lined trabeculations and sinusoids that constituted more than half of the inner part of the LV wall. The right ventricular (RV) wall also was affected. Histopathology identified myofiber disarray, which is characteristic of HCM, although heart weight was normal and LV wall thickness was not increased.
Asunto(s)
Cardiomiopatía Hipertrófica/veterinaria , Enfermedades de los Gatos/patología , Ventrículos Cardíacos/patología , No Compactación Aislada del Miocardio Ventricular/veterinaria , Animales , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Enfermedades de los Gatos/genética , Gatos , Ecocardiografía/veterinaria , No Compactación Aislada del Miocardio Ventricular/genética , No Compactación Aislada del Miocardio Ventricular/patología , Masculino , MutaciónRESUMEN
BACKGROUND: Ventricular noncompaction is characterized by excessive trabeculations and is associated with heart failure. The lesion is hypothesized to result from failed compaction and thus retention of embryonic trabeculations. Here, we assess for the first time the identity of trabeculations in noncompaction to test whether noncompacted hearts show retention of embryonic trabeculations. METHODS: Using immunohistochemistry, we analyzed cardiac sections of the heart of a control embryo, 3 cases of fetal noncompaction (a set of twins and an unrelated fetus) and 3 fetal hearts without noncompaction. RESULTS: In the embryo, the ventricular trabeculations strongly expressed ANF/NPPA whereas the compact wall did not. In the noncompaction hearts, trabeculations constituted an excessively thick layer. In noncompaction and control fetal hearts alike, however, only a miniscule subset of sub-endocardial myocardium of the trabeculations most proximal to the central ventricular lumen exhibited strong expression of ANF/NPPA, representing Purkinje myocardium. The trabeculations of both fetal control and noncompaction hearts were ANF-negative and orders of magnitude wider than those of the embryo. Both the compact and noncompaction trabeculated myocardium were rich in coronary vasculature. Like embryonic trabeculations, the ANF+ Purkinje myocardium had little if any vasculature. CONCLUSION: The excessive trabeculations in noncompaction do not have the embryonic identity and noncompaction is probably not the result of failed compaction. We propose the lesion results from the compact wall growing into the ventricular lumen in a trabecular fashion.