RESUMEN
Pulmonary arterial hypertension (PAH) is a well-known complication of congenital heart disease (CHD). The lack of a satisfactory animal model for PAH associated with CHD (PAH-CHD) has limited progress in understanding the pathogenesis of PAH and the development of therapeutic agents. The development of a rat model for PAH associated with atrial septal defect (ASD) was achieved through atrial septal puncture and thermal ablation. Two and 4 weeks after modeling, hematoxylin and eosin staining showed that the vascular thickness, vascular thickness index, vascular area, and vascular area index in pulmonary arteries with an outer diameter of 50-300 µm in the PAH-ASD 2 and 4 weeks group were higher than those in the sham group (all P < 0.05). Alpha-smooth muscle actin (É-SMA) staining showed that the medial thickness, medial thickness index, medial area, and medial area index in pulmonary arteries with an outer diameter of 50-300 µm at 2 and 4 weeks after modeling were significantly higher than those in the sham group (all P < 0.05). Additionally, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in the PAH-ASD 2 and 4 weeks groups were significantly higher than those in the sham group (both P < 0.05). Elastin van Gieson staining showed that the vascular obstruction score in the PAH-ASD 2 and 4 weeks group was significantly higher than that in the sham group (both P < 0.05). The PAH-ASD rats were successfully generated. These findings suggest that our model would be useful for further research into the pathogenesis, prevention, and treatment of PAH-ASD.
Asunto(s)
Modelos Animales de Enfermedad , Defectos del Tabique Interatrial , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Animales , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interatrial/fisiopatología , Ratas , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Masculino , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Ratas Sprague-Dawley , Resistencia VascularRESUMEN
The development of a fully functional four-chambered heart is critically dependent on the correct formation of the structures that separate the atrial and ventricular chambers. Perturbation of this process typically results in defects that allow mixing of oxygenated and deoxygenated blood. Atrioventricular septal defects (AVSD) form a class of congenital heart malformations that are characterized by the presence of a primary atrial septal defect (pASD), a common atrioventricular valve (cAVV), and frequently also a ventricular septal defect (VSD). While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well. The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs, and in addition, preliminary data suggest that the mesenchymal cap situated on the leading edge of the primary atrial septum may be involved in certain situations as well. In this chapter, we review what is currently known about the molecular mechanisms and animal models that are associated with the pathogenesis of AVSD.
Asunto(s)
Modelos Animales de Enfermedad , Defectos de los Tabiques Cardíacos , Animales , Defectos de los Tabiques Cardíacos/genética , Defectos de los Tabiques Cardíacos/fisiopatología , Defectos de los Tabiques Cardíacos/patología , Humanos , Transducción de Señal , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/fisiopatología , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interventricular/genética , Defectos del Tabique Interventricular/fisiopatología , Defectos del Tabique Interventricular/patologíaRESUMEN
The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.
Asunto(s)
Modelos Animales de Enfermedad , Defectos del Tabique Interatrial , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interatrial/fisiopatología , Animales , Humanos , Mutación , Tabique Interatrial/patología , Transducción de Señal/genéticaRESUMEN
PRKACA-related, atrial defects-polydactyly-multiple congenital malformation syndrome is a recently described skeletal ciliopathy, which is caused by disease-causing variants in PRKACA. The primary phenotypic description includes atrial septal defects, and limb anomalies including polydactyly and short limbs. To date, only four molecularly proven patients have been reported in the literature with a recurrent variant, c.409G>A p.Gly137Arg in PRKACA. In this study, we report the fifth affected individual with the same variant and review the clinical features and radiographic findings of this rare syndrome.
Asunto(s)
Anomalías Múltiples , Polidactilia , Humanos , Polidactilia/genética , Polidactilia/patología , Polidactilia/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Anomalías Múltiples/diagnóstico , Femenino , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/diagnóstico , Defectos del Tabique Interatrial/patología , Masculino , Fenotipo , Mutación/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/diagnóstico por imagen , IndiaRESUMEN
Background: Paraganglioma is a rare neuroendocrine tumor and is highly associated with hereditary susceptibility genes, often occurring as part of a genetic syndrome. The genetic heterogeneity of paraganglioma poses challenges in diagnosis, counseling, and clinical management. Case summary: We present the case of a 60-year-old woman with hypertension, atrial septal defect, and polycythemia, who experienced paroxysmal palpitations, sweating, headache, abdominal pain, nausea, and vomiting. Her blood pressure was severely unstable. Blood laboratory tests revealed elevated catecholamine levels, contrast-enhanced CT of her whole abdomen showed a round retroperitoneal mass with soft tissue density, and somatostatin receptor imaging (68Ga PET-CT) indicated a retroperitoneal mass with abnormally increased expression of somatostatin receptor. It is interesting to note that whole exome sequencing (WES) analyses on both blood and tumor samples revealed a novel EPAS1 mutation, specifically the c.2501A > G; p.Tyr834Cys variant, which has never been reported. The patient was diagnosed with paraganglioma and underwent successful Da Vinci robot-assisted laparoscopic resection of the retroperitoneal tumor. During a 3-month follow-up period, her blood pressure stabilized, and her symptoms significantly improved. Conclusion: This case reveals that the EPSA1 mutation may be the primary driver of paraganglioma complicated by atrial septal defect and polycythemia. Additionally, the utilization of Da Vinci robot-assisted laparoscopic surgery contributed to a favorable prognosis for the patient.
Asunto(s)
Defectos del Tabique Interatrial , Paraganglioma , Policitemia , Humanos , Femenino , Persona de Mediana Edad , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/patología , Paraganglioma/terapia , Policitemia/genética , Policitemia/patología , Policitemia/terapia , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interatrial/terapiaRESUMEN
AIMS: Atrial septal defects (ASD) are associated with atrial arrhythmias, but the arrhythmia substrate in these patients is poorly defined. We hypothesized that bi-atrial fibrosis is present and that right atrial fibrosis is associated with atrial arrhythmias in ASD patients. We aimed to evaluate the extent of bi-atrial fibrosis in ASD patients and to investigate the relationships between bi-atrial fibrosis, atrial arrhythmias, shunt fraction, and age. METHODS AND RESULTS: Patients with uncorrected secundum ASDs (n = 36; 50.4 ± 13.6 years) underwent cardiac magnetic resonance imaging with atrial late gadolinium enhancement. Comparison was made to non-congenital heart disease patients (n = 36; 60.3 ± 10.5 years) with paroxysmal atrial fibrillation (AF). Cardiac magnetic resonance parameters associated with atrial arrhythmias were identified and the relationship between bi-atrial structure, age, and shunt fraction studied. Bi-atrial fibrosis burden was greater in ASD patients than paroxysmal AF patients (20.7 ± 14% vs. 10.1 ± 8.6% and 14.8 ± 8.5% vs. 8.6 ± 6.1% for right and left atria respectively, P = 0.001 for both). In ASD patients, right atrial fibrosis burden was greater in those with than without atrial arrhythmias (33.4 ± 18.7% vs. 16.8 ± 10.3%, P = 0.034). On receiver operating characteristic analysis, a right atrial fibrosis burden of 32% had a 92% specificity and 71% sensitivity for predicting the presence of atrial arrhythmias. Neither age nor shunt fraction was associated with bi-atrial fibrosis burden. CONCLUSION: Bi-atrial fibrosis burden is greater in ASD patients than non-congenital heart disease patients with paroxysmal AF. Right atrial fibrosis is associated with the presence of atrial arrhythmias in ASD patients. These findings highlight the importance of right atrial fibrosis to atrial arrhythmogenesis in ASD patients.
Asunto(s)
Fibrilación Atrial , Defectos del Tabique Interatrial , Fibrilación Atrial/complicaciones , Medios de Contraste , Fibrosis , Gadolinio , Atrios Cardíacos , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/patología , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia MagnéticaRESUMEN
The proband with congenital heart disease and abnormal thumb was clinically diagnosed as Holt-Oram syndrome (HOS). A novel variant, T-box transcription factor 5 (TBX5) c.755 + 1 G > A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III-1), her brother (III-2), and her mother (II-2) were 50%, 48.3%, and 38.1%, respectively, indicating that III-1 and III-2 harbored heterozygous variants, while II-2 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal TBX5 transcripts. Reverse transcription-quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated TBX5 expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.
Asunto(s)
Cardiopatías Congénitas , Defectos del Tabique Interatrial , Deformidades Congénitas de las Extremidades Inferiores , Deformidades Congénitas de las Extremidades Superiores , Anomalías Múltiples , Femenino , Cardiopatías Congénitas/diagnóstico , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Humanos , Deformidades Congénitas de las Extremidades Inferiores/genética , Deformidades Congénitas de las Extremidades Inferiores/patología , Masculino , Proteínas de Dominio T Box/genética , Deformidades Congénitas de las Extremidades Superiores/patologíaAsunto(s)
Humanos , Femenino , Anciano , Ecocardiografía Tridimensional/métodos , Cardiopatías Congénitas/diagnóstico , Defectos del Tabique Interatrial/patología , Defectos del Tabique Interatrial/diagnóstico por imagen , Cateterismo/métodos , Ecocardiografía/métodos , Ecocardiografía Transesofágica/métodos , Defectos del Tabique Interatrial/complicacionesRESUMEN
Invariant Natural Killer T (iNKT) cells respond to the ligation of lipid antigen-CD1d complexes via their T-cell receptor and are implicated in various immunometabolic diseases. We considered that immunometabolic factors might affect iNKT cell function. To this end, we investigated iNKT cell phenotype and function in a cohort of adolescents with chronic disease and immunometabolic abnormalities. We analyzed peripheral blood iNKT cells of adolescents with cystic fibrosis (CF, n = 24), corrected coarctation of the aorta (CoA, n = 25), juvenile idiopathic arthritis (JIA, n = 20), obesity (OB, n = 20), and corrected atrial septal defect (ASD, n = 25) as controls. To study transcriptional differences, we performed RNA sequencing on a subset of obese patients and controls. Finally, we performed standardized co-culture experiments using patient plasma, to investigate the effect of plasma factors on iNKT cell function. We found comparable iNKT cell numbers across patient groups, except for reduced iNKT cell numbers in JIA patients. Upon ex-vivo activation, we observed enhanced IFN-γ/IL-4 cytokine ratios in iNKT cells of obese adolescents versus controls. The Th1-skewed iNKT cell cytokine profile of obese adolescents was not explained by a distinct transcriptional profile of the iNKT cells. Co-culture experiments with patient plasma revealed that across all patient groups, obesity-associated plasma factors including LDL-cholesterol, leptin, and fatty-acid binding protein 4 (FABP4) coincided with higher IFN-γ production, whereas high HDL-cholesterol and insulin sensitivity (QUICKI) coincided with higher IL-4 production. LDL and HDL supplementation in co-culture studies confirmed the effects of lipoproteins on iNKT cell cytokine production. These results suggest that circulating immunometabolic factors such as lipoproteins may be involved in Th1 skewing of the iNKT cell cytokine response in immunometabolic disease.
Asunto(s)
Artritis Juvenil/inmunología , Fibrosis Quística/inmunología , Defectos del Tabique Interatrial/inmunología , Células T Asesinas Naturales/inmunología , Obesidad/fisiopatología , Células TH1/inmunología , Adolescente , Artritis Juvenil/metabolismo , Artritis Juvenil/patología , Estudios de Casos y Controles , Enfermedad Crónica , Estudios Transversales , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Citocinas/metabolismo , Femenino , Defectos del Tabique Interatrial/metabolismo , Defectos del Tabique Interatrial/patología , Humanos , Interferón gamma/metabolismo , MasculinoRESUMEN
OBJECTIVE: Atrial septal defect, secundum (ASD â ¡, OMIM: 603642) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive. METHODS AND RESULTS: Using whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant Arg1822_Glu1823dup co-segregated with the disease in this family with autosomal dominant inheritance. The insertion variant located in the coiled-coil domain of the MYH6 protein, which is highly conserved across homologous myosin proteins and species. In transfected myoblast C2C12 cell lines, the MYH6 Arg1822_Glu1823dup variant significantly impaired myofibril formation and increased apoptosis but did not significantly reduce cell viability. Furthermore, molecular simulations revealed that the Arg1822_Glu1823dup variant impaired the myosin α-helix, increasing the stability of the coiled-coil myosin dimer, suggesting that this variant has an effect on the coiled-coil domain self-aggregation. These findings indicate that Arg1822_Glu1823dup variant plays a crucial role in the pathogenesis of ASD II. CONCLUSION: Our findings expand the spectrum of MYH6 variations associated with familial ASD II and may provide a molecular basis in genetic counseling and prenatal diagnosis for this Chinses family.
Asunto(s)
Miosinas Cardíacas/genética , Defectos del Tabique Interatrial/genética , Mutagénesis Insercional , Cadenas Pesadas de Miosina/genética , Adulto , Animales , Apoptosis , Miosinas Cardíacas/química , Miosinas Cardíacas/metabolismo , Línea Celular , Supervivencia Celular , Niño , Femenino , Defectos del Tabique Interatrial/metabolismo , Defectos del Tabique Interatrial/patología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mioblastos/metabolismo , Cadenas Pesadas de Miosina/química , Cadenas Pesadas de Miosina/metabolismo , Linaje , Conformación Proteica en Hélice alfa , Estabilidad ProteicaRESUMEN
Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.
Asunto(s)
Anomalías Múltiples/genética , Enfermedades de la Mama/genética , Cardiopatías Congénitas/genética , Defectos del Tabique Interatrial/genética , Deformidades Congénitas de las Extremidades Inferiores/genética , Fenotipo , Proteínas de Dominio T Box/genética , Cúbito/anomalías , Deformidades Congénitas de las Extremidades Superiores/genética , Anomalías Múltiples/patología , Enfermedades de la Mama/complicaciones , Enfermedades de la Mama/patología , Femenino , Duplicación de Gen , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/patología , Humanos , Deformidades Congénitas de las Extremidades Inferiores/complicaciones , Deformidades Congénitas de las Extremidades Inferiores/patología , Masculino , Linaje , Cúbito/patología , Deformidades Congénitas de las Extremidades Superiores/complicaciones , Deformidades Congénitas de las Extremidades Superiores/patologíaRESUMEN
The GORE® CARDIOFORM ASD occluder (ASDO) is approved for closure of ASDs up to 35 mm diameter. With an adaptable central waist, each device size is suitable over a range of defect diameters. Understanding deployed dimensions across various defect sizes will assist operators. Therefore, this study investigates the deployed dimensions of the ASDO as a function of defect size. A 2-mm-thick ASD model with circular defects ranging from 5 to 35 mm was 3D printed. Diameter, width, and left-right disc diameter were measured by fluoroscopy after ASDO devices were deployed in applicable defects. Linear regression evaluated relationships between device size, defect size, and deployed dimensions. Six ASDOs of each size (27, 32, 37, 44, and 48 mm) were deployed in all applicable defects. There was significant ASDO size-defect size interaction in determining deployed ASDO diameter. Diameter was positively associated with defect size for 48-mm (B = 0.13, p < 0.001) and 44-mm (B = 0.11, p < 0.001) ASDOs, while no association was seen for 27-mm, 32-mm, or 37-mm ASDOs. No such interaction existed for deployed width or left-right disc difference. Controlling for ASDO size, width (B = - 0.12, p < 0.001) and left-right disc difference (B = - 0.06, p < 0.001) were negatively associated with defect size. In smaller defects, the 44-mm and 48-mm ASDOs display progressive diameter foreshortening, and all devices display progressive increase in width and left-right disc asymmetry. Anticipating the degree of diameter foreshortening may be critical when attempting closure of fenestrated lesions and/or in patients with limited total atrial septal length.
Asunto(s)
Defectos del Tabique Interatrial/patología , Diseño de Prótesis/métodos , Dispositivo Oclusor Septal , Cateterismo Cardíaco/instrumentación , Defectos del Tabique Interatrial/cirugía , Humanos , Factores de TiempoRESUMEN
Holt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Deformidades Congénitas de las Extremidades Inferiores/genética , Deformidades Congénitas de las Extremidades Inferiores/patología , Proteínas de Dominio T Box/genética , Deformidades Congénitas de las Extremidades Superiores/genética , Deformidades Congénitas de las Extremidades Superiores/patología , Adulto , Anciano de 80 o más Años , Células Cultivadas , Análisis Citogenético , Análisis Mutacional de ADN , Estudios de Asociación Genética , Heterogeneidad Genética , Células HEK293 , Humanos , Masculino , Mutación/fisiología , Fenotipo , Proteínas de Dominio T Box/fisiologíaRESUMEN
Severe cardiomegaly with an atrial septal defect was discovered during necropsy of a subadult White-tailed Eagle (Haliaeetus albicilla) found dead in the wild. A thin membrane composed of fibromuscular tissue separated the left atrium into two chambers, most consistent with that described for cor triatriatum sinister (CTS) in other species. Seventeen months later, necropsy of an adult White-tailed Eagle again revealed CTS. This lesion has not been reported previously in raptors.
Asunto(s)
Enfermedades de las Aves/patología , Cardiomegalia/veterinaria , Corazón Triatrial/veterinaria , Águilas , Defectos del Tabique Interatrial/veterinaria , Animales , Cardiomegalia/patología , Corazón Triatrial/patología , Defectos del Tabique Interatrial/patología , Masculino , SueciaRESUMEN
The Eustachian valve (EV) of the inferior vena cava and the Thebesian valve (TV) of the coronary sinus are incompletely regressed structures of embryonic sinus venosus. In the majority of cases, the EV and TV disappear completely after birth or are represented only by a thin crescentic fold. On echocardiography, these vestiges may mimic abnormal structures. We report a case with giant EV and TV which were initially misinterpreted as rims of an atrial septal defect (ASD) leading to the false diagnosis of ostium secundum ASD.
Asunto(s)
Defectos del Tabique Interatrial/patología , Vena Cava Inferior/diagnóstico por imagen , Vena Cava Inferior/patología , Adulto , Ecocardiografía , Defectos del Tabique Interatrial/diagnóstico por imagen , Humanos , MasculinoRESUMEN
Holt-Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T-box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non-ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long-term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.
Asunto(s)
Anomalías Múltiples/genética , Cardiomiopatía Dilatada/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Defectos del Tabique Interatrial/genética , Deformidades Congénitas de las Extremidades Inferiores/genética , Proteínas de Dominio T Box/genética , Deformidades Congénitas de las Extremidades Superiores/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adulto , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/patología , Femenino , Estudios de Asociación Genética , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/patología , Humanos , Deformidades Congénitas de las Extremidades Inferiores/diagnóstico por imagen , Deformidades Congénitas de las Extremidades Inferiores/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Fenotipo , Deformidades Congénitas de las Extremidades Superiores/diagnóstico por imagen , Deformidades Congénitas de las Extremidades Superiores/patología , Adulto JovenRESUMEN
Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.
Asunto(s)
Síndrome de Down/mortalidad , Defectos de la Almohadilla Endocárdica/mortalidad , Cardiopatías Congénitas/mortalidad , Defectos del Tabique Interatrial/mortalidad , Coartación Aórtica , Niño , Preescolar , Síndrome de Down/complicaciones , Síndrome de Down/patología , Defectos de la Almohadilla Endocárdica/complicaciones , Defectos de la Almohadilla Endocárdica/patología , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/patología , Humanos , Masculino , Morbilidad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Congenital atrial aneurysms are a rare malformation, often associated with supraventricular arrhythmias. Here, we present the case of a child with biatrial aneurysms and a type 2 atrioseptal defect. Directly after birth the girl became symptomatic with incessant ectopic atrial tachyarrhythmia. On echocardiography, multiple biatrial aneurysms and septations were observed. The diagnosis was confirmed with computed tomography. After 7 months of antiarrhythmic therapy, the child underwent surgical intervention by aneurysm resection, atrioseptal defect closure, and ablation. Since then the patient has been in stable sinus rhythm.
Asunto(s)
Aneurisma Cardíaco/cirugía , Defectos del Tabique Interatrial/cirugía , Femenino , Aneurisma Cardíaco/congénito , Aneurisma Cardíaco/patología , Atrios Cardíacos/patología , Defectos del Tabique Interatrial/patología , Humanos , LactanteRESUMEN
Transcatheter closure of large atrial septal defects (ASDs) remains controversial. The aim of this study was to evaluate the feasibility and safety of transthoracic echocardiography (TTE)-guided transcatheter closure of large ASDs. Patients with large secundum ASDs (≥ 30 mm) who underwent device closure were retrospectively reviewed. TTE was performed to guide ASD occluder positioning and assess the immediate and long-term outcomes. A total of 60 patients (median age 43.5 years, range 15-78 years) were enrolled in the study. The median ASD size was 35 mm (range 30-42 mm). Mild to moderate pulmonary hypertension was observed in 36 patients (60%). Thirty-one patients (51.7%) had one short rim, and 18 patients (30.0%) had two deficient rims. Placement of the device was successful in 57 patients (95%), and the median device size was 42 mm (range 40-50 mm). Dislodgement of the device occurred in three patients with two deficient rims: a larger device was redeployed in one case, and two patients required surgical repair. During a median follow-up of 37 months (range 6-83 months), no residual shunts, erosion, or embolization were noted, and pulmonary hypertension resolved in 75% of the patients. Thus t vast majority (95%) of large ASDs can be successfully closed percutaneously using the Chinese-made Shanghai Shape Memory Alloy (SHSMA) occluder under TTE guidance. Long-term follow-up showed that transcatheter closure could become a safe and effective alternative to surgery in select large ASDs.