Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

Genetics; Heritable pulmonary arterial hypertension; Pediatric pulmonary hypertensionGenética; Hipertensión arterial pulmonar hereditaria; Hipertensión pulmonar pediátricaGenètica; Hipertensió arterial pulmonar hereditària; Hipertensió pulmonar pediàtricaBackground: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.This project was funded by project “Bases Genético-Moleculares de la Medicina de Precisión en la Hipertensión Arterial Pulmonar”. Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Gobierno de España. Co-funded by “Fondo Europeo de Desarrollo Regional, Programa Operativo Crecimiento Inteligente 2014–2020” (Award number: PI 18/01233). A.C.-U. holds a research-training contract “Rio Hortega” (CM20/00164) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). REHIPED is supported by unrestricted grants of Janssen and Ferrer

Utilidad de la tomografía computarizada en la sospecha de rotura cardíaca

We present the case of a patient with a history of recent ACS, who is diagnosed with severe pericardial effusion of a hematic appearance in our center. This article discusses the usefulness of computed tomography in suspected cardiac rupture.Se presenta el caso de un paciente con historia de SCA reciente, que es diagnosticado de derrame pericárdico severo de aspecto hemático. En este artículo se expone la utilidad de la tomografía computarizada en la sospecha de la rotura cardíaca

Prevalencia e impacto en el fenotipo de las variantes genéticas en la hipertensión arterial pulmonar pediátrica y del adulto

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 30-03-2023. Tesis formato europeo (compendio de artículos)La hipertensión arterial pulmonar (HAP) es una enfermedad rara y heterogénea, con un mal pronóstico si no se realiza un tratamiento correcto y precoz. En los últimos años se han descrito diversos mecanismos moleculares implicados en el desarrollo de esta entidad, en sus diferentes formas. Es por ello de suma importancia la ampliación en el conocimiento de las bases genéticas de la enfermedad. En esta tesis por publicaciones, se muestran los hallazgos encontrados en el estudio genético dela población pediátrica y adulta española con HAP, además de diversos estudios genéticos realizados con el objetivo de buscar variantes genéticas en la HAP asociada a las cardiopatías congénitas, un subtipo de enfermedad en la que el conocimiento es todavía más escaso. Gracias a la colaboración clínico-genética entre los centros implicados en el estudio de la enfermedad, la información recogida en las bases de datos poblacionales en esta enfermedad (REHAP y REHIPED) y los investigadores implicados en la búsqueda de variantes genéticas, este proyecto se ha podido llevar a cabo con éxito, mostrando un rendimiento del estudio genético global cercano al 20% en la población adulta y mayor del 40% en la población pediátrica. Probablemente el hallazgo más interesante, que se replica en las dos cohortes, es la utilidad dela genética en la reclasificación de la enfermedad, pasando muchos casos de unas formas a otras de HAP tras la realización del análisis genético...Pulmonary arterial hypertension (PAH) is a rare and heterogeneous disease, with a poor prognosis without correct and early treatment. In recent years, several molecular mechanisms involved in the development of this entity have been described in its different forms. It is therefore of utmost importance to expand the knowledge of the genetic basis of the disease. In this thesis by publications, we show the findings of the genetic study of the Spanish pediatric and adult population with PAH. In addition, we performed various genetic studies with the aim of searching for genetic variants in PAH associated with congenital heart disease, a subtype of PAH in which knowledge is even more scarce. Thanks to the clinical-genetic collaboration between the centers involved in the study of the disease, the information collected in the population databases on this disease (REHAP and REHIPED) and the researchers involved in the search for genetic variants, this project has been successfully carried out, showing an overall yield of the genetic studies close to 20% in the adult population and higher than 40% in the pediatric population. Probably the most interesting finding, which is replicated in the two cohorts, is the usefulness of genetics in the reclassification of the disease, with many cases passing from one form of PAH to another after genetic analysis...Fac. de MedicinaTRUEunpu

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH