The Biological Bases of Group 2 Pulmonary Hypertension.

Pulmonary hypertension (PH) is a potentially fatal condition with a prevalence of around 1% in the world population and most commonly caused by left heart disease (PH-LHD). Usually, in PH-LHD, the increase of pulmonary pressure is only conditioned by the retrograde transmission of the left atrial pressure. However, in some cases, the long-term retrograde pressure overload may trigger complex and irreversible biomechanical and biological changes in the pulmonary vasculature. This latter clinical entity, designated as combined pre- and post-capillary PH, is associated with very poor outcomes. The underlying mechanisms of this progression are poorly understood, and most of the current knowledge comes from the field of Group 1-PAH. Treatment is also an unsolved issue in patients with PH-LHD. Targeting the molecular pathways that regulate pulmonary hemodynamics and vascular remodeling has provided excellent results in other forms of PH but has a neutral or detrimental result in patients with PH-LHD. Therefore, a deep and comprehensive biological characterization of PH-LHD is essential to improve the diagnostic and prognostic evaluation of patients and, eventually, identify new therapeutic targets. Ongoing research is aimed at identify candidate genes, variants, non-coding RNAs, and other biomarkers with potential diagnostic and therapeutic implications. In this review, we discuss the state-of-the-art cellular, molecular, genetic, and epigenetic mechanisms potentially involved in PH-LHD. Signaling and effective pathways are particularly emphasized, as well as the current knowledge on -omic biomarkers. Our final aim is to provide readers with the biological foundations on which to ground both clinical and pre-clinical research in the field of PH-LHD.

Expresividad variable de una mutación fundadora en el gen EIF2AK4 en pacientes con enfermedad venooclusiva pulmonar hereditaria. Impacto en la supervivencia / Variable expressivity of a founder mutation in the EIF2AK4 gene in hereditary pulmonary veno-occlusive disease and its impact on survival

Introducción y objetivos: La enfermedad venooclusiva pulmonar (EVOP) hereditaria se relaciona con mutaciones bialélicas en EIF2AK4 y se ha descrito una mutación fundadora en pacientes ibéricos de etnia gitana con EVOP familiar. Los objetivos son la caracterización fenotípica y el análisis de supervivencia de pacientes ibéricos de etnia gitana con EVOP familiar portadores de la mutación fundadora p.Pro1115Leu en EIF2AK4, según su tolerancia clínica a vasodilatadores pulmonares (VDP). Estudio genético familiar y análisis de factores socioculturales de la etnia con potencial impacto en la propagación de la enfermedad. Métodos: Estudio observacional de pacientes de etnia gitana con EVOP familiar incluidos en el Registro Español de Hipertensión Arterial Pulmonar. Se realizó estudio genético de EIF2AK4 a casos afectados y familiares (noviembre 2011-julio 2016) y estudio histopatológico pulmonar en caso de trasplante pulmonar o fallecimiento. Los pacientes se clasificaron en tolerantes y no tolerantes a VDP, comparando sus características basales y la supervivencia libre de fallecimiento o el trasplante. Resultados: Se estudió a 18 pacientes (9 casos índice y 9 familiares afectados). Se halló la mutación fundadora en homocigosis en EIF2AK4 en todos ellos y en 2 familiares sanos, y en heterocigosis en el 34,2% de familiares sanos. Se observó elevada consanguineidad, edad joven de reproducción con multiparidad y pronóstico sombrío de nuestra cohorte existiendo diferencias significativas entre pacientes tolerantes y no tolerantes. Conclusiones: Se describen 2 fenotipos de EVOP hereditaria en etnia gitana según tolerancia a VDP e histología pulmonar, con impacto pronóstico y distribución familiar. Destacamos el papel de la consanguineidad en la propagación de la enfermedad y una alta rentabilidad del cribado genético familiar (AU)

Introduction and objectives: Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course. Methods: Observational study of Romani patients with familial PVOD included in the Spanish Registry of Pulmonary Arterial Hypertension. Genetic screening of EIF2AK4 was performed in index cases and relatives between November 2011 and July 2016 and histological pulmonary examination was carried out in patients who received a lung transplant or died. The patients were divided into 2 groups depending on their tolerance to PVD, with comparison of baseline characteristics and survival free of death or lung transplant. Results: Eighteen Romani patients were included: 9 index cases and 9 relatives. The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD. Conclusions: We describe 2 phenotypes of hereditary PVOD depending on tolerance to PVD, with prognostic impact and familial distribution. Consanguinity may have a negative impact on the transmission of PVOD, with familial genetic screening showing high effectiveness (AU)

Variable Expressivity of a Founder Mutation in the EIF2AK4 Gene in Hereditary Pulmonary Veno-occlusive Disease and Its Impact on Survival.

INTRODUCTION AND OBJECTIVES: Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course. METHODS: Observational study of Romani patients with familial PVOD included in the Spanish Registry of Pulmonary Arterial Hypertension. Genetic screening of EIF2AK4 was performed in index cases and relatives between November 2011 and July 2016 and histological pulmonary examination was carried out in patients who received a lung transplant or died. The patients were divided into 2 groups depending on their tolerance to PVD, with comparison of baseline characteristics and survival free of death or lung transplant. RESULTS: Eighteen Romani patients were included: 9 index cases and 9 relatives. The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD. CONCLUSIONS: We describe 2 phenotypes of hereditary PVOD depending on tolerance to PVD, with prognostic impact and familial distribution. Consanguinity may have a negative impact on the transmission of PVOD, with familial genetic screening showing high effectiveness.

La evolución de la hipertensión arterial pulmonar a lo largo de 30 años: experiencia de un centro de referencia / Trends in pulmonary hypertension over a period of 30 years: experience from a single referral centre

Introducción y objetivos: La hipertensión arterial pulmonar (HAP) se caracteriza por aumento de resistencias vasculares pulmonares, disfunción progresiva del ventrículo derecho y muerte. A pesar de los avances, sigue asociada a alta morbimortalidad. El objetivo del estudio es describir el tratamiento de esta enfermedad y determinar factores pronósticos de pacientes con HAP tratados en un centro de referencia nacional a lo largo de 30 años. Métodos: Se estudió a 379 pacientes consecutivos diagnosticados de HAP (enero de 1984-diciembre de 2014). Se los distribuyó en 3 intervalos de tiempo: previo a 2004, 2004-2009 y 2010-2014, y se analizaron los factores pronósticos de deterioro clínico. Resultados: La mediana de edad de los pacientes es 44 años (el 68,6% eran mujeres) y estaban en clase funcional III-IV el 72%. Se observó un incremento en etiologías más complejas: enfermedad venooclusiva e hipertensión portopulmonar en el último periodo. La terapia combinada de inicio aumentó (el 5% previo a 2004 frente al 27% posterior a 2010; p < 0,05). El análisis multivariable mostró como factores independientes de deterioro clínico edad, sexo, etiología y variables combinadas (p < 0,05). La supervivencia libre de muerte o trasplante al primero, el tercero y el quinto año fueron del 92,2, el 80,6 y el 68,5% respectivamente. La mediana de supervivencia fue 9 años (intervalo de confianza del 95%, 7,532-11,959). Conclusiones: La HAP es una enfermedad heterogénea y compleja. La mediana de supervivencia libre de muerte o trasplante en nuestra serie es 9 años. La estructura de una unidad multidisciplinaria de HAP debe adaptarse con rapidez a los cambios que se producen en el tiempo incorporando nuevas técnicas diagnósticas y terapéuticas (AU)

Introduction and objectives: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, right ventricular dysfunction and death. Despite scientific advances, is still associated with high morbidity and mortality. The aim is to describe the clinical approach and determine the prognostic factors of patients with PAH treated in a national reference center over 30 years. Methods: Three hundred and seventy nine consecutive patients with PAH (January 1984 to December 2014) were studied. Were divided into 3 periods of time: before 2004, 2004-2009 and 2010-2014. Prognostic factors (multivariate analysis) were analyzed for clinical deterioration. Results: Median age was 44 years (68.6% women), functional class III-IV: 72%. An increase was observed in more complex etiologies in the last period of time: Pulmonary venooclusive disease and portopulmonary hypertension. Upfront combination therapy significantly increased (5% before 2004 vs 27% after 2010; P < .05). Multivariate analysis showed prognostic significance in age, sex, etiology and combined clinical variables as they are independent predictors of clinical deterioration (P < .05). Survival free from death or transplantation for the 1st, 3rd and 5th year was 92.2%, 80.6% and 68.5% respectively. The median survival was 9 years (95% confidence interval, 7.532-11.959) Conclusions: The PAH is a heterogeneous and complex disease, the median survival free from death or transplantation in our series is 9 years after diagnosis. The structure of a multidisciplinary unit PAH must adapt quickly to changes that occur over time incorporating new diagnostic and therapeutic techniques (AU)

Trends in Pulmonary Hypertension Over a Period of 30 Years: Experience From a Single Referral Centre.

INTRODUCTION AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, right ventricular dysfunction and death. Despite scientific advances, is still associated with high morbidity and mortality. The aim is to describe the clinical approach and determine the prognostic factors of patients with PAH treated in a national reference center over 30 years. METHODS: Three hundred and seventy nine consecutive patients with PAH (January 1984 to December 2014) were studied. Were divided into 3 periods of time: before 2004, 2004-2009 and 2010-2014. Prognostic factors (multivariate analysis) were analyzed for clinical deterioration. RESULTS: Median age was 44 years (68.6% women), functional class III-IV: 72%. An increase was observed in more complex etiologies in the last period of time: Pulmonary venooclusive disease and portopulmonary hypertension. Upfront combination therapy significantly increased (5% before 2004 vs 27% after 2010; P < .05). Multivariate analysis showed prognostic significance in age, sex, etiology and combined clinical variables as they are independent predictors of clinical deterioration (P < .05). Survival free from death or transplantation for the 1st, 3rd and 5th year was 92.2%, 80.6% and 68.5% respectively. The median survival was 9 years (95% confidence interval, 7.532-11.959) CONCLUSIONS: The PAH is a heterogeneous and complex disease, the median survival free from death or transplantation in our series is 9 years after diagnosis. The structure of a multidisciplinary unit PAH must adapt quickly to changes that occur over time incorporating new diagnostic and therapeutic techniques.

Four chamber right ventricular longitudinal strain versus right free wall longitudinal strain. Prognostic value in patients with left heart disease.

BACKGROUND: There is no consensus on which right ventricle (RV) strain parameter should be used in the clinical practice: four chamber RV longitudinal strain (4CH RV-LS) or free wall longitudinal strain (FWLS). The aim of this study was to analyze which RV strain parameter better predicts prognosis in patients with left heart disease. METHODS: One hundred and three outpatients with several degrees of functional tricuspid regurgitation severity secondary to left heart disease were prospectively included. 4CH RV-LS and FWLS were assessed using speckle tracking. Left ventricular (LV) systolic function was determined using LV ejection fraction and RV systolic function using tricuspid annular plane systolic excursion (TAPSE). Patients were followed up for 23.1 ± 12.4 months for an endpoint of cardiac hospitalization due to heart failure. RESULTS: The cutoff value related to RV dysfunction (TAPSE < 17 mm) was lower, in absolute value, for 4CH RV-LS (4CH RV-LS = -17.3%; FWLS = -19.5%). There were 33 adverse events during the follow-up. Patients with 4CH RV-LS > -17.3% (log rank [LR] = 22.033; p < 0.001); FWLS > -19.5% (LR = 12.2; p < 0.001), TAPSE < 17 mm (LR = 17.4; p < 0.001) and LV systolic dysfunction (LR = 13.3; p < 0.001) had lower event-free survival (Kaplan Meier). In Cox multivariate analysis, 4CH RV-LS > -17.3% (hazard ratio [HR] = 3.593; p < 0.002), TAPSE < 17 (HR = 2.093; p < 0.055) and LV systolic dysfunction (HR = 2.087; p < 0,054) had prognostic value, whereas FWLS did not reach significance. CONCLUSIONS: Although both 4CH RV-LS and FWLS have prognostic value, 4CH RV-LS is a better predictor of episodes of heart failure in patients with left heart disease, providing additional information to that obtained by TAPSE.

Inoperable chronic thromboembolic pulmonary hypertension treated with riociguat: A case study.

A 51-year-old woman presented with a one-year history of progressive dyspnea, WHO functional class III-IV and exercise-related syncope. Transthoracic echocardiography and computed tomography pulmonary angiography were performed, leading to a diagnosis of pulmonary arterial hypertension. She was referred to our pulmonary hypertension unit, where a complete study was performed, including ventilation/perfusion scan, which was consistent with chronic thromboembolic pulmonary hypertension. Risk factors for this condition were excluded and therapeutic options were evaluated. Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected. Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat. After one year of treatment, significant improvement in functional class, 6-minute walk test and NT-proBNP were seen, without significant secondary effects.