Early reduction of pulmonary arterial hypertension in patients using a long-term mechanical ventricular assistance device: a cross-sectional study

ABSTRACT BACKGROUND: Severe pulmonary arterial hypertension (PAH) is a contraindication for heart transplantation (HT). It has been correlated with increased early and late mortality, mainly associated with right ventricular failure. Ventricular assistance devices (VADs) can promote reduction of intracardiac pressures and consequent reduction of PAH over the medium and long terms, thus enabling future candidature for HT. The diminution of early pulmonary pressure within this scenario remains unclear. OBJECTIVE: To evaluate the reduction of PAH and correlate data from right catheterization with the earliness of this reduction. DESIGN AND SETTING: Cross-sectional study in a general hospital in São Paulo, Brazil. METHODS: This was a retrospective analysis on the medical records of patients undergoing VAD implantation in a single hospital. Patients for whom VAD had been indicated as a bridge to candidature for HT due to their condition of constant PAH were selected. RESULTS: Four patients with VADs had constantly severe PAH. Their mean pulmonary artery systolic pressure (PASP) before VAD implantation was 66 mmHg. Over the 30-day period after the procedure, all the patients evolved with a drop in PASP to below 60 mmHg. Their new average was 36 mmHg, which was a drop of close to 50% from baseline values. The one-year survival of this sample was 100%. CONCLUSION: VAD implantation can reduce PAH levels. Early reduction occurred in all patients. Thus, use of VAD is an important bridge tool for enabling candidature for HT among patients with constantly severe PAH.

Estimuladores de Guanilato Ciclase Solúvel (Riociguate) na Hipertensão Pulmonar: Dados da Prática Clínica Real em 3 Anos de Acompanhamento / Soluble Guanylate Cyclase Stimulators (Riociguat) in Pulmonary Hypertension: Data from Real-Life Clinical Practice in a 3-Year Follow-Up

Resumo Fundamento A hipertensão pulmonar (HP) é uma doença rara e complexa com prognóstico ruim, que exige tratamento pela vida toda. Objetivo Descrever dados de 3 anos de acompanhamento da vida real sobre o tratamento com estimuladores de guanilato ciclase solúvel (Riociguate) de pacientes com HP, medindo parâmetros atuais de avaliação de risco. Métodos Coletamos dados clínicos e epidemiológicos retrospectivamente de pacientes com HP do grupo 1 (hipertensão arterial pulmonar) e do grupo 4 (HP tromboembólica crônica). Parâmetros não invasivos e invasivos correspondentes à avaliação de risco foram analisados na linha de base e no acompanhamento. Foram realizadas análises estatísticas usando o software SPSS 18.0, e os p-valores <0,050 foram considerados estatisticamente significativos. Resultados No total, 41 pacientes tratados com riociguate foram incluídos no estudo. Entre eles, 31 já concluíram 3 anos de tratamento e foram selecionados para a seguinte análise. Na linha de base, 70,7% dos pacientes estavam nas classes funcionais III ou IV da OMS. Depois de 3 anos de tratamento, a classe funcional da OMS melhorou significativamente em todos os pacientes. Além disso, a mediana do teste de caminhada de 6 minutos (TC6M) aumentou significativamente de 394 ± 91 m na linha de base para 458 ± 100 m após 3 anos de acompanhamento (p= 0,014). O índice de sobrevida após três anos foi de 96,7%. Conclusão Em nossa coorte de vida real, a maioria dos pacientes com HP tratados com riociguate demonstraram parâmetros de risco estáveis ou melhores, especialmente no TC6M, aos 3 anos de acompanhamento.

Abstract Background Pulmonary hypertension (PH) is a rare and complex disease with poor prognosis, which requires lifelong treatment. Objective To describe 3-year follow-up real-life data on treatment with soluble guanylate cyclase stimulators (Riociguat) of patients with PH, measuring current risk assessment parameters. Methods This study retrospectively collected clinical and epidemiological data of patients with PH of group 1 (pulmonary arterial hypertension) and group 4 (chronic thromboembolic PH). Non-invasive and invasive parameters corresponding to the risk assessment were analyzed at baseline and follow-up. Statistical analyses were performed using the SPSS 18.0 software, and p-values < 0.050 were considered statistically significant. Results In total, 41 patients receiving riociguat were included in the study. Of them, 31 had already completed 3 years of treatment and were selected for the following analysis. At baseline, 70.7% of patients were in WHO functional class III or IV. After 3 years of treatment, the WHO functional class significantly improved in all patients. In addition, the median of the 6-minute walk test (6MWT) significantly increased from 394 ± 91 m at baseline to 458 ± 100 m after 3 years of follow-up (p= 0.014). The three-year survival rate was 96.7%. Conclusion In our real-life cohort, most patients with PH treated with riociguat showed stable or improved risk parameters, especially in the 6MWT, at 3 years of follow-up.

Disfunción ventricular derecha en paciente adulto con comunicación interventricular posinfarto

RESUMEN Introducción: La disfunción ventricular derecha es la alteración aguda o crónica de la morfología y función de dicha estructura, de origen multifactorial. En los últimos años existe consenso acerca de su función como determinante del estado funcional y factor pronóstico en diversas enfermedades. Objetivo: Destacar la importancia del manejo multidisciplinario y algunas de las opciones terapéuticas que se les pueden brindar a estos pacientes. Presentación del caso: Paciente de 58 años de edad, con antecedentes de salud aparente, que acudió al Servicio de emergencias, donde se le diagnosticó un infarto agudo de miocardio de topografía inferior. Se trasladó a la unidad de cuidados intensivos quirúrgicos del Servicio de Cirugía Cardiovascular debido a una complicación mecánica por comunicación interventricular. Se recibió con elementos clínicos de insuficiencia cardíaca aguda clase funcional IV. Progresivamente presentó deterioro del estado hemodinámico por lo que requirió el uso de apoyo vasoactivo con norepinefrina; hipoxia, hipercapnia, presiones venosas centrales entre 15 y 18 cmH2O y elementos clínicos de disfunción de ventrículo derecho; se decidió instrumentar vía aérea, administrar sedación y relajación por asincronías a paciente ventilado. Sin otra opción que el tratamiento quirúrgico se llevó a discusión donde se decidió esperar a la mejoría del estado hemodinámico con tratamiento médico. Conclusiones: Las enfermedades cardiovasculares no dejan de aparecer en escenarios cada vez más complejos con elevada morbimortalidad. Se evidencia la importancia del consenso clínico-quirúrgico en el momento de la toma de decisiones.

ABSTRACT Introduction: Right ventricular dysfunction is the acute or chronic alteration of the morphology and function of this structure, of multifactorial origin. In recent years there is consensus about its role as a determinant of functional status and prognostic factor in various diseases. Objective: Highlight the importance of multidisciplinary management and some of the therapeutic options that can be provided to these patients. Case Presentation: A 58-year-old patient with an apparent health history went to the Emergency Service, where he was diagnosed with an acute myocardial infarction of lower topography. He was transferred to the surgical intensive care unit of the Cardiovascular Surgery Service due to a mechanical complication from ventricular septal defect. He was received presenting clinical elements of acute heart failure functional class IV. He progressively presented deterioration of the hemodynamic state, so it required the use of vasoactive support with norepinephrine; hypoxia, hypercapnia, central venous pressures between 15 and 18 cmH2O and clinical elements of right ventricular dysfunction; it was decided to implement airway, administer sedation and relaxation by asynchrony to ventilated patient. With no other option than surgical treatment, it was brought to discussion and it was decided to wait for the improvement of the hemodynamic state with medical treatment. Conclusions: Cardiovascular diseases do not cease to appear in increasingly complex scenarios with high morbidity and mortality. The importance of clinical-surgical consensus at the time of decision-making is evident.

Características clínicas, evolución y tratamiento de hipertensión arterial pulmonar en un hospital peruano de referencia / Clinical characteristics, evolution and treatment of pulmonary arterial hypertension at a Peruvian referral hospital

RESUMEN Objetivo: Describir las características epidemiológicas y clínicas, la evolución y el tratamiento de los pacientes con hipertensión arterial pulmonar. Materiales y métodos: Estudio descriptivo que incluyó a 47 pacientes con diagnóstico primario de hipertensión pulmonar. Resultados: La edad promedio de los pacientes fue de 48 años, y el 91,49 % fueron mujeres. El promedio de seguimiento fue 39 meses. Los tipos predominantes de hipertensión arterial pulmonar fueron los siguientes: asociada a cardiopatía congénita (48,93 %), asociada a enfermedad del tejido conectivo (21,28 %) e hipertensión idiopática (17,02 %). En el 78,72 % de los pacientes se empleó la monoterapia (principalmente con sildenafilo), y en 21,28 % de los casos se usó la terapia combinada secuencial (sildenafilo más bosentan). Durante el seguimiento, el 70,21 % tuvo por lo menos una hospitalización y cinco pacientes fallecieron, lo que significó una mortalidad total acumulada de 10,64 %. Conclusiones: La hipertensión arterial pulmonar afecta predominantemente a personas jóvenes y de sexo femenino. La cardiopatía congénita es la principal etiología asociada. La monoterapia con sildenafilo es el tratamiento específico que se utiliza con más frecuencia. La mortalidad encontrada fue menor a la reportada en otros estudios.

ABSTRACT Objective: To describe the clinical and epidemiological characteristics, evolution and treatment of patients with pulmonary arterial hypertension. Materials and methods: A descriptive study that included 47 patients with a primary diagnosis of pulmonary arterial hypertension. Results: The average age of the patients was 48 years and 91.49 % were females. The average follow-up was 39 months. The main types of pulmonary arterial hypertension were the one associated with congenital heart diseases (48.93 %), the one associated with connective tissue diseases (21.28 %) and idiopathic hypertension (17.02 %). Monotherapy (mainly with sildenafil) and sequential combination therapy (sildenafil plus bosentan) were used in 78.72 % and 21.28 % of the patients, respectively. During the follow-up, 70.21 % of the patients were hospitalized at least once and five patients died, resulting in a cumulative total mortality of 10.64 %. Conclusions: Pulmonary arterial hypertension predominantly affects young people and females. The main associated etiology is congenital heart disease. The most frequently used specific treatment is sildenafil monotherapy. The mortality rate was lower than that reported in other studies.

Progress of researches on schistosomiasis-associated pulmonary arterial hypertension / 中国血吸虫病防治杂志

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is categorized as WHO Group I PAH because its clinical manifestations, laboratory and hemodynamic features share with PAH of other etiologies, such as idiopathic, heritable, HIV and autoimmune disorders. Sch-PAH is usually a life-threatening complication of hepatosplenic schistosomiasis characterized by changes in the vascular wall, remodeling and vasoconstriction with lesions primarily located in the precapillary segments of the pulmonary vasculature, which may result in a marked and sustained increase in pulmonary vascular resistance, right ventricular failure and ultimately death. Although egg deposition into lung and subsequent inflammatory cascades are key factors in the pathogenesis of Sch-PAH, the exact pathogenesis, course of disease and treatment of Sch-PAH remain largely uncertain. This review mainly discusses the pathophysiological and immunological mechanisms of Sch-PAH, so as to provide insights into the clinical diagnosis and treatment of Sch-PAH.

Serum 25-hydroxyvitamin D level in patients with connective tissue disease-related pulmonary arterial hypertension / 中华风湿病学杂志

Objective:To investigate the clinical significance of serum 25-hydroxyvitamin D [25(OH)D] level in patients with connective tissue disease (CTD) related-pulmonary arterial hypertension (PAH).Methods:CTD patients with PAH (CTD-PAH) and without PAH (CTD-non-PAH) were colle-cted. All data were analyzed.Results:The serum 25(OH)D in the CTD-PAH group was significantly lower than that in the CTD-non-PAH group [(14±8) ng/ml vs (20±8) ng/ml, t=-5.94, P<0.001]. The 25(OH)D deficiency rate in the CTD-PAH group 86.2%(112/130) was significantly higher than that in the CTD-non-PAH group 57.7% (75/130) ( χ2=26.07, P<0.001), while the insufficiency rate was significantly lower [10.0%(13/130) vs 32.3% (42/130), χ2=19.39, P<0.001]. Serum 25(OH)D levels in the systemic lupus erythematosus (SLE), systemic sclerosis (SSc) associated PAH group were lower than those in the SLE [14(8, 17) ng/ml vs 19(15, 23) ng/ml, Z=-3.66, P<0.001], SSc [11(8, 17) ng/ml vs 24(18, 30) ng/ml, Z=-4.97, P<0.001] without PAH group. The levels of serum 25(OH)D in CTD-PAH youthful group, in the middle age group were lower than that in CTD-non-PAH youthful group [(12±8) ng/ml vs (19±8) ng/ml, t=-4.36, P<0.001] and in the middle age group [(14±7) ng/ml vs (21±8) ng/ml, t=-3.75, P<0.001]. Serum levels of 25(OH)D [ OR (95% CI)=1.100 (1.058, 1.144), P<0.001], uric acid [ OR(95% CI)=0.996(0.993, 0.998), P=0.003], immune globulin (Ig)G [ OR(95% CI)=1.123(1.057, 1.194), P<0.001] were associated with PAH in CTD patients. Serum 25(OH)D was positively correlated with calcium ( r=0.24, P=0.007), while negatively correlated between serum 25(OH)D and IgM ( r=-0.34, P<0.001). Conclusion:The occurrence and development of CTD-PAH may be related to the decrease of 25(OH)D level. Serum 25(OH)D level is associated with PAH in CTD patients.

Budget impact analysis of treatment for pulmonary arterial hypertension included in special and chronic disease outpatient reimbursement policy / 中国药房

OBJECTIVE To evaluate the budget impact on medical insurance fund upon the treatment of pulmonary arterial hypertension（PAH）included in the outpatient special and chronic disease management policy （hereinafter refer to as the Policy ）， so as to provide reference for medical insurance reimbursement decision-making. METHODS Based on the perspective of medical insurance payer ，a budget impact model with 10 million people was built to calculate the budget impact on the medical insurance fund in the next three years （2021-2023）after PAH treatment included in the Policy. The measured cost mainly included the cost of medicine，outpatient registration ，examinations，hospitalizations，and death events. RESULTS A total of 34-36 patients with PAH per year were expected to use targeted therapy during 2021-2023. For cities with outpatient costs not covered by the pooling fund of basic medical insurance ，upon the treatment of PAH included the Policy ，the annual expenditure of the medical insurance fund increased by about 40 000 yuan，i.e. an increase of about 1 000 yuan per patient. For cities with outpatient costs covered by the pooling fund ，the annual expenditure of the medical insurance fund increased by about 80 000 yuan，which was equal to 2 000 yuan increase per patient. The increment of above cost decreased year by year. CONCLUSIONS The incremental expenditure of the medical insurance fund is controllable after the treatment of PAH included the Policy ；with the implementation of the Policy ，the incremental expenditure of the medical insurance fund will be reduced year by year.

Free energy perturbation (FEP)-guided scaffold hopping

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔG FEP between ligands and their target, which were more consistent with the experimental binding potencies ΔG EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those ΔG MM-PBSA or ΔG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery.

Eficácia e segurança da tripla terapia com Selexipague comparada à dupla terapia para tratamento de hipertensão arterial pulmonar: revisão rápida de evidências / Effectiveness and safety of triple therapy with Selexipag compared dual therapy for treatment of pulmonary arterial hypertension: rapid response review of evidence

Selexipague e outros medicamentos de controle da Hipertensão Arterial Pulmonar grupo 1. Indicação: Tratamento de Hipertensão Arterial Pulmonar grupo 1. Pergunta: Há superioridade em eficácia e segurança da tripla terapia com selexipague, comparado a dupla terapia, disponível no SUS, no tratamento de Hipertensão Arterial Pulmonar grupo 1? Métodos: Revisão rápida de evidências (overview) de ensaios clínicos randomizados e revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada pela ferramenta risco de viés da Cochrane. Resultados: Foi selecionado um ensaio clínico randomizado, especificamente um artigo contendo análise de subgrupo de dados desse estudo. Conclusão: As evidências demonstraram redução do número de hospitalizações relacionadas à HAP e de eventos de progressão da doença no tratamento de selexipague em tripla terapia em pacientes na classe funcional II, quando comparada à dupla terapia sem selexipague. A tripla terapia é tão segura quanto a dupla terapia, pois tem riscos similares de eventos adversos e eventos adversos sérios. A tripla terapia não é diferente da dupla terapia no risco da mortalidade geral

Selexipag and other drugs for the control of Pulmonary Arterial Hypertension group 1. Indication: Treatment of Pulmonary Arterial Hypertension group 1. Question: Is there superiority in efficacy and safety of triple therapy with selexipag, compared to dual therapy, available in the SUS, in the treatment of ulmonary Arterial Hypertension group 1? Methods: Rapid review of evidence (overview) of randomized clinical trials and systematic reviews, with a bibliographic survey carried out in the PUBMED database, using a structured search strategy. Results: A randomized clinical trial was selected, specifically an article showing a subgroup analysis of data from this study. Conclusion: Evidence showed a reduction in the number of Pulmonary Arterial Hypertension related hospitalizations and disease progression events in the treatment of selexipag in triple therapy in patients in functional class II, when compared to dual therapy without selexipag. Triple therapy is as safe as dual therapy, as it has similar risks of adverse events and serious adverse events. Triple therapy is no different from dual therapy in the risk of overall mortality

Atualização no Tratamento da Hipertensão Arterial Pulmonar / Update on the Treatment of Pulmonary Arterial Hypertension

Resumo Muitos avanços ocorreram nas últimas décadas na terapêutica da hipertensão arterial pulmonar (HAP), uma doença grave, progressiva, incurável e potencialmente fatal. Para seu tratamento adequado, são fundamentais o diagnóstico hemodinâmico e a classificação de sua etiologia, em que várias delas (colagenoses, hipertensão portal, cardiopatia congênitas, esquistossomose) requerem medidas específicas, além do tratamento farmacológico característico para HAP. O tratamento com fármacos-alvo para HAP baseia-se em produtos farmacêuticos que interferem em três vias fisiopatológicas moleculares: da prostaciclina, da endotelina e do óxido nítrico. Tais fármacos apresentam múltiplas apresentações (oral, endovenosa, subcutânea e inalatória) e mudaram a história da HAP. Essas medicações e suas estratégias de uso, assim como particularidades das diferentes formas de HAP, são o foco desta revisão.

Abstract In the last decades, important advances have been made in the treatment of pulmonary arterial hypertension (PAH), a severe, progressive, incurable, and potentially fatal disease. For an adequate therapy, correct hemodynamic diagnosis and etiology classification are fundamental. Many etiologies - rheumatic disease, portal hypertension, congenital heart diseases, schistosomiasis - require specific measures, in addition to drug therapy for PAH. The specific therapy for PAH is based on medications that act on three pathophysiological pathways - prostacyclin, endothelin, and nitric oxide pathways. These drugs have multiple presentations (oral, intravenous, subcutaneous, and inhaled) and have changed the history of PAH. This review presents an overview of drug therapy strategies and different forms and peculiarities of PAH.

Can serum 8-hydroxy-2'-deoxyguanosine levels reflect the severity of pulmonary arterial hypertension?

SUMMARY OBJECTIVE: Oxidative stress plays a pivotal role in the pathogenesis of pulmonary arterial hypertension. 8-Hydroxy-2'-deoxyguanosine is a sensitive biomarker that reflects the degree of oxidative damage to DNA. We investigated whether serum 8-Hydroxy-2'-deoxyguanosine is a clinically useful biomarker for the severity of pulmonary arterial hypertension. METHODS: We measured serum 8-Hydroxy-2'-deoxyguanosine levels in 25 patients (age 37±13 years, 68% women) diagnosed with idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease. The severity of pulmonary arterial hypertension was evaluated by six-min walking distance, World Health Organization functional class, and serum brain natriuretic peptide levels. Age and gender-matched 22 healthy subjects served as the control group. RESULTS: The comparison of 8-Hydroxy-2'-deoxyguanosine levels between patients and controls was not statistically different [(19.86±9.79) versus (18.80±3.94) ng/mL, p=0.622)]. However, there was a significant negative correlation between 8-Hydroxy-2'-deoxyguanosine levels and six-min walking distance (r= −0.614, p=0.001). Additionally, serum 8-Hydroxy-2'-deoxyguanosine levels in patients with functional class III-IV were significantly higher than those with functional class I-II (functional class III-IV 32.31±10.63 ng/mL versus functional class I-II 16.74±6.81 ng/mL, respectively, p=0.003). CONCLUSION: The 8-Hydroxy-2'-deoxyguanosine levels were significantly correlated with exercise capacity (six-min walking distance) and symptomatic status (functional class), both of which show the severity of pulmonary arterial hypertension in patients.

Manejo clínico de la hipertensión arterial pulmonar. Relevancia del ventrículo derecho / Relevance of right ventricle in the clinical management of pulmonary arterial hypertension

Resumen La hipertensión arterial pulmonar (HAP) requiere procesos estructurados de diagnóstico y estratificación de riesgo, siendo la función del ventrículo derecho (VD) un marcador pronóstico central. Los principales objetivos terapéuticos en la HAP son mejorar y/o intentar revertir la disfunción del VD y mantener condición de bajo riesgo. Actualmente existen múltiples fármacos con diferentes mecanismos de acción cuya combinación en doble o triple terapia ha mostrado mejores resultados que la monoterapia. Evidencia actual demuestra la importancia de incorporar tempranamente prostanoides parenterales al esquema, mejorando la funcionalidad del VD y la supervivencia. En esta revisión se refleja el papel de la función del VD en el diagnós tico, pronóstico y seguimiento de la HAP. Se recomienda la evaluación sistemática y estandarizada del VD, así como el inicio temprano de tratamiento combinado en riesgo intermedio-alto para obtener las metas de alcanzar y mantener un riesgo bajo y/o evitar la progresión de la HAP.

Abstract Pulmonary arterial hypertension (PAH) requires structured processes of diagnosis and risk stratifica tion, being the function of the right ventricle (RV) a hallmark prognosis determinant. The main therapeutic goals in PAH are to improve and try to revert RV dysfunction and maintaining a low risk. Currently, there are multiple treatments with different mechanisms of action, the combination of which in double or triple therapy has shown improved results compared to monotherapy. Recent clinical evidence shows the importance of early incorpora tion of parenteral prostanoids to the scheme, improving RV function and survival. In this review, we discuss the role of the RV function in the diagnosis, prognosis, and follow-up of PAH. We recommend the systematic and standardised evaluation of the RV as well as the early initiation of combined treatment in cases of intermediate-high risk to try to reach and keep the patient with PAH at a low risk and / or avoid the progression of PAH.

Collaborative registry of pulmonary hypertension in Argentina (RECOPILAR). Final analysis / Registro colaborativo de hipertensión pulmonar en Argentina (RECOPILAR): análisis final

Abstract The epidemiology of pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), has not been evaluated in our country, therefore there is no reference parameter to establishing the representativeness of this information in the national order. This registry represents the first collaborative effort to provide a knowledge base of this disease, including 5 scientific societies that represent different specialties (pediatrics, rheumatology, pulmonology and cardiology) with data from 23 Argentine provinces. These efforts involved five societies of various adult (cardiology, rheumatology, and pulmonology) and pediatric (cardiology) specialties. Subjects were grouped (1-5) in accord with the 2013 Nice classification. A total of 627 patients (mean age, 50.8±18 years; women, 69.2%) were recruited. Incident cases accounted for 53%. Functional class III-IV accounted for 69% at time of diagnosis and 33.4% at time of inclusion. Distributions in groups 1-5 were 63.6%, 15.9%, 8.3%, 9.7%, and 2.4%, respectively. Treatment consisted of diuretics (51.2%), mineralocorticoid receptor antagonists (44.7%), digoxin (16.6%), anticoagulants (39.2%), renin-angiotensin antagonists (15.5%), beta blockers (15.6%), and calcium channel blockers (8%). Rates of specific therapies usage in PAH vs. non-PAH group were 80.5% vs. 40.8% (phosphodiesterase-5 inhibitors: 71% vs. 38.6%; endothelin receptor antagonists: 54.4% vs. 14.5%; prostanoids: 14.3 vs. 3.1%; all p < 0.001). Three-year survival in PAH and non-PAH differed significantly (82.8% vs. 73.3%; p = 0.001). In the Argentine RECOPILAR registry, the clinic-epidemiologic profile was that of advanced-stage disease. Diagnostic workups and therapeutics interventions, including use of specific therapy for PAH, were consistent with current recommendations. Despite delays in diagnosis, survival was aligned with other contemporary registries.

Resumen La epidemiología de la hipertensión pulmonar (HP), especialmente la arterial (HAP), no ha sido evaluada en nuestro país, por lo cual no existe un parámetro de referencia para establecer la representatividad de esta información en el orden nacional. El presente registro representa el primer esfuerzo colaborativo para una base de conocimiento de esta enfermedad, incluyendo 5 sociedades científicas que representan a distintas especiali dades médicas (pediatría, reumatología, neumonología y cardiología) con datos de 23 provincias argentinas. Los sujetos se agruparon (1-5) de acuerdo con la clasificación de Niza de 2013. El seguimiento se completó en 583 pacientes (93%) un año después del final de la inscripción. Se incluyeron 627 pacientes (edad media, 50.8 ± 18 años; mujeres, 69.2%). Los casos incidentes representaron el 53%. La clase funcional III-IV representaba 69% en el momento del diagnóstico y 33.4% en el momento de la inclusión. Las manifestaciones clínicas fueron disnea (81.8%), fatiga (54.1%), síncope (10.8%), dolor torácico (14.7%), palpitaciones (20.9%) e insuficiencia cardíaca (20.4%). Las tasas de uso de terapias específicas en la hipertensión arterial pulmonar (HAP) frente al grupo sin HAP fueron del 80.5% frente al 40.8%. La supervivencia a tres años en los subconjuntos de HAP y no HAP difirió significativamente (82.8% vs. 73.3%; p = 0.001). En el registro RECOPILAR argentino, que aborda principalmente la HAP, el perfil clínico-epidemiológico fue el d e una enfermedad en estadios avanzados. El diag nóstico y las intervenciones terapéuticas, incluido el uso de terapia específica para la HAP, fueron consistentes con las recomendaciones actuales.

Conducción anestésica perioperatoria en gestante a término con hipertensión pulmonar idiopática / Perioperative anesthetic management in term pregnant women with idiopathic pulmonary hypertension

Introducción: La hipertensión arterial pulmonar es una enfermedad con una baja incidencia en la gestante, aunque trae consigo una alta mortalidad una vez presentada. Un diagnóstico oportuno y un manejo perioperatorio adecuado minimizan el riesgo de desenlace fatal tanto para la madre como el feto. Objetivo: Describir el comportamiento de la hipertensión arterial pulmonar en la gestante a término y su conducción anestésica. Presentación del caso: Paciente de 23 años, antecedentes de salud, edad gestacional de 35.2 semanas. Luego de presentar dolor de espalda y ardor en el pecho relacionado con el esfuerzo, palpitaciones, disnea y bloqueo de rama derecha en electrocardiograma, se ingresa en UTI con sospecha de tromboembolismo pulmonar, el cual queda descartado tras diagnóstico confirmatorio de hipertensión pulmonar después de realizar angio TAC y ecocardiografía. Se decide realizar cesárea programada bajo técnica regional peridural, sin complicaciones tanto para la madre como el niño. Después de 2 días bajo vigilancia intensiva se traslada a su centro hospitalario de cabecera. Conclusiones: La vía del parto, así como una elección adecuada de la técnica anestésica, puede ser la diferencia entre el éxito y la fatalidad. Las técnicas regionales suelen recomendarse por encima de la técnica de anestesia general siempre que no se presenten contraindicaciones(AU)

Introduction: Pulmonary arterial hypertension is a disease with low incidence in the pregnant woman, although it brings about high mortality once presented. Timely diagnosis and adequate perioeprative management minimize the risk of fatal outcome for both mother and fetus. Objective: To describe pulmonary arterial hypertension and its anesthetic management in the term pregnant woman. Case presentation: 23-year-old female patient, with health history and gestational age of 35.2 weeks. After presenting back pain and chest burning associated with exertion, palpitations, dyspnea and right bundle branch block in the electrocardiogram, the patient was admitted to the intensive care unit with suspected pulmonary thromboembolism, which was ruled out due to the confirmatory diagnosis of pulmonary hypertension after performing computerized tomography angiography and echocardiography. Scheduled cesarean section was decided to be perform using the regional peridural technique, without complications for both the mother and the child. After two days under intensive surveillance, she was transferred to her primary hospital. Conclusions: The route of delivery, as well as an adequate choice of the anesthetic technique, can be the difference between success and fatality. Regional techniques are usually recommended over the general anesthesia technique, as long as there are no contraindications(AU)

Do the Different Types of Pulmonary Hypertension Cause the Same Effect on Right Heart and Serum Asymmetrical Dimethylarginine Levels in Female Patients?

ABSTRACT Objective: Right-heart function is a major determinant of clinical outcome in patients with elevated pulmonary artery pressure due to pulmonary venous hypertension (PVH) and pulmonary arterial hypertension (PAH). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. This study aimed to evaluate if different types of pulmonary hypertension (PH) would cause the same effect on right-heart functions and serum ADMA levels in female patients. Methods: This study included patients with PAH as group I, patients with PVH due to mitral stenosis (mitral valve area ≤ 1.5 cm2, without any additional valve or left-heart disease and systolic pulmonary artery pressure ≥ 50 mmHg in transthoracic echocardiography) as group II, and healthy control subjects as group III. Transthorasic echocardiographic evaluations for right-heart functions were performed according to the guidelines of the American Society of Echocardiography. Venous blood samples were collected, and the serum ADMA concentrations were obtained with the ELISA kit (DRG® International Inc., Springfield, NJ, USA). Results: Patients in groups I and II had higher ADMA levels than healthy control subjects. Right-atrium area and dimensions, right-ventricular (RV) volumes, grade of tricuspid regurgitation, systolic pulmonary arterial pressure, RV wall thickness, and RV outflow tract diameters were significantly higher in group I patients than in group II patients. Right-ventricular myocardial performance index was lower, and RV fractional area change and tricuspid valve systolic tissue Doppler velocity were higher in group II patients than in group I patients. Conclusion: This study demonstrated that both PAH and PVH caused increase in right-heart dimensions and impairment in right-heart functions.

Osthole attenuates pulmonary arterial hypertension by modulation of phospholipid metabolism / 中国药理学与毒理学杂志

OBJECTIVE Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease lacking efficacy therapeutics. Therefore, it urgently needs to develop safe and effective drugs for PAH treatment. Osthole derived from Cnidium monnieri (L.) Cusson (Shechuangzi) or Angelica pubescens Maxim (Duhuo) has the capacity to alleviate PAH by decreasing pulmonary arterial pressure and alleviating pulmonary vascular remodeling in rats, which is a candi?date drug for the prevention of PAH, but the underlying modulatory mechanism is still unclear. Our study aims at investi?gating the metabolic modulatory mechanism of osthole against PAH employing functional metabolomics strategy. METH?ODS PAH model rats were successfully established with MCT, following osthole administration, then functional metabo?lomics based on untargeted metabolomics assay, targeted lipidomics analysis, qRT-PCR, Western blotting and ELISA were performed to investigate the modulatory mechanism of osthole against pulmonary arterial pressure and pulmonary vascular remodeling in PAH. RESULTS Untargeted metabolomics results found that sphingosine 1-phosphate (S1P) was the differential metabolites characterized PAH and reversed by osthole treatment. S1P is a crucial sphingolipid metabolite catalyzed by sphingosine kinases1 (Sphk1) and functions as promoting PASMCs proliferation contributing to pulmonary vascular remodeling and pulmonary arterial pressure increase. We revealed that osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 via inactivating microRNA-21-PI3K/Akt/mTOR signal pathway to decrease pulmonary arterial pressure in rats with PAH. Then, targeted phospholipid metabolomics results uncovered that decadienyl-L-carnitine (C10:2) was the differential metabolite characterized PAH and corrected by osthole treatment in rat with PAH. C10:2 is the intermediate metabolite of fatty acid oxidation (FAO), and C10:2 accumulation indicated mitochondrial dysfunction and FAO increase. CONCLUSION Osthole could block lipid metabolic reprogramming through functional modulating the expression of fatty acid translocase, fatty acid synthase, phospholipase A2, carnitine palmitoyltransferase 1A to inhibit C10:2, thus to improve mitochondrial dysfunction and inhibit utilizing lipid to biosyn?thesize necessary essence for pulmonary artery smooth muscle cells (PASMCs) proliferation. Moreover, we delineated that C10:2 and metabolic reprogramming enzymes were modulated by miRNA-22-3p which was involved in PASMCs proliferation and pulmonary vascular remodeling. Therefore, osthole inhibited miRNA-22-3p mediated lipid metabolic reprogramming to ameliorate pulmonary vascular remodeling.

Drugs and drug delivery strategies for treatment of pulmonary arterial hypertension / 药学学报

Pulmonary arterial hypertension (PAH), also named as a cancer of cardiovascular disease, is a rare disease and has complicated pathogenesis. Recently, there are more understandings of PAH pathogeneses. According to the pathogenesis and active pathways, the clinically used drugs are classified into several groups incluidng prostacyclin analogues and prostacyclin receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase inhibitors, etc. To elevate the efficacy of the drugs, numerous drug delivery systems are developed. This review mainly summarized the pathological mechanism of PAH, drugs and drug delivery approaches in the treatment of PAH.

Mechanism of pulmonary artery remodeling induced by calcium overload induced by hypoxia / 药学学报

Patients with hypoxia pulmonary hypertension (HPH) are often accompanied by dyspnea, fatigue, and headache. With the development of the disease, the right ventricle gradually collapses and eventually leads to death. Hypoxic pulmonary vascular remodeling is an important pathological basis of HPH, and the remodeled pulmonary vessels will form permanent thickening. The mechanism of hypoxic pulmonary vascular remodeling is relatively complex. At present, there are few studies on drugs for pulmonary vascular remodeling on the market, mainly focusing on the alleviation of pulmonary vasoconstriction. It was found that hypoxia induces calcium overload in pulmonary artery smooth muscle cells (PASMCs), resulting in the proliferation of PASMCs. The main mechanisms include: ① abnormal expression of calcium pumps; ② abnormal calcium channels in the plasma membrane of pulmonary artery smooth muscle cells; ③ overexpression of calcium-sensitive receptors in cells; ④ the expression of Na+/Ca2+ exchanger type-1 was abnormal. This review summarized several mechanisms of hypoxia induced calcium overload leading to pulmonary artery remodeling, hoping to provide a new idea for the treatment of HPH.

Rhodiola crenulata extract decreases fatty acid oxidation and autophagy to ameliorate pulmonary arterial hypertension by targeting inhibiton of acylcarnitine in rats / 中国天然药物

Pulmonary arterial hypertension (PAH) is a devastating pulmonary circulation disease lacking high-efficiency therapeutics. The present study aims to decipher the therapeutic mechanism of Rhodiola crenulata, a well-known traditional chinese medicine with cardiopulmonary protection capacity, on PAH by exploiting functional lipidomics. The rat model with PAH was successfully established for first, following Rhodiola crenulata water extract (RCE) treatment, then analysis of chemical constituents of RCE was performed, additional morphologic, hemodynamic, echocardiographic measurements were examined, further targeted lipidomics assay was performed to identify differential lipidomes, at last accordingly mechanism assay was done by combining qRT-PCR, Western blot and ELISA. Differential lipidomes were identified and characterized to differentiate the rats with PAH from healthy controls, mostly assigned to acylcarnitines, phosphatidylcholines, sphingomyelin associated with the PAH development. Excitingly, RCE administration reversed high level of decadienyl-L-carnitine by the modulation of metabolic enzyme CPT1A in mRNA and protein level in serum and lung in the rats with PAH. Furthermore, RCE was observed to reduce autophagy, confirmed by significantly inhibited PPARγ, LC3B, ATG7 and upregulated p62, and inactivated LKB1-AMPK signal pathway. Notably, we accurately identified the constituents in RCE, and delineated the therapeutic mechansim that RCE ameliorated PAH through inhibition of fatty acid oxidation and autophagy. Altogether, RCE might be a potential therapeutic medicine with multi-targets characteristics to prevent the progression of PAH. This novel findings pave a critical foundation for the use of RCE in the treatment of PAH.