Elevated Interleukin-6 Levels Predict Clinical Worsening in Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To assess whether circulating interleukin-6 (IL-6) is associated with measures of disease severity and clinical worsening in pediatric pulmonary arterial hypertension (PAH). STUDY DESIGN: IL-6 was measured by enzyme-linked immunosorbent assay in serum samples from a cross-sectional cohort from the National Heart, Lung, and Blood Institute Pulmonary Arterial Hypertension Biobank (n = 175) and a longitudinal cohort from Children's Hospital Colorado (CHC) (n = 61). Associations between IL-6, disease severity, and outcomes were studied with regression and Kaplan-Meier analysis. RESULTS: In analyses adjusted for age and sex, each log-unit greater IL-6 was significantly associated in the Pulmonary Arterial Hypertension Biobank cohort with greater pulmonary vascular resistance indices, lower odds of having idiopathic PAH or treatment with prostacyclin, and greater odds of having PAH associated with a repaired congenital shunt. In the CHC cohort, each log-unit greater IL-6 was significantly associated with greater mean pulmonary arterial pressure over time. Kaplan-Meier analysis in the CHC cohort revealed that IL-6 was significantly associated with clinical worsening (a composite score of mortality, transplant, or palliative surgery) (P = .037). CONCLUSIONS: IL-6 was significantly associated with worse hemodynamics at baseline and over time and may be associated with clinical worsening. IL-6 may provide a less-invasive method for disease monitoring and prognosis in pediatric PAH as well as a potential therapeutic target.

Serial Measurements of N-Terminal Pro-B-Type Natriuretic Peptide Serum Level for Monitoring Pulmonary Arterial Hypertension in Children.

OBJECTIVE: To assess the association between serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum levels and disease severity in children with pulmonary arterial hypertension (PAH), and to assess its predictive value for death or (heart-)lung transplantation. STUDY DESIGN: This was a longitudinal cohort study of the Dutch National Network for Pediatric Pulmonary Hypertension conducted between 2003 and 2017. Data on NT-proBNP and disease severity markers (World Health Organization Functional Class [WHO-FC], 6-minute walking distance [6MWD], and tricuspid annular plane systolic excursion [TAPSE]) were collected every 3 to 6 months from 82 children with PAH. The outcome measure was death or (heart-)lung transplantation. Also, NT-proBNP levels over time were compared between survivors and nonsurvivors. RESULTS: The median patient age was 8.8 years (IQR, 4.6-13.5 years), and 61% were female. The median duration of follow-up was 4.8 years (IQR, 1.9-10.0 years). At all times during the course of disease, higher NT-proBNP levels were associated with higher WHO-FC (ß = 0.526; 95% CI, 0.451-0.600), lower 6MWD z-score (ß = -0.587; 95% CI, -0.828 to -0.346), lower TAPSE z-score (ß = -0.783; 95% CI, -1.016 to -0.549), and elevated risk of death or (heart-)lung transplantation (hazard ratio 16.61; 95% CI, 7.81-35.33). Compared with survivors, nonsurvivors had NT-proBNP levels that were higher at first measurement and increased exponentially over time (P = .005). Changes in NT-proBNP serum level over time were predictive of outcome. CONCLUSIONS: Throughout the disease course of pediatric PAH, serial measurements of NT-proBNP are associated with disease severity and transplant-free survival. Monitoring NT-proBNP levels over time provides important prognostic information that can support clinical decision making in combination with other established prognostic markers.

Demographic and clinical characteristics of pulmonary arterial hypertension caused by schistosomiasis are indistinguishable from other etiologies.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious pulmonary circulation disease caused by several etiologies, including schistosomiasis. The present study retrospectively evaluated the clinical and hemodynamic characteristics of patients with schistosomal PAH (PAH-Sch) compared to those of non-Sch PAH patients (non-Sch PAH). METHODS: Patients treated at the Pronto-Socorro Cardiológico de Pernambuco and diagnosed by right cardiac catheterization were divided into PAH-Sch and non-Sch PAH groups. Their socio-demographic and clinical characteristics, N-terminal-pro B-type natriuretic peptide (NT-proBNP), and echocardiography and hemodynamic parameters were retrospectively reviewed. RESULTS: Among the included 98 patients (mean age, 45 ± 14 years; 68 women [69.4%]), we found 56 PAH-Sch and 42 non-Sch PAH. The age distribution was heterogeneous in the PAH-Sch group, with patients predominantly ranging from 50-59 (p <0.004). Dyspnea was the most common symptom, reported by 92 patients (93.8%), and commonly present for over two years prior to diagnosis. Clinical symptoms were similar in both groups, with no differences in functional class, pulmonary artery systolic pressure (p = 0.102), 6-minute walk test score (p = 0.234), NT-proBNP serum levels (p = 0.081), or hemodynamic parameters. CONCLUSIONS: Patients with PAH-Sch present clinical, laboratory, and hemodynamic profiles similar to those with PAH resulting from other etiologies of poor prognosis. PAH is an important manifestation of schistosomiasis in endemic regions that is often diagnosed late.

Demographic and clinical characteristics of pulmonary arterial hypertension caused by schistosomiasis are indistinguishable from other etiologies

Abstract INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious pulmonary circulation disease caused by several etiologies, including schistosomiasis. The present study retrospectively evaluated the clinical and hemodynamic characteristics of patients with schistosomal PAH (PAH-Sch) compared to those of non-Sch PAH patients (non-Sch PAH). METHODS: Patients treated at the Pronto-Socorro Cardiológico de Pernambuco and diagnosed by right cardiac catheterization were divided into PAH-Sch and non-Sch PAH groups. Their socio-demographic and clinical characteristics, N-terminal-pro B-type natriuretic peptide (NT-proBNP), and echocardiography and hemodynamic parameters were retrospectively reviewed. RESULTS: Among the included 98 patients (mean age, 45 ± 14 years; 68 women [69.4%]), we found 56 PAH-Sch and 42 non-Sch PAH. The age distribution was heterogeneous in the PAH-Sch group, with patients predominantly ranging from 50-59 (p <0.004). Dyspnea was the most common symptom, reported by 92 patients (93.8%), and commonly present for over two years prior to diagnosis. Clinical symptoms were similar in both groups, with no differences in functional class, pulmonary artery systolic pressure (p = 0.102), 6-minute walk test score (p = 0.234), NT-proBNP serum levels (p = 0.081), or hemodynamic parameters. CONCLUSIONS: Patients with PAH-Sch present clinical, laboratory, and hemodynamic profiles similar to those with PAH resulting from other etiologies of poor prognosis. PAH is an important manifestation of schistosomiasis in endemic regions that is often diagnosed late.

Menores niveles circulantes del péptido vasoactivo y cardioprotector angiotensina-(1-9) en pacientes con hipertension arterial pulmonar / Lower circulating levels of angiotensin-(1-9), a vasoactive and cardio-protective peptide in patients with pulmonary artery hypertension

RESUMEN: Introducción: La vía clásica del sistema renina-angiotensina (SRA) está activado en pacientes con hipertensión arterial pulmonar (HAP). Previamente, hemos encontrado que en la disfunción ventricular post infarto al miocardio experimental la activación del eje clásico del SRA, dado por la enzima convertidora de angiotensina I (ECA) y angiotensina (Ang ) II se correlaciona negativamente con el eje paralelo del SRA dado por la ECA homóloga (ECA2) y el péptido vasoactivo y cardioprotector Ang-(1-9). Resultados preclínicos muestran la eficacia de la administración de Ang-(1-9) en el tratamiento del remodelamiento cardiovascular patológico. Hasta la fecha no existen antecedentes de los niveles circulantes de Ang-(1-9) en pacientes con hipertensión arterial pulmonar comparados con sujetos sanos. Objetivo: Determinar los niveles circulantes del péptido vasoactivo y cardiprotector Ang-(1-9) en pacientes con HAP y compararlos con sujetos sanos pareados por edad y sexo. Métodos: Estudio comparativo transversal en pacientes con HAP (grupo I, OMS) con presión de arteria pulmonar media (mPAP) ≥25 mmHg bajo tratamiento con furosemida (40%), espironolactona (53%), Acenocumarol/Warfarina (47%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) y digoxina (13%). Los sujetos controles correspondieron a sujetos asintomáticos sanos sin enfermedad cardiovascular, cardiopatía estructural ni pulmonar (n=14). En todos los pacientes se determinó mPAP, proBNP, resistencia vascular pulmonar (RVP, WU), presión capilar pulmonar (PCP, mmHg), gasto cardíaco (L/min), capacidad funcional por test de caminata 6 minutos (TC6M), cambio del área fraccional del ventrículo derecho VD (FAC, %). Se utilizó prueba t de Student y programa estadístico SPSS10.0. Un valor de p < 0,05 fue considerado como estadísticamente significativo. Resultados: Los pacientes ingresados al estudio mostraron: etiología de la HAP, idiopática (86,7%), VIH (13,3%), capacidad funcional I (6,2%), II (68,3) y III (25%) y promedio mPAP 51,3±1,9. Pacientes con HAP (grupo I, OMS) versus sujetos sanos mostraron disminución significativa de FAC, actividad plasmática de la ECA2 y niveles circulantes de Ang-(1-9). En la vía clásica del RAAS pacientes con HAP mostraron mayor actividad plasmática de ECA y niveles circulantes e Ag II. Correlaciones significativas se encontraron entre niveles de Ang-(1-9) y mPAP (r = -0.701, p < 0,001) y Ang-(1-9) vs FAC (r = 0.549, p < 0,01). Conclusiones: En pacientes con HAP (grupo I, OMS), los niveles circulantes de Ang-(1-9) están significativamente disminuidos y se asocian inversamente con la PAP, severidad del remodelamiento y disfunción del ventrículo derecho. El uso terapéutico de Ang-(1-9) como agente vasodilatador y cardioprotector podría ser relevante y potencialmente útil, desde una perspectiva clínica, en la HAP. Ang-(1-9) podría reducir la PAP y mejorar el remodelamiento vascular y del ventrículo derecho en la HAP. Por lo tanto, este péptido podría ser útil como blanco terapéutico en la HAP.

ABSTRACTS: Classic renin-angiotensis pathway (RAP) is activated in patients with pulmonary artery hypertension (PAH). We have previously shown that in patients with post myocardial infarction systolic dysfunction the activation of RAP mediated by angiotensin converting enzyme (ACE) and angiotensin II (Ang II) is inversely correlated with the parallel RAP axis mediated by homologous ACE (ACE2) and by the vasoactive and cardioprotective peptide Ang-(1-9). Pre clinical studies show that administration of Ang-(1-9) leads to a favorable ventricular remodelling. At present there is no information regarding levels of Ang-(1-9) in PAH patients compared to healthy subjects. Methods: 16 PAH patients (WHO group 1), with mean PA pressure > 25mmHg being treated with furosemide (40%), Bosentan/Ambrisentan (27%), Sildenafil (80%), iloprost (7%) were compared with healthy subjects (n=14). mPAP, pro BNP, pulmonary vascular resistance (Wu), pulmonary capillary pressure (PCP mmHg), cardiac output (L/min), functional capacity (6 min walking test) (6mWT), and changes in right ventricular fractional area (RV FA), were measured in all subjects. Results: In HAP subjects, the eiotology of PAH was unknown in 87%, or HIV (13%). Functional class was I (6.2 %), II (68.3%) or III (25%). Mean PAP was 51.3±1.9. Compared to healthy subjects, PAH patients had significantly lower RV FA, ACE2 and Ang-(19) levels. Also they had greater ACE plasma activity and AngII circulating levels. Significant correlations were found between Ang-(1-9) and mPAP (-0.701, p < 0,001) and between Ang-(1-9) and RV FA (r = 0.549, p < 0,01). Conclusion: group I PAH subjects, circulating levels of Ang-(1-9) are significantly lower than in healthy subjects and are inversely related to PAP, severity of ventricular remodeling and right ventricular dysfunction. The use of Ang-(1-9) as a vasodilator and cardioprotector agent could be clinically useful in PAH subjects.