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BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.
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Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF) associated pulmonary hypertension (PH) (PF-PH). Weighted gene co-expression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR) and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, while the tan and darkgrey modules positively correlated with PVR. Additionally, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for Treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for Bone morphogenetic protein loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated co-expression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.
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Pulmonary hypertension is one of the highest risk medical conditions in pregnancy and carries significant maternal morbidity and mortality as well as neonatal morbidity. Diagnosis is commonly delayed due to the nonspecific nature of early symptoms. Disease progression can lead to right ventricular failure, which carries mortality rates as high as 25% to 56%. Pregnancy-related complications arise from cardiac inability to accommodate increased plasma volume and cardiac output, decreased systemic vascular resistance, and hypercoagulability. Patients in this high-risk cohort necessitate preconception risk stratification and multidisciplinary care throughout their pregnancy and delivery planning.
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Insuficiência Cardíaca , Hipertensão Pulmonar , Complicações Cardiovasculares na Gravidez , Gravidez , Recém-Nascido , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/diagnóstico , Período Pós-Parto , Débito Cardíaco , Insuficiência Cardíaca/complicações , Medição de RiscoRESUMO
BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.
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Hipertensão Arterial Pulmonar , Humanos , Voluntários Saudáveis , Óxido Nítrico , Estudos de Coortes , Hipertensão Pulmonar Primária Familiar , Imagem de Perfusão , Biomarcadores , OxigênioRESUMO
Rationale: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.Objectives: To determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.Methods: Single-cell RNA sequencing was performed on the lungs of monocrotaline (MCT), Sugen-hypoxia (SuHx), and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.Measurements and Main Results: Distinct changes in genes and pathways in numerous cell types were identified in SuHx and MCT lungs. Widespread upregulation of NF-κB signaling and downregulation of IFN signaling was observed across cell types. SuHx nonclassical monocytes and MCT conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in SuHx nonclassical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.research.idre.ucla.edu/PVDSingleCell/).Conclusions: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.
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Anti-Hipertensivos/uso terapêutico , Células Cultivadas/efeitos dos fármacos , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O2) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9-/- mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
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Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adesão Celular/fisiologia , Hipóxia/fisiopatologia , Circulação Pulmonar/fisiologia , Embolia Pulmonar/fisiopatologia , Transdução de Sinais/fisiologia , Animais , Plaquetas/fisiologia , Células Cultivadas/fisiologia , Células Endoteliais/fisiologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos AnimaisRESUMO
Extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) in the setting of pulmonary arterial hypertension (PAH) is an increasingly recognized disease entity. LMCA compression has been associated with angina, arrhythmia, heart failure, and sudden cardiac death in patients with PAH. Recent studies suggest that at least 6% of patients with PAH have significant LMCA compression. Screening for LMCA compression can be achieved with computed coronary tomography angiography, with a particular emphasis on assessment of PA size and any associated downward displacement and reduced takeoff angle of the LMCA. Indeed, evidence of a dilated PA (>40 mm), a reduced LMCA takeoff angle (<60°), and/or LMCA stenosis on CCTA imaging should prompt further diagnostic evaluation. Coronary angiography in conjunction with intravascular imaging has proven effective in diagnosing LMCA compression and guiding subsequent treatment. While optimal medical therapy and surgical correction remain in the clinician's arsenal, percutaneous coronary intervention has emerged as an effective treatment for LMCA compression. Given the prevalence of LMCA compression, its associated morbidity, and mortality, and the wide array of successful treatment strategies, maintaining a high degree of suspicion for this condition, and understanding the potential treatment strategies is critical.
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Angioplastia Coronária com Balão , Estenose Coronária , Hipertensão Pulmonar , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/terapia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Artéria Pulmonar/diagnóstico por imagem , Stents , Resultado do TratamentoRESUMO
Treatment of patients with intermediate and high-risk pulmonary embolism (PE) is a controversial area. Many therapeutic options exist, and deciding on appropriate treatment can be difficult. In addition, multiple specialties are often involved in the care of PE patients. To better organize the response to serious PE patients, several hospitals and academic centers throughout the world have created pulmonary embolism response teams (PERTs). The goal of a PERT is to have a single multidisciplinary team of experts in thromboembolic disease, who can respond rapidly to patients with acute PE, and offer consultation and implementation of the full spectrum of therapeutic options. PERT teams were modeled after rapid response teams and are meant to generate a prompt, patient-specific plan for patients with PE without having to consult multiple individual specialists. Data are emerging demonstrating the value of PERTs in reducing hospital length of stay and, possibly, patient outcomes.
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Equipe de Assistência ao Paciente , Embolia Pulmonar , Doença Aguda , Humanos , Embolia Pulmonar/terapia , Encaminhamento e ConsultaRESUMO
BACKGROUND: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting the use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) provides an opportunity to assess the prognostic value of NT-proBNP thresholds in a controlled clinical trial and to evaluate the response to selexipag according to these thresholds. METHODS: The event-driven GRIPHON trial randomly assigned patients to selexipag or placebo. NT-proBNP was measured at regular intervals in GRIPHON. Here, patients were categorized post hoc into low, medium, and high NT-proBNP subgroups according to 2 independent sets of thresholds: (1) baseline tertiles: <271 ng/L; 271 to 1165 ng/L; >1165 ng/L; and (2) 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs: <300 ng/L; 300 to 1400 ng/L; >1400 ng/L. Hazard ratios (selexipag versus placebo) with 95% CIs were calculated for the primary end point (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazards models, and at any time during the exposure period using a time-dependent Cox model. RESULTS: With both thresholds, baseline and follow-up NT-proBNP categories were highly prognostic for future morbidity/mortality events during the study ( P<0.0001). In the time-dependent analysis, the risk of experiencing a morbidity/mortality event was 92% and 83% lower in selexipag-treated patients with a low and medium NT-proBNP level, and 90% and 56% lower in placebo-treated patients with a low and medium NT-proBNP level, in comparison with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all 3 NT-proBNP categories in both the baseline and time-dependent analyses, with a more pronounced treatment benefit of selexipag seen in the medium and low NT-proBNP subgroups (interaction P values 0.20 and 0.007 in the baseline and time-dependent analyses). CONCLUSIONS: These analyses further establish the prognostic relevance of NT-proBNP levels in PAH and provide first evidence for the association of NT-proBNP level and treatment response. Using 2 similar sets of thresholds, these analyses support the relevance of the low, medium, and high NT-proBNP categories as part of the multiparametric risk assessment approach outlined in the European Society of Cardiology/European Respiratory Society guidelines for the management of PAH patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01106014.
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Pressão Arterial , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Hipertensão Arterial Pulmonar/sangue , Artéria Pulmonar/fisiopatologia , Acetamidas/uso terapêutico , Adolescente , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/mortalidade , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Pirazinas/uso terapêutico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemAssuntos
Hipertensão Pulmonar , Pneumonias Intersticiais Idiopáticas , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Pneumonias Intersticiais Idiopáticas/complicações , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Idoso , Pulmão/diagnóstico por imagem , Pulmão/irrigação sanguínea , Pulmão/fisiopatologiaRESUMO
RATIONALE: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. OBJECTIVES: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. MEASUREMENTS AND MAIN RESULTS: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.
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Proteínas Morfogenéticas Ósseas/metabolismo , Hipertensão Portal/metabolismo , Hipertensão Portal/fisiopatologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Pulmonary arterial hypertension (PAH) remains a severe clinical condition despite the availability over the past 15â years of multiple drugs interfering with the endothelin, nitric oxide and prostacyclin pathways. The recent progress observed in medical therapy of PAH is not, therefore, related to the discovery of new pathways, but to the development of new strategies for combination therapy and on escalation of treatments based on systematic assessment of clinical response. The current treatment strategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric risk stratification approach. Clinical, exercise, right ventricular function and haemodynamic parameters are combined to define a low-, intermediate- or high-risk status according to the expected 1-year mortality. The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Further treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Lung transplantation may be required in most advanced cases on maximal medical therapy.
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Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/terapia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Transplante de Pulmão , Inibidores da Fosfodiesterase 5/uso terapêutico , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
The original version of the article unfortunately contained an error in conflict of interest. This erratum is published with the correct conflict of interest.
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Multidisciplinary pulmonary embolism response teams (PERTs) are being implemented to improve care of patients with life-threatening PE. We sought to determine how the creation of PERT affects treatment and outcomes of patients with serious PE. A pre- and post-intervention study was performed using an interrupted time series design, to compare patients with PE before (2006-2012) and after (2012-2016) implementation of PERT at a university hospital. T-tests, Chi square tests and logistic regression were used to compare outcomes, and multivariable regression were used to adjust for differences in PE severity. Two-sided p-value < 0.05 was considered significant. For the interrupted time-series analysis, data was divided into mutually exclusive 6-month time periods (11 pre- and 7 post-PERT). To examine changes in treatment and outcomes associated with PERT, slopes and change points were compared pre- and post-PERT. Two-hundred and twelve pre-PERT and 228 post-PERT patients were analyzed. Patient demographics were generally similar, though pre-PERT, PE were more likely to be low-risk (37% vs. 19%) while post-PERT, PE were more likely to be submassive (32% vs. 49%). More patients underwent catheter directed therapy (1% vs. 14%, p = < 0.0001) or any advanced therapy (19 [9%] vs. 44 [19%], p = 0.002) post PERT. Interrupted time series analysis demonstrated that this increase was sudden and coincident with implementation of PERT, and most noticeable among patients with submassive PE. There were no differences in major bleeding or mortality pre- and post-PERT. While the use of advanced therapies, particularly catheter-directed therapies, increased after creation of PERT, especially among patients with submassive PE, there was no apparent increase in bleeding.
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Atenção à Saúde/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Embolia Pulmonar/terapia , Atenção à Saúde/tendências , Medicina de Emergência/tendências , Feminino , Hospitais Universitários , Humanos , Estudos Longitudinais , Masculino , Equipe de Assistência ao Paciente/tendências , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoRESUMO
Pulmonary thromboendarterectomy (PTE) remains the only curative surgery for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative intensive care unit care challenges providers with unique disease physiology, operative sequelae, and the potential for detrimental complications. Central concerns in patients with CTEPH immediately after PTE relate to neurologic, pulmonary, hemodynamic, and hematologic aspects. Institutional experience in critical care for the CTEPH population, a multidisciplinary team approach, patient risk assessment, and integration of current concepts in critical care determine outcomes after PTE surgery. In this review, the authors will focus on specific aspects unique to this population, with integration of current available evidence and future directions. The goal of this review is to provide the cardiac anesthesiologist and intensivist with a comprehensive understanding of postoperative physiology, potential complications, and contemporary intensive care unit management immediately after pulmonary endarterectomy.
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Cuidados Críticos/métodos , Gerenciamento Clínico , Endarterectomia , Hipertensão Pulmonar/cirurgia , Cuidados Pós-Operatórios/métodos , Artéria Pulmonar/cirurgia , Embolia Pulmonar/cirurgia , Humanos , Hipertensão Pulmonar/etiologia , Embolia Pulmonar/complicaçõesRESUMO
BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 µg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).
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Acetamidas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Pirazinas/uso terapêutico , Acetamidas/efeitos adversos , Idoso , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/efeitos adversos , Pirazinas/efeitos adversosRESUMO
BACKGROUND: Health disparities have a major impact in the quality of life and clinical care received by minorities in the United States. Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder that affects children and adults and that, if untreated, results in premature death. The impact of health disparities in the diagnosis, treatment, and clinical outcome of patients with PAH has not been systematically investigated. OBJECTIVES: The specific goals of this research statement were to conduct a critical review of the literature concerning health disparities in PAH, identify major research gaps and prioritize direction for future research. METHODS: Literature searches from multiple reference databases were performed using medical subject headings and text words for pulmonary hypertension and health disparities. Members of the committee discussed the evidence and provided recommendations for future research. RESULTS: Few studies were found discussing the impact of health disparities in PAH. Using recent research statements focused on health disparities, the group identified six major study topics that would help address the contribution of health disparities to PAH. Representative studies in each topic were discussed and specific recommendations were made by the group concerning the most urgent questions to address in future research studies. CONCLUSIONS: At present, there are few studies that address health disparities in PAH. Given the potential adverse impact of health disparities, we recommend that research efforts be undertaken to address the topics discussed in the document. Awareness of health disparities will likely improve advocacy efforts, public health policy and the quality of care of vulnerable populations with PAH.
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Anti-Hipertensivos/normas , Política de Saúde , Disparidades em Assistência à Saúde , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Guias de Prática Clínica como Assunto , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sociedades Médicas , Estados Unidos , Adulto JovemRESUMO
Aims: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. Methods and results: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively). Conclusions: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.
Assuntos
Antagonistas dos Receptores de Endotelina/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Cateterismo Cardíaco , Progressão da Doença , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Pirimidinas/efeitos adversos , Fatores de Risco , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Disfunção Ventricular Direita/mortalidade , Disfunção Ventricular Direita/fisiopatologiaRESUMO
Patients with connective tissue disease-associated pulmonary arterial hypertension (PAH-CTD) have a poor prognosis compared with other aetiologies. The underlying CTD can influence treatment response and outcomes. We characterised the GRIPHON study PAH-CTD subgroup and evaluated response to selexipag.Of 334 patients with PAH-CTD, PAH was associated with systemic sclerosis (PAH-SSc) in 170, systemic lupus erythematosus (PAH-SLE) in 82 and mixed CTD/CTD-other in 82. For the primary composite endpoint of morbidity/mortality, hazard ratios (HR) and 95% CI were calculated using Cox proportional hazard models.Compared with the overall GRIPHON population, the CTD subgroup was slightly older with a greater proportion of females and shorter time since diagnosis. Patients with PAH-SSc appeared to be more impaired at baseline, with a more progressive disease course. The converse was observed for PAH-SLE. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41-0.85). Treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype (interaction p=0.87 and 0.89, respectively). Adverse events were predominately prostacyclin-related and known for selexipag treatment.GRIPHON has allowed the comprehensive characterisation of patients with PAH-CTD. Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH-SSc and PAH-SLE.