RESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17, which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. METHODS: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico-predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17-signal 1 enhancer region (SOX17-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. RESULTS: CRISPR inhibition of SOX17-signal 2 and deletion of SOX17-signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Ratones , Animales , Hipertensión Pulmonar/metabolismo , Estudio de Asociación del Genoma Completo , Células Endoteliales/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar , Hipoxia/metabolismo , Hipertensión Pulmonar Primaria Familiar/metabolismo , Factores de Transcripción/metabolismo , Proteínas HMGB/genética , Proteínas HMGB/metabolismo , Factores de Transcripción SOXF/genética , Factores de Transcripción SOXF/metabolismoRESUMEN
Atrial natriuretic peptide (ANP) protects against acute lung injury (ALI), but the receptor that mediates this effect is not known. Transgenic mice with 0 (knockout), 1 (heterozygote), or 2 (wild-type) functional copies of Npr3, the gene that encodes for natriuretic peptide receptor-C (NPR-C), were treated with intravenous infusion of ANP or saline vehicle before oropharyngeal aspiration of Pseudomonas aeruginosa (PA103) or saline vehicle. Lung injury was assessed 4 h following aspiration by measurement of lung wet/dry (W/D) weight, whole lung leukocyte and cytokine levels, and protein, leukocyte, and cytokine concentration in bronchoalveolar lavage fluid (BALF). PA103 induced acute lung injury as evidenced by increases in lung W/D ratio and protein concentration in BALF. The severity of PA103-induced lung injury did not differ between NPR-C genotypes. Treatment with intravenous ANP infusion reduced PA103-induced increases in lung W/D and BALF protein concentration in all three NPRC genotypes. PA103 increased the percentage of leukocytes that were neutrophils and cytokine levels in whole lung and BALF in NPR-C wild-type and knockout mice. This effect was blunted by ANP in wild-type mice but not in the NPR-C knockout mice. NPR-C does not mediate the protective effect of ANP on endothelial cell permeability in settings of PA103-induced injury but may mediate the effect of ANP on inhibition of the recruitment of neutrophils to the lung and thereby attenuate the release of inflammatory cytokines.
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Lesión Pulmonar Aguda , Factor Natriurético Atrial , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Factor Natriurético Atrial/farmacología , Citocinas/metabolismo , Pulmón/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Infiltración Neutrófila , Receptores del Factor Natriurético Atrial/genética , Receptores del Factor Natriurético Atrial/metabolismoRESUMEN
INTRODUCTION: While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States. METHODS: Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score. RESULTS: We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0â years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0â points (range -5.0--7.6â points). CONCLUSIONS: The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Adulto , Anciano , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Calidad de Vida , Reino UnidoRESUMEN
Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Adulto , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéuticoRESUMEN
Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect are unknown. We sought to determine the efficacy and mechanism of mesenchymal stem cells' extracellular vesicles in attenuating pulmonary hypertension in rats with Sugen/hypoxia-induced pulmonary hypertension. Male rats were treated with mesenchymal stem cell extracellular vesicles or an equal volume of saline vehicle by tail vein injection before or after subcutaneous injection of Sugen 5416 and exposure to 3 weeks of hypoxia. Pulmonary hypertension was assessed by right ventricular systolic pressure, right ventricular weight to left ventricle + septum weight, and muscularization of peripheral pulmonary vessels. Immunohistochemistry was used to measure macrophage activation state and recruitment to lung. Mesenchymal stem cell extracellular vesicles injected before or after induction of pulmonary hypertension normalized right ventricular pressure and reduced right ventricular hypertrophy and muscularization of peripheral pulmonary vessels. The effect was consistent over a range of doses and dosing intervals and was associated with lower numbers of lung macrophages, a higher ratio of alternatively to classically activated macrophages (M2/M1 = 2.00 ± 0.14 vs. 1.09 ± 0.11; P < 0.01), and increased numbers of peripheral blood vessels (11.8 ± 0.66 vs. 6.9 ± 0.57 vessels per field; P < 0.001). Mesenchymal stem cell extracellular vesicles are effective at preventing and reversing pulmonary hypertension in Sugen/hypoxia pulmonary hypertension and may offer a new approach for the treatment of pulmonary arterial hypertension.
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Vesículas Extracelulares/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Hipoxia/complicaciones , Indoles/efectos adversos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Pirroles/efectos adversos , Animales , Fibroblastos/metabolismo , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Activación de Macrófagos , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso/patología , Neovascularización Fisiológica , Ratas Sprague-Dawley , Remodelación Vascular , Factor de von Willebrand/metabolismoRESUMEN
Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis.
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Arteria Pulmonar , Enfermedades Vasculares , Catéteres , Células Cultivadas , Células Endoteliales , Humanos , PulmónRESUMEN
Pulmonary arterial hypertension (PAH) is a rare form of pulmonary hypertension characterized by a progressive obliterative vasculopathy of the distal pulmonary arterial circulation that usually leads to right ventricular failure and death. Over the last 25 years, more than a dozen drugs representing five drug classes have been developed and approved for the treatment of this devastating disease. Due to the small number of patients afflicted by PAH, most health care providers have little experience with its management. To address this gap in medical knowledge, treatment guidelines have been developed by professional organizations and expert committees. Over the last few years, these guidelines have been updated to address findings from recent clinical trials and ongoing experience with these drugs. This review provides an update on the most recently published treatment guidelines for pharmacologic treatment of PAH and incorporates them into a contemporary approach to the treatment of this disease.
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Hipertensión Arterial Pulmonar/terapia , Humanos , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/etiologíaRESUMEN
Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling and ultimately death. Two rodent models of PH include treatment with monocrotaline or exposure to a vascular endothelial growth factor receptor inhibitor and hypoxia. Studies in these models indicated that damaged lung cells evolve extracellular vesicles which induce production of progenitors that travel back to the lung and induce PH. A study in patients with pulmonary myelofibrosis and PH indicated that 100 cGy lung irradiation could remit both diseases. Previous studies indicated that murine progenitors were radiosensitive at very low doses, suggesting that 100 cGy treatment of mice with induced PH might be an effective PH therapy. Our hypothesis is that the elimination of the PH-inducing marrow cells by low dose irradiation would remove the cellular influences creating PH. Here we show that low dose whole-body irradiation can both prevent and reverse established PH in both rodent models of PH.
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Hipertensión Pulmonar , Irradiación Corporal Total , Animales , Células de la Médula Ósea/efectos de la radiación , Ratones , RadioterapiaRESUMEN
Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.
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Hipertensión Pulmonar/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Remodelación Vascular , Animales , Humanos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Venas Pulmonares/metabolismo , Venas Pulmonares/patología , Transducción de Señal/fisiologíaRESUMEN
High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55â years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1â µg·dL-1) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.
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Enfermedades del Tejido Conjuntivo/complicaciones , Sulfato de Deshidroepiandrosterona/sangre , Estradiol/sangre , Cardiopatías Congénitas/complicaciones , Hipertensión Pulmonar/sangre , Posmenopausia/sangre , Anciano , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión Pulmonar/complicaciones , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Prueba de PasoRESUMEN
RATIONALE: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown. OBJECTIVES: We aimed to determine the safety and efficacy of anastrozole in PAH. METHODS: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers. MEASUREMENTS AND MAIN RESULTS: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17ß-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: -40%; interquartile range [IQR], -61 to -26% vs. -4%; IQR, -14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = -12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo -2%; IQR, -7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events. CONCLUSIONS: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH. Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).
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Inhibidores de la Aromatasa/uso terapéutico , Hormonas Esteroides Gonadales/sangre , Hipertensión Pulmonar/tratamiento farmacológico , Nitrilos/uso terapéutico , Esteroides/sangre , Triazoles/uso terapéutico , Anastrozol , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/efectos adversos , Biomarcadores/sangre , Método Doble Ciego , Estradiol/sangre , Estrona/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Progesterona/sangre , Triazoles/administración & dosificación , Triazoles/efectos adversosRESUMEN
Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct type of pulmonary hypertensive disease, characterized by incomplete or abnormal resolution of acute pulmonary embolism such that residual emboli become organized and fibrotic. CTEPH can occur in patients without a prior history of venous thromboembolism, and is diagnosed based on precapillary pulmonary hypertension on right heart catheterization with evidence of chronic emboli on ventilation/perfusion scan, chest imaging, or pulmonary angiogram. Pulmonary endarterectomy (PEA) is often curative, and results in improved survival. In patients for whom PEA is not feasible, medical therapy has been effective in improving hemodynamics and functional capacity.
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Hipertensión Pulmonar/etiología , Embolia Pulmonar/complicaciones , Cateterismo Cardíaco/métodos , Enfermedad Crónica , Endarterectomía/métodos , Hemodinámica , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/terapia , Arteria Pulmonar/patología , Embolia Pulmonar/terapiaRESUMEN
A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440â m, cardiac index <3.0â L·min-1·m-2 and pulmonary vascular resistance >400â dyn·s·cm-5 underwent a 1-3â day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5â mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63â m, NT-proBNP decreased by 347±1235â pg·mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.
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Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Antihipertensivos/efectos adversos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Europa (Continente) , Femenino , Humanos , Hipertensión Pulmonar/mortalidad , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , América del Norte , Fragmentos de Péptidos/sangre , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Estudios Prospectivos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacos , Prueba de Paso , Organización Mundial de la Salud , Adulto JovenRESUMEN
RATIONALE: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. OBJECTIVES: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. METHODS: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. CONCLUSIONS: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.
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Sulfato de Deshidroepiandrosterona/sangre , Estradiol/sangre , Hipertensión Pulmonar/sangre , Anciano , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Although frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate end point for clinical events in pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We performed a patient-level pooled analysis of 4 randomized, placebo-controlled trials to determine whether treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, or escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 years (37-59 years), and 23% were men. A total of 656 patients (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance and increased cardiac output and index (P<0.01 for all). Changes in hemodynamic values (except for right atrial pressure and mean pulmonary artery pressure) were significantly associated with the risk of a clinical event (P<0.02 for all). Although active treatment approximately halved the odds of a clinical event compared with placebo (P<0.001), changes in hemodynamics accounted for only 1.2% to 13.9% of the overall treatment effect. CONCLUSIONS: Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate end points for short-term events in PAH clinical trials.
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Hemodinámica , Hipertensión Pulmonar/fisiopatología , Adulto , Biomarcadores , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Acute pulmonary embolism (PE) can diminish patient quality of life (QoL). The objective was to test whether treatment with tenecteplase has an independent effect on a measurement that reflects QoL in patients with submassive PE. This was a secondary analysis of an 8-center, prospective randomized controlled trial, utilizing multivariate regression to control for predefined predictors of worsened QoL including: age, active malignancy, history of PE or deep venous thrombosis (DVT), recurrent PE or DVT, chronic obstructive pulmonary disease and heart failure. QoL was measured with the physical component summary (PCS) of the SF-36. Analysis included 76 patients (37 randomized to tenecteplase, 39 to placebo). Multivariate regression yielded an equation f(8, 67), P < 0.001, with R(2) = 0.303. Obesity had the largest effect on PCS (ß = -8.6, P < 0.001), with tenecteplase second (ß = 4.73, P = 0.056). After controlling for all interactions, tenecteplase increased the PCS by +5.37 points (P = 0.027). In patients without any of the defined comorbidities, the coefficient on the tenecteplase variable was not significant (-0.835, P = 0.777). In patients with submassive PE, obesity had the greatest influence on QoL, followed by use of fibrinolysis. Fibrinolysis had a marginal independent effect on patient QoL after controlling for comorbidities, but was not significant in patients without comorbid conditions.
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Fibrinólisis/efectos de los fármacos , Fibrinolíticos/administración & dosificación , Embolia Pulmonar/tratamiento farmacológico , Calidad de Vida , Activador de Tejido Plasminógeno/administración & dosificación , Enfermedad Aguda , Adulto , Anciano , Femenino , Fibrinolíticos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Obesidad , Estudios Prospectivos , Factores de Riesgo , Tenecteplasa , Activador de Tejido Plasminógeno/efectos adversosRESUMEN
Female sex is a risk factor for pulmonary arterial hypertension (PAH), yet females have better survival than males. We sought to determine if sex was associated with baseline haemodynamics in subjects with PAH, and whether age modified these relationships. We conducted a pooled analysis from 11 randomised trials submitted to the US Food and Drug Administration. The study sample included 1211 subjects with idiopathic PAH, 25% of whom were males, and 489 subjects with connective tissue disease-associated PAH, 13% of whom were males. After multivariable adjustment, right atrial pressure was 1.36 mmHg higher (95% CI 0.44-2.27, p=0.004), cardiac index was -0.14 L · min(-1) · m(-2) lower (95% CI -0.23-0.04, p=0.01) and pulmonary vascular resistance was 1.23 Wood units higher (95% CI 0.18-2.27, p=0.02) in males compared with females. Younger males had 5.43 mmHg (95% CI 2.20-8.66, p=0.001) higher mean pulmonary arterial pressures than younger females, but these relationships were attenuated after age 45 years. In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure. These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH.