RESUMO
OBJECTIVE: Total cavo-pulmonary connection (TCPC) is a palliative treatment for single ventricular malformations. For high-risk patients (preoperative mean pulmonary arterial pressure, mPAP > 15 mmHg), between the inhaled and oral targeted medications, the application of intravenous treprostinil as a bridge therapy to achieve "seamless" management is core postoperative treatment. This study intends to explore the effect of different administration regimens on early postoperative recovery. METHODS: This was a retrospective cohort study. High-risk pediatric patients (age ≤ 14 years) who underwent TCPC procedure in Fu Wai Hospital from 2015 to 2022 were included. Since the regimen of treprostinil was standardized in our center in 2021, the patients in 2020 and before were included in group 1, patients in 2021 and 2022 were included in group 2. The hemodynamic parameters were compared before and after the maintenance dose of treprostinil. The differences of demographic characteristics, surgical data and postoperative recovery were compared between the two groups. RESULTS: A total of 51 pediatric patients were included. Group 1 included 35 patients who received treprostinil at 1-3 postoperative days and an average dose of 12 ± 4 ng/(kg·min). Group 2 included 16 patients who received treprostinil within postoperative 1 day and an average dose of 22 ± 7 ng/(kg·min). There were no significant differences between the two groups in terms of age, weight, preoperative percutaneous oxygen saturation and mPAP, heterotaxy syndrome, TCPC procedure type, other concurrent procedure, cardiopulmonary bypass time and aortic cross-clamp proportion (p > 0.05). After 24 h of treprostinil treatment, the mPAP in group 1 reduced from 17 ± 3 mmHg to 15 ± 2 mmHg (p < 0.001), and in group 2 from 17 ± 2 mmHg to 14 ± 2 mmHg (p < 0.001), with no difference between groups. In the postoperative recovery, patients in Group 2 exhibited a reduced duration of mechanical ventilation, 19 (11, 25) hours vs 69 (23, 189) hours, p = 0.001; a shorter stay in the ICU, 8 (6, 12) days vs 16 (9,26) days, p = 0.006; and a shorter postoperative length of stay, 27 (17,55) days vs 39 (29,58) days, p = 0.032. Patients in Group 2 also exhibited a lower incidence of thromboembolic events, 0 (0/26) vs 26% (9/35), p = 0.043; and the need for renal replacement therapy, 0 (0/26) vs 31% (11/35), p = 0.011. CONCLUSION: Treprostinil reduces pulmonary artery pressure after TCPC procedure. The standardized application of treprostinil may improve the postoperative recovery which should be proven by randomized controlled trials or matched cohort studies in the future.
Assuntos
Anti-Hipertensivos , Epoprostenol , Hipertensão Arterial Pulmonar , Humanos , Epoprostenol/análogos & derivados , Epoprostenol/administração & dosagem , Epoprostenol/uso terapêutico , Feminino , Masculino , Estudos Retrospectivos , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Criança , Pré-Escolar , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/cirurgia , Adolescente , Lactente , Administração Intravenosa , Cardiopatias Congênitas/cirurgia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Técnica de Fontan/métodos , Técnica de Fontan/efeitos adversosRESUMO
Connective tissue diseases-related pulmonary arterial hypertension (CTD-PAH) is a disease characterized by an elevated pulmonary artery pressure that arises as a complication of connective tissue diseases. The number of patients with CTD-PAH accounts for 25.3% of all PAH patients. The main pathological features of CTD-PAH are thickening of intima, media and adventitia of pulmonary arterioles, increased pulmonary vascular resistance, autoimmune activation and inflammatory reaction. It is worth noting that abnormal immune activation will produce autoantibodies and release cytokines, and abnormal immune cell recruitment will promote inflammatory environment and vascular remodeling. Therefore, almost all forms of connective tissue diseases are related to PAH. In addition to general therapy and targeted drug therapy for PAH, high-dose glucocorticoid combined with immunosuppressant can quickly alleviate and stabilize the basic CTD-PAH disease. Given this, the development of therapeutic approaches targeting immune dysregulation and heightened inflammation is recognized as a promising strategy to prevent or reverse the progression of CTD-PAH. This review explores the potential mechanisms by which immune cells contribute to the development of CTD-PAH and examines the clinical application of immunosuppressive therapies in managing CTD-PAH.
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Doenças do Tecido Conjuntivo , Hipertensão Arterial Pulmonar , Humanos , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/complicações , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/imunologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Animais , Imunossupressores/uso terapêutico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/tratamento farmacológicoRESUMO
Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis, which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Nontargeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCTPAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCTPAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCTinduced PAH in rats by reducing the Warburg effect.
Assuntos
Flavonoides , Glicólise , Monocrotalina , Hipertensão Arterial Pulmonar , Animais , Ratos , Masculino , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Glicólise/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Ratos Sprague-Dawley , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Scutellaria baicalensis/química , Modelos Animais de Doenças , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Efeito Warburg em Oncologia/efeitos dos fármacosAssuntos
Acetamidas , Pirazinas , Humanos , Acetamidas/uso terapêutico , Pirazinas/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Hipertensão Pulmonar/tratamento farmacológico , Adulto , Anti-Hipertensivos/uso terapêutico , IdosoRESUMO
Importance: A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied. Objective: To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i. Design, Setting, and Participants: This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023. Interventions: TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT. Main Outcomes and Measures: Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up. Results: A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90). Conclusions and Relevance: This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.
Assuntos
Acetamidas , Quimioterapia Combinada , Inibidores da Fosfodiesterase 5 , Pirazinas , Humanos , Acetamidas/uso terapêutico , Acetamidas/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Pirazinas/uso terapêutico , Pirazinas/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores da Fosfodiesterase 5/administração & dosagem , Adulto , Hipertensão Arterial Pulmonar/tratamento farmacológico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Antagonistas dos Receptores de Endotelina/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Resultado do Tratamento , IdosoRESUMO
BACKGROUND: Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. OBJECTIVES: Investigate the therapeutic effects and the mechanism of SAL on PAH. METHODS: Monocrotaline was used to establish a PAH rat model. SAL's impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL's metabolic regulatory mechanisms. RESULTS: SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. CONCLUSIONS: SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling.
Assuntos
Arginina , Glucosídeos , Óxido Nítrico , Fenóis , Hipertensão Arterial Pulmonar , Animais , Glucosídeos/farmacologia , Fenóis/farmacologia , Fenóis/uso terapêutico , Óxido Nítrico/metabolismo , Ratos , Masculino , Arginina/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Disponibilidade Biológica , Remodelação Vascular/efeitos dos fármacosRESUMO
INTRODUCTION: Traditional Chinese medicinal plant, safflower, shows effective for treating pulmonary arterial hypertension (PAH), yet the underlying mechanisms remain largely unexplored. This study is aimed at exploring the potential molecular mechanisms of safflower in the treatment of PAH. METHODS: Network pharmacology approach and molecular docking were applied to identify the core active compounds, therapeutic targets, and potential signaling pathways of safflower against PAH. Meanwhile, high-performance liquid chromatography (HPLC) assay was performed to determine the core compounds from safflower. Further, the mechanism of action of safflower on PAH was verified by in vivo and in vitro experiments. RESULTS: A total of 15 active compounds and 177 targets were screened from safflower against PAH. Enrichment analysis indicated that these therapeutic targets were mainly involved in multiple key pathways, such as TNF signaling pathway and Th17 cell differentiation. Notably, molecular docking revealed that quercetin (core compound in safflower) displayed highest binding capacity with NLRP3. In vivo, safflower exerted therapeutic effects on PAH by inhibiting right ventricular hypertrophy, inflammatory factor release, and pulmonary vascular remodeling. Mechanistically, it significantly reduced the expression of proangiogenesis-related factors (MMP-2, MMP-9, Collagen 1, and Collagen 3) and NLRP3 inflammasome components (NLRP3, ASC, and Caspase-1) in PAH model. Similarly, these results were observed in vitro. Besides, we further confirmed that NLRP3 inhibitor had the same therapeutic effect as safflower in vitro. CONCLUSION: Our findings suggest that safflower mitigates PAH primarily by inhibiting NLRP3 inflammasome activation. This provides novel insights into the potential use of safflower as an alternative therapeutic approach for PAH.
Assuntos
Carthamus tinctorius , Simulação de Acoplamento Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Farmacologia em Rede , Hipertensão Arterial Pulmonar , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Carthamus tinctorius/química , Animais , Simulação de Acoplamento Molecular/métodos , Farmacologia em Rede/métodos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Modelos Animais de Doenças , Ratos , Masculino , Humanos , Transdução de Sinais/efeitos dos fármacos , Camundongos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy that, if not promptly treated, culminates in right heart failure. Therefore, pre-clinical studies are needed to support and optimize therapeutic approaches of PAH. Here, we explore a prospective function of sevoflurane in experimental PAH through regulating TRAF6. Monocrotaline (MCT)-induced PAH rats were subjected to sevoflurane inhalation and intratracheal instillation of lentivirus overexpressing TRAF6. Platelet-derived growth factor (PDGF)-treated pulmonary artery smooth muscle cells (PASMCs) were exposed to sevoflurane and genetically manipulated for TRAF6 overexpression. It was found that MCT and PDGF challenge upregulated the levels of TRAF6 in rat lung tissues and PASMCs, but sevoflurane treatment led to reduced TRAF6 expression. Sevoflurane inhalation in MCT-induced rats resulted in alleviative pulmonary vascular remodeling, mitigated right ventricular dysfunction and hypertrophy, improved mitochondrial function and dynamics, and inactivation of NF-κB pathway. In vitro studies confirmed that exposure to sevoflurane repressed PDGF-induced proliferation, migration, and phenotype switching of PASMCs, and suppressed mitochondrial dysfunction and NF-κB activation in PDGF-stimulated PASMCs. The beneficial impact of sevoflurane on pathological changes of lung and cell phenotype of PASMCs were reversed by overexpression of TRAF6. In summary, our study suggested the protective properties of sevoflurane in targeting PAH by downregulating TRAF6 expression, providing a novel avenue for the management of PAH.
Assuntos
Regulação para Baixo , Miócitos de Músculo Liso , Hipertensão Arterial Pulmonar , Artéria Pulmonar , Ratos Sprague-Dawley , Sevoflurano , Fator 6 Associado a Receptor de TNF , Animais , Sevoflurano/farmacologia , Sevoflurano/toxicidade , Regulação para Baixo/efeitos dos fármacos , Ratos , Masculino , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Monocrotalina/toxicidade , NF-kappa B/metabolismo , Proliferação de Células/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Células CultivadasAssuntos
Gadolínio , Ventrículos do Coração , Humanos , Ventrículos do Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/diagnóstico por imagem , Meios de Contraste , Masculino , FemininoRESUMO
INTRODUCTION: Risk assessment can aid management of pulmonary arterial hypertension (PAH) and clinical decision-making. This analysis describes characteristics, treatment patterns and outcomes of patients with PAH, categorised by risk status at time of treatment escalation with selexipag in clinical settings. METHODS: Patients initiating selexipag in the ongoing multicentre, prospective EXPOSURE (EUPAS19085) study were grouped as low, intermediate-low, intermediate-high or high risk of 1-year mortality according to the ESC/ERS 4-strata method. RESULTS: As of November 2022, 77% (535/698) of patients initiating selexipag had data allowing for risk calculation; 14% (N = 76) were low, 31% (N = 168) intermediate-low, 34% (N = 182) intermediate-high and 20% (N = 109) high risk of 1-year mortality. Overall, patients were predominantly female (71%), with idiopathic/heritable PAH (56%) or PAH associated with connective tissue disease (CTD-PAH; 27%), median age of 60 years and prevalent (2 years) disease. From low to high risk, proportion of CTD-PAH and age increased (from 12%-40% and 46-68 years, respectively); time from diagnosis decreased and presence of cardiovascular risk factors increased. Most patients across risk groups (74-81%) initiated selexipag as part of triple oral combination therapy. Overall median (Q1, Q3) selexipag exposure duration was 10.1 (3.5, 24.1) months. Proportions of hospitalised patients increased with increasing risk group (16-42% from low to high, respectively); more hospitalisations were PAH-related for the high risk (71%) versus other risk groups (47-54%). Kaplan-Meier survival estimates were 98%, 98%, 93% and 80% at 1-year and 98%, 92%, 81% and 67% at 2-years, from low to high risk, respectively. CONCLUSIONS: In clinical settings, selexipag is initiated across all risk groups, predominantly as triple therapy. Only 45% of patients being at low/intermediate-low risk at selexipag initiation suggests an opportunity for more frequent patient monitoring and earlier treatment escalation, given that 4-strata risk assessment was prognostic for hospitalisations and survival in this contemporary PAH cohort. A graphical abstract is available with this article.
Pulmonary arterial hypertension (PAH) is a disease that gets worse over time. To make decisions about treatment, we need to know the stage of the disease. We can do this by measuring the patient's risk of death during the next few years. Selexipag is a medication for PAH. This analysis included patients living in Europe and Canada who started treatment with selexipag for their PAH disease. Our findings suggest that the monitoring of patients' health and the timing of starting selexipag can be improved. This analysis includes 698 patients taking part in the EXPOSURE study (EUPAS19085), which looks at the real-life treatment of patients with PAH. Overall, 71% of patients were female, the median age was 60 years, most had been diagnosed with PAH for around 2 years and were already taking two other medications for their PAH disease. At the beginning of selexipag treatment, 14% of patients were classified as low risk, 31% as intermediate-low risk, 34% as intermediate-high risk and 20% as high risk of mortality within the next year. More high-risk patients were hospitalised compared with the lower risk groups. After 1 year of treatment, more patients in the low (98%) and intermediate-low groups (98%) were alive than those in the intermediate-high (93%) and high risk groups (80%). The same was true after 2 years of treatment with selexipag (98%, 92%, 81% and 67%, respectively). This study confirms that assessing patients' risk levels can indicate how well they will do over time and shows that earlier treatment with selexipag should be considered to potentially prevent worsening of the disease.
Assuntos
Acetamidas , Pirazinas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Acetamidas/uso terapêutico , Medição de Risco/métodos , Pirazinas/uso terapêutico , Pirazinas/efeitos adversos , Idoso , Estudos Prospectivos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Adulto , Anti-Hipertensivos/uso terapêuticoAssuntos
Pressão Propulsora Pulmonar , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pressão Propulsora Pulmonar/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF. STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD. RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE. CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.
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Medicamentos de Ervas Chinesas , Hipertensão Arterial Pulmonar , Biologia de Sistemas , Remodelação Ventricular , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Hipertensão Arterial Pulmonar/tratamento farmacológico , Masculino , Remodelação Ventricular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Ratos , Insuficiência Cardíaca/tratamento farmacológico , Modelos Animais de Doenças , Cromatografia Líquida de Alta PressãoRESUMO
Pulmonary arterial hypertension (PAH) is a complex fatal condition that requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH, but, despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies, which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to use an activin signaling inhibitor for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm, based on the available evidence, with special focus on the U.S. patient population. This review also provides an expert opinion of the current treatment algorithm in important subgroups of patients with comorbidities from the U.S. perspective.
Assuntos
Hipertensão Arterial Pulmonar , Humanos , Estados Unidos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/terapia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Anti-Hipertensivos/uso terapêutico , AtivinasRESUMO
OBJECTIVE: This retrospective study using claims data compared demographics, clinical characteristics, treatment patterns, healthcare resource utilization, and clinical outcomes in Black and White patients with pulmonary arterial hypertension (PAH) in the United States. METHODS: Patients (aged ≥18 years) had ≥1 pharmacy claim for PAH medication, ≥6 months' continuous healthcare plan enrollment, ≥1 inpatient/outpatient medical claim with a pulmonary hypertension diagnosis ≤6 months before first PAH medication, and race recorded. RESULTS: This analysis included 836 Black and 2896 White patients. Black patients were younger, with lower levels of education and annual household income, and higher comorbidity scores versus White patients. Only â¼14% of Black and White patients received index combination therapy. Lower adherence to index treatment was observed in Black patients. Although adjusted regression analysis in the overall population showed no differences in outcomes between groups, Black patients <65 years were 36% less likely to receive index combination therapy (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.41-0.99), and 46% less likely to adhere to index treatment (OR 0.54; 95% CI 0.33-0.90). Other disparities included 24% higher all-cause health care resource utilization, 75% higher all-cause costs, and higher risk of clinical composite outcome. Social determinants of health (education, income, health insurance plan) partially mediated these race effects. CONCLUSIONS: Differences in demographics, clinical characteristics, and treatment patterns between Black and White patients with PAH were observed. Disparities between Black and White patients <65 years were only partially mediated through social determinants of health variables, suggesting other factors may be involved.
Assuntos
Disparidades em Assistência à Saúde , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto , Idoso , Estudos Retrospectivos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/etnologia , Hipertensão Arterial Pulmonar/terapia , População Branca/estatística & dados numéricos , Resultado do Tratamento , Hipertensão Pulmonar/etnologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/terapia , Recursos em Saúde/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , AdolescenteRESUMO
Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.
Assuntos
Proteínas de Choque Térmico HSP110 , Guanilil Ciclase Solúvel , Animais , Guanilil Ciclase Solúvel/metabolismo , Humanos , Ratos , Proteínas de Choque Térmico HSP110/metabolismo , Proteínas de Choque Térmico HSP110/antagonistas & inibidores , Ratos Sprague-Dawley , Descoberta de Drogas , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Masculino , Relação Estrutura-Atividade , Hipertensão Pulmonar/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacosRESUMO
ABSTRACT: Angiomotin-like 2 (AMOTL2) is related to numerous physiological and pathological conditions by affecting signal transduction. However, whether AMOTL2 is linked to pulmonary arterial hypertension (PAH) has not been addressed. This work aimed to investigate the potential role of AMOTL2 in PAH. A decrease in AMOTL2 abundance was observed in the lungs of PAH rats. The upregulation of AMOTL2 significantly decreased right ventricle systolic pressure and right ventricular hypertrophy in PAH rats. Overexpression of AMOTL2 also led to a noteworthy decrease in vascular wall thickness, pulmonary artery area, and collagen deposition in rats with PAH. AMOTL2 was downregulated in hypoxia-stimulated pulmonary arterial smooth muscle cells (PASMCs). Moreover, AMOTL2 overexpression impeded hypoxia-evoked proliferation, migration, and phenotypic transformation in rat PASMCs. Mechanistic investigation revealed that Yes-associated protein 1 (YAP1) activation in PAH rats or hypoxia-stimulated PASMCs was markedly inhibited by AMOTL2 overexpression, which was associated with increased large tumor suppressor 1/2 phosphorylation. The inhibition of large tumor suppressor 1/2 reversed the AMOTL2-mediated inactivation of YAP1. Restoring the activity of YAP1 reversed the inhibitory effect of AMOTL2 on hypoxia-evoked proliferation, migration, and phenotypic transformation of PASMCs. Collectively, these results suggest that AMOTL2 can ameliorate PAH in a rat model by interfering with pulmonary arterial remodeling via the inactivation of YAP1 signaling. Our work indicates that AMOTL2 may be a candidate target for novel drug development for the treatment of PAH.
Assuntos
Angiomotinas , Proliferação de Células , Modelos Animais de Doenças , Músculo Liso Vascular , Miócitos de Músculo Liso , Hipertensão Arterial Pulmonar , Artéria Pulmonar , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima , Remodelação Vascular , Proteínas de Sinalização YAP , Animais , Proteínas de Sinalização YAP/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Células Cultivadas , Proliferação de Células/efeitos dos fármacos , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/patologia , Movimento Celular/efeitos dos fármacos , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Função Ventricular Direita/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Fenótipo , Ratos , FosforilaçãoRESUMO
Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFRα/ß phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68+ macrophage infiltration around the pulmonary artery. In vitro, WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFRß Y751, decreased collagen â synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling.
Assuntos
Proliferação de Células , Monocrotalina , Hipertensão Arterial Pulmonar , Ratos Sprague-Dawley , Remodelação Vascular , Animais , Remodelação Vascular/efeitos dos fármacos , Ratos , Proliferação de Células/efeitos dos fármacos , Masculino , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Humanos , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Fosforilação/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/prevenção & controle , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidoresRESUMO
Pulmonary hypertension is a pathophysiologic manifestation of a heterogeneous group of diseases, with the main pathophysiologic mechanisms being persistent pulmonary vasoconstriction and irreversible vascular remodeling. The impact significantly affects the prognosis of patients with pulmonary hypertension. If it is not treated and intervened in time, it may lead to right ventricular failure and further endanger the patient's life. Within the past decade or so, nebulized inhalation therapy is considered to have advantages in the treatment of pulmonary hypertension as a safe, limited, and rapid therapy, for example, inhaled vasodilators (prostate analogs, nitroglycerin, carbon monoxide analogs sildenafil, and nitroprusside), inhaled anti-inflammatory and antiproliferative agents (simvastatin, and selatinib), and inhaled peroxides (levocetirizine) have been recognized as emerging therapeutic approaches in the treatment of pulmonary hypertension as emerging therapeutic approaches. Therefore, this article provides a brief review of recent advances in the potential of nebulized inhaled vasodilators, anti-inflammatory and antiproliferative agents, and anti-peroxides for the treatment of pulmonary hypertension, with the aim of providing different therapeutic options for the treatment of pulmonary hypertension, enhancing the quality of survival, alleviating symptoms, and improving the prognosis of patients with this condition.
Assuntos
Nebulizadores e Vaporizadores , Vasodilatadores , Humanos , Administração por Inalação , Vasodilatadores/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologiaRESUMO
Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary microvasculature leading to elevated precapillary pulmonary hypertension. Pulmonary vascular remodeling, a characteristic of PAH, is driven by dysfunctions in the signaling between the pulmonary smooth muscle and endothelial cells with abnormalities that affect cell proliferation and immune dysregulation. Sotatercept, an activin signaling inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of PAH based on two pivotal clinical trials. Evidence-based clinical trials have provided a framework to guide clinicians treating the disease; however, they are not tailored to the individual patient. Often, recommendations from these data are unclear or too general, due to remaining gaps in knowledge. In this edition of "How I Do It," we provide a case-based discussion of common clinical decisions regarding diagnostic testing, choice of first-line agents, escalation of therapy, potential timing of sotatercept, safety awareness, practical use, potential management changes, and the future use of sotatercept in other pulmonary hypertension cohorts.
Assuntos
Hipertensão Arterial Pulmonar , Proteínas Recombinantes de Fusão , Humanos , Receptores de Activinas Tipo II/antagonistas & inibidores , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
BACKGROUND: Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. METHODS: This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3-7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)/B-type natriuretic peptide from baseline to first follow-up visit (months 3-7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. RESULTS: From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. CONCLUSION: This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.