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1.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805419

RESUMO

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.


Assuntos
Antivirais/farmacocinética , Reposicionamento de Medicamentos/métodos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Antivirais/sangue , Medicamentos Biossimilares , Bloqueadores dos Canais de Cálcio/farmacocinética , Simulação por Computador , Bases de Dados de Produtos Farmacêuticos , Desenvolvimento de Medicamentos/métodos , Humanos , Hipertensão Pulmonar/virologia , Distribuição Tecidual
3.
Wiad Lek ; 74(3 cz 1): 546-553, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33813466

RESUMO

Right heart catheterization is a unique tool not only in the diagnosis but also in the management of patients with a wide range of cardiovascular diseases. The technique dates back to the 18th century, but the biggest advances were made in the 20th century. This review focuses on pulmonary hypertension for which right heart catheterization remains the diagnostic gold standard. Right heart catheterization-derived parameters help classify pulmonary hypertension into several subgroups, assess risk of adverse events or mortality and make therapeutic decisions. According to the European Society of Cardiology guidelines pulmonary hypertension (PH) is defined as an increase in mean pulmonary artery pressure (PAPm) > 25 mmHg, whereas a distinction between pre- and post-capillary PH is made based on levels of pulmonary artery wedge pressure (PAWP). Moreover, right atrial pressure (RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2) are the only parameters recommended to assess prognosis and only in patients with pulmonary arterial hypertension (PAH). Patients with RAP > 14 mmHg, CI < 2.0 l/min/m2 and SvO2 < 60% are at high (> 10%) risk of death within the next year. The purpose of this paper is to show that RHC-derived parameters can be used on a considerably larger scale than currently recommended. Several prognostic parameters, with specific thresholds have been identified for each subtype of pulmonary hypertension and can be helpful in everyday practice for treatment of PH.


Assuntos
Hipertensão Pulmonar , Cateterismo Cardíaco , Humanos , Hipertensão Pulmonar/diagnóstico , Prognóstico
4.
Medicine (Baltimore) ; 100(14): e25375, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832123

RESUMO

RATIONALE: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare congenital malformation in neonates that results in severe respiratory distress and pulmonary hypertension. ACD/MPV is caused by mutations in the FOXF1 gene. Herein, a new case of a girl with ACD/MPV carrying a novel pathogenic variant of FOXF1 was reported. PATIENT CONCERNS: A 3-month-old Chinese girl was admitted to the hospital presenting a complaint of cyanosis for 10 days and respiratory distress for 2 days. The history of foreign body inhalation was denied. DIAGNOSES: Blood routine, liver and kidney function, electrolytes, type B natriuretic peptide, electrocardiogram, cardiac computed tomography (CT), and echocardiography were done after admission. Dysplasia of the alveolar and the left upper pulmonary vein was displayed through cardiac CT. Echocardiography showed atrial septal defect, tricuspid valve malformation, and pulmonary hypertension. Sequence analysis of FOXF1 from genomic deoxyribonucleic acid (DNA) revealed that the patient was heterozygous for a novel missense variant (c.418 C>T, p.Pro140Gly). Furthermore, genetic analysis of both parents confirmed the de novo occurrence of the variant. Conservation analysis showed that the locus was highly conserved across species. Then, ACD/MPV was a clinical diagnosis. INTERVENTIONS: After admission, nasal catheter oxygen inhalation, cefazoxime sodium, furosemide diuretic, milrinone lactate, and Bosentan were given to the patient. OUTCOMES: After 6 days of hospitalization, the patient's condition did not improved, the parents gave up treatment and discharged. The patient died half a month after discharge. LESSONS: ACD/MPV is a rare congenital malformation with a poor prognosis. A new de novo mutation of FOXF1 was found in our case. Non-invasive methods such as DNA sequencing and FOXF1 analysis are helpful in the clinical diagnosis of ACD/MPV especially in early infants with respiratory distress and pulmonary hypertension.


Assuntos
Fatores de Transcrição Forkhead/genética , Síndrome da Persistência do Padrão de Circulação Fetal/diagnóstico , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Alvéolos Pulmonares/anormalidades , Veias Pulmonares/anormalidades , Ecocardiografia/métodos , Evolução Fatal , Feminino , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/genética , Heterozigoto , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/genética , Lactente , Mutação de Sentido Incorreto , Oxigenoterapia/métodos , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Análise de Sequência/métodos , Falha de Tratamento , Valva Tricúspide/anormalidades , Valva Tricúspide/diagnóstico por imagem
5.
J Am Coll Cardiol ; 77(13): 1644-1655, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33795039

RESUMO

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cianose , Cardiopatias Congênitas , Hipertensão Pulmonar , Adulto , /terapia , Procedimentos Cirúrgicos Cardíacos/métodos , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Causalidade , Comorbidade , Cianose/diagnóstico , Cianose/etiologia , Cianose/mortalidade , Feminino , Saúde Global/estatística & dados numéricos , Cardiopatias Congênitas/classificação , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/terapia , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Masculino , Mortalidade , Gravidade do Paciente , Fatores de Risco , Avaliação de Sintomas
8.
Arq Bras Cardiol ; 116(2): 219-226, 2021 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33656068

RESUMO

BACKGROUND: Elevated pulmonary vascular resistance remains a major problem for heart transplant (HT) candidate selection. OBJECTIVE: This study sought at assess the effect of pre-HT sildenafil administration in patients with fixed pulmonary hypertension. METHODS: This retrospective, single-center study included 300 consecutive, HT candidates treated between 2003 and 2013, in which 95 patients had fixed PH, and of these, 30 patients were treated with sildenafil and eventually received a transplant, forming Group A. Group B included 205 patients without PH who underwent HT. Pulmonary hemodynamics were evaluated before HT, as well as 1 week after and 1 year after HT. Survival was compared between the groups. In this study, a p value < 0.05 was considered statistically significant. RESULTS: After treatment with sildenafil but before HT, PVR (-39%) and sPAP (-10%) decreased significantly. sPAP decreased after HT in both groups, but it remained significantly higher in group A vs. group B (40.3 ± 8.0 mmHg vs 36.5 ± 11.5 mmHg, p=0.022). One year after HT, sPAP was 32.4 ± 6.3 mmHg in group A vs 30.5 ± 8.2 mmHg in group B (p=0.274). The survival rate after HT at 30 days (97% in group A versus 96% in group B), at 6 months (87% versus 93%) and at one year (80% vs 91%) were not statistically significant (Log-rank p=0.063). After this first year, the attrition rate was similar among both groups (conditional survival after 1 year, Log-rank p=0.321). CONCLUSION: In patients with severe PH pre-treated with sildenafil, early post-operative hemodynamics and prognosis are numerically worse than in patients without PH, but after 1 year, the medium to long-term mortality proved to be similar. (Arq Bras Cardiol. 2021; 116(2):219-226).


Assuntos
Transplante de Coração , Hipertensão Pulmonar , Hemodinâmica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento
9.
Medicine (Baltimore) ; 100(8): e24896, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663121

RESUMO

INTRODUCTION: Hemodynamically-instable ventricular arrhythmias (VAs) are rare in patients with pulmonary hypertension (PH). To the best of our knowledge, only 1 case has been reported so far. Moreover, the pathogenesis of this kind of arrhythmia remains obscured and its treatment is challenging. Here we report another case and presented the substrate for VAs initiation and therapeutic effect of radiofrequency ablation. PATIENT CONCERNS: This is a 57-year-old man who presented paroxysmal palpitation associated with presyncope at rest. Surface electrocardiogram (ECG) revealed frequent ventricular premature contractions and non-sustained ventricular tachycardia when symptoms occurred. He also had a history of severe PH which was secondary to atrial septal defect and partial anomalous pulmonary venous drainage and suffered from obvious dyspnea when climbing stairs World Health Organization Class III (WHO Class III). DIAGNOSIS: Hemodynamically-instable VAs associated with severe PH. INTERVENTION: Echocardiography revealed enlargement of right ventricle (right ventricle [RV]: 43 mm). Electrophysiological examination showed the origin of VAs is next to a small low-voltage zone of RV. Radiofrequency delivery at the origin successfully terminated VAs without occurrence of complication. OUTCOME: The patient was free from arrhythmias and got an improvement of exercise tolerance, just with mild dyspnea when climbing stairs World Health Organization Class II (WHO class II), during six-month follow up. LESSONS: This case suggests the low-voltage zone of remodeled RV, which may be secondary to increased pulmonary artery pressure, serves as the substrate for VAs initiation in patient with PH. Radiofrequency ablation can successfully terminate VAs and the termination of VAs can significantly improve the patient's impaired exercise tolerance.


Assuntos
Hipertensão Pulmonar/complicações , Ablação por Radiofrequência/métodos , Complexos Ventriculares Prematuros/complicações , Ecocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Complexos Ventriculares Prematuros/fisiopatologia , Complexos Ventriculares Prematuros/terapia , Remodelação Ventricular
10.
Cochrane Database Syst Rev ; 3: CD004434, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33765691

RESUMO

BACKGROUND: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020. SELECTION CRITERIA: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality. MAIN RESULTS: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA.   We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide.  As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome. AUTHORS' CONCLUSIONS: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.


Assuntos
Anti-Hipertensivos/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Viés , Humanos , Hipertensão Pulmonar/mortalidade , Inibidores da Fosfodiesterase 5/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Teste de Caminhada
12.
Adv Exp Med Biol ; 1303: 57-69, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788187

RESUMO

Reductionist approaches have served as the cornerstone for traditional mechanistic endeavors in biomedical research. However, for pulmonary hypertension (PH), a relatively rare but deadly vascular disease of the lungs, the use of traditional reductionist approaches has failed to define the complexities of pathogenesis. With the development of new -omics platforms (i.e., genomics, transcriptomics, proteomics, and metabolomics, among others), network biology approaches have offered new pipelines for discovery of human disease pathogenesis. Human disease processes are driven by multiple genes that are dysregulated which are affected by regulatory networks. Network theory allows for the identification of such gene clusters which are dysregulated in various disease states. This framework may in part explain why current therapeutics that seek to target a single part of a dysregulated cluster may fail to provide clinically significant improvements. Correspondingly, network biology could further the development of novel therapeutics which target clusters of "disease genes" so that a disease phenotype can be more robustly addressed. In this chapter, we seek to explain the theory behind network biology approaches to identify drivers of disease as well as how network biology approaches have been used in the field of PH. Furthermore, we discuss an example of in silico methodology using network pharmacology in conjunction with gene networks tools to identify drugs and drug targets. We discuss similarities between the pathogenesis of PH and other disease states, specifically cancer, and how tools developed for cancer may be repurposed to fill the gaps in research in PH. Finally, we discuss new approaches which seek to integrate clinical health record data into networks so that correlations between disease genes and clinical parameters can be explored in the context of this disease.


Assuntos
Hipertensão Pulmonar , Biologia de Sistemas , Genômica , Humanos , Hipertensão Pulmonar/genética , Metabolômica , Proteômica
13.
Adv Exp Med Biol ; 1303: 13-32, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788185

RESUMO

Pulmonary Arterial Hypertension (PAH) is a progressive vascular disease arising from the narrowing of pulmonary arteries (PA) resulting in high pulmonary arterial blood pressure and ultimately right ventricular (RV) failure. A defining characteristic of PAH is the excessive remodeling of PA that includes increased proliferation, inflammation, and fibrosis. There is no cure for PAH nor interventions that effectively impede or reverse PA remodeling, and research over the past several decades has sought to identify novel molecular mechanisms of therapeutic benefit. Galectin-3 (Gal-3; Mac-2) is a carbohydrate-binding lectin that is remarkable for its chimeric structure, comprised of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Gal-3 is a regulator of changes in cell behavior that contribute to aberrant PA remodeling including cell proliferation, inflammation, and fibrosis, but its role in PAH is poorly understood. Herein, we summarize the recent literature on the role of Gal-3 in the development of PAH and provide experimental evidence supporting the ability of Gal-3 to influence reactive oxygen species (ROS) production, NOX enzyme expression, inflammation, and fibrosis, which contributes to PA remodeling. Finally, we address the clinical significance of Gal-3 as a target in the development of therapeutic agents as a treatment for PAH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Modelos Animais de Doenças , Fibrose , Galectina 3/genética , Inflamação/patologia , Artéria Pulmonar/patologia , Espécies Reativas de Oxigênio , Remodelação Vascular
14.
Adv Exp Med Biol ; 1303: 107-127, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788190

RESUMO

In addition to studies focused on estrogen mediation of sex-different regulation of systemic circulations, there is now increasing clinical relevance and research interests in the pulmonary circulation, in terms of sex differences in the morbidity and mortality of lung diseases such as inherent-, allergic- and inflammatory-based events. Thus, female predisposition to pulmonary artery hypertension (PAH) is an inevitable topic. To better understand the nature of sexual differentiation in the pulmonary circulation, and how heritable factors, in vivo- and/or in vitro-altered estrogen circumstances and changes in the live environment work in concert to discern the sex bias, this chapter reviews pulmonary events characterized by sex-different features, concomitant with exploration of how alterations of genetic expression and estrogen metabolisms trigger the female-predominant pathological signaling. We address the following: PAH (Sect.7.2) is characterized as an estrogenic promotion of its incidence (Sect. 7.2.2), as a function of specific germline mutations, and as an estrogen-elicited protection of its prognosis (Sect.7.2.1). More detail is provided to introduce a less recognized gene of Ephx2 that encodes soluble epoxide hydrolase (sEH) to degrade epoxyeicosatrienic acids (EETs). As a susceptible target of estrogen, Ephx2/sEH expression is downregulated by an estrogen-dependent epigenetic mechanism. Increases in pulmonary EETs then evoke a potentiation of PAH generation, but mitigation of its progression, a phenomenon similar to the estrogen-paradox regulation of PAH. Additionally, the female susceptibility to chronic obstructive pulmonary diseases (Sect. 7.3) and asthma (Sect.7.4), but less preference to COVID-19 (Sect. 7.5), and roles of estrogen in their pathogeneses are briefly discussed.


Assuntos
Hipertensão Pulmonar , Pneumopatias , Estrogênios , Feminino , Predisposição Genética para Doença , Humanos , Pneumopatias/epidemiologia , Pneumopatias/genética , Masculino , Prevalência , Sexismo
15.
Adv Exp Med Biol ; 1303: 173-182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788193

RESUMO

Systemic sclerosis is a complex, often progressive, multisystem autoimmune disease. It is commonly categorized into limited cutaneous or diffuse cutaneous systemic sclerosis. There is near universal involvement of skin fibrosis and gastrointestinal dysfunction, but lung disease is not only common but also a most serious complication. Severe lung disease is the top cause of mortality, displacing scleroderma renal crisis as the leading cause of death. Whether there is limited cutaneous or diffuse cutaneous manifestations can be predictive of what type of lung disease that can present in the patient. Limited cutaneous systemic sclerosis patients tend to have pulmonary hypertension whereas diffuse cutaneous systemic sclerosis patients tend to have interstitial lung disease. There are more rare phenotypes associated with antibodies Th/To and U3RNP that can have both pulmonary hypertension and interstitial lung disease concomitantly. There are inherent challenges in the management for both pulmonary hypertension and interstitial lung disease but with the focus on early diagnosis for each of these lung complications, treatment may have a higher chance of efficacy.


Assuntos
Hipertensão Pulmonar , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Dermatopatias , Humanos , Hipertensão Pulmonar/etiologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Pele
16.
Adv Exp Med Biol ; 1303: 209-241, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788196

RESUMO

Group 3 pulmonary hypertension (PH), which occurs secondary to hypoxia lung diseases, is one of the most common causes of PH worldwide and has a high unmet clinical need. A deeper understanding of the integrative pathological and adaptive molecular mechanisms within this group is required to inform the development of novel drug targets and effective treatments. The production of oxidants is increased in PH Group 3, and their pleiotropic roles include contributing to disease progression by promoting prolonged hypoxic pulmonary vasoconstriction and pathological pulmonary vascular remodeling, but also stimulating adaptation to pathological stress that limits the severity of this disease. Inflammation, which is increasingly being viewed as a key pathological feature of Group 3 PH, is subject to complex regulation by redox mechanisms and is exacerbated by, but also augments oxidative stress. In this review, we investigate aspects of this complex crosstalk between inflammation and oxidative stress in Group 3 PH, focusing on the redox-regulated transcription factor NF-κB and its upstream regulators toll-like receptor 4 and high mobility group box protein 1. Ultimately, we propose that the development of specific therapeutic interventions targeting redox-regulated signaling pathways related to inflammation could be explored as novel treatments for Group 3 PH.


Assuntos
Hipertensão Pulmonar , Humanos , Hipóxia , Inflamação , Oxirredução , Estresse Oxidativo
17.
Adv Exp Med Biol ; 1303: 351-372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33788202

RESUMO

Pulmonary artery hypertension (PAH) is a devastating cardiopulmonary disease characterized by vascular remodeling and obliteration of the precapillary pulmonary arterioles. Alterations in the structure and function of pulmonary vessels result in the resistance of blood flow and can progress to right-sided heart failure, causing significant morbidity and mortality. There are several types of PAH, and the disease can be familial or secondary to an underlying medical condition such as a connective tissue disorder or infection. Regardless of the cause, the exact pathophysiology and cellular interactions responsible for disease development and progression are largely unknown.There is significant evidence to suggest altered immune and vascular cells directly participate in disease progression. Inflammation has long been hypothesized to play a vital role in the development of PAH, as an altered or skewed immune response favoring a proinflammatory environment that can lead to the infiltration of cells such as lymphocytes, macrophages, and neutrophils. Current treatment strategies focus on the dilation of partially occluded vessels; however, such techniques have not resulted in an effective strategy to reverse or prevent vascular remodeling. Therefore, current studies in human and animal models have attempted to understand the underlying pathophysiology of pulmonary hypertension (PH), specifically focusing on the inflammatory cascade predisposing patients to disease so that better therapeutic targets can be developed to potentially reverse or prevent disease progression.The purpose of this chapter is to provide a comprehensive review of the expanding literature on the inflammatory process that participates in PH development while highlighting important and current studies in both animal and human models. While our primary focus will be on cells found in the adaptive and innate immune system, we will review all potential causes of PAH, including cells of the endothelium, pulmonary lymphatics, and genetic mutations predisposing patients. In addition, we will discuss current therapeutic options while highlighting potential future treatments and the questions that still remain unanswered.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Hipertensão Pulmonar Primária Familiar , Humanos , Inflamação , Artéria Pulmonar , Remodelação Vascular
18.
Zhonghua Er Ke Za Zhi ; 59(4): 294-298, 2021 Apr 02.
Artigo em Chinês | MEDLINE | ID: mdl-33775048

RESUMO

Objective: To analyze the clinical characteristics and treatment of tricuspid valve prolapse caused by chordal rupture complicated with persistent pulmonary hypertension in neonates. Methods: The clinical data of a male neonate with tricuspid valve prolapse complicated with persistent pulmonary hypertension admitted to the Neonatal Intensive Care Unit of Children's Hospital of Hebei Province in November 2018 was analyzed retrospectively. Related literature up to September 2020 was searched with the strategy of "(neonate OR newborn) AND (tricuspid valve prolapse) AND (rupture OR necrosis) AND (papillary muscle OR chordae tendineae) AND (pulmonary hypertension)" in Wanfang, CNKI and PubMed database in Chinese and English. The characteristics of the disease were summarized. Results: A male full-term neonate was admitted due to presenting severe cyanosis for 9 hours. He was born by caesarean section and presented severe cyanosis and dyspnea at 10 min of ages, unresponsive to the positive airway pressure resuscitation. After 9 hours of mechanical ventilation, there was no improvement. Thus he was transferred to Children's Hospital of Hebei Province. On admission, the initial blood gas analysis showed an arterial partial pressure of oxygen of 22.5 mmHg (1 mmHg=0.133 kPa). The echocardiography revealed prolapsed anterior leaflet of tricuspid valve, severe tricuspid regurgitation (TR) and pulmonary artery hypertension, and right to left shunt via a patent foramen ovale. The arterial duct was closed. The chest X-ray was normal. The boy was treated with nitric oxide, milrinone, and continued mechanical ventilation initially. Addition of prostacyclin analog (treprostinil) on day 3 led to significant improvement of pulmonary blood flow, oxygenation, and stabilization, so that the extracorporeal membrane oxygenation therapy was avoided. At 11 months after birth, the boy underwent cardiac surgery. At surgery, the rupture of chordal tendineae in anterior leaflet of tricuspid valve was found. Tricuspid annuloplasty, valvuloplasty and repair of patent foramen ovale were successfully performed. The follow-up echocardiogram at postoperative 3 months showed only mild tricuspid insufficiency. The boy was well at last follow-up at 22 months of age with normal cognitive skill development. According to literature, 20 cases of papillary muscle or chordae tendineae rupture in neonates had been reported in 12 English papers. Among the total 21 neonates, there were 12 male infants and only one premature infant with gestational age of 33 weeks. They presented with profound cyanosis soon after birth. All of them received endotracheal intubation and mechanical ventilation. Other treatments included inhalation of nitric oxide, intravenous milrinone, vasoactive drugs, diuretics and prostacyclin, etc. Extracorporeal membrane oxygenation (ECMO) was used in 6 infants as a bridge to surgical treatment. Two cases reported earlier death of cardiopulmonary failure without operation and the rest 19 survived after surgery. The followed surgery or autopsy revealed that all of them had tricuspid valve prolapse, rupture of papillary muscle or chordae tendineae. Conclusions: The severe TR resulting from rupture of papillary muscle or chordate tendineae in neonates is rare and could cause severe hypoxemia. Early recognition, adequate cardiopulmonary support to stabilize the hemodynamic status and timely surgery can significantly reduce the mortality.


Assuntos
Hipertensão Pulmonar , Valva Tricúspide , Cesárea , Criança , Cordas Tendinosas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/cirurgia
19.
Med Hypotheses ; 149: 110539, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33662863

RESUMO

Using folic acid (FA) as placebo complicates the interpretation of the findings of few RCTs evaluating safety and efficacy of hydroxychloroquine prophylaxis in COVID-19. FA is found to bind to furin-protease and spike: ACE2 interface of SARS-CoV-2. In clinical studies, FA level was lowest among severe patients compared to mild and moderate disease. A single controlled study reported the benefit of combination of folic acid with Pyridoxine & cyanocobalamin in terms of clinical and laboratory cure parameters. One hypothesis associates the differences in geographical variation of disease severity with prevalence of methyl tertahydrofolic acid reductase (MTHFR) C677T polymorphism. Other possible domains, where FA is hypothesized to be beneficial are COVID-19 associated pulmonary hypertension and hyper-homocystinemia. So, scientific justification of using folic acid as placebo in COVID-19 trials seems scientifically not credible and this may be one of the major factors for failure of many agents. We need to be more careful in choosing our placebo especially when conducting a placebo controlled trial.


Assuntos
/prevenção & controle , Ácido Fólico/uso terapêutico , Hidroxicloroquina/uso terapêutico , Placebos , /metabolismo , /tratamento farmacológico , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/tratamento farmacológico , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/tratamento farmacológico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Modelos Teóricos , Óxido Nítrico Sintase Tipo III/metabolismo , Ligação Proteica , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
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