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1.
Biomed Environ Sci ; 33(9): 647-659, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-33106210

RESUMO

Objective: This panel study aimed to determine the acute effects of exposure to fine particulate matter (PM 2.5) on schoolchildren's pulmonary function. Methods: We selected 51 schoolchildren aged 9-12 years attending a full-time boarding school in Beijing, China, measured the indoor and outdoor PM 2.5 concentrations for five consecutive days, calculated the PM 2.5 time-weighted individual exposure levels based on the school micro-environmental concentrations and the time activity pattern recorded by schoolchildren, measured schoolchildren's pulmonary function on the fifth day. The survey was performed three times from December 2018 to April 2019. We used a linear mixed-effects model to evaluate the associations between PM 2.5 and pulmonary function. Results: During the three surveys, the median PM 2.5 time-weighted individual exposure concentrations were 15.30 µg/m 3, 48.92 µg/m 3, and 42.89 µg/m 3, respectively. There was a significant difference between the three surveys in vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) and forced expiratory volume in one second/forced vital capacity (FEV 1/FVC) ( P < 0.05). The relevance analysis found that PM 2.5 had lag effect on schoolchildren's pulmonary function, each 10 µg/m 3increase in PM 2.5could cause largest decreases in FEF 25%-75%, FEV 1/FVC, FEF 75%, and FEV 1 on lag 0-1 d (80.44 mL/s, 35.85%, 78.58 mL/s, and 61.34 mL, respectively), and largest decreases in FEF 25% on lag 1 d (83.68 mL/s), in VC on lag 4 d (32.34 mL), and in FVC on lag 0-4 d (37.76 mL). Gender subgroup analysis revealed that the increase in PM 2.5 caused a decrease in FEV 1/FVC and VC on the day of physical examination only in boys, and on lag days it caused changes in different pulmonary function indicators, both for boys and girls, but most of the pulmonary function indicators decreased more in boys than in girls. Conclusion: Our findings show that acute PM 2.5 exposure has significant effects on pulmonary function within 0-4 d, on both small airway indicators and large airway indicators. Boys' pulmonary function is more sensitive to PM 2.5 than girls.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental/efeitos adversos , Pulmão/fisiologia , Material Particulado/efeitos adversos , Capacidade Vital , Criança , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/efeitos dos fármacos , Masculino
2.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32938776

RESUMO

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.


Assuntos
Pneumopatias/fisiopatologia , Pulmão/fisiologia , Criança , Feminino , Humanos , Lactente , Recém-Nascido Prematuro , Doenças do Prematuro , Pulmão/embriologia , Pneumopatias/prevenção & controle , Assistência Perinatal , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Testes de Função Respiratória
3.
Adv Physiol Educ ; 44(4): 516-519, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32880483

RESUMO

This paper describes the process involved in conducting an online spirometry practical through Zoom. The teacher demonstrated the practical from the medical school, and the students observed the procedure from the comfort of their own homes. Students were able to analyze the graphs captured in the teacher's laptop by remotely controlling the teacher's laptop. This method may be useful for places where face-to-face classes are suspended due to the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Instrução por Computador , Infecções por Coronavirus/prevenção & controle , Educação a Distância , Educação de Graduação em Medicina , Pulmão/fisiologia , Pandemias/prevenção & controle , Fisiologia/educação , Pneumonia Viral/prevenção & controle , Espirometria , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Volume Expiratório Forçado , Humanos , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Faculdades de Medicina , Capacidade Vital
4.
J Breath Res ; 14(4): 046010, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32969351

RESUMO

Inhalation of smoke is shown to be associated with adverse respiratory outcomes in firefighters. Due to invasiveness of procedures to obtain airways lining fluid, the immediate responses of the target organ (i.e. lung) are secondarily assessed through biomarkers in blood and urine. The objective of this study was to identify changes in metabolic profile of exhaled breath condensate (EBC) and lung function of firefighters exposed to wildfires smoke. A total of 29 subjects were studied over 16 events; 14 of these subjects provided cross-shift EBC samples. The predominant types of non-exchangeable hydrogen in EBC were saturated oxygenated hydrogen, aliphatic alkyl and allylic. Non-exchangeable allylic and oxygenated hydrogen concentrations decreased in post-exposure EBC samples. Longer exposures were correlated with increased abundance of oxidized carbon in ketones, acids and esters. Post-exposure lung function declines (forced expiratory volume in 1 s (FEV1): 0.08 l, forced vital capacity (FVC): 0.07 l, FEV1/FVC: 0.03 l, peak expiratory flow (PEF): 0.39 l s-1) indicated airways inflammation. They were related to exposure intensity (FEV1 and FVC) and exposure duration (PEF). This study showed that EBC characterization of non-exchangeable hydrogen types by NMR may provide insights on EBC molecular compositions in response to smoke inhalation and facilitate targeted analysis to identify specific biomarkers.


Assuntos
Testes Respiratórios/métodos , Expiração , Bombeiros , Hidrogênio/análise , Pulmão/fisiologia , Testes de Função Respiratória , Incêndios Florestais , Adulto , Biomarcadores/análise , Biomassa , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Capacidade Vital
6.
Cell Transplant ; 29: 963689720952089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32830527

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical trials have treated COVID-19 patients with DPSCs, this therapy has not been approved. Here, we review the potential use of DPSCs and their significance in the development of a therapy for COVID-19.


Assuntos
Infecções por Coronavirus/terapia , Polpa Dentária/citologia , Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Pneumonia Viral/terapia , Betacoronavirus/imunologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Polpa Dentária/imunologia , Humanos , Imunoterapia/métodos , Inflamação/imunologia , Inflamação/terapia , Pulmão/imunologia , Pulmão/fisiologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/terapia , Células-Tronco Mesenquimais/citologia , Pandemias , Pneumonia Viral/imunologia , Regeneração
7.
PLoS One ; 15(8): e0237434, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797096

RESUMO

OBJECTIVES: To systematically evaluate the influence of acquisition settings in conjunction with raw-data based iterative image reconstruction (IR) on lung densitometry based on multi-row detector computed tomography (CT) in an anthropomorphic chest phantom. MATERIALS AND METHODS: Ten porcine heart-lung explants were mounted in an ex vivo chest phantom shell, six with highly and four with low attenuating chest wall. CT (Somatom Definition Flash, Siemens Healthineers) was performed at 120kVp and 80kVp, each combined with current-time products of 120, 60, 30, and 12mAs, and was reconstructed with filtered back projection (FBP) and IR (Safire, Siemens Healthineers). Mean lung density (LD), air density (AD) and noise were measured by semi-automated region-of interest (ROI) analysis, with 120kVp/120 mAs serving as the standard of reference. RESULTS: Using IR, noise in lung parenchyma was reduced by ~ 31% at high attenuating chest wall and by ~ 22% at low attenuating chest wall compared to FBP, respectively (p<0.05). IR induced changes in the order of ±1 HU to mean absolute LD and AD compared to corresponding FBP reconstructions which were statistically significant (p<0.05). CONCLUSIONS: Densitometry is influenced by acquisition parameters and reconstruction algorithms to a degree that may be clinically negligible. However, in longitudinal studies and clinical research identical protocols and potentially other measures for calibration may be required.


Assuntos
Pulmão/fisiologia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Tomografia Computadorizada por Raios X , Algoritmos , Animais , Antropometria , Densitometria , Pulmão/diagnóstico por imagem , Pulmão/efeitos da radiação , Exposição à Radiação , Razão Sinal-Ruído , Suínos , Tórax/diagnóstico por imagem
9.
PLoS One ; 15(8): e0237769, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817718

RESUMO

Concerns exist that the positive association of physical activity with better lung function, which has been suggested in previous longitudinal studies in smokers, is due to reverse causation. To investigate this, we applied structural equation modeling (SEM), an exploratory approach, and marginal structural modeling (MSM), an approach from the causal inference framework that corrects for reverse causation and time-dependent confounding and estimates causal effects, on data from participants in the European Community Respiratory Health Survey (ECRHS, a multicentre European cohort study initiated in 1991-1993 with ECRHS I, and with two follow-ups: ECRHS II in 1999-2003, and ECRHS III in 2010-2014). 753 subjects who reported current smoking at ECRHS II, with repeated data on lung function at ECRHS I, II and III, physical activity at ECRHS II and III, and potential confounders at ECRHS I and II, were included in the analyses. SEM showed positive associations between physical activity and lung function in both directions. MSM suggested a protective causal effect of physical activity on lung function (overall difference in mean ß (95% CI), comparing active versus non-active individuals: 58 mL (21-95) for forced expiratory volume in one second and 83 mL (36-130) for forced vital capacity). Our results suggest bi-directional causation and support a true protective effect of physical activity on lung function in smokers, after accounting for reverse causation and time-dependent confounding.


Assuntos
Asma/terapia , Exercício Físico , Pulmão/fisiologia , Infecções Respiratórias/terapia , Adolescente , Adulto , Asma/etiologia , Asma/fisiopatologia , Peso Corporal/fisiologia , Dieta , Feminino , Volume Expiratório Forçado/fisiologia , Inquéritos Epidemiológicos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Fumantes , Fumar/efeitos adversos , Capacidade Vital/fisiologia , Adulto Jovem
11.
Br J Anaesth ; 125(5): 773-778, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32859360

RESUMO

BACKGROUND: Increasing fresh gas flow (FGF) to a circle breathing system reduces carbon dioxide (CO2) absorbent consumption. We assessed the environmental and economic impacts of this trade-off between gas flow and absorbent consumption when no inhalational anaesthetic agent is used. METHODS: A test lung with fixed CO2 inflow was ventilated via a circle breathing system of an anaesthetic machine (Dräger Primus or GE Aisys CS2) using an FGF of 1, 2, 4, or 6 L min-1. We recorded the time to exhaustion of the CO2 absorbent canister, defined as when inspired partial pressure of CO2 exceeded 0.3 kPa. For each FGF, we calculated the economic costs and the environmental impact associated with the manufacture of the CO2 absorbent canister and the supply of medical air and oxygen. Environmental impact was measured in 100 yr global-warming potential, analysed using a life cycle assessment 'cradle to grave' approach. RESULTS: Increasing FGF from 1 to 6 L min-1 was associated with up to 93% reduction in the combined running cost with minimal net change to the 100 yr global-warming potential. Most of the reduction in cost occurred between 4 and 6 L min-1. Removing the CO2 absorbent from the circle system, and further increasing FGF to control CO2 rebreathing, afforded minimal further economic benefit, but more than doubled the global-warming potential. CONCLUSIONS: In the absence of inhalational anaesthetic agents, increasing FGF to 6 L min-1 reduces running cost compared with lower FGFs, with minimal impact to the environment.


Assuntos
Anestésicos Inalatórios/química , Dióxido de Carbono/química , Poluição Ambiental/análise , Gases/química , Anestesia com Circuito Fechado , Anestesia por Inalação , Anestésicos Inalatórios/economia , Poluição Ambiental/economia , Poluição Ambiental/prevenção & controle , Gases/economia , Aquecimento Global , Humanos , Pulmão/fisiologia , Modelos Anatômicos , Respiração Artificial , Hidróxido de Sódio
13.
Life Sci ; 257: 118113, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32687919

RESUMO

AIMS: To create a low-cost ventilator that could be constructed with readily-available hospital equipment for use in emergency or low-resource settings. MAIN METHODS: The novel ventilator consists of an inspiratory limb composed of an elastic flow-inflating bag encased within a non-compliant outer sheath and an expiratory limb composed of a series of two, one-way bidirectional splitter valves derived from a self-inflating bag system. An Arduino Uno microcontroller controls a solenoid valve that can be programmed to open and close to produce a set respiratory rate and inspiratory time. Using an ASL 5000 Lung Simulator, we obtained flow, pressure, and volume waveforms at different lung compliances. KEY FINDINGS: At a static lung compliance of 50 mL/cm H2O and an airway resistance of 6 cm H2O/L/s, ventilated at a PIP and PEEP of 16 and 5 cm H2O, respectively, tidal volumes of approximately 540 mL were achieved. At a static lung compliance of 20 mL/cm H2O and an airway resistance of 6 cm H2O/L/s, ventilated at a PIP and PEEP of 38 and 15 cm H2O, respectively, tidal volumes of approximately 495 mL were achieved. SIGNIFICANCE: This novel ventilator is able to safely and reliably ventilate patients with a range of pulmonary disease in a simulated setting. Opportunities exist to utilize our ventilator in emergency situations and low-resource settings.


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Resistência das Vias Respiratórias/fisiologia , Betacoronavirus/patogenicidade , Humanos , Pulmão/fisiologia , Pandemias , Taxa Respiratória/fisiologia , Volume de Ventilação Pulmonar/fisiologia , Ventiladores Mecânicos/provisão & distribução
14.
Artigo em Inglês | MEDLINE | ID: mdl-32599726

RESUMO

Background: Local spirometric prediction equations are of great importance for interpreting lung function results and deciding on the management strategies for respiratory patients, yet available data from African countries are scarce. The aim of this study was to collect lung function data using spirometry in healthy adults living in Maputo, Mozambique and to derive first spirometric prediction equations for this population. Methods: We applied a cross-sectional study design. Participants, who met the inclusion criteria, underwent a short interview, anthropometric measurements, and lung function testing. Different modelling approaches were followed for generating new, Mozambican, prediction equations and for comparison with the Global Lung Initiative (GLI) and South African equations. The pulmonary function performance of participants was assessed against the different reference standards. Results: A total of 212 males and females were recruited, from whom 155 usable spirometry results were obtained. The mean age of participants was 35.20 years (SD 10.99) and 93 of 155 (59.35%) were females. The predicted values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and the FEV1/FVC ratio based on the Mozambican equations were lower than the South African-and the GLI-based predictions. Conclusions: This study provides first data on pulmonary function in healthy Mozambican adults and describes how they compare to GLI and South African reference values for spirometry.


Assuntos
Volume Expiratório Forçado , Pulmão , Espirometria , Adulto , Estudos Transversais , Feminino , Previsões , Humanos , Pulmão/fisiologia , Masculino , Moçambique , Valores de Referência , Capacidade Vital
16.
Nat Commun ; 11(1): 3280, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612128

RESUMO

The atmospheric pressure that decreases with altitude affects lung physiology. However, these changes in physiology are not usually considered in ventilator design and testing. We argue that high altitude human populations require special attention to access the international supply of ventilators.


Assuntos
Altitude , Infecções por Coronavirus/terapia , Desenho de Equipamento , Pneumonia Viral/terapia , Ventiladores Mecânicos/provisão & distribução , Pressão Atmosférica , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Humanos , Pulmão/fisiologia , Pandemias , Pneumonia Viral/fisiopatologia
17.
Curr Protoc Stem Cell Biol ; 54(1): e118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640120

RESUMO

The normal development of the pulmonary system is critical to transitioning from placental-dependent fetal life to alveolar-dependent newborn life. Human lung development and disease have been difficult to study due to the lack of an in vitro model system containing cells from the large airways and distal alveolus. This article describes a system that allows human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to differentiate and form three-dimensional (3D) structures that emulate the development, cytoarchitecture, and function of the lung ("organoids"), containing epithelial and mesenchymal cell populations, and including the production of surfactant and presence of ciliated cells. The organoids can also be invested with mesoderm derivatives, differentiated from the same human pluripotent stem cells, such as alveolar macrophages and vasculature. Such lung organoids may be used to study the impact of environmental modifiers and perturbagens (toxins, microbial or viral pathogens, alterations in microbiome) or the efficacy and safety of drugs, biologics, and gene transfer. © 2020 Wiley Periodicals LLC. Basic Protocol: hESC/hiPSC dissection, definitive endoderm formation, and lung progenitor cell induction.


Assuntos
Infecções por Coronavirus/patologia , Pulmão/citologia , Organoides/citologia , Pneumonia Viral/patologia , Infecções Respiratórias/patologia , Betacoronavirus , Técnicas de Cultura de Células , Diferenciação Celular , Infecções por Coronavirus/terapia , Endoderma/citologia , Células-Tronco Embrionárias Humanas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Pulmão/crescimento & desenvolvimento , Pulmão/fisiologia , Modelos Biológicos , Pandemias , Modelagem Computacional Específica para o Paciente , Pneumonia Viral/terapia , Infecções Respiratórias/terapia , Imagem com Lapso de Tempo
19.
Spine (Phila Pa 1976) ; 45(14): 983-992, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32609467

RESUMO

STUDY DESIGN: Retrospective review of a prospective multicenter database. OBJECTIVE: The aim of this study was to study the effects of thoracic kyphosis (TK) restoration in adolescent idiopathic scoliosis (AIS) Type 1 and 2 curves on postoperative thoracic volume (TV) and pulmonary function. SUMMARY OF BACKGROUND DATA: Surgical correction of AIS is advocated to preserve or improve pulmonary function, prevent progressive deformity and pain, and improve self-appearance. Restoration of sagittal and 3D alignment, particularly TK, has become increasingly emphasized in efforts to improve pulmonary function, TVs, sagittal balance, and prevent adjacent-segment degeneration and deformity. METHODS: AIS patients 10 to 21years undergoing surgical correction of Lenke Type 1 and 2 curves with baseline, 1-erect-postoperative, and 5-year (5Y) postoperative visits including stereoradiographic assessment and pulmonary function tests (PFTs) were included. 3D-radiographic analysis was performed to assess spinal-alignment, chest-wall, and rib-cage dimensions at each time point. Outcome variables were analyzed between time points with one-way analysis of variance and between variables with linear regression analysis. RESULTS: Thirty-nine patients (37 females, 14.4 ± 2.2 years) were included. 3D-spinal-alignment analyses demonstrated significant reduction in preoperative to first-erect thoracic and lumbar Cobb-angles, an increase in TK:T2-12 (19.67°-39.69°) and TK:T5-12 (9.47°-28.05°), and reduction in apical vertebral rotation (AVR) (P < 0.001 for all). Spinal-alignment remained stable from 1-erect to 5Y. 3D rib-cage analysis demonstrated small reductions in baseline to first-erect depth (145-139 mm), width (235-232 mm), and increase in height (219-230 mm, P < 0.01), but no significant change in volume (5161-5222 cm,P = 0.184). From 1-erect to 5Y, significant increases in depth, width, height, and volume (all P < 0.001) occurred. PFTs showed preoperative to 5Y improvement in first second of Forced Expiratory Volume (FEV1) (2.74-2.98 L, P = 0.005) and forced vital capacity (FVC) (3.23-3.47 L, P = 0.008); however, total lung capacity (TLC) did not change (P = 0.517). Percent-predicted TLC decreased (Pre: 101.3% to 5Y: 89.3%, P < 0.001); however, percent-predicted forced expiratory volume and FVC did not (P = 0.112 and P = 0.068). CONCLUSION: Although TK increases, coronal-Cobb and AVR decrease postoperatively; these do not directly influence TV, which increases from 1-erect to 5Y due to growth, corresponding with increases in FEV1 and FVC at 5Y; however, surgical restoration of kyphosis does not directly improve pulmonary function. LEVEL OF EVIDENCE: 3.


Assuntos
Pulmão/fisiologia , Escoliose , Vértebras Torácicas , Tórax , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Testes de Função Respiratória , Estudos Retrospectivos , Escoliose/fisiopatologia , Escoliose/cirurgia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/fisiopatologia , Vértebras Torácicas/cirurgia , Tórax/diagnóstico por imagem , Tórax/fisiopatologia , Resultado do Tratamento
20.
Am J Hum Genet ; 107(2): 211-221, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32649856

RESUMO

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/genética , Receptores de Trombina/genética , Transdução de Sinais/genética , Trombina/genética , Alelos , Embolia/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Insuficiência Cardíaca/genética , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Receptor PAR-1/genética , Acidente Vascular Cerebral/genética
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