RESUMEN
OBJECTIVE: The aim of this study was to assess right atrial (RA) function, including RA phase strain, via speckle-tracking echocardiography (STE) in a cohort of systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH) and in particular to explore the relationship between RA phase strain and the occurrence of cardiovascular events. METHODS: STE analyses of RA function were evaluated in patients with SLE-PAH and in 33 healthy control subjects. Clinical associations, serum biomarkers, echocardiographic data, survival times, and adverse cardiovascular events were evaluated. RESULTS: A total of 66 patients with SLE-PAH were enrolled; they were divided into two groups based on the occurrence of adverse clinical events. RA phase strain was significantly reduced in patients with events than in patients without events. The endpoint was defined as the combined outcome of all-cause mortality, right heart failure, and rehospitalization due to disease progression. During a mean follow-up of 17.2 ± 9.9 months, 23 patients (35%) reached the endpoint. Compared with patients with RA reservoir strain (RASr) ≥33.45%, patients with RASr < 33.45% had more adverse long-term outcomes (log rank p < .0001). RASr was independently associated with adverse clinical outcomes according to multivariate analysis (p = .010). CONCLUSION: Our data suggest that RA function has prognostic value for SLE-PAH patients, and strain analysis revealed that the worse the RA function is, the worse the prognosis.
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Ecocardiografía , Atrios Cardíacos , Lupus Eritematoso Sistémico , Humanos , Femenino , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Pronóstico , Ecocardiografía/métodos , Persona de Mediana Edad , Adulto , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/complicaciones , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/sangre , Función del Atrio Derecho/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/etiología , Estudios de SeguimientoRESUMEN
Background: Iron deficiency (ID) is common in patients with pulmonary arterial hypertension and has been associated with increased morbidity and mortality. We aimed to evaluate the therapeutic effects of iron supplementation in iron deficient patients with group 1 to 4 pulmonary hypertension (PH). Methods: A total of 85 PH patients (mean age 69.8 ± 12.0 years, 56.5% female) were included in this prospective trial. Patients were screened for ID at baseline. PH patients with ID received intravenous iron supplementation (500-1000 mg ferric carboxymaltose). PH patients without ID served as control group. At baseline and 16-week follow up, six-minute walk test (6MWT), laboratory testing and echocardiography were performed. Additionally, World Health Organization (WHO) functional class, fatigue score and quality of life (QoL) by the SF-36 questionnaire were assessed. Results: Overall, ID was present in 26.7% (n=8/30), 37.5% (n=9/24), 45.5% (n=10/22) and 44.4% (n=4/9) of patients in PH groups 1-4, respectively. In the total study population, iron restoration led to a significant mitigation of fatigue (p=0.01). However, 6MWT, WHO function class, NT-proBNP levels, QoL and right ventricular function did not change significantly. With regard to the underlying PH group, only PH group 3 patients experienced significant improvements in 6MWT distance (p=0.019), WHO functional class (p=0.017), fatigue (p=0.009) and some QoL domains, as compared to controls. Conclusions: ID was common in PH groups 1 to 4. Though intravenous iron supplementation adequately restored iron status and improved fatigue throughout all patients, in the underlying PH groups treatment was accompanied by improvements in exercise capacity, WHO function class and fatigue only in group 3 PH.
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Hipertensión Pulmonar , Calidad de Vida , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Hipertensión Pulmonar/tratamiento farmacológico , Estudios Prospectivos , Maltosa/análogos & derivados , Maltosa/administración & dosificación , Anciano de 80 o más Años , Compuestos Férricos/administración & dosificación , Anemia Ferropénica/tratamiento farmacológico , Anemia Ferropénica/sangre , Prueba de Paso , Administración Intravenosa , Resultado del Tratamiento , Hierro/administración & dosificación , Ecocardiografía , Suplementos DietéticosRESUMEN
Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described. Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung. In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.
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Arritmias Cardíacas , Modelos Animales de Enfermedad , Arteria Pulmonar , Animales , Ratas , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Remodelación Ventricular/fisiología , Masculino , Hipertensión Pulmonar/fisiopatologíaRESUMEN
Hyperuricemia is a known predictor of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension), but its role in excluding PH secondary to chronic lung diseases (WHO Group 3) remains unclear. We retrospectively analyzed data from 323 patients with severe chronic pulmonary diseases who underwent evaluation for lung transplantation at a tertiary medical center between June 2017 and February 2023. We examined the association between hyperuricemia (serum uric acid > 6 mg/dL or > 0.357 mmol/L) and PH [mean pulmonary arterial pressure (MPAP) > 20 mmHg]. Compared to the normouricemia group (n = 211), hyperuricemic patients (n = 112) were more likely to be younger (P = 0.02), male (P < 0.001), and present with PH (P = 0.001) and severe PH (MPAP > 35 mmHg; P < 0.001). These patients also had a higher body mass index (P = 0.004), plasma N-terminal pro-B-type natriuretic peptide (P < 0.001), serum creatinine (P < 0.001), and C-reactive protein levels (P = 0.03). Significant associations with PH included higher body mass index (P = 0.005), uric acid levels (P < 0.001), total lung capacity (P = 0.02), and residual volume (P = 0.01); shorter 6-min walk test distance (P = 0.005); and lower forced expiratory volume in one second (P = 0.006) and diffusing capacity for carbon monoxide (P < 0.001). Multivariate analysis showed elevated uric acid levels remained significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, P = 0.01). In conclusion, normal serum uric acid levels serve as a significant predictor for excluding pulmonary hypertension in patients with severe chronic lung diseases.
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Hipertensión Pulmonar , Hiperuricemia , Centros de Atención Terciaria , Ácido Úrico , Humanos , Masculino , Persona de Mediana Edad , Ácido Úrico/sangre , Femenino , Estudios Retrospectivos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/fisiopatología , Anciano , Hiperuricemia/sangre , Hiperuricemia/complicaciones , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/complicaciones , Adulto , Enfermedad CrónicaRESUMEN
The system of nitric oxide synthases (NOSs) is comprised of three isoforms: nNOS, iNOS, and eNOS. The roles of NOSs in respiratory diseases in vivo have been studied by using inhibitors of NOSs and NOS-knockout mice. Their exact roles remain uncertain, however, because of the non-specificity of inhibitors of NOSs and compensatory up-regulation of other NOSs in NOS-KO mice. We addressed this point in our triple-n/i/eNOSs-KO mice. Triple-n/i/eNOSs-KO mice spontaneously developed pulmonary emphysema and displayed exacerbation of bleomycin-induced pulmonary fibrosis as compared with wild-type (WT) mice. Triple-n/i/eNOSs-KO mice exhibited worsening of hypoxic pulmonary hypertension (PH), which was reversed by treatment with sodium nitrate, and WT mice that underwent triple-n/i/eNOSs-KO bone marrow transplantation (BMT) also showed aggravation of hypoxic PH compared with those that underwent WT BMT. Conversely, ovalbumin-evoked asthma was milder in triple-n/i/eNOSs-KO than WT mice. These results suggest that the roles of NOSs are different in different pathologic states, even in the same respiratory diseases, indicating the diversity of the roles of NOSs. In this review, we describe these previous studies and discuss the roles of NOSs in respiratory health and disease. We also explain the current state of development of inorganic nitrate as a new drug for respiratory diseases.
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Ratones Noqueados , Animales , Ratones , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa/genética , Humanos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patologíaRESUMEN
OBJECTIVE: This study aims to assess the tricuspid annular plane systolic excursion (TAPSE)/PASP ratio as a potential indicator for predicting the probability of developing pulmonary arterial hypertension (PAH) in hyperthyroidism patients. A nomogram model will be developed based on our findings, as well as the receiver operating characteristic (ROC) curve. METHODS: The study involved 166 hyperthyroid patients treated at Yijishan Hospital, and the period covered August 2021 to August 2022. Patients were divided into two groups according to pulmonary artery systolic pressure ≥35 mmHg. Univariate and multivariate logistic analyses were performed on the two groups' demographic and laboratory data to identify potential diagnostic markers. These parameters were evaluated using ROC curves to determine their precision in forecasting PAH. The findings were validated by plotting a calibration curve based on a line chart model. RESULTS: In the study, eventually, 80 patients were enrolled: 30 in the PAH group and 50 in the No PAH group. Multipleistic regression analysis predicted the occurrence risk of developing PAH. When paired with other conventional echocardiographic parameters (such as TAPSE, MPI, and SV) and serological markers (such as FT3 and FT4), the developed model demonstrated outstanding predictive performance with an area under the ROC curve of 0.985, a Youden index of 0.971, a sensitivity of 100%, and a specificity of 97.1%. CONCLUSIONS: The nomogram model constructed by combining the TAPSE/PASP ratio with FT3 and FT4 serum markers, as well as conventional ultrasound parameters SV and MPI in hyperthyroidism patients, demonstrates robust discriminatory ability and consistency.
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Hipertiroidismo , Humanos , Hipertiroidismo/complicaciones , Hipertiroidismo/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Ecocardiografía/métodos , Adulto , Nomogramas , Valor Predictivo de las Pruebas , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Curva ROC , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/fisiopatología , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/complicaciones , Medición de Riesgo/métodosRESUMEN
BACKGROUND: Pulmonary hypertension is a condition that involves the remodeling of the right ventricle. Ongoing remodeling is also associated with disease prognosis. During the restructuring process, complex changes such as hypertrophy and dilatation may also be reflected in electrocardiographic parameters. OBJECTIVES: Our study aimed to investigate the relationship between prognosis and electrocardiographic parameters in patients with pulmonary arterial hypertension. METHODS: The study was designed retrospectively and included patients diagnosed with pulmonary arterial hypertension between 2010 and 2022. The patients were divided into two groups based on their survival outcome. Various parameters, including electrocardiographic, demographic, echocardiographic, catheter, and blood parameters, were compared between the two groups. A p-value of <0.05 was considered statistically significant. RESULTS: In the multivariate Cox analyses, the parameters that were found to be independently associated with survival were the 6-minute walk test, mean pulmonary artery pressure, presence of pericardial effusion, and time between the beginning of the QRS and the peak of the S wave (RS time) (p<0.05 for each). Of all the parameters, RS time demonstrated the best diagnostic performance (AUC:0.832). In the survival analysis, a significant correlation was found between RS time and survival when using a cut-off value of 59.5 ms (HR: 0.06 [0.02-0.17], p < 0.001). CONCLUSIONS: According to the results of our study, a longer RS time is associated with poor prognosis in patients with pulmonary arterial hypertension. We can obtain information about the course of the disease with a simple, non-invasive parameter.
FUNDAMENTO: A hipertensão pulmonar é uma condição que envolve a remodelação do ventrículo direito. A remodelação contínua também está associada ao prognóstico da doença. Durante o processo de reestruturação, alterações complexas como hipertrofia e dilatação também podem se refletir nos parâmetros eletrocardiográficos. OBJETIVOS: Nosso estudo teve como objetivo investigar a relação entre prognóstico e parâmetros eletrocardiográficos em pacientes com hipertensão arterial pulmonar. MÉTODOS: O estudo foi desenhado retrospectivamente e incluiu pacientes com diagnóstico de hipertensão arterial pulmonar entre 2010 e 2022. Os pacientes foram divididos em dois grupos com base no resultado de sobrevida. Vários parâmetros, incluindo parâmetros eletrocardiográficos, demográficos, ecocardiográficos, de cateter e sanguíneos, foram comparados entre os dois grupos. Um valor de p <0,05 foi considerado estatisticamente significativo. RESULTADOS: Na análise multivariada de Cox, os parâmetros que se mostraram independentemente associados à sobrevida foram o teste de caminhada de 6 minutos, pressão média da artéria pulmonar, presença de derrame pericárdico e tempo entre o início do QRS e o pico da onda S (tempo de RS) (p<0,05 para cada). De todos os parâmetros, o tempo de RS demonstrou o melhor desempenho diagnóstico (AUC: 0,832). Na análise de sobrevida, foi encontrada correlação significativa entre o tempo de RS e a sobrevida ao utilizar o valor de corte de 59,5 ms (HR: 0,06 [0,02-0,17], p < 0,001). CONCLUSÕES: De acordo com os resultados do nosso estudo, um tempo de RS mais longo está associado a um pior prognóstico em pacientes com hipertensão arterial pulmonar. Podemos obter informações sobre o curso da doença com um parâmetro simples e não invasivo.
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Electrocardiografía , Humanos , Femenino , Masculino , Pronóstico , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Factores de Tiempo , Ecocardiografía , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/mortalidad , Anciano , Valores de Referencia , Prueba de PasoRESUMEN
BACKGROUND: There are limited data assessing the spectrum of systemic sclerosis-associated pulmonary hypertension (PH). METHODS: Data for 912 systemic sclerosis patients assessed between 2000 and 2020 were retrieved from the Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre (ASPIRE) registry and classified based on 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines and multimodality investigations. RESULTS: Reduction in pulmonary vascular resistance (PVR) diagnostic threshold to >2WU resulted in a 19% increase in precapillary PH diagnoses. Patients with PVR ≤2WU had superior survival to PVR >2-3WU which was similar to PVR >3-4WU. Survival in pulmonary arterial hypertension (PAH) was superior to PH associated with lung disease. However, patients with mild parenchymal disease on CT had similar characteristics and outcomes to patients without lung disease. Combined pre- and postcapillary PH had significantly poorer survival than isolated postcapillary PH. Patients with mean pulmonary arterial wedge pressure (PAWP) 13-15 mm Hg had similar haemodynamics and left atrial volumes to those with PAWP >15 mm Hg. Unclassified-PH had more frequently dilated left atria and higher PAWP than PAH. Although Unclassified-PH had a similar survival to No-PH, 36% were subsequently diagnosed with PAH or PH associated with left heart disease. The presence of 2-3 radiological signs of pulmonary veno-occlusive disease was noted in 7% of PAH patients and was associated with worse survival. Improvement in incremental shuttle walking distance of ≥30 m following initiation of PAH therapy was associated with superior survival. PAH patients diagnosed after 2011 had greater use of combination therapy and superior survival. CONCLUSION: A number of systemic sclerosis PH phenotypes can be recognized and characterized using haemodynamics, lung function and multimodality imaging.
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Hipertensión Pulmonar , Sistema de Registros , Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/fisiopatología , Masculino , Femenino , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Persona de Mediana Edad , Tasa de Supervivencia/tendencias , Estudios Retrospectivos , Resistencia Vascular/fisiología , Presión Esfenoidal Pulmonar/fisiología , Adulto , Estudios de SeguimientoRESUMEN
BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.
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Hipertensión Pulmonar , Pulmón , Schistosoma mansoni , Animales , Ratones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/parasitología , Hipertensión Pulmonar/inmunología , Pulmón/parasitología , Pulmón/inmunología , Pulmón/patología , Schistosoma mansoni/inmunología , Clorhidrato de Fingolimod/farmacología , Femenino , Linfocitos T CD4-Positivos/inmunología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/patología , Modelos Animales de Enfermedad , Interleucina-4/metabolismo , Citocinas/metabolismo , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Esquistosomiasis/complicaciones , Esquistosomiasis/inmunología , Esquistosomiasis/parasitologíaAsunto(s)
Antihipertensivos , Hipertensión Pulmonar , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Presión Arterial/efectos de los fármacosRESUMEN
BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-ß) to investigate the effect of DAPA. RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.
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Compuestos de Bencidrilo , Colágeno , Fibrosis , Glucósidos , Insuficiencia Cardíaca , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Ratas , Colágeno/metabolismo , Masculino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: In pulmonary hypertension (PH), the identification of easily obtainable prognostic markers associated with right ventricular (RV) dysfunction and survival is needed. OBJECTIVE: To evaluate the association of red cell distribution width (RDW) with clinical, echocardiographic parameters and survival in patients with pre-capillary PH, with the development of a mortality prediction model. METHODS: Observational, longitudinal, and prospective study conducted from May 2019 to December 2022. Thirty-four patients with pre-capillary PH underwent two-dimensional echocardiography and complete blood count. A cutoff point of 14.5% was considered to define RDW as altered (≥14.5%) or normal (<14.5%). P values <0.05 were considered significant. RESULTS: The median RDW was 14.4%. There was a significant difference in peripheral arterial oxygen saturation (SpO2) (p=0.028), RV strain (p=0.047), and pericardial effusion (p=0.002) between the normal and elevated RDW groups. During a median follow-up of 15 months, 20.6% died. Patients with increased RDW had a shorter overall survival (44.7%, log-rank p=0.019), which was a predictor of mortality in univariate Cox regression (HR 8.55, p=0.048). The addition of RV strain <16% and SpO2 ≤93% to the model including RDW alone showed incremental value in predicting mortality (χ2=8.2, p=0.049; χ2=12.4, p=0.041), with increased area under the receiver operating characteristic curve (0.729 vs. 0.837 vs. 0.909) and decreased probability of survival (44.7% vs. 35.6% vs. 25%, log-rank p=0.019). CONCLUSIONS: RDW provides information on the severity of pre-capillary PH by correlating with echocardiographic parameters of RV dysfunction and mortality, which is best predicted by a model including RDW, RV strain and SpO2.
FUNDAMENTO: Na hipertensão pulmonar (HP), é necessária a identificação de marcadores prognósticos de fácil obtenção associados com disfunção do ventrículo direito (VD) e sobrevida. OBJETIVO: Avaliar a associação do índice de anisocitose eritrocitária (RDW, do inglês red cell distribution width) com parâmetros ecocardiográficos e sobrevida em pacientes com HP pré-capilar, com o desenvolvimento de um modelo de predição de mortalidade. MÉTODOS: Estudo observacional, longitudinal, prospectivo, conduzido entre maio de 2019 e dezembro de 2022. Trinta e quatro pacientes com HP pré-capilar submeteram-se à realização de ecocardiograma bidimensional e hemograma. Um ponto de corte de 14,5% foi adotado para definir o RDW como alterado (≥14,5%) ou normal (<14,5%). Valores de p<0,05 foram considerados significativos. RESULTADOS: O RDW médio foi 14,4%. Houve uma diferença significativa na saturação periférica de oxigênio (SpO2) (p=0,028), strain do VD (p=0,047) e derrame pericárdico (p=0,002) entre os grupos com RDW normal e elevado. Durante um período mediano de 15 meses, 20,6% dos pacientes foram a óbito. Os pacientes com RDW aumentado tiveram uma sobrevida global mais curta (44,7%, log-rank p=0,019), sendo um preditor de mortalidade na regressão univariada de Cox. A adição do strain do VD < 16% e da SpO2 ≤93% ao modelo incluindo somente RDW mostrou valor incremental na predição de mortalidade (χ2=8,2, p=0,049; χ2=12,4, p=0,041), com área sob a curva ROC (do inglês, Receiver Operating Characteristic) aumentada (0,729 vs. 0,837 vs. 0,909) e probabilidade de sobrevida diminuída (44.7% vs. 35.6% vs. 25%, log-rank p=0,019). CONCLUSÕES: O RDW fornece informações sobre a gravidade da HP pré-capilar pela sua correlação com parâmetros ecocardiográficos de disfunção do VD e mortalidade, a qual é melhor predita por um modelo incluindo RDW, strain do VD e SpO2.
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Ecocardiografía , Índices de Eritrocitos , Hipertensión Pulmonar , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Pronóstico , Anciano , Estudios Longitudinales , Disfunción Ventricular Derecha/mortalidad , Disfunción Ventricular Derecha/sangre , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Adulto , Curva ROC , Valor Predictivo de las PruebasRESUMEN
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious pulmonary vascular disease characterized by residual thrombi in the pulmonary arteries and distal pulmonary microvascular remodeling. The pathogenesis of CTEPH remains unclear, but many factors such as inflammation, immunity, coagulation and angiogenesis may be involved. Monocytes are important immune cells that can differentiate into macrophages and dendritic cells and play an important role in thrombus formation. However, the distribution, gene expression profile and differentiation trajectory of monocyte subsets in CTEPH patients have not been systematically studied. This study aims to reveal the characteristics and functions of monocytes in CTEPH patients using single-cell sequencing technology, and to provide new insights for the diagnosis and treatment of CTEPH. Methods: Single-cell RNA sequencing (scRNA-seq) were performed to analyze the transcriptomic features of peripheral blood mononuclear cells (PBMCs) from healthy controls, CTEPH patients and the tissues from CTEPH patients after the pulmonary endarterectomy (PEA). We established a CTEPH rat model with chronic pulmonary embolism caused by repeated injection of autologous thrombi through a central venous catheter, and used flow cytometry to detect the proportion changes of monocyte subsets in CTEPH patients and CTEPH rat model. We also observed the infiltration degree of macrophage subsets in thrombus tissue and their differentiation relationship with peripheral blood monocyte subsets by immunofluorescence staining. Results: The results showed that the monocyte subsets in peripheral blood of CTEPH patients changed significantly, especially the proportion of CD16+ monocyte subset increased. This monocyte subset had unique functional features at the transcriptomic level, involving processes such as cell adhesion, T cell activation, coagulation response and platelet activation, which may play an important role in pulmonary artery thrombus formation and pulmonary artery intimal remodeling. In addition, we also found that the macrophage subsets in pulmonary endarterectomy tissue of CTEPH patients showed pro-inflammatory and lipid metabolism reprogramming features, which may be related to the persistence and insolubility of pulmonary artery thrombi and the development of pulmonary hypertension. Finally, we also observed that CD16+ monocyte subset in peripheral blood of CTEPH patients may be recruited to pulmonary artery intimal tissue and differentiate into macrophage subset with high expression of IL-1ß, participating in disease progression. Conclusion: CD16+ monocytes subset had significant gene expression changes in CTEPH patients, related to platelet activation, coagulation response and inflammatory response. And we also found that these cells could migrate to the thrombus and differentiate into macrophages with high expression of IL-1ß involved in CTEPH disease progression. We believe that CD16+ monocytes are important participants in CTEPH and potential therapeutic targets.
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Hipertensión Pulmonar , Monocitos , Embolia Pulmonar , Receptores de IgG , Análisis de la Célula Individual , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/inmunología , Hipertensión Pulmonar/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptores de IgG/metabolismo , Embolia Pulmonar/inmunología , Embolia Pulmonar/metabolismo , Animales , Masculino , Enfermedad Crónica , Ratas , Femenino , Persona de Mediana Edad , Proteínas Ligadas a GPI/metabolismo , Modelos Animales de Enfermedad , Transcriptoma , Anciano , Arteria Pulmonar/metabolismo , Arteria Pulmonar/inmunología , Arteria Pulmonar/patologíaRESUMEN
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension with a low incidence. Despite pulmonary endarterectomy(PEA) being the preferred treatment for CTEPH, for patients who failed medical therapy and who are not suitable candidates for PEA, lung transplantation (LT) is still the only effective treatment for end-stage CTEPH; however, there are currently very few reports on the efficacy of LT for CTEPH. METHODS: We retrospectively analyzed the clinical data of seven patients diagnosed with CTEPH between July 2019 and July 2021. The follow-up deadline was March, 2022. RESULTS: The mean age at admission was 54 ± 12 years. The average value of mean pulmonary artery pressure (mPAP) was 40 ± 5 mmHg. The mean preoperative oxygenation index(PaO2/FiO2) was 203 ± 56 mm Hg. After evaluation, one patient underwent left LT and the rest underwent bilateral LT. Three patients received intraoperative veno-venous extracorporeal membrane oxygenation (ECMO) support, and four patients received intraoperative veno-arterial ECMO support. The average postoperative mPAP was 19 ± 4 mmHg. The mean postoperative oxygenation index(PaO2/FiO2) was 388 ± 83 mmHg. There was a significant difference between the preoperative and postoperative mPAP and oxygenation index(PaO2/FiO2). All patients recovered well and were discharged 37 ± 19 days postoperatively. The mean follow-up duration was 19 ± 8 months. There was no recurrence of CTEPH. CONCLUSIONS: LT is an effective treatment for end-stage CTEPH, which can improve cardiopulmonary function and quality of life and prolong survival. Patients who are unable to tolerate PEA should be considered for LT as early as possible when internal medicine failed.
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Hipertensión Pulmonar , Trasplante de Pulmón , Embolia Pulmonar , Humanos , Persona de Mediana Edad , Femenino , Masculino , Estudios Retrospectivos , Hipertensión Pulmonar/cirugía , Embolia Pulmonar/cirugía , Embolia Pulmonar/complicaciones , Adulto , Enfermedad Crónica , Resultado del Tratamiento , Oxigenación por Membrana Extracorpórea/métodos , Anciano , Endarterectomía/métodosRESUMEN
Induction of resistin-like molecule ß (Relm-ß) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-ß regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-ß promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-ß increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-ß was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-ß receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-ß promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
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Proliferación Celular , GTP Fosfohidrolasas , MicroARNs , Mitocondrias , Ratas Sprague-Dawley , Transducción de Señal , Proteína 1 Relacionada con Twist , Ubiquitina Tiolesterasa , Animales , Masculino , Ratas , Proliferación Celular/efectos de los fármacos , GTP Fosfohidrolasas/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales , Monocrotalina/toxicidad , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genéticaRESUMEN
ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by persistently elevated pulmonary artery pressure and vascular resistance. Sympathetic overactivity in hypertension participates in pulmonary vascular remodeling and heart failure. The present study aims to explore the efficacy of highly selective thoracic sympathectomy (HSTS) on lowering pulmonary artery pressure, reversing pulmonary vascular remodeling, and improving right ventricular function in rats. A total of 24 Sprague-Dawley rats were randomly assigned into the control group ( n = 8) and experimental group ( n = 16). Rats in the control group were intraperitoneally injected with 0.9% normal saline, and those in the experimental group were similarly administered with received monocrotaline (MCT) injections at 60 mg/kg. Two weeks later, rats in the experimental group were further subdivided randomly into the MCT-HSTS group ( n = 8) and MCT-sham group ( n = 8), and they were surgically treated with HSTS and sham operation, respectively. Two weeks later, significantly lowered mean pulmonary artery pressure (mPAP), pulmonary artery systolic pressure (sPAP), and the ratio of sPAP to femoral artery systolic pressure (sFAP) were detected in the MCT-HSTS group than those of the MCT-sham group. In addition, rats in the MCT-HSTS group presented a significantly lower ratio of vascular wall area to the total vascular area (WT%), right ventricular hypertrophy index, and degrees of right ventricular fibrosis and lung fibrosis in comparison to those of the MCT-sham group. HSTS significantly downregulated protein levels of inflammasomes in pulmonary artery smooth muscle cells (PASMCs). Collectively, HSTS effectively reduces pulmonary artery pressure, pulmonary arteriolar media hypertrophy, and right ventricular hypertrophy in MCT-induced PAH rats. It also exerts an anti-inflammatory effect on PASMCs in PAH rats by suppressing inflammasomes and the subsequent release of inflammatory cytokines.