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1.
BMC Pulm Med ; 24(1): 101, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38413932

RESUMEN

BACKGROUND: Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. METHODS: From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm's ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm's detection ability was superior to that of the doctors. CONCLUSION: The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.


Asunto(s)
Aprendizaje Profundo , Hipertensión Arterial Pulmonar , Humanos , Inteligencia Artificial , Hipertensión Arterial Pulmonar/diagnóstico por imagen , Rayos X , Tórax
2.
Surg Today ; 53(3): 369-378, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36018416

RESUMEN

PURPOSE: Neurologic adverse events (NAEs) are a major complication after pulmonary endarterectomy (PEA) performed under periods of deep hypothermic circulatory arrest (HCA) for chronic thromboembolic pulmonary hypertension. We modified the PEA strategy to prevent NAEs and evaluated the effectiveness of these modifications. METHODS: We reviewed the surgical outcomes of 87 patients divided into the following three groups based on the surgical strategy used: group S (n = 49), periods of deep HCA with alpha-stat strategy; group M1 (n = 19), deep HCA with modifications of slower cooling and rewarming rates and the pH-stat strategy for cooling: and group M2 (n = 13), multiple short periods of moderate HCA. RESULTS: PEA provided significant improvement of pulmonary hemodynamics in each group. Sixteen (29%) of the 49 group S patients suffered NAEs, associated with total circulatory arrest time (cutoff, 57 min) and Jamieson type I disease. The Group M1 and M2 patients did not suffer NAEs, although the group M1 patients had prolonged cardiopulmonary bypass (CPB) and more frequent respiratory failure. CONCLUSIONS: NAEs were common after PEA performed under periods of deep HCA. The modified surgical strategy could decrease the risk of NAEs but increase the risk of respiratory failure. Multiple short periods of moderate HCA may be useful for patients at risk of NAEs.


Asunto(s)
Hipotermia Inducida , Insuficiencia Respiratoria , Humanos , Puente Cardiopulmonar , Endarterectomía , Hipotermia Inducida/efectos adversos , Pulmón , Insuficiencia Respiratoria/etiología
3.
BMC Pulm Med ; 22(1): 282, 2022 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-35858889

RESUMEN

BACKGROUND: The prognostic value of mixed venous oxygen tension (PvO2) at pulmonary hypertension diagnosis treated with selective pulmonary vasodilators remains unclear. This study sought to investigate the association of PvO2 with long-term prognosis in pulmonary arterial hypertension (PAH) and medically treated chronic thromboembolic pulmonary hypertension (CTEPH) and to identify the distinct mechanisms influencing tissue hypoxia in patients with CTEPH or PAH. METHODS: We retrospectively analyzed data from 138 (age: 50.2 ± 16.6 years, 81.9% women) and 268 (age: 57.4 ± 13.1 years, 72.8% women) patients with PAH and CTEPH, respectively, diagnosed at our institution from 1983 to 2018. We analyzed the survival rates of patients with/without tissue hypoxia (PvO2 < 35 mmHg) and identified their prognostic factors based on the pulmonary hypertension risk stratification guidelines. RESULTS: Survival was significantly poorer in patients with tissue hypoxia than in those without it for PAH (P = 0.001) and CTEPH (P = 0.017) treated with selective pulmonary vasodilators. In patients with PAH, PvO2 more strongly correlated with prognosis than other hemodynamic prognostic factors regardless of selective pulmonary vasodilators usage. PvO2 was the only significant prognostic factor in patients with CTEPH treated with pulmonary hypertension medication. Patients with CTEPH experiencing tissue hypoxia exhibited significantly poorer survival than those in the intervention group (P < 0.001). PvO2 more strongly correlated with the cardiac index (CI) than the alveolar-arterial oxygen gradient (A-aDO2) in PAH; whereas in CTEPH, PvO2 was more strongly correlated with A-aDO2 than with CI. CONCLUSIONS: PvO2 may represent a crucial prognostic factor for pulmonary hypertension. The prognostic impact of tissue hypoxia affects different aspects of PAH and CTEPH, thereby reflecting their distinct pathogenesis.


Asunto(s)
Hipertensión Pulmonar , Embolia Pulmonar , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Crónica , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Hipoxia/complicaciones , Oxígeno , Pronóstico , Embolia Pulmonar/tratamiento farmacológico , Estudios Retrospectivos , Vasodilatadores/uso terapéutico
4.
BMC Pulm Med ; 22(1): 138, 2022 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-35395844

RESUMEN

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be associated with chronic inflammation; however, the underlying mechanism remains unclear. Recently, altered gut microbiota were found in patients with pulmonary arterial hypertension (PAH) and in experimental PAH models. The aim of this study was to characterize the gut microbiota in patients with CTEPH and assess the relationship between gut dysbiosis and inflammation in CTEPH. METHODS: In this observational study, fecal samples were collected from 11 patients with CTEPH and 22 healthy participants. The abundance of gut microbiota in these fecal samples was assessed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Inflammatory cytokine and endotoxin levels were also assessed in patients with CTEPH and control participants. RESULTS: The levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were elevated in patients with CTEPH. Plasma endotoxin levels were significantly increased in patients with CTEPH (P < 0.001), and were positively correlated with TNF-α, IL-6, IL-8, and MIP-1α levels. The 16S rRNA gene sequencing and the principal coordinate analysis revealed the distinction in the gut microbiota between patients with CTEPH (P < 0.01) and control participants as well as the decreased bacterial alpha-diversity in patients with CTEPH. A random forest analysis for predicting the distinction in gut microbiota revealed an accuracy of 80.3%. CONCLUSION: The composition of the gut microbiota in patients with CTEPH was distinct from that of healthy participants, which may be associated with the elevated inflammatory cytokines and endotoxins in CTEPH.


Asunto(s)
Microbioma Gastrointestinal , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Citocinas , Endotoxinas , Humanos , Inflamación , Interleucina-8 , Japón , ARN Ribosómico 16S/genética , Factor de Necrosis Tumoral alfa
5.
Circ Res ; 124(6): 846-855, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30636542

RESUMEN

RATIONALE: Although many familial cases of pulmonary arterial hypertension exhibit an autosomal dominant mode of inheritance with the majority having mutations in essential constituents of the BMP (bone morphogenetic protein) signaling, the specific contribution of the long-term loss of signal transduction triggered by the BMPR2 (type 2 BMP receptor) remains poorly characterized. OBJECTIVE: To investigate the role of BMP9, the main ligand of ALK1 (Activin receptor-like kinase 1)/BMPR2 heterocomplexes, in pulmonary hypertension. METHOD AND RESULTS: The absence of BMP9 in Bmp9-/- mice and its inhibition in C57BL/6 mice using neutralizing anti-BMP9 antibodies substantially prevent against chronic hypoxia-induced pulmonary hypertension judged by right ventricular systolic pressure measurement, right ventricular hypertrophy, and pulmonary distal arterial muscularization. In agreement with these observations, we found that the BMP9/BMP10 ligand trap ALK1ECD administered in monocrotaline or Sugen/hypoxia (SuHx) rats substantially attenuate proliferation of pulmonary vascular cells, inflammatory cell infiltration, and regresses established pulmonary hypertension in rats. Our data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin. We reproduced these in vitro observations in mice chronically exposed to hypoxia, with Bmp9-/- mice exhibiting lower mRNA levels of the vasoconstrictor peptide ET-1 (endothelin-1) and higher levels of the 2 potent vasodilator factors apelin and ADM (adrenomedullin) compared with Bmp9+/+ littermates. CONCLUSIONS: Taken together, our data indicate that the loss of BMP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.


Asunto(s)
Factor 2 de Diferenciación de Crecimiento/antagonistas & inhibidores , Hipertensión Pulmonar/prevención & control , Receptores de Activinas Tipo II/farmacología , Animales , Células Cultivadas , Endotelina-1/genética , Factor 2 de Diferenciación de Crecimiento/fisiología , Humanos , Hipoxia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Wistar
6.
BMC Pulm Med ; 21(1): 260, 2021 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-34372826

RESUMEN

BACKGROUND: The 6th World Symposium on Pulmonary Hypertension (Nice 2018) proposed a new definition of pre-capillary pulmonary hypertension (PH) as a condition with mean pulmonary artery pressure (mPAP) > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU). The characteristics and prognosis of patients with pre-capillary PH, according to this new definition, is unclear. Therefore, we determined the characteristics and survival of patients with borderline pre-capillary PH. METHODS: We retrospectively enrolled 683 patients who underwent their first right heart catheterization at Chiba University, Japan. Among them, 489 patients met the pre-capillary PH requirement with mPAP ≥ 25 mmHg (conventional pre-capillary PH group), while 22 patients met the borderline pre-capillary PH criteria (borderline pre-capillary PH group). Additionally, 16 patients with a mean PAP of 20-25 and PVR of 2-3 WU were also examined. RESULTS: The borderline pre-capillary PH group comprised 4.3% of the total patients with pre-capillary PH, and the majority was in Group 3 (40.9%) or 4 (45.5%). The survival of the borderline pre-capillary PH group tended to be better than that of the conventional pre-capillary PH group. The prognosis of Group3 PH was the worst among the patients with borderline precapillary PH. There was no significant difference in survival between the borderline pre-capillary PH group with PVR ≥ 3 WU and that with PVR of 2-3 2WU, although none of the patients in the latter group died due to right heart failure. CONCLUSIONS: This is the first study conducted in a PH center in an Asian country to reveal the characteristics of patients with pre-capillary PH, according to the Nice 2018 definition. They comprised 4.3% of the total population with pre-capillary PH, and the majority of the pre-capillary PH cases were in either Group3 or 4. The prognosis may be affected by the patients' underlying diseases. Further prospective studies are needed to determine whether the new definition, including the PVR cut-off, is beneficial in clinical practice.


Asunto(s)
Hipertensión Pulmonar/diagnóstico , Capilares , Femenino , Hospitales Especializados , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Japón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resistencia Vascular
7.
BMC Pulm Med ; 21(1): 407, 2021 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-34886828

RESUMEN

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown. METHODS: We retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment. RESULTS: A total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV 1.0 had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment. CONCLUSION: %FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.


Asunto(s)
Hipertensión Pulmonar/fisiopatología , Embolia Pulmonar/fisiopatología , Resistencia Vascular , Anciano , Cateterismo Cardíaco , Enfermedad Crónica , Endarterectomía , Femenino , Flujo Espiratorio Forzado , Humanos , Hipertensión Pulmonar/diagnóstico , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico , Estudios Retrospectivos , Espirometría
8.
Respirology ; 22(1): 179-186, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27614712

RESUMEN

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in some patients, despite improved treatments. Microvasculopathy has been implicated in the poor outcomes of patients with CTEPH. A reduction in the diffusing capacity for carbon monoxide (DLCO ) was previously suggested to indicate microvasculopathy in CTEPH patients; therefore, we assessed DLCO /alveolar ventilation (DLCO /VA ) as a prognostic and pathophysiological marker in CTEPH. METHODS: We performed a retrospective cohort study of 214 CTEPH patients consecutively diagnosed between 1986 and 2011. After exclusion of 24 patients because of missing DLCO data or severe obstructive impairment, the mortality rates of medically treated patients classified with normal or decreased DLCO values were compared, and prognostic factors were determined. The relationship between long-term surgical outcomes and DLCO /VA was also investigated. RESULTS: Ninety-one inoperable patients were treated medically, two of whom underwent balloon pulmonary angioplasty. Ninety-nine underwent pulmonary endarterectomy. The 5-year survival rate of medically treated patients was significantly lower in patients with decreased DLCO /VA than in those with normal values (61.4% vs 90.4%, P = 0.017). Decreased preoperative DLCO /VA was associated with a smaller percent decrease in post-operative pulmonary vascular resistance, but not with the extent of proximal thrombi; these results may support our hypothesis that DLCO reflects microvascular involvement. CONCLUSION: Decreased DLCO /VA was associated with poor outcomes of medically treated CTEPH patients; and may be useful for identifying high-risk patients, potentially leading to earlier and more appropriate interventions.


Asunto(s)
Monóxido de Carbono/análisis , Hipertensión Pulmonar , Capacidad de Difusión Pulmonar , Embolia Pulmonar , Angioplastia de Balón/métodos , Angioplastia de Balón/estadística & datos numéricos , Biomarcadores/análisis , Enfermedad Crónica , Femenino , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/terapia , Japón/epidemiología , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Microvasos , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Valor Predictivo de las Pruebas , Pronóstico , Arteria Pulmonar/cirugía , Embolia Pulmonar/complicaciones , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/cirugía , Intercambio Gaseoso Pulmonar , Pruebas de Función Respiratoria/métodos , Estudios Retrospectivos , Tasa de Supervivencia
9.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1130-42, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27059286

RESUMEN

Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues.


Asunto(s)
Antígeno AC133/metabolismo , Células Progenitoras Endoteliales/metabolismo , Animales , Biomarcadores/metabolismo , Proliferación Celular , Forma de la Célula , Células Cultivadas , Endotelio Vascular/citología , Homeostasis , Pulmón/irrigación sanguínea , Pulmón/crecimiento & desarrollo , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Cultivo Primario de Células , Arteria Pulmonar/citología , Cicatrización de Heridas
10.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1185-98, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27106288

RESUMEN

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.


Asunto(s)
Lesión Pulmonar Aguda/inmunología , Células Progenitoras Endoteliales/fisiología , Lipopolisacáridos/farmacología , Lesión Pulmonar Aguda/patología , Animales , Apoptosis , Proliferación Celular , Transdiferenciación Celular , Células Cultivadas , Células Progenitoras Endoteliales/inmunología , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Femenino , Expresión Génica , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta2/biosíntesis , Factor de Crecimiento Transformador beta2/genética
11.
Circ J ; 80(4): 970-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26888150

RESUMEN

BACKGROUND: The postoperative changes in the coagulation-fibrinolysis system and the association between the system and postoperative course of patients with chronic thromboembolic pulmonary hypertension (CTEPH) who have undergone pulmonary endarterectomy (PEA) remain unclear. METHODS AND RESULTS: Between 1986 and 2013, 117 patients (55.1±11.2 years, preoperative mean pulmonary arterial pressure 46.5±10.5 mmHg) underwent PEA, and 15 patients died during the perioperative period. We studied the association between the preoperative coagulation-fibrinolysis markers and surgical outcomes of all patients, and the long-term outcomes of the 102 survivors from the date of PEA. We also investigated the postoperative changes in coagulation-fibrinolysis markers and their association with residual pulmonary hypertension (PH) in 20 consecutive patients. Only an elevated factor VIII level was associated with perioperative death. Thrombomodulin and plasminogen values were significantly increased after PEA. Univariate logistic regression analysis revealed that D-dimer positivity at follow-up was a risk factor for residual PH. Patients with both an elevated fibrinogen level (≥291 mg/dl [median]) and decreased plasminogen activity (<100% [median]) had significantly worse disease-specific survival than the other patients (5-year disease-specific survival: 84.0% vs. 100%, respectively; P=0.0041 [log-rank test]). CONCLUSIONS: Preoperatively high fibrinogen and low plasminogen values in patients with CTEPH are associated with poor long-term postoperative outcome. PEA benefited not only the pulmonary hemodynamics but also the coagulation-fibrinolysis system of patients.


Asunto(s)
Endarterectomía/efectos adversos , Fibrinógeno/metabolismo , Fibrinólisis , Hipertensión Pulmonar , Plasminógeno/metabolismo , Complicaciones Posoperatorias , Embolia Pulmonar , Adulto , Anciano , Presión Sanguínea , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/cirugía , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/mortalidad , Embolia Pulmonar/sangre , Embolia Pulmonar/mortalidad , Embolia Pulmonar/cirugía , Estudios Retrospectivos , Tasa de Supervivencia
12.
Respiration ; 91(2): 132-40, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26821322

RESUMEN

BACKGROUND: The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein ß3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH. OBJECTIVES: We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH. METHODS: This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes. RESULTS: Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD. CONCLUSIONS: ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.


Asunto(s)
Proteínas de Unión al GTP Heterotriméricas/genética , Hipertensión Pulmonar/tratamiento farmacológico , Peptidil-Dipeptidasa A/genética , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Hipertensión Pulmonar/genética , Mutación INDEL , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Estudios Retrospectivos , Citrato de Sildenafil/uso terapéutico , Tadalafilo/uso terapéutico , Resultado del Tratamiento
13.
Am J Respir Cell Mol Biol ; 53(4): 500-12, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25719275

RESUMEN

Vascular disruption is one of the pathological hallmarks in acute respiratory distress syndrome. Bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) and lung tissue-resident EPCs have been considered to play a pivotal role in pulmonary vascular repair; however, which population is predominant in local pulmonary vasculogenesis remains to be clarified. We therefore examined the origin of EPCs participating in the regenerative process of pulmonary vascular endothelial cells (PVECs) in experimental acute respiratory distress syndrome. Lung samples from mice administered LPS intratracheally were investigated for cell dynamics and EPC functions. Quantitative flow cytometric analysis demonstrated that the number of PVECs decreased by roughly 20% on Day 1 and then recovered on Day 7 of LPS challenge. Bromodeoxyuridine-incorporation assays and immunofluorescence microscopy demonstrated that proliferating PVECs preferentially located in the capillary vessels. Experiments using BM chimera mice revealed that most of the regenerating PVECs were tissue-resident cells, and BM-derived cells hardly engrafted as PVECs. The population of circulating putative phenotypical EPCs decreased during the first week after LPS challenge. The regenerating PVECs were characterized by high colony-forming and vasculogenic capacities, intracellular reactive oxygen species scavenging and aldehyde dehydrogenase activites, and enhanced gene expression of Abcb1b (a drug-resistant gene), suggesting that the population of PVECs included tissue-resident EPCs activated during regenerative process of PVECs. The proliferating PVECs expressed CD34, Flk-1/KDR, and c-kit more strongly and Prom1/CD133 less strongly on the surface than nonproliferating PVECs. Our findings indicated that lung tissue-resident EPCs predominantly contribute to pulmonary vascular repair after endotoxin-induced injury.


Asunto(s)
Células Progenitoras Endoteliales/fisiología , Lesión Pulmonar/fisiopatología , Aldehído Deshidrogenasa/metabolismo , Animales , Trasplante de Médula Ósea , Proliferación Celular , Células Cultivadas , Endotelio Vascular/inmunología , Endotelio Vascular/fisiopatología , Femenino , Lipopolisacáridos/farmacología , Lesión Pulmonar/inmunología , Lesión Pulmonar/terapia , Ratones Endogámicos C57BL , Neovascularización Fisiológica , Especies Reactivas de Oxígeno , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapia , Cicatrización de Heridas
14.
Am J Physiol Lung Cell Mol Physiol ; 308(8): L746-58, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25502500

RESUMEN

Exposure to hypoxia induces changes in the structure and functional phenotypes of the cells composing the pulmonary vascular wall from larger to most peripheral vessels. Endothelial progenitor cells (EPCs) may be involved in vascular endothelial repair. Resident EPCs with a high proliferative potential are found in the pulmonary microcirculation. However, their potential location, identification, and functional role have not been clearly established. We investigated whether resident EPCs or bone marrow (BM)-derived EPCs play a major role in hypoxic response of pulmonary vascular endothelial cells (PVECs). Mice were exposed to hypoxia. The number of PVECs transiently decreased followed by an increase in hypoxic animals. Under hypoxic conditions for 1 wk, prominent bromodeoxyuridine incorporation was detected in PVECs. Some Ki67-positive cells were detected among PVECs after 1 wk under hypoxic conditions, especially in the capillaries. To clarify the origin of proliferating endothelial cells, we used BM chimeric mice expressing green fluorescent protein (GFP). The percentage of GFP-positive PVECs was low and constant during hypoxia in BM-transplanted mice, suggesting little engraftment of BM-derived cells in lungs under hypoxia. Proliferating PVECs in hypoxic animals showed increased expression of CD34, suggesting hypoxia-induced gene expression and cell surface antigen of EPC or stem/progenitor cells markers. Isolated PVECs from hypoxic mice showed colony- and tube-forming capacity. The present study indicated that hypoxia could induce proliferation of PVECs, and the origin of these cells might be tissue-resident EPCs.


Asunto(s)
Proliferación Celular , Células Progenitoras Endoteliales/fisiología , Células Madre Adultas/fisiología , Animales , Trasplante de Médula Ósea , Hipoxia de la Célula , Células Cultivadas , Endotelio Vascular/citología , Pulmón/irrigación sanguínea , Pulmón/citología , Masculino , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo
15.
Circ J ; 79(12): 2696-702, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26467079

RESUMEN

BACKGROUND: This study aimed to investigate the predictors of quality of life (QOL) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), changes in QOL after surgical and medical treatments, and the relationship between baseline QOL and survival. METHODS AND RESULTS: QOL was measured in 128 patients with CTEPH (male/female: 42/86, age: 56±12 years, surgical/medical: 65/63) using the Short-Form 36 (SF-36) questionnaire. Multiple regression analysis showed pulmonary vascular resistance (PVR) and 6-min walking distance (6MWD) were associated with physical functioning (PF) (P<0.01) and physical component summary (PCS) (P<0.01). In the surgical group, 7 subscales and 2 summary scores improved significantly, and in the medical group 6 subscales and the mental component summary, although the change in QOL was greater in the surgical group. The patients in the conventional therapy group with higher PF had significantly better survival than those with lower PF (5-years survival: 89.5% vs. 50.8%, P=0.002). This difference in survival was not observed in the group receiving pulmonary arterial hypertension (PAH)-specific therapy (100% vs. 100%, P=0.746). CONCLUSIONS: PVR and 6MWD were associated with PF or PCS in CTEPH patients. QOL improved after surgical or medical therapy, with a greater change in the surgical group. PAH-specific therapy improved survival in patients with lower PF at diagnosis.


Asunto(s)
Embolia Pulmonar , Calidad de Vida , Adulto , Anciano , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Embolia Pulmonar/mortalidad , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/terapia , Tasa de Supervivencia
16.
Circ J ; 78(7): 1754-61, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24909805

RESUMEN

BACKGROUND: It is unclear whether abnormalities of coagulation or fibrinolysis are associated with disease progression of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to investigate the association of these factors with the severity and prognosis of CTEPH. METHODS AND RESULTS: Between 1986 and 2011, plasma fibrinogen and plasminogen were measured in 89 of 106 consecutive patients with inoperable CTEPH (17 men; mean age, 55.9±14.1 years old; mean pulmonary arterial pressure, 44.0±12.4 mmHg) and the association of level with severity and prognosis were also examined. Seventeen patients had high fibrinogen and low plasminogen (medians, ≥291 mg/dl and <101%, respectively). These patients had significantly lower cardiac index (2.26±0.68 vs. 2.70±0.57 L·min(-1)·m(-2), P=0.007), higher pulmonary vascular resistance (PVR; 13.29±7.54 vs. 9.15±4.14 Wood units, P=0.003), and poor survival (5-year survival, 35.3% vs. 88.0%, P<0.001) compared to the other 72 patients. Additional analysis showed significantly poor survival in these patients compared with the other patients who did not have modern therapy. On multivariate analysis plasma fibrinogen, plasminogen and PVR were independent predictors of survival in medically treated patients. CONCLUSIONS: High plasma fibrinogen and low plasminogen are associated with poor survival in CTEPH patients without modern therapy.


Asunto(s)
Fibrinógeno/metabolismo , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/mortalidad , Plasminógeno/metabolismo , Embolia Pulmonar/sangre , Embolia Pulmonar/mortalidad , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia
17.
Circ J ; 77(8): 2110-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23615047

RESUMEN

BACKGROUND: The surgical indication for chronic thromboembolic pulmonary hypertension (CTEPH) has been modified due to recognition of peripheral type CTEPH and changes in surgical methods and skill. Bosentan and sildenafil are used as modern oral therapy (mod Tx) in patients with inoperable CTEPH, although it remains unknown whether they have positive effects on survival. METHODS AND RESULTS: A total of 202 patients were diagnosed with CTEPH at Chiba University Hospital between 1986 and 2010, 100 of whom underwent pulmonary endarterectomy. Seven medically treated patients with pulmonary vascular resistance (PVR) ≤ 300 dyn·s·cm(-5) were regarded as having mild disease. Survival rate was stratified by date of diagnosis (group 1, 1986-1998; group 2, 1999-2004; group 3, 2005-2010), and prognostic factors in the remaining 95 medically treated patients were investigated. Group 3 included the most patients treated with mod Tx (group 1, 9.1%; group 2, 24.2%; group 3, 65.0%) and had significantly better survival than either group 1 or 2 (5-year survival: group 1, 54.6%; group 2, 69.7%; group 3, 87.3%). Patients receiving mod Tx had significantly better survival than those not on mod Tx (5-year survival: 88.9% vs. 60.2%). Multivariate analysis showed that mod Tx, lower PVR, and lack of comorbidity were significant predictors of better outcome. CONCLUSIONS: Medically treated patients with CTEPH had a better survival rate, and the use of mod Tx contributed to improved survival.


Asunto(s)
Hipertensión Pulmonar , Embolia Pulmonar , Resistencia Vascular , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/terapia , Masculino , Persona de Mediana Edad , Embolia Pulmonar/metabolismo , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/terapia , Estudios Retrospectivos , Tasa de Supervivencia
18.
Pulm Circ ; 13(3): e12287, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37701143

RESUMEN

The percentage cross-sectional area of the lung under five (%CSA<5) is the percentage of pulmonary vessels with <5 mm2 area relative to the total lung area on computed tomography (CT). The extent that %CSA<5 is related to pulmonary hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is unclear, as is the effect of pulmonary endarterectomy (PEA) on %CSA<5. Therefore, we aimed to evaluate the clinical significance of %CSA<5 in patients with CTEPH. We studied 98 patients (64 females, mean age 62.5 ± 11.9 years), who underwent CT with %CSA<5 measurement and right heart catheterization (RHC). Patients were classified into groups based on eligibility for PEA. We compared the %CSA<5 with pulmonary hemodynamics measured by RHC in various groups. In 38 patients who underwent PEA, the relationship between %CSA<5 and pulmonary hemodynamics was also evaluated before and after PEA. Significant correlations between %CSA<5 and pulmonary vascular resistance, and compliance, and pulmonary artery pulse pressure were observed in all patients. Pulmonary hemodynamics in the patients who underwent or were eligible for PEA showed a significant correlation with %CSA<5. Additionally, %CSA<5 was significantly lower in the postoperative than in the preoperative group. There was no correlation between changes in %CSA<5 and pulmonary hemodynamics before and after PEA. Furthermore, %CSA<5 did not correlate significantly with prognosis. %CSA<5 may reflect pulmonary hemodynamics in CTEPH with central thrombosis. Furthermore, %CSA<5 was reduced by PEA postoperatively. However, %CSA<5 is not a prognostic indicator, its clinical usefulness in CTEPH patients is limited, and further validation is required.

19.
Respir Med Case Rep ; 42: 101829, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36936868

RESUMEN

RNF213 p.Arg4810Lys is linked to various vascular diseases, including pulmonary arterial hypertension (PAH); however, its pathogenesis remains unclear. Here, we report the unique features of two cases of severe PAH with this variant: one is the first reported case with stenosis of the thoracic and abdominal aorta, femoral arteries, and subclavian veins. Coexistence of severe and continuous eosinophilic inflammation, which has been suspected to be implicated in the pathogenesis of PAH in previous fundamental studies, was also present in both cases. Further studies are needed to clarify the pathogenetic mechanisms in vascular lesions with this variant.

20.
Pulm Circ ; 13(2): e12215, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37051490

RESUMEN

Residual pulmonary hypertension (PH) negatively impacts long-term results following pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). We sought to reveal whether modern PH therapy with PH-targeted medicine and balloon pulmonary angioplasty (BPA) improved long-term results of residual PH after PEA. Long-term findings of 80 patients who survived PEA between 2011 and 2019 were retrospectively investigated. One month after PEA, 30 patients developed residual PH defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg, of whom 23 were treated by PH-targeted medicine and 9 by BPA. Patients with residual PH acquired considerably better functional status and exercise capacity after PEA, however, exhibited significantly worse survival rates than those without. Eleven patients died during follow-up: 8 patients with residual PH and 3 controls. Among patients with residual PH, the deceased had a significantly lower %decrease in mPAP from 1 month to 1 year following PEA (7.4 [-32.6 to 8.0] % vs. 10.4 [3.7-27.8] %, p = 0.03) and higher mPAP at 1 year following PEA (39.5 [33.25-42.5] vs. 27 [26-34] mmHg, p < 0.01) despite PH-targeted medicine than the survived. No patients passed away from right heart failure, and there was no difference between the groups in CTEPH-related mortality. Modern PH therapy was used to address the majority of residual PH. Long-term survival after PEA was negatively impacted by residual PH, but it appeared that long-term mortality was also correlated with unrelieved residual PH despite PH-targeted medicine. Modern PH therapy may have enhanced functional status and excercise capacity, and averted fatal right heart failure.

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