RESUMO
BACKGROUND AND OBJECTIVE: Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH. METHODS: PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline-pyrrole (MCT-P) in wild-type (WT) and periostin-/- mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)-2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH-induced WT and periostin-/- mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated. RESULTS: In PH induced by SuHx and MCT-P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin-/- mice. PA remodelling post-SuHx treatment was also mild in periostin-/- mice compared to WT mice. Expression of macrophage-associated chemokines and FGF-2 in lung tissue, and accumulation of CD68-positive cells in the RV were less in SuHx periostin-/- than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor-ß. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls. CONCLUSION: Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.
Assuntos
Moléculas de Adesão Celular , Fator 2 de Crescimento de Fibroblastos , Hipertensão Pulmonar , Macrófagos , Animais , Moléculas de Adesão Celular/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Artéria Pulmonar/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. APPROACH AND RESULTS: The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. CONCLUSIONS: LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.
Assuntos
Proliferação de Células , Hipertensão Pulmonar/metabolismo , Hipóxia/complicações , Proteínas de Membrana Transportadoras/deficiência , Músculo Liso Vascular/metabolismo , Neointima , Receptores de LDL/deficiência , Remodelação Vascular , Animais , Pressão Arterial , Células Cultivadas , Genótipo , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/prevenção & controle , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Fenótipo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Receptores de LDL/genética , Transdução de Sinais , Transfecção , Resistência Vascular , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita , Pressão VentricularRESUMO
Pulmonary artery hypertension (PAH) has been reported to be a severe adverse event associated with dasatinib therapy. Among the 76 chronic myeloid patients who were treated with dasatinib at our hospital, six patients showed high estimated pulmonary arterial systolic pressure, as observed by echocardiography. PAH was confirmed using right heart catheterization in three (3.9%) patients with increased mean pulmonary artery pressure (mPAP). In one patient, although mPAP was higher than the normal range, it did not fulfill the criteria of pulmonary hypertension. After the discontinuation of dasatinib, BNP and dyspnea were improved in five patients. Therefore, it should be noted that dasatinib can cause PAH at higher rates than those reported previously, and if PAH is confirmed or suspected during dasatinib therapy, then dasatinib should be immediately discontinued.
Assuntos
Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Hipertensão Pulmonar/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Idoso , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: The prognosis of pulmonary hypertension (PH) associated with connective tissue diseases related to interstitial pneumonia (CTD-IP PH) is relatively good among patients with PH and lung disease. However, the impact of pulmonary vasodilator treatment on the prognosis of CTD-IP PH compared with that of PH-induced chronic lung disease (group-3 PH) remains unclear. METHODS: From 2012 to 2022, 50 patients with lung parenchymal lesions diagnosed with PH (mean pulmonary arterial pressure >20 mmHg) at Juntendo University Hospital were divided into two groups: CTD-IP PH (30 patients) and group 3-PH (20 patients). The impact of pulmonary vasodilator treatment and the use of long-term oxygen therapy (LTOT) on the prognosis of each group was examined retrospectively. RESULTS: The prognosis of CTD-IP PH was significantly better compared to group-3 PH. While the treatment with pulmonary vasodilators did not affect the prognosis in group 3-PH, the prognosis of the patients treated with vasodilators in the CTD-IP PH group was significantly better than that of the non-treated patients. Treatment with multi-pulmonary vasodilators did not affect the prognosis in CTD-IP PH. Although the prognosis for the patients with LTOT was poor in all registered patients in the present study, treatment with pulmonary vasodilators improved the prognosis even under the use of LTOT in CTD-IP PH (P = 0.002). In a multivariate analysis of the CTD-IP PH group, pulmonary vasodilator treatment was an independent factor for better prognosis. CONCLUSION: Treatment with a pulmonary vasodilator for CTD-IP PH may improve the prognosis, even in patients requiring LTOT.
Assuntos
Doenças do Tecido Conjuntivo , Hipertensão Pulmonar , Humanos , Prognóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Estudos Retrospectivos , Pulmão , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: Group 2 pulmonary hypertension (PH) represents PH caused by left heart disease (PH-LHD). LHD induces left-sided filling and PH, finally leading to pulmonary vascular remodeling. Tofogliflozin (TOFO) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the treatment of diabetes. Recent studies have shown that SGLT2 inhibitors have beneficial effects on heart failure, but the effects of SGLT2 inhibitors on PH-LHD remain unclear. We hypothesized that TOFO has protective effects against pulmonary vascular remodeling in PH-LHD mice. METHODS: We generated two murine models of PH-LHD: a transverse aortic constriction (TAC) model; and a high-fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3â¯mg/kg/day) for 3â¯weeks. AKR/J mice were fed HFD and treated with TOFO (3â¯mg/kg/day) for 20â¯weeks. We then measured physical data and right ventricular systolic pressure (RVSP) and performed cardiography. Human pulmonary artery smooth muscle cells (PASMCs) were cultured and treated with TOFO. RESULTS: Mice treated with TOFO demonstrated increased urine glucose levels. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RVSP. HFD increased body weight (BW) and RVSP compared with the normal chow group. TOFO treatment ameliorated increases in BW and RVSP induced by HFD. Moreover, PASMCs treated with TOFO showed suppressed migration. CONCLUSIONS: TOFO treatment ameliorated right heart overload and pulmonary vascular remodeling for PH-LHD models, suggesting that SGLT2 inhibitors are effective for treating PH-LHD.
Assuntos
Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Camundongos , Animais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Remodelação Vascular , Camundongos Endogâmicos C57BL , Glucose , SódioRESUMO
BACKGROUND: Heart failure is a severe condition often involving pulmonary hypertension (PH). Soluble low-density lipoprotein receptor with 11 ligand-binding repeats (sLR11) has been associated with pulmonary artery hypertension. We examined whether sLR11 correlates with PH in left heart disease and can be used as a predictive marker. METHOD: We retrospectively analyzed patients with severe mitral regurgitation who underwent right heart catheterization before surgery for valve replacement or valvuloplasty from November 2005 to October 2012 at Juntendo University. We measured sLR11 levels before right heart catheterization and analyzed correlations with pulmonary hemodynamics. We compared prognoses between a group with normal sLR11 (≤9.4 ng/ml) and a group with high sLR11 (>9.4 ng/ml). Follow-up was continued for 5 years, with end points of hospitalization due to HF and death due to cardiovascular disease. RESULTS: Among 34 patients who met the inclusion criteria, sLR11 correlated with mean pulmonary artery pressure (r = 0.54, p<0.001), transpulmonary pressure gradient (r = 0.42, p = 0.012), pulmonary vascular resistance (r = 0.36, p<0.05), and log brain natriuretic peptide (BNP). However, logBNP did not correlate with pulmonary vascular resistance (p = 0.6). Levels of sLR11 were significantly higher in the 10 patients with PH (14.4±4.3 ng/ml) than in patients without PH (9.9±3.9 ng/ml; p = 0.002). At 5 years, the event rate was higher in the high-sLR11 group than in the normal-sLR11 group. The high-sLR11 group showed 5 hospitalizations due to HF (25.0%) and 2 deaths (10.0%), whereas the normal-sLR11 group showed no hospitalizations or deaths. Analyses using receiver operating characteristic curves showed a higher area under the concentration-time curve (AUC) for sLR11 level (AUC = 0.85; 95% confidence interval (CI) = 0.72-0.98) than for BNP (AUC = 0.80, 95%CI = 0.62-0.99) in the diagnosis of PH in left heart disease. CONCLUSIONS: Concentration of sLR11 is associated with severity of PH and offers a strong predictor of severe mitral regurgitation in patients after surgery.
Assuntos
Insuficiência Cardíaca/metabolismo , Hipertensão Pulmonar/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
AIM: Pneumococcal and influenza infections can cause serious morbidity and mortality in patients with cardiovascular diseases. The purpose of this study was to investigate the safety and efficacy of simultaneous inoculations of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and trivalent influenza vaccine (TIV) in patients with coronary artery disease (CAD). METHODS: This was a prospective, randomized, single-blind, placebo-controlled study. A total of 40 patients with CAD were randomly assigned to the TIVï¼PPSV23 (simultaneous inoculations of TIV and PPSV23) and TIVï¼Placebo (inoculations of TIV and placebo) groups. Primary outcomes were the safety of simultaneous vaccinations and the changing of circulating cardiovascular biomarkers before, at 4-, and at 12-weeks after vaccinations. RESULTS: The baseline characteristics between the two groups were identical. The prevalence of injection-site pain, swelling, and reddening were 47%, 37%, and 37% in the TIVï¼PPSV23 group, and 10%, 5%, and 0% in the TIVï¼Placebo group, respectively. All reactions were self-limited. Body temperature ï¼37.0â or serious injection-related reaction was not observed. The levels of white blood cells, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, pentraxin-3, and malondialdehide-modified low-density lipoprotein (LDL), were not significantly different between the two groups before and after vaccinations. The levels of anti-oxidized LDL were significantly and step-wisely decreased from baseline, to 4-, and 12-weeks vaccinations in the both groups. No significant changes of other markers were observed in both groups at each time point. CONCLUSION: Simultaneous inoculations of TIV and PPSV23 were safety in patients with CAD, suggesting that dual vaccinations can be considered even in patients with CAD.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Segurança do Paciente/estatística & dados numéricos , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinação/métodos , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Seguimentos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/imunologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/imunologia , Influenza Humana/virologia , Japão/epidemiologia , Masculino , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/efeitos adversos , Prognóstico , Estudos Prospectivos , Método Simples-Cego , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/imunologia , Vacinação/efeitos adversosRESUMO
The patient was a 73-year-old man with a history of hypertension, diabetes mellitus, dyslipidemia, rheumatoid arthritis, repeated percutaneous coronary intervention and percutaneous peripheral intervention procedures. He was frequently admitted to our hospital for congestive heart failure with orthopnea. The myocardial washout rate of iodine-123-ß-methyl iodophenyl-pentadecanoic acid was defective on scintigraphy. He was diagnosed with triglyceride deposit cardiomyovasculopathy (TGCV). Proton magnetic resonance spectroscopy (1H-MRS) indicated the level of myocardial triglyceride (TG) content to be extremely high (4.92%). This is the first report to confirm a massive accumulation of TG in the myocardium of a patient with TGCV using 1H-MRS noninvasively.
Assuntos
Lipase , Prótons , Idoso , Humanos , Masculino , Miocárdio , Espectroscopia de Prótons por Ressonância Magnética , TriglicerídeosRESUMO
Cholinergic angiogenesis is mediated by an endothelial nicotinic acetylcholine receptor (EC nAChR). Short-term administration of nicotine stimulates angiogenesis via EC nAChRs.The long-term effects of nicotine upon cholinergic angiogenesis are unknown. The objective of this study was to determine whether chronic nicotine exposure blunts angiogenesis. We exposed C57/Bl6 male mice (n = 42) to nicotine (200 microg/ml drinking water) or vehicle for 8 or 16 weeks. Subsequently, hindlimb ischemia was induced by ligation of the left femoral artery. After surgery, animals in the vehicle-treated group were re-randomized to vehicle (vehicle group) or nicotine (acute exposure group) for 2 weeks; whereas animals that had been previously treated (for 8 or 16 weeks with nicotine) continued to receive nicotine (8 WK or 16 WK groups). After 2 weeks, animals were sacrificed for immunohistochemical, gene expression, and angiogenesis studies. Capillary density of the ischemic hindlimb was increased by nicotine in naïve animals (vehicle vs acute exposure: 2.40 +/- 0.09 vs 2.82 +/- 0.10 capillaries/myocyte, p < 0.05). However, prior exposure to nicotine for 16 weeks (16 WK) abolished the effects of nicotine to increase capillary density in the ischemic hindlimb (acute vs 16 WK: 2.82 +/- 0.10 vs 2.47 +/- 0.03 capillaries/ myocyte; p < 0.05). The impairment of cholinergic angiogenesis was associated with a reduction in nAChR expression and plasma VEGF levels. Chronic exposure to nicotine impaired capillary sprouting of aortic segments ex vivo (vehicle vs 16 WK: 0.303 +/- 0.029 vs 0.204 +/- 0.017 mm(2), p < 0.05, n = 3 in each group). In conclusion, the current study shows for the first time that chronic exposure to nicotine impairs cholinergic angiogenesis, an effect mediated by downregulation of the vascular nAChR, and attenuation of nicotine-induced VEGF release. These studies may explain the impairment in angiogenic processes observed in long-term smokers.
Assuntos
Células Endoteliais/efeitos dos fármacos , Isquemia/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Capilares/efeitos dos fármacos , Capilares/metabolismo , Capilares/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Células Endoteliais/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Membro Posterior , Isquemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase/genética , RNA Mensageiro/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor Nicotínico de Acetilcolina alfa7RESUMO
OBJECTIVE: Previous studies suggest that nitric oxide (NO) may modulate insulin-induced uptake of glucose in insulin-sensitive tissues. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We hypothesized that a reduction in endogenous ADMA would increase NO synthesis and thereby enhance insulin sensitivity. METHODS AND RESULTS: To test this hypothesis we used a transgenic mouse in which we overexpressed human dimethylarginine dimethylaminohydrolase (DDAH-I). The DDAH-I mice had lower plasma ADMA at all ages (22 to 70 wk) by comparison to wild-type (WT) littermates. With a glucose challenge, WT mice showed a prompt increase in ADMA, whereas DDAH-I mice had a blunted response. Furthermore, DDAH-I mice had a blunted increase in plasma insulin and glucose levels after glucose challenge, with a 50% reduction in the insulin resistance index, consistent with enhanced sensitivity to insulin. In liver, we observed an increased Akt phosphorylation in the DDAH-I mice after i.p. glucose challenge. Incubation of skeletal muscle from WT mice ex vivo with ADMA (2 mumol/L) markedly suppressed insulin-induced glycogen synthesis in fast-twitch but not slow-twitch muscle. CONCLUSIONS: These findings suggest that the endogenous NOS inhibitor ADMA reduces insulin sensitivity, consistent with previous observations that NO plays a role in insulin sensitivity.
Assuntos
Amidoidrolases/metabolismo , Resistência à Insulina/fisiologia , Amidoidrolases/genética , Animais , Arginina/análogos & derivados , Arginina/sangue , Arginina/metabolismo , Feminino , Expressão Gênica , Teste de Tolerância a Glucose , Glicogênio/biossíntese , Humanos , Insulina/farmacologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Óxido Nítrico/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
Relative changes in B-type natriuretic peptide (BNP) and amino terminal pro-BNP (NT-proBNP) levels may help to assess the risk of congestive heart failure (CHF). However, whether these levels at the time of admission enable the prediction of outcomes with acute exacerbation remains unknown. The current study determined the abilities of BNP, NT-proBNP and their ratio to predict in-hospital and long-term outcomes of patients with CHF. Patients who were admitted to the cardiac care unit of Juntendo University Hospital (Tokyo, Japan) with acute CHF onset were consecutively enrolled into the present observational study. Serum levels of BNP and NT-proBNP were immediately measured on admission, and other biomarkers and clinical data were also investigated. Of 195 enrolled patients, 16 (8.2%) succumbed to CHF in hospital and 124 (69.3%) reached the endpoint of mortality or readmission following a median follow-up of 14 months. Multiple linear regression analysis revealed body mass index, low density lipoprotein cholesterol, hemoglobin, estimated glomerular filtration rate and C-reactive protein as independent predictors of the NT-proBNP/BNP ratio. BNP, NT-proBNP and their ratio were significantly higher among those who succumbed to CHF than in those who remained alive in hospital (P<0.05). Logistic regression analysis indicated that the ratio was an independent predictor for in-hospital mortality and long-term outcomes. In conclusion, the ratio of NT-proBNP to BNP more effectively predicts in-hospital outcomes than either factor alone and it may also help to predict outcomes among patients with acute exacerbation of HF.
RESUMO
BACKGROUND: Platelet adhesion on components of the extracellular matrix and platelet activation by those components are crucial for the arrest of posttraumatic bleeding, but they can also harm tissue by occluding diseased vessels. Recent studies have shown that the activation of platelets by collagen is mediated through the same pathway used by immune receptors, with an immunoreceptor tyrosine-based activation motif on the Fc receptor gamma chain (FcRgamma) playing a pivotal role. METHODS AND RESULTS: We examined the role of collagen-stimulated platelets in the development of injury-induced neointimal formation by using mice deficient in FcRgamma. The left femoral arteries of 8- to 12-week-old FcRgamma-deficient mice (n=16) and C57BL/6 (wild-type) mice (n=16) were injured by a straight spring wire (0.35-mm diameter). Segments of the injured and uninjured femoral arteries were excised at 7 days and 28 days after the vascular injury. Arterial segments were examined by immunohistochemistry and electron microscopy. Two hours after injury, electron microscopy showed marked decreases in platelet adhesion and neutrophil attachment to the vascular wall surface in FcRgamma-knockout mice compared with wild-type mice. At 7 days after injury, staining with anti-neutrophil antibody showed fewer neutrophils in FcRgamma-knockout mice than in wild-type mice. Computer-aided morphometry performed to measure the neointimal area, intima/media ratio, and stenotic area at 28 days after injury showed a significantly smaller ratio and area in FcRgamma-knockout mice than in wild-type mice (for neointimal area, 16 635 +/- 1406 versus 31 483 +/- 2309 microm2, respectively; for intima/media ratio, 1.25 +/- 0.40 versus 2.68 +/- 0.04, respectively; and for stenotic area, 26.8 +/- 2.1% versus 49.3 +/- 4.1%, respectively). CONCLUSIONS: These results demonstrate that FcRgamma may play important roles in the initiation and generation of neointimal hyperplasia after balloon injury through the activation of platelets by collagen.
Assuntos
Plaquetas/metabolismo , Colágeno/metabolismo , Receptores de IgG/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Motivos de Aminoácidos/fisiologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/ultraestrutura , Colágeno/farmacologia , Progressão da Doença , Artéria Femoral/patologia , Artéria Femoral/fisiopatologia , Artéria Femoral/ultraestrutura , Hiperplasia/patologia , Hiperplasia/fisiopatologia , Citometria por Imagem , Imuno-Histoquímica , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores Imunológicos , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Túnica Íntima/ultraestrutura , Grau de Desobstrução Vascular/efeitos dos fármacosRESUMO
BACKGROUND: Bone marrow stromal cells (BMSCs) have many characteristics of mesenchymal stem cells that can differentiate into smooth muscle cells (SMCs). However, there have been few studies closely following the cell development of smooth muscle lineage among BMSCs. METHODS AND RESULTS: To investigate the possible existence of a cell population committed to the SMC lineage among bone marrow adhesion cells, we tried to detect and follow the in vitro differentiation of such a cell type by using a promoter-sorting method with a human SM22alpha promoter (-480 bp)/green fluorescent protein (GFP) construct. The construct was transfected to adhesion cells that appeared 5 days after the seeding of mononuclear cells from bone marrow. GFP was first detectable 5 days after the transfection in a cell population [Ad(G) cells], which expressed PDGF-beta but neither mature (calponin) nor immature (SMemb) SMC-specific proteins at that time. However, the cells were eventually grown into individual clones that expressed SMC-specific proteins (alpha-smooth muscle actin, calponin, and SM-1), suggesting that Ad(G) cells have partly at least progenitor properties. Because early studies have reported that PDGF-beta signaling plays pivotal roles in the differentiation of mesenchymal smooth muscle progenitor cells, Ad(G) cells might be putative mesenchymal smooth muscle progenitors expressing PDGF-beta. CONCLUSIONS: We demonstrated the presence of a cell population fated to become SMCs and followed their differentiation into SMCs among BMSCs.
Assuntos
Células da Medula Óssea/citologia , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Músculo Liso Vascular/citologia , Células-Tronco/fisiologia , Células Estromais/fisiologia , Animais , Anticorpos , Proteínas de Ligação ao Cálcio/análise , Proteínas de Ligação ao Cálcio/imunologia , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Células Clonais , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/química , Músculo Liso Vascular/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Receptor beta de Fator de Crescimento Derivado de Plaquetas/análise , Receptor beta de Fator de Crescimento Derivado de Plaquetas/imunologia , Proteínas Recombinantes de Fusão/análise , Miosinas de Músculo Liso/análise , Miosinas de Músculo Liso/biossíntese , Miosinas de Músculo Liso/genética , Transfecção , CalponinasRESUMO
The aim of the present study was to determine the long-term outcomes of bifurcation lesions following a rotational atherectomy (ROTA). In this retrospective study, patients that had undergone a ROTA of the bifurcation coronary lesions in Juntendo University Hospital (Tokyo, Japan) were enrolled between January 2007 and December 2009, and received follow-up for a median duration of 48 months (range, 12-84 months). A total of 337 patients were enrolled. Each patient was treated with an average of 1.2±0.4 ROTA burrs (mean size, 2.9±0.3 mm). Baseline lesion length, reference diameter, minimal lumen diameter (MLD) and percentage of diameter stenosis (%DS) prior to the procedure were comparable between the DM and non-DM patients. Furthermore, MLD, %DS and acute gain following the procedure were similar between the two groups. At follow-up, DM patients exhibited a significantly decreased MLD (1.97±0.92 vs. 2.26±0.73 mm; P=0.0038), increased %DS (27.9±21.3 vs. 20.2±13.3%; P=0.022) and late loss (0.70±0.45 vs. 0.42±0.36 mm; P=0.0047) compared with the non-DM patients. Follow-up examinations (mean duration, 52.2±19.4 months) revealed that the DM patients experienced significantly higher rates of target lesion revascularization (TLR) [28 (15.7%) vs. 8 (5.0%); P=0.0011], target lesion (TL) restenosis [46 (25.8%) vs. 20 (12.6%); P=0.0019] and major adverse cardiac events (MACE) [36 (20.2%) vs. 19 (12.0%), P=0.039] compared with the non-DM patients. Although the usage of ROTA and drug-eluting stent evidently improved long-term outcomes in patients with bifurcation lesions, DM remained an independent risk factor for TLR, TL restenosis and MACE. Therefore, the management of DM in bifurcation lesions treated with ROTA requires increased investigation in future clinical practice.
RESUMO
The present study compared short- and long-term prognostic values of red blood cell distribution width (RDW) with those of hemoglobin (Hgb) among patients with acute congestive heart failure (CHF) in a cardiac care unit. The cross-sectional study examined data from 521 patients with acute CHF who were admitted to a cardiac care unit and followed up for 24 months (median). Mean Hgb levels in patients who succumbed (DIH) or remained alive (AIH) were 11.0±1.8 and 11.8±2.6 g/l (P>0.05), respectively. Median values of RDW were 16.2% and 14.4%, respectively (P<0.0001). During the 24-month follow-up, mean levels of Hgb in groups with and without endpoints were 11.4±2.5 and 12.5±2.4 g/dl (P<0.0001), respectively. Median RDW values were 14.9 and 13.8%, respectively (P<0.0001). Logistic regression analysis showed that in-hospital mortality was significantly associated with RDW (P=0.044), New York Heart Association (NYHA) functional class IV (P=0.0037), estimated glomerular filtration rate (eGFR) (P=0.042) and C-reactive protein (P=0.0044), but not with Hgb (P=0.10). The multivariate Cox proportional hazard model selected RDW [hazard ratio (HR), 2.19; P<0.0001], left ventricular ejection fraction (HR 0.81, P=0.0016), age (10-year increase; HR 1.19, P=0.0017) and NYHA functional classes III/IV (HR 1.52, P=0.0029) as independent predictors of long-term outcomes after adjustment, but not Hgb (HR 1.01, P=0.86). Higher RDW values in acute CHF patients at admission were associated with worse short- and long-term outcomes and RDW values were more prognostically relevant than Hgb levels.
RESUMO
Calcified amorphous tumour is a rare, non-neoplastic, endocardially based, intracavitary cardiac mass. This report describes a 59-year old man in whom a mobile mass was found incidentally in the heart by routine echocardiography after he had been on haemodialysis for 3 years. Transoesophageal echocardiography revealed a high-echoic swinging tumour that originated from the annulus of the anterior commissure of the mitral valve. Surgical resection was performed to prevent embolization, and his clinical course was excellent.
Assuntos
Calcinose/diagnóstico , Neoplasias Cardíacas/diagnóstico , Falência Renal Crônica/terapia , Diálise Renal , Calcinose/patologia , Calcinose/cirurgia , Procedimentos Cirúrgicos Cardíacos , Ecocardiografia Transesofagiana , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Valva Mitral/patologia , Resultado do TratamentoRESUMO
The first case was a 68-year-old woman who had acute migratory pain from back to anterior chest and the second case was 66-year-old man with a cardiac tamponade. Two cases were demonstrated with a low density area of the left ventricular postero-lateral wall with conventional contrast-enhanced computed tomography (CE-CT) performed to differentiate the diagnosis of acute coronary syndrome and acute aortic dissection. Subsequent coronary angiograms showed the lesions of left circumflex. These cases of early contrast-defect corresponded to a decreased myocardial blood flow with AMI. CE-CT image facilitated the diagnosis of AMI preceding CAG examination.
Assuntos
Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: We sought to determine if a reduction in asymmetric dimethylarginine (ADMA) enhances endothelial regeneration. BACKGROUND: Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA are associated with endothelial vasodilator dysfunction in patients with vascular disease or risk factors. Asymmetric dimethylarginine is eliminated largely by the action of dimethylarginine dimethylaminohydrolase (DDAH), which exists in 2 isoforms. Dimethylarginine dimethylaminohydrolase-1 transgenic (TG) mice manifest increased DDAH activity, reduced plasma and tissue ADMA levels, increased nitric oxide synthesis, and reduced systemic vascular resistance. METHODS: The left femoral arteries of DDAH1 TG mice and wild-type (WT) mice were injured by a straight spring wire, and regeneration of the endothelial cell (EC) monolayer was assessed. Endothelial sprouting was assayed with growth factor-reduced Matrigel. RESULTS: Regeneration of the EC monolayer was more complete 1 week after injury in TG mice (WT vs. TG: 40.0 +/- 6.5% vs. 61.2 +/- 6.4%, p < 0.05). The number of CD45 positive cells at the injured sites was reduced by 62% in DDAH TG mice (p < 0.05). Four weeks after injury, the neointima area and intima/media ratio were attenuated in DDAH TG mice (WT vs. TG: 0.049 +/- 0.050 mm2 vs. 0.031 +/- 0.060 mm2, 3.1 +/- 0.5 vs. 1.7 +/- 0.2, respectively, p < 0.05). Endothelial cell sprouting from vascular segments increased in TG mice (WT vs. TG: 24.3 +/- 3.9 vs. 39.0 +/- 2.2, p < 0.05). CONCLUSIONS: We find for the first time an important role for DDAH in EC regeneration and in neointima formation. Strategies to enhance DDAH expression or activity might be useful in restoring the endothelial monolayer and in treating vascular disease.
Assuntos
Amidoidrolases/metabolismo , Artéria Femoral/metabolismo , Neovascularização Fisiológica/fisiologia , Doenças Vasculares/tratamento farmacológico , Animais , Arginina/análogos & derivados , Proliferação de Células , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Indução Enzimática , Artéria Femoral/lesões , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Óxido Nítrico/fisiologia , Probabilidade , Distribuição Aleatória , Sensibilidade e Especificidade , Especificidade da Espécie , Doenças Vasculares/patologiaRESUMO
Platelet activation and the formation of platelet microaggregates in coronary vessels play pivotal roles in myocardial ischemia and reperfusion injury. The Fc receptor gamma-chain (FcR gamma) is coexpressed with glycoprotein (GP) VI, forming a platelet collagen receptor, and the activation of platelets by collagen is closely coupled with tyrosine phosphorylation of the FcRgamma. To examine the functional significance of platelet FcR gamma/GPVI complex in the early phase of myocardial ischemia and reperfusion injury in mice, we performed coronary occlusion and reperfusion experiments using wild type mice and FcRgamma-deficient (FcRgamma(-/-)) mice that lack GPVI. The infarct size was significantly smaller in FcRgamma(-/-) mice subjected to occlusion and reperfusion of the coronary artery than in control FcR gamma(+/+) mice. Twenty-four hours after the reperfusion, electron microscopy of the injured tissue showed substantially more platelet aggregation and occlusive platelet microthrombi in the capillaries of the damaged areas of the wild type mice than in those of the FcR gamma(-/-) mice. Platelet Syk was scarcely activated in the FcR gamma(-/-) mice after myocardial ischemia and reperfusion, but significantly activated in the FcR gamma(+/+) mice. CD11b expression on neutrophils was elevated after myocardial ischemia and reperfusion in both mouse groups, whereas myeloperoxidase activity in the injured areas was significantly lower in the FcRgamma(-/-) mice than in the FcRgamma(+/+) mice. These results suggest that the collagen-induced activation of platelets through the FcR gamma plays a pivotal role in the extension of myocardial ischemia-reperfusion injury. FcRgamma and GPVI may be important therapeutic targets for myocardial ischemia-reperfusion injury.