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1.
Cardiovasc Res ; 116(1): 63-77, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424497

RESUMO

AIMS: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. METHODS AND RESULTS: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. CONCLUSION: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.


Assuntos
Proteínas Sanguíneas/genética , Displasia Fibromuscular/sangue , Displasia Fibromuscular/genética , Proteogenômica , Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas do Citoesqueleto/sangue , Proteínas do Citoesqueleto/genética , Feminino , Displasia Fibromuscular/diagnóstico , Marcadores Genéticos , Predisposição Genética para Doença , Ensaios de Triagem em Larga Escala , Humanos , Lipídeos/sangue , Aprendizado de Máquina , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Reprodutibilidade dos Testes , Biologia de Sistemas , Adulto Jovem
2.
Intern Med ; 57(18): 2689-2694, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29709926

RESUMO

A 33-year-old man was admitted to our hospital to undergo an evaluation to determine the cause of secondary hypertension. Computerized tomography angiography (CTA) showed bilateral multiple renal arteries with significant stenosis of the right extra-renal artery due to fibromuscular dysplasia and segmental impairment of renal perfusion. Although the plasma aldosterone concentration and plasma renin activity were within the normal ranges, percutaneous balloon dilatation of the stenotic lesion resolved his hypertension, leading to a diagnosis of renovascular hypertension caused by segmental renal ischemia due to extra-renal artery stenosis. CTA should be considered during the examination of patients with early-age hypertension, even if the plasma renin activity is not sufficiently elevated.


Assuntos
Displasia Fibromuscular/complicações , Hipertensão Renovascular/etiologia , Obstrução da Artéria Renal/etiologia , Adulto , Aldosterona/sangue , Angioplastia com Balão , Angiografia por Tomografia Computadorizada , Displasia Fibromuscular/sangue , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/terapia , Humanos , Hipertensão Renovascular/sangue , Hipertensão Renovascular/diagnóstico por imagem , Masculino , Obstrução da Artéria Renal/sangue , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/terapia , Renina/sangue
3.
Wien Klin Wochenschr ; 122(5-6): 159-64, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20361379

RESUMO

BACKGROUND: The aim of the study was to establish whether increased levels of serum lipoprotein(a) significantly contribute to an increase in intima-media thickness and the number of carotid artery plaques, and consequently to cardiovascular risk in patients with type 2 diabetes mellitus. METHODS: Lipoprotein(a) levels, intima-media thickness and the number of carotid artery plaques were determined at the beginning of the study in 146 patients with type 2 diabetes. Patients were divided into two groups according to serum lipoprotein(a) levels (> or 30 mg/dl had more cardiovascular events, the difference was not statistically significant. CONCLUSIONS: These results indicate that lipoprotein(a) is an independent, genetically determined risk factor closely associated with progression of intima-media thickness in type 2 diabetes.


Assuntos
Estenose das Carótidas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico por imagem , Displasia Fibromuscular/sangue , Displasia Fibromuscular/diagnóstico por imagem , Lipoproteína(a)/sangue , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Croácia , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/mortalidade , Feminino , Displasia Fibromuscular/mortalidade , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos , Fumar/sangue , Taxa de Sobrevida , Triglicerídeos/sangue , Ultrassonografia , Relação Cintura-Quadril
4.
FASEB J ; 16(7): 724-6, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11923215

RESUMO

The somatostatin analogs octreotide and lanreotide, selective to receptor subtypes 2 and 5, failed clinical efficacy for the prevention of restenosis after percutaneous transluminal angioplasty. These findings might have been the result of targeting a wrong subset of receptors. In rat arteries, subtypes 1 and 4 are expressed 3-4 times more prominently than 2 and 5, and subtype 1 is the nearly exclusive subtype in atherosclerotic human vessels. Here, we demonstrate that daily s.c. injections (50-500 microg/kg/d) of CH275 (DesAA1,2,5(D-W8,IAmp9)Somatostatine-14), selective to subtypes 1 and 4, dose-dependently inhibited intimal hyperplasia 14 days after rat carotid denudation injury (for intimal area P=0.0002 across the dose range). CH275 was more effective than somatostatin-14 (equal affinity to all five subtypes, P=0.03), or octreotide (selective to subtypes 2 and 5, P=0.098). When rats were given the peptides for 14 days with end-point at 28 days, CH275 still significantly inhibited intimal area expansion. Both CH275 and octreotide inhibited the outgrowth of cells from postinjury aortic tissue punch-explants and the distance migrated in vitro, but not cell replication, which indicated that the effects of somatostatin analogs were directed on the migration of intimal cell progenitors rather than on their proliferation.


Assuntos
Displasia Fibromuscular/prevenção & controle , Receptores de Somatostatina/agonistas , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Animais , Vasos Sanguíneos/citologia , Vasos Sanguíneos/efeitos dos fármacos , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/prevenção & controle , Divisão Celular , Movimento Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Displasia Fibromuscular/sangue , Displasia Fibromuscular/patologia , Meia-Vida , Masculino , Proteínas de Membrana , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Octreotida/uso terapêutico , Ratos , Ratos Wistar , Somatostatina/administração & dosagem , Somatostatina/sangue , Túnica Íntima/patologia , Aumento de Peso
5.
Neurol Sci ; 22(1): 31-5, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11487190

RESUMO

A case of fibromuscular dysplasia (FMD), presenting with a non-hemorrhagic infarct is reported. Positivity of anticardiolipin antibodies suggested an immune response. A 40-year-old man presented with sudden onset of stroke, preceded by similar ischemic attacks. Computed tomography (CT) of the brain showed a recent non-hemorrhagic infarct in the left middle cerebral artery (MCA) territory and an old right MCA territory infarct. Serum was positive for anticardiolipin antibodies. These above findings were confirmed at autopsy. A portion of the internal carotid artery and the middle cerebral arteries on both sides revealed features of FMD, with thrombosis. This case suggests an immune mechanism for FMD, hitherto unobserved in the cerebral circulation.


Assuntos
Anticorpos Anticardiolipina/sangue , Anticorpos Anticardiolipina/imunologia , Displasia Fibromuscular/sangue , Infarto da Artéria Cerebral Média/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Displasia Fibromuscular/imunologia , Displasia Fibromuscular/fisiopatologia , Humanos , Masculino , Fenitoína/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Resultado do Tratamento
6.
Wien Klin Wochenschr ; 111(3): 81-9, 1999 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-10093889

RESUMO

Intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) or vascular surgical procedures remains a significant problem despite current antithrombotic therapy. The use of the current antithrombotic drugs, namely heparin + chronic aspirin (ASA) +/- oral anticoagulants, is based upon the assumptions that: i) heparin blocks thrombin generation and/or accelerates thrombin inhibition by antithrombin III (ATIII); ii) aspirin acetylates platelet cyclooxygenase, thereby preventing thromboxane A2 (TxA2) synthesis; and iii) oral anticoagulants reduce the availability of vitamin K-dependent procoagulants, thereby reducing the risk of thrombus formation. Albeit beneficial, this approach has a number of shortcomings and limitations: i) when thrombin binds to an injured vessel wall, it becomes resistant to inhibition by heparin/ATIII; thus, surface-bound thrombin remains active, stimulating further thrombus formation, smooth muscle cell proliferation and subsequent hyperplasia; ii) while TxA2 inhibition reduces platelet reactivity, platelets are able to respond to multiple stimuli generated at the time of, or after, vessel wall injury; and iii) heparin, aspirin and the oral anticoagulants all render the patient hemostatically defective and at risk of bleeding. Recent studies suggest that alternate therapeutic approaches can inhibit thrombogenesis more effectively at the time of injury, thereby not only inhibiting hyperplasia more effectively than the currently used drugs, but also reducing (or eliminating) the need for long-term therapy. For example, we suggest that the heparin cofactor II (HCII) catalysts, dermatan sulfate and Intimatan, inhibit surface-bound thrombin more effectively than heparin/ATIII, thereby inhibiting intimal hyperplasia effectively. Their effects are achieved when the drug is given only at the time of injury; i.e. with no further antithrombotic therapy. Other studies indicate that injured vessel wall thrombogenicity can be reduced by pretreatment with Persantine (dipyridamole) or with certain fatty acid supplements which either increase vessel wall cAMP and/or 13HODE synthesis. These increases are associated with decreased vessel wall thrombogenicity, which, in turn, is associated with decreased intimal hyperplasia. Such results suggest that vessel wall repair is achieved more effectively by targeting antithrombotic drugs directly at the vessel wall thrombogenicity per se rather than indirectly by altering the circulating blood cells and systemic coagulant system.


Assuntos
Dermatan Sulfato/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Displasia Fibromuscular/prevenção & controle , Trombina/metabolismo , Animais , Displasia Fibromuscular/sangue , Humanos , Recidiva
7.
J Am Soc Nephrol ; 7(8): 1169-77, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8866409

RESUMO

Vascular access dysfunction is an important cause of morbidity for dialysis patients and a major contributor to hemodialysis cost. Thrombosis is a leading cause of vascular access failure, and usually results from stenotic lesions in the venous outflow system. This study was designed to explore the impact of serum levels of various risk factors for thrombosis and accelerated fibrointimal hyperplasia on progressive stenosis, and the subsequent thrombosis of hemodialysis fistula. A cross-sectional and 2-yr prospective pilot study was performed in 30 nondiabetic hemodialysis patients with primary arteriovenous fistula. Venous dialysis pressure, urea recirculation, color Doppler sonography, and angiography were used to monitor vascular access patency. Eleven patients (37%) developed a progressive stenosis in the venous circuit, which was complicated by thrombosis in three patients. Compared with the patients without fistula dysfunction, these patients had higher serum levels of monocyte chemoattractant protein-1 and interleukin-6, two cytokines that regulate the proliferation of vascular smooth muscle cells, which is the key mechanism in the pathogenesis of fistula stenosis. In addition, they had hyperinsulinemia, hyperlipidemia, and increased plasma levels of two hemostasis-derived risk factors for thrombosis: plasminogen activator inhibitor type 1 and factor VII. Monocyte chemoattractant protein-1, interleukin-6, plasminogen activator inhibitor type 1, factor VII, triglycerides, and the ratios for cholesterol/HDL-cholesterol, apolipoprotein (apo) A-I/ apo C-III, apo A-I/apo B, and glucose/insulin were independent predictors of fistula dysfunction. This study demonstrates the influece of cytokines, hemostasis-derived vascular risk factor, hyperinsullnemia, and abnormallties of lipids and apolipoproteins on primary fistula survival. The assessment of these factors might be useful for the identification of the patients at risk of fistula stenosis and thrombosis.


Assuntos
Derivação Arteriovenosa Cirúrgica/efeitos adversos , Displasia Fibromuscular/epidemiologia , Diálise Renal , Trombose/epidemiologia , Idoso , Fatores de Coagulação Sanguínea/análise , Glicemia/análise , Quimiocina CCL2/sangue , Comorbidade , Estudos Transversais , Citocinas/sangue , Feminino , Displasia Fibromuscular/sangue , Displasia Fibromuscular/etiologia , Humanos , Hiperinsulinismo/epidemiologia , Hiperlipidemias/epidemiologia , Hipertensão/epidemiologia , Interleucina-6/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Projetos Piloto , Inibidor 1 de Ativador de Plasminogênio/análise , Fator de Crescimento Derivado de Plaquetas/análise , Estudos Prospectivos , Fatores de Risco , Fumar/epidemiologia , Trombose/sangue , Trombose/etiologia
8.
Methods Find Exp Clin Pharmacol ; 16(2): 153-7, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8007744

RESUMO

The erythrocyte Na+/Li(+)-countertransport activity was studied in patients with essential hypertension (n = 59), chronic glomerulonephritis (n = 30), chronic pyelonephritis (n = 26), renovascular hypertension (n = 35) and pheochromocytoma (n = 3). The erythrocyte Na+/Li(+)-countertransport (SLC) activity was on average higher (p < 0.02) in the patients with essential hypertension as compared to those with secondary hypertension, although a clear distinction between both groups was not possible. After surgical treatment of the patients with atherosclerotic renal artery stenosis, fibromuscular dysplasia or pheochromocytoma, no change in erythrocyte SLC activity was observed. However, blood pressure was significantly reduced.


Assuntos
Antiporters/sangue , Eritrócitos/metabolismo , Hipertensão Renal/sangue , Hipertensão/sangue , Lítio/sangue , Sódio/sangue , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Arteriosclerose/sangue , Arteriosclerose/complicações , Arteriosclerose/cirurgia , Pressão Sanguínea/fisiologia , Feminino , Displasia Fibromuscular/sangue , Displasia Fibromuscular/cirurgia , Glomerulonefrite/sangue , Glomerulonefrite/complicações , Humanos , Hipertensão/fisiopatologia , Hipertensão Renal/etiologia , Hipertensão Renal/fisiopatologia , Hipertensão Renovascular/sangue , Masculino , Feocromocitoma/sangue , Feocromocitoma/complicações , Feocromocitoma/cirurgia , Pielonefrite/sangue , Pielonefrite/complicações
9.
Wien Klin Wochenschr ; 105(15): 417-24, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8379153

RESUMO

Fibrin appears to be a multi-potential component of atherogenesis, intervening at virtually all stages of lesion development. Fibrin and microthrombus deposition on normal intima is associated with endothelial disruption and intimal oedema, and oedema is a primary characteristic of early proliferative lesions. Fibrin strands on or in the intima encourage smooth muscle cell (SMC) migration and proliferation, and contribute to the growth of plaques. Fibrin also provides a continuing source of fibrin degradation products (FDP), and these have mitogenic activity which will sustain SMC proliferation in growing plaques, and act as chemoattractants for blood leucocytes. Accumulation of the lipid core in fibrous plaques may also be influenced by fibrin which appears to bind the lipoprotein Lp(a) with high affinity, thereby immobilizing its lipid moiety within the lesion.


Assuntos
Arteriosclerose/sangue , Fibrinogênio/metabolismo , Arteriosclerose/patologia , Proteínas Sanguíneas/metabolismo , Divisão Celular/fisiologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Displasia Fibromuscular/sangue , Displasia Fibromuscular/patologia , Humanos , Lipídeos/sangue , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia
10.
Am J Kidney Dis ; 20(5): 500-3, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1442763

RESUMO

A relationship appears to exist between antiphospholipid autoantibodies (APLA) and vascular occlusion, although the exact mechanism is still a matter of debate. We present and comment on two cases of renal artery occlusion in patients with concomitant presence of arterial fibromuscular dysplasia and high APLA titers.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Displasia Fibromuscular/patologia , Obstrução da Artéria Renal/patologia , Adulto , Constrição Patológica/patologia , Feminino , Displasia Fibromuscular/sangue , Humanos , Infarto/patologia , Pessoa de Meia-Idade , Obstrução da Artéria Renal/sangue
12.
Urol Clin North Am ; 11(3): 383-92, 1984 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6464247

RESUMO

From 1969 to 1979, 169 patients with two or more renal angiograms for renovascular disease (85 atherosclerotic, 75 fibrous, 9 atherosclerotic and fibrous) were reviewed in an attempt to characterize progression of disease and to determine clinical markers of progression. Progression of renal artery atherosclerosis was observed in 37 patients (44 per cent); progression to complete occlusion was observed in 14 patients (16 per cent). In the 66 patients with medial fibroplasia, progression was observed in 22 patients (33 per cent). Serial serum creatinine measurements in conjunction with measurements of kidney size may be used as markers of progressive atherosclerotic renovascular disease. These clinical markers did not represent progressive disease for individuals with medial fibroplasia.


Assuntos
Arteriopatias Oclusivas/fisiopatologia , Arteriosclerose/fisiopatologia , Displasia Fibromuscular/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Obstrução da Artéria Renal/fisiopatologia , Adulto , Idoso , Arteriosclerose/sangue , Arteriosclerose/diagnóstico por imagem , Pressão Sanguínea , Creatinina/sangue , Feminino , Displasia Fibromuscular/sangue , Displasia Fibromuscular/diagnóstico por imagem , Humanos , Hipertensão Renovascular/sangue , Hipertensão Renovascular/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Radiografia , Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/sangue , Obstrução da Artéria Renal/diagnóstico por imagem , Fatores de Tempo
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