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1.
J Endovasc Ther ; 22(1): 130-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25775693

RESUMO

PURPOSE: To examine the long-term outcomes of bare metal stent placement for exclusion of extracranial internal carotid artery (ICA) aneurysms. METHODS: From 2006 to 2011, 7 consecutive symptomatic patients (4 men; mean age 52 years) with surgically inaccessible extracranial ICA aneurysms were treated with a bare stent at a single center. Patients received clopidogrel for 3 months after the procedure and aspirin for life. Clinical follow-up with duplex ultrasound and/or computed tomographic angiography was performed at 3, 6, and 12 months and yearly thereafter. RESULTS: All procedures were technically successful; no neurological complications occurred. After 6 months, there was complete thrombosis of the aneurysm in all except one case. In this asymptomatic patient, the residual active flow was successfully obliterated by additional coil embolization. Over a mean follow-up of 57 ± 22 months, all patients were alive and free of local or central neurological symptoms. All stents were patent, and thrombosis of the aneurysms was complete. CONCLUSION: In this small series, treatment of extracranial ICA aneurysms with a bare stent seems technically feasible and safe. All treated extracranial ICA aneurysms were excluded by primary intervention or secondary coil embolization.


Assuntos
Aneurisma/diagnóstico , Aneurisma/terapia , Artéria Carótida Interna/patologia , Procedimentos Endovasculares , Stents , Adulto , Idoso , Clopidogrel , Procedimentos Endovasculares/métodos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Metais , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Estudos Retrospectivos , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Resultado do Tratamento
2.
Circ Res ; 113(2): 153-66, 2013 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-23658436

RESUMO

RATIONALE: Mesenchymal precursor cells (MPCs) are a specific Stro-3+ subpopulation of mesenchymal stem cells isolated from bone marrow. MPCs exert extensive cardioprotective effects, and are considered to be immune privileged. OBJECTIVE: This study assessed the safety, feasibility, and efficacy of intracoronary delivery of allogeneic MPCs directly after acute myocardial infarction in sheep. METHODS AND RESULTS: Initially, intracoronary delivery conditions were optimized in 20 sheep. These conditions were applied in a randomized study of 68 sheep with an anterior acute myocardial infarction. Coronary flow was monitored during MPC infusion, and cardiac function was assessed using invasive hemodynamics and echocardiography at baseline and during 8 weeks follow-up. Coronary flow remained within thrombolysis in myocardial infarction III definitions in all sheep during MPC infusion. Global left ventricular ejection fraction as measured by pressure-volume loop analysis deteriorated in controls to 40.7±2.6% after 8 weeks. In contrast, MPC treatment improved cardiac function to 52.8±0.7%. Echocardiography revealed significant improvement of both global and regional cardiac functions. Infarct size decreased by 40% in treated sheep, whereas infarct and border zone thickness were enhanced. Left ventricular adverse remodeling was abrogated by MPC therapy, resulting in a marked reduction of left ventricular volumes. Blood vessel density increased by >50% in the infarct and border areas. Compensatory cardiomyocyte hypertrophy was reduced in border and remote segments, accompanied by reduced collagen deposition and apoptosis. No microinfarctions in remote myocardial segments or histological abnormalities in unrelated organs were found. CONCLUSIONS: Intracoronary infusion of allogeneic MPCs is safe, feasible, and markedly effective in a large animal model of acute myocardial infarction.


Assuntos
Vasos Coronários/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Animais , Seguimentos , Infusões Intra-Arteriais , Infarto do Miocárdio/fisiopatologia , Distribuição Aleatória , Ovinos , Transplante Homólogo
3.
Curr Vasc Pharmacol ; 11(1): 21-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23391419

RESUMO

OBJECTIVE: The adaptive growth of blood vessels is important to prevent tissue loss following arterial occlusion. Extravasation of monocytes is essential for this process. The peptidase CD26 targets SDF-1 alpha, a chemokine regulating monocyte trafficking. We hypothesized that blocking SDF-1 alpha inactivation, using a commercially available CD26 inhibitor, accelerates perfusion recovery without detrimental side effects on plaque stability. METHODS AND RESULTS: Atherosclerosis prone ApoE-/- mice underwent femoral artery ligation and received a CD26 inhibitor or placebo. CD26 inhibition increased short term (7 days) perfusion recovery after both single and daily doses compared to placebo, 36% ± 2 (p=0.017) and 39% ± 2 (p=0.008) vs. 29% ± 3 respectively. Long term (56 days) perfusion recovery increased after daily treatment compared to placebo 83% ± 3 vs. 60% ± 2, (p<0.001). CD26 inhibition did not result in increased atherosclerotic plaque instability or inflammatory cell infiltration. CD26 inhibition increased macrophage number around growing collaterals, SDF-1 alpha plasma levels and monocyte expression of the activation marker CD11b and the SDF-1 alpha receptor CXCR-4. CONCLUSIONS: CD26 inhibition enhanced perfusion recovery following arterial occlusion via attenuated SDF-1 alpha inactivation and increased monocyte activation. There was no observable aggravation of atherosclerosis and CD26 inhibition could therefore offer a novel approach for therapeutic arteriogenesis in patients.


Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Quimiocina CXCL12/metabolismo , Dipeptidil Peptidase 4/metabolismo , Artéria Femoral/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/patologia , Antígeno CD11b/metabolismo , Movimento Celular/genética , Movimento Celular/fisiologia , Quimiocina CXCL12/genética , Artéria Femoral/patologia , Inflamação/metabolismo , Inflamação/patologia , Ligadura/métodos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Perfusão/métodos , Receptores CXCR4/metabolismo
4.
Eur J Clin Invest ; 41(9): 943-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21314827

RESUMO

BACKGROUND: Lack of tissue perfusion because of arterial occlusion can result in mortality and morbidity. In response to local tissue ischaemia, extravasation of leucocytes into the region at risk is initiated to facilitate matrix remodelling and subsequent perfusion recovery. However, it is unknown if local tissue ischaemia also induces a more generalized response of leucocyte trafficking and compartmentalization. This study was designed to gain insight into the temporal changes in circulating and bone marrow-derived leucocyte fractions following peripheral arterial occlusion in mice. MATERIALS AND METHODS: Mouse peripheral blood and bone marrow samples were collected at baseline and subsequently at day 1, 2, 3, 4 and 7 after femoral artery ligation. Leucocyte and bone marrow cell subsets were quantified using flow cytometry. RESULTS: After arterial occlusion, peripheral blood leucocyte numbers did not vary significantly over time. However, significant intrinsic temporal changes in cell numbers were observed for monocytes, lymphocytes, neutrophils and their subsets with fluctuations of > 50%. Granulocytes, for example, showed an initial upregulation, while monocytes and lymphocytes numbers initially decreased. These variations in the circulation were largely preceded by changes in the corresponding bone marrow lineages. Progenitor cells of the myeloid and lymphoid lineage in the bone marrow were upregulated after the decrease in the numbers of their progeny in the peripheral blood. CONCLUSIONS: Local arterial occlusion results in an orchestrated systemic response of leucocyte trafficking. This response substantiates the pivotal role of leucocytes as mediators of processes leading to perfusion recovery and tissue remodelling.


Assuntos
Arteriopatias Oclusivas/sangue , Células da Medula Óssea/fisiologia , Leucócitos/fisiologia , Análise de Variância , Animais , Citocinas/metabolismo , Citocinas/fisiologia , Citometria de Fluxo , Isquemia/metabolismo , Contagem de Leucócitos , Camundongos , Camundongos Endogâmicos C57BL
5.
Am J Physiol Heart Circ Physiol ; 300(1): H408-14, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20952668

RESUMO

Therapeutic stimulation of collateral artery growth is a promising approach for treatment of cardiovascular diseases. Unfortunately, translation into clinical practice yet remains cumbersome. Cardiovascular physiology and anatomy are major determinants of vascular growth processes. Hence, large-animal models are needed to improve clinical translatability of preclinical research. Furthermore, acute complete occlusions are mostly applied in experimental research, whereas stepwise occlusions are more often observed in human disease. We developed a model of coronary collateral artery growth in which 1) the artery is occluded in a step wise approach, and 2) effects of local treatment can be measured individually for each supplying coronary vessel. A hemodynamically relevant stenosis was created by implantation of a tapered stent at day 0 (d0) in the left circumflex artery (LCX), followed by complete arterial occlusion at day 14 (d14). Fluorescent microspheres were injected for demarcation of perfusion territories at each time point. Three and four weeks after induction of stenosis, collateral conductance measurements were performed for each coronary artery separately using differently labeled fluorescent microspheres. Postmortem angiography after acute LCX occlusion confirmed the presence of preexistent coronary anastomoses in the pig. The tapered stent created a hemodynamically significant stenosis immediately postplacement (fractional flow reserve, 0.70 ± 0.03). Between day 21 and 28, collateral conductance significantly increased in both the left anterior descending (LAD) and the right coronary artery (RCA)-supplied, collateral-dependent territories (LAD d21, 0.77 ± 0.14; LAD d28, 1.35 ± 0.12; RCA d21, 0.88 ± 0.29; RCA d28, 1.70 ± 0.16 ml · min(-1) · g(-1) · 100 mmHg(-1)), indicating collateral artery growth. We here describe a new translational minimally invasive model of coronary collateral artery growth in pigs, according to a defined protocol of LCX-stenosis and subsequent occlusion, allowing preclinical evaluation of arteriogenic therapies.


Assuntos
Artérias/fisiopatologia , Circulação Colateral/fisiologia , Oclusão Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Animais , Circulação Coronária/fisiologia , Imuno-Histoquímica , Stents , Suínos
6.
J Mol Cell Cardiol ; 50(1): 25-32, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20708624

RESUMO

Adaptive collateral growth (arteriogenesis) is an important protective mechanism against ischemic injury in patients with cardiovascular disease. Arteriogenesis involves enlargement of pre-existent arterial anastomoses and shares many mechanistic similarities with inflammatory processes. Although infusion of the Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) has shown to result in a significant stimulation of arteriogenesis and both Toll-like receptor 2 and 4 are involved in structural arterial adaptations, the requirement for TLRs in arteriogenesis has not yet been established. We therefore subjected TLR 2 null and TLR 4 defective mice to unilateral femoral artery occlusion. At 7 days, both TLR 2 null and TLR 4 defective mice showed a significant reduction (~35%) of collateral perfusion. Histological staining showed that TLR 2 and TLR 4 expression during arteriogenesis is mostly restricted to infiltrating leukocytes. To distinguish between the functional importance of vascular and leukocytic TLRs in arteriogenesis, cross-over bone marrow transplantation was performed 6 weeks before femoral artery occlusion. Perfusion measurements showed that transplantation of wild-type bone marrow into TLR 2 null and TLR 4 defective mice rescued the impaired arteriogenesis, while injection of TLR 2 null and TLR 4 defective bone marrow into wild-type mice significantly reduced collateral vessel growth to levels of TLR null/defective mice. RT-PCR analysis demonstrated a significant upregulation of two endogenous TLR ligands EDA and Hsp60 (91.7 fold and 1.9 fold respectively) in regions of collateral vessel formation. This study illustrates the involvement of TLR 2 and TLR 4 in adaptive collateral artery growth and shows the importance of TLR 2 and 4 expression by bone-marrow derived cells for this process.


Assuntos
Artérias/citologia , Células da Medula Óssea/metabolismo , Neovascularização Fisiológica/fisiologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Células da Medula Óssea/citologia , Transplante de Medula Óssea , Citometria de Fluxo , Imunidade Inata/genética , Imunidade Inata/fisiologia , Camundongos , Camundongos Mutantes , Neovascularização Fisiológica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
7.
Cardiovasc Res ; 88(1): 179-85, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20495189

RESUMO

AIMS: Adaptive collateral artery growth (arteriogenesis) is an important mechanism to maintain tissue perfusion upon arterial obstruction. Leucocytes and inflammatory mediators play a crucial role in this process. Depletion of the nuclear factor kappa B (NF-κB) p50 subunit modulates inflammatory processes in cardiovascular disease. We hypothesized that NF-κB p50 is a regulator of the inflammatory response after arterial occlusion and subsequent collateral perfusion. METHODS AND RESULTS: Unilateral femoral artery ligation was performed in NF-κB p50-/- and wild-type (Wt, B6/129PF2) mice. Seven days after arterial occlusion, tissue perfusion restoration was significantly enhanced in NF-κB p50-/- mice compared with Wt mice (42.9 ± 3.9 vs. 32.0 ± 2.6% perfusion recovery, P = 0.04). Transplantation of NF-κB p50-/- bone marrow (bm) into Wt mice and vice versa showed that the effect of p50 subunit depletion can be predominantly attributed to the bone marrow-derived circulating cells (NF-κB p50-/- bm in Wt mice 42.1 ± 1.5%, Wt bm in NF-κB p50-/- mice 35.4±1.5% perfusion recovery). Histological analyses revealed a more elaborate extravasation of monocytes in hindlimb tissue of NF-κB p50-/- mice. Chemotaxis assays confirmed the increased migration ability of NF-κB p50-/- monocytes, which may be due to an observed increased integrin expression. Upon stimulation of blood from NF-κB p50-/- and Wt mice more interleukin-6 was produced, confirming the pro-inflammatory phenotype in absence of the p50 subunit. CONCLUSION: Depletion of the NF-κB p50 subunit enhances collateral artery growth. Its absence in circulating cells improves tissue perfusion restoration after femoral artery ligation by increasing macrophage influx into the growing collateral vessels.


Assuntos
Arteriopatias Oclusivas/imunologia , Células da Medula Óssea/imunologia , Circulação Colateral , Deleção de Genes , Subunidade p50 de NF-kappa B/deficiência , Neovascularização Fisiológica , Animais , Arteriopatias Oclusivas/genética , Arteriopatias Oclusivas/fisiopatologia , Transplante de Medula Óssea , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Feminino , Artéria Femoral/cirurgia , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Ligadura , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Monócitos/imunologia , Subunidade p50 de NF-kappa B/genética , Fatores de Tempo
8.
J Cell Mol Med ; 13(9B): 3463-74, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19438808

RESUMO

UNLABELLED: During collateral artery growth, monocytes adhere to the endothelium and secrete cytokines from the perivascular space promoting arteriogenesis. Recently, the endothelial glycocalyx has been shown to modulate leucocyte infiltration in atherogenic regions. The role of this endothelial surface coating in arteriogenesis, however, has not been investigated so far. We now report that local plasma levels of hyaluronic acid are specifically increased in collateral arterial blood of coronary artery disease patients and hypothesized that components of the endothelial glycocalyx are shed during arteriogenesis, resulting in decreased glycocalyx dimensions and an increased leucocyte extravasation. In a rabbit model of femoral artery ligation, electron microscopy revealed a decrease in glycocalyx dimensions in collateral arteries compared with quiescent anastomoses (67.5 +/- 47.2 nm versus 101.0 +/- 11.3 nm; P < 0.001). This decrease was correlated with a higher number of perivascular macrophages around collateral arteries. The additional glycocalyx perturbation by local hyaluronidase infusion almost completely removed the endothelial surface layer and temporarily stimulated leucocyte accumulation in the perivascular space. However, complete perturbation of the glycocalyx by hyaluronidase infusion resulted in a significant attenuation of collateral artery growth assessed by microsphere-based perfusion measurements (ml/min/100 mmHg: hyaluronidase: 27.5 +/- 3.5; CONTROLS: 47.1 +/- 3.83; P < 0.001) and a lower percentage of actively proliferating vascular smooth muscle cells. A decreased expression of the shear-stress regulated pro-arteriogenic genes eNOS and TGF-beta1 suggests an impaired mechanotransduction as the underlying mechanisms. For the first time, we describe the role of the endothelial glycocalyx in collateral artery growth. Although complete abrogation led to attenuated arteriogenesis, shedding of glycocalyx components is observed during collateral artery growth.


Assuntos
Artérias/patologia , Regulação da Expressão Gênica , Glicocálix/metabolismo , Leucócitos/citologia , Neovascularização Fisiológica , Idoso , Animais , Adesão Celular , Constrição Patológica/patologia , Células Endoteliais/citologia , Feminino , Humanos , Masculino , Microscopia Eletrônica/métodos , Microesferas , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/metabolismo , Coelhos
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