RESUMO
[Figure: see text].
Assuntos
Circulação Colateral , Circulação Coronária , Oclusão Coronária/fisiopatologia , Artéria Radial/fisiopatologia , Polegar/irrigação sanguínea , Idoso , Determinação da Pressão Arterial , Cateterismo Cardíaco , Doença Crônica , Oclusão Coronária/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo RegionalRESUMO
OBJECTIVE: Inducible myocardial ischemia is influenced by contributions of both the epicardial artery and the coronary microcirculation. Experimental studies have found adverse microcirculatory remodeling to occur downstream of severe coronary stenoses. Coronary physiology studies in patients contradict the experimental findings, as the minimal microvascular resistance is not modified by stenoses. The objective was to determine whether microcirculatory remodeling occurs downstream of coronary stenoses in the human coronary circulation. Approach and Results: Myocardium corresponding to 115 coronary arteries of 55 deceased patients was investigated. Histopathologic staining of the microcirculation was performed using antibodies against SMA-α (smooth muscle actin-α) and CD31, to stain arterioles and capillaries, respectively. The following parameters were analyzed: ratio between lumen and vesel area, ratio between lumen and vessel diameter (both ratios for arterioles of <40, 40-100, and 100-200 µm diameter), arteriolar density, and capillary density. From the 55 patients, 32 pairs of an unobstructed coronary artery and a coronary artery with a stenosis were formed. No statistically significant differences between any of the microcirculatory parameters were found. A confirmatory unpaired analysis compared 3 groups: (1) coronary arteries in patients without coronary artery disease (n=53), (2) unobstructed coronary arteries in patients with a stenosis in one of the other coronary arteries (n=23), and (3) coronary stenoses (n=39). No statistically significant differences were observed between the groups. CONCLUSIONS: The microcirculation distal to noncritical stenoses does not undergo structural remodeling in the human coronary circulation.
Assuntos
Circulação Coronária/fisiologia , Estenose Coronária/patologia , Vasos Coronários/patologia , Microcirculação/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Remodelação Vascular/fisiologia , Idoso , Autopsia , Estenose Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVES: Native T1 mapping and late gadolinium enhancement (LGE) imaging offer detailed characterisation of the myocardium after acute myocardial infarction (AMI). We evaluated the effects of microvascular injury (MVI) and intramyocardial haemorrhage on local T1 and T2* values in patients with a reperfused AMI. METHODS: Forty-three patients after reperfused AMI underwent cardiovascular magnetic resonance imaging (CMR) at 4 [3-5] days, including native MOLLI T1 and T2* mapping, STIR, cine imaging and LGE. T1 and T2* values were determined in LGE-defined regions of interest: the MI core incorporating MVI when present, the core-adjacent MI border zone (without any areas of MVI), and remote myocardium. RESULTS: Average T1 in the MI core was higher than in the MI border zone and remote myocardium. However, in the 20 (47%) patients with MVI, MI core T1 was lower than in patients without MVI (MVI 1048±78ms, no MVI 1111±89ms, p=0.02). MI core T2* was significantly lower in patients with MVI than in those without (MVI 20 [18-23]ms, no MVI 31 [26-39]ms, p<0.001). CONCLUSION: The presence of MVI profoundly affects MOLLI-measured native T1 values. T2* mapping suggested that this may be the result of intramyocardial haemorrhage. These findings have important implications for the interpretation of native T1 values shortly after AMI. KEY POINTS: ⢠Microvascular injury after acute myocardial infarction affects local T1 and T2* values. ⢠Infarct zone T1 values are lower if microvascular injury is present. ⢠T2* mapping suggests that low infarct T1 values are likely haemorrhage. ⢠T1 and T2* values are complimentary for correctly assessing post-infarct myocardium.
Assuntos
Vasos Coronários/diagnóstico por imagem , Hemorragia/diagnóstico por imagem , Imageamento por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Meios de Contraste , Vasos Coronários/patologia , Feminino , Gadolínio , Hemorragia/patologia , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Miocárdio/patologiaRESUMO
Coronary artery disease (CAD), also known as ischemic heart disease (IHD), is the leading cause of mortality in the western world, with developing countries showing a similar trend. With the increased understanding of the role of the immune system and inflammation in coronary artery disease, it was shown that macrophages play a major role in this disease. Costimulatory molecules are important regulators of inflammation, and especially, the CD40L-CD40 axis is of importance in the pathogenesis of cardiovascular disease. Although it was shown that CD40 can mediate macrophage function, its exact role in macrophage biology has not gained much attention in cardiovascular disease. Therefore, the goal of this review is to give an overview on the role of macrophage-specific CD40 in cardiovascular disease, with a focus on coronary artery disease. We will discuss the function of CD40 on the macrophage and its (proposed) role in the reduction of atherosclerosis, the reduction of neointima formation, and the stimulation of arteriogenesis.
Assuntos
Antígenos CD40/imunologia , Doença da Artéria Coronariana/patologia , Macrófagos/patologia , Animais , Doença da Artéria Coronariana/imunologia , Humanos , Macrófagos/imunologiaRESUMO
AIMS: Lack of gadolinium-contrast wash-in on first-pass perfusion imaging, early gadolinium-enhanced imaging, or late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) imaging after revascularized ST-elevation myocardial infarction (STEMI) is commonly referred to as microvascular obstruction (MVO). Additionally, T2-weighted imaging allows for the visualization of infarct-related oedema and intramyocardial haemorrhage (IMH) within the infarction. However, the exact histopathological correlate of the contrast-devoid core and its relation to IMH is unknown. METHODS AND RESULTS: In eight Yorkshire swine, the circumflex coronary artery was occluded for 75 min by a balloon catheter. After 7 days, CMR with cine imaging, T2-weighted turbospinecho, and LGE was performed. Cardiovascular magnetic resonance images were compared with histological findings after phosphotungstic acid-haematoxylin and anti-CD31/haematoxylin staining. These findings were compared with CMR findings in 27 consecutive PCI-treated STEMI patients, using the same scanning protocol. In the porcine model, the infarct core contained extensive necrosis and erythrocyte extravasation, without intact vasculature and hence, no MVO. The surrounding-gadolinium-enhanced-area contained granulation tissue, leucocyte infiltration, and necrosis with morphological intact microvessels containing microthrombi, without erythrocyte extravasation. Areas with IMH (median size 1.92 [0.36-5.25] cm(3)) and MVO (median size 2.19 [0.40-4.58] cm(3)) showed close anatomic correlation [intraclass correlation coefficient (ICC) 0.85, r = 0.85, P = 0.03]. Of the 27 STEMI patients, 15 had IMH (median size 6.60 [2.49-9.79] cm(3)) and 16 had MVO (median size 4.31 [1.05-7.57] cm(3)). Again, IMH and MVO showed close anatomic correlation (ICC 0.87, r = 0.93, P < 0.001). CONCLUSION: The contrast-devoid core of revascularized STEMI contains extensive erythrocyte extravasation with microvascular damage. Attenuating the reperfusion-induced haemorrhage may be a novel target in future adjunctive STEMI treatment.
Assuntos
Cardiomiopatias/patologia , Oclusão Coronária/patologia , Hemorragia/patologia , Infarto do Miocárdio/patologia , Adulto , Idoso , Animais , Oclusão com Balão , Meios de Contraste , Trombose Coronária/patologia , Modelos Animais de Doenças , Feminino , Humanos , Angiografia por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Masculino , Meglumina , Microvasos/patologia , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Revascularização Miocárdica/efeitos adversos , Necrose/patologia , Compostos Organometálicos , Intervenção Coronária Percutânea , Sus scrofaRESUMO
AIMS: In patients with obstructive coronary artery disease (CAD), the growth of collateral arteries, i.e. arteriogenesis, can preserve myocardial tissue perfusion and function. Monocytes modulate this process, supplying locally the necessary growth factors and degrading enzymes. Knowledge on factors involved in human arteriogenesis is scarce. Thus, the aim of the present study is to identify targets in monocytes that are critical for arteriogenesis in patients with CAD. METHODS AND RESULTS: A total of 50 patients with a chronic total coronary occlusion were dichotomized according to their collateral flow index. From each patient, RNA was isolated from unstimulated peripheral blood monocytes, monocytes stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, and from macrophages. Increased mRNA expression of galectin-2 was found in three out of four monocytic cell types of patients with a low capacity of the collateral circulation (P= 0.03 for unstimulated monocytes; P= 0.02 for LPS-stimulated monocytes; P= 0.20 for IL-4-stimulated monocytes; P= 0.02 for macrophages). Additionally, galectin-2 mRNA expression was significantly associated with the rs7291467 polymorphism in LGALS2 encoding galectin-2 in all four monocytic cell types. Patient with the rs7291467 CC genotype displayed highest galectin-2 expression, and also tended to have a lower arteriogenic response. To evaluate the effect of galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model. Treatment with galectin-2 markedly impaired the perfusion restoration at Day 7. CONCLUSION: Collectively, these results identify galectin-2 as a novel inhibitor of arteriogenesis. Modulation of galectin-2 may constitute a new therapeutic strategy for the stimulation of arteriogenesis in patients with CAD.
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Circulação Colateral/genética , Oclusão Coronária/genética , Galectina 2/metabolismo , Polimorfismo Genético/genética , Idoso , Animais , Fármacos Cardiovasculares/farmacologia , Circulação Colateral/efeitos dos fármacos , Oclusão Coronária/metabolismo , Oclusão Coronária/fisiopatologia , Feminino , Galectina 2/genética , Galectina 2/farmacologia , Membro Posterior , Humanos , Interleucina-4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , RNA Mensageiro/metabolismoRESUMO
Background In the presence of arterial stenosis, collateral artery growth (arteriogenesis) can alleviate ischemia and preserve tissue function. In patients with poorly developed collateral arteries, Gal-2 (galectin 2) expression is increased. In vivo administration of Gal-2 inhibits arteriogenesis. Blocking of Gal-2 potentially stimulates arteriogenesis. This study aims to investigate the effect of Gal-2 inhibition on arteriogenesis and macrophage polarization using specific single-domain antibodies. Methods and Results Llamas were immunized with Gal-2 to develop anti-Gal-2 antibodies. Binding of Gal-2 to monocytes and binding inhibition of antibodies were quantified. To test arteriogenesis in vivo, Western diet-fed LDLR.(low-density lipoprotein receptor)-null Leiden mice underwent femoral artery ligation and received treatment with llama antibodies 2H8 or 2C10 or with vehicle. Perfusion restoration was measured with laser Doppler imaging. In the hind limb, arterioles and macrophage subtypes were characterized by histology, together with aortic atherosclerosis. Llama-derived antibodies 2H8 and 2C10 strongly inhibited the binding of Gal-2 to monocytes (93% and 99%, respectively). Treatment with these antibodies significantly increased perfusion restoration at 14 days (relative to sham, vehicle: 41.3±2.7%; 2H8: 53.1±3.4%, P=0.016; 2C10: 52.0±3.8%, P=0.049). In mice treated with 2H8 or 2C10, the mean arteriolar diameter was larger compared with control (vehicle: 17.25±4.97 µm; 2H8: 17.71±5.01 µm; 2C10: 17.84±4.98 µm; P<0.001). Perivascular macrophages showed a higher fraction of the M2 phenotype in both antibody-treated animals (vehicle: 0.49±0.24; 2H8: 0.73±0.15, P=0.007; 2C10: 0.75±0.18, P=0.006). In vitro antibody treatment decreased the expression of M1-associated cytokines compared with control (P<0.05 for each). Atherosclerotic lesion size was comparable between groups (overall P=0.59). Conclusions Inhibition of Gal-2 induces a proarteriogenic M2 phenotype in macrophages, improves collateral artery growth, and increases perfusion restoration in a murine hind limb model.
Assuntos
Anticorpos/farmacologia , Aterosclerose/metabolismo , Circulação Colateral/fisiologia , Artéria Femoral/metabolismo , Galectina 2/antagonistas & inibidores , Membro Posterior/irrigação sanguínea , Animais , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Feminino , Artéria Femoral/fisiopatologia , Galectina 2/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de SinaisRESUMO
BACKGROUND: Transradial intervention (TRI) may impair digital perfusion with hand dysfunction as a result. However, the effect of TRI on digital perfusion has never been investigated, including the influence of variations of the collateral arterial network and the effect on hand dysfunction. METHODS AND RESULTS: We investigated the effect of TRI on digital perfusion by laser Doppler perfusion imaging. Laser Doppler perfusion imaging was performed at baseline, during radial access, TR band application, and at discharge. We compared tissue perfusion of the homolateral thumb (access site) with the contralateral thumb (comparator) during radial access as primary outcome. The hand circulation was assessed with angiography. Upper extremity function was evaluated with the validated QuickDASH questionnaire at baseline and follow-up. A significant reduction of tissue perfusion was observed during radial access and TR band application in the homolateral thumb (-32%, -32%, respectively) and contralateral thumb (-34%, -21%, respectively). We detected no perfusion difference between the homolateral and contralateral thumb during radial access (217; interquartile range, 112-364 versus 209; interquartile range, 99-369 arbitrary flux units; P=0.59). Reduced perfusion of the thumb during radial access was not associated with incompleteness of the superficial palmar arch ( P=0.13). Digital perfusion improved at discharge, though it remained below baseline levels (homolateral -11% and contralateral -14%). Hand dysfunction at 18 months was not associated with TRI-induced perfusion reduction ( P=0.54). CONCLUSIONS: TRI is safe. Digital perfusion is reduced in both hands during radial access and TR band application but is not associated with future loss of hand function and variations of the arterial hand supply.
Assuntos
Cateterismo Periférico/efeitos adversos , Dedos/irrigação sanguínea , Isquemia/etiologia , Artéria Radial/fisiopatologia , Idoso , Velocidade do Fluxo Sanguíneo , Circulação Colateral , Avaliação da Deficiência , Feminino , Humanos , Isquemia/diagnóstico por imagem , Isquemia/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão , Estudos Prospectivos , Punções , Artéria Radial/diagnóstico por imagem , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Inquéritos e Questionários , Fatores de TempoRESUMO
Coronary microvascular resistance is increasingly measured as a predictor of clinical outcomes, but there is no accepted gold-standard measurement. We compared the diagnostic accuracy of 2 invasive indices of microvascular resistance, Doppler-derived hyperemic microvascular resistance (hMR) and thermodilution-derived index of microcirculatory resistance (IMR), at predicting microvascular dysfunction. A total of 54 patients (61 ± 10 years) who underwent cardiac catheterization for stable coronary artery disease (n = 10) or acute myocardial infarction (n = 44) had simultaneous intracoronary pressure, Doppler flow velocity and thermodilution flow data acquired from 74 unobstructed vessels, at rest and during hyperemia. Three independent measurements of microvascular function were assessed, using predefined dichotomous thresholds: (1) coronary flow reserve (CFR), the average value of Doppler- and thermodilution-derived CFR; (2) cardiovascular magnetic resonance (CMR) derived myocardial perfusion reserve index; and (3) CMR-derived microvascular obstruction. hMR correlated with IMR (rho = 0.41, p <0.0001). hMR had better diagnostic accuracy than IMR to predict CFR (area under curve [AUC] 0.82 vs 0.58, p <0.001, sensitivity and specificity 77% and 77% vs 51% and 71%) and myocardial perfusion reserve index (AUC 0.85 vs 0.72, p = 0.19, sensitivity and specificity 82% and 80% vs 64% and 75%). In patients with acute myocardial infarction, the AUCs of hMR and IMR at predicting extensive microvascular obstruction were 0.83 and 0.72, respectively (p = 0.22, sensitivity and specificity 78% and 74% vs 44% and 91%). We conclude that these 2 invasive indices of coronary microvascular resistance only correlate modestly and so cannot be considered equivalent. In our study, the correlation between independent invasive and noninvasive measurements of microvascular function was better with hMR than with IMR.
Assuntos
Angina Estável/diagnóstico por imagem , Angina Estável/fisiopatologia , Ecocardiografia Doppler , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Resistência Vascular/fisiologia , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Cateterismo Cardíaco , Débito Cardíaco/fisiologia , Circulação Coronária/fisiologia , Feminino , Humanos , Hiperemia/diagnóstico por imagem , Hiperemia/etiologia , Hiperemia/fisiopatologia , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Sensibilidade e Especificidade , TermodiluiçãoRESUMO
AIMS: Previous studies on invasive assessment of collateral function in patients with a chronic total occlusion (CTO) have displayed only a limited increase in collateral flow and high occurrence of coronary steal during pharmacological stress. This could question the necessity for ischaemia testing prior to revascularization of CTOs in the presence of myocardial viability. The purpose of the present study was to determine the prevalence of perfusion impairments in patients with a CTO as assessed by [15O]H2O positron emission tomography (PET). METHODS AND RESULTS: Seventy-six consecutive patients (60 men, 62 ± 10 years) with a documented CTO and preserved left ventricular ejection fraction (LVEF) were included. All patients underwent PET to assess (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR). Collateral connection score was 0 in 7 (9%), 1 in 13 (17%), and 2 in 56 (74%) of the cases, with predominantly a high Rentrop grade (96% ≥2). MBF of the target area during hyperaemia was significantly lower when compared with the remote area (1.37 ± 0.37 vs. 2.63 ± 0.71 mL min-1 g-1, P < 0.001). Target to remote ratio during hyperaemia was on average 0.54 ± 0.13, and 73 (96%) patients demonstrated a significantly impaired target to remote ratio (≤0.75). Only 7 (9%) patients displayed a preserved CFR of ≥2.50, whereas coronary steal (CFR <1.0) was observed in 10 (13%) patients. CONCLUSIONS: Even in the presence of angiographically well-developed collateral arteries, the vast majority of CTO patients with a preserved LVEF showed significantly impaired perfusion. These results suggest that collateral function during increased blood flow demand in viable myocardium is predominantly insufficient.
Assuntos
Oclusão Coronária/diagnóstico por imagem , Imagem Multimodal/métodos , Isquemia Miocárdica/epidemiologia , Revascularização Miocárdica/métodos , Volume Sistólico , Idoso , Doença Crônica , Estudos de Coortes , Circulação Colateral , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Circulação Coronária/fisiologia , Oclusão Coronária/mortalidade , Oclusão Coronária/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/terapia , Tomografia por Emissão de Pósitrons/métodos , Prevalência , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
AIMS: This study aims primarily to assess the extent of the collateral circulation of the hand in a combined population of healthy individuals and patients who underwent transradial catheterisation, using both the Nexfin system and laser Doppler perfusion imaging. METHODS AND RESULTS: In total, 85 adults were included in the study (18 healthy volunteers; 67 patients who underwent transradial catheterisation). The perfusion of the thumb was assessed prior to and during complete radial artery compression using laser Doppler perfusion imaging (LDPI) and the Nexfin system. The palmar collateral flow index (PCFI) was compared between both devices and PCFINEXFIN was related to hand angiography and the upper limb function, using the QuickDASH questionnaire. Mean PCFILDPI was 0.77±0.15 and mean PCFINEXFIN was 0.88±0.08. Both were significantly related (Pearson correlation=0.49, 95% CI: 0.31-0.64, p<0.001, agreement -0.11±0.13). PCFINEXFIN correlated with the maximal diameter of the superficial palmar arch (R=0.49, p=0.04) and total minimal arch diameter (R=0.51, p<0.02). High PCFINEXFIN, measured at baseline, was correlated with a lower QuickDASH score for pain, activity and total at one month post transradial catheterisation (p=0.02, p<0.01, p<0.01), but not with discomfort or disability. CONCLUSIONS: The Nexfin monitoring system is comparable with laser Doppler perfusion imaging in the quantification of the collateral perfusion in the hand. In patients, the Nexfin-derived collateral flow index measured at baseline is associated with clinical outcome at 30 days post transradial catheterisation.
Assuntos
Cateterismo Periférico/métodos , Circulação Colateral/fisiologia , Mãos/fisiopatologia , Artéria Radial/cirurgia , Fluxo Sanguíneo Regional/fisiologia , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Feminino , Mãos/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Radial/fisiopatologiaRESUMO
BACKGROUND: The palmar arches serve as the most important conduits for digital blood supply, and incompleteness may lead to digital ischemia when the radial artery becomes obstructed after cardiac catheterization. The rate of palmar arch incompleteness and the clinical consequences after transradial access are currently unknown. METHODS AND RESULTS: The vascular anatomy of the hand was documented by angiography in 234 patients undergoing transradial cardiac catheterization. In all patients, a preprocedural modified Allen test and Barbeau test were performed. Upper-extremity function was assessed at baseline and 2-year follow-up by the QuickDASH. Incompleteness of the superficial palmar arch (SPA) was present in 46%, the deep palmar arch was complete in all patients. Modified Allen test and Barbeau test results were associated with incompleteness of the SPA (P=0.001 and P=0.001). The modified Allen test had a 33% sensitivity and 86% specificity for SPA incompleteness with a cutoff value of >10 seconds and a 59% sensitivity and 60% specificity with a cutoff value of >5 seconds. The Barbeau test had a 7% sensitivity and 98% specificity for type D and a 21% sensitivity and 93% specificity for types C and D combined. Upper-extremity dysfunction was not associated with SPA incompleteness (P=0.77). CONCLUSIONS: Although incompleteness of the SPA is common, digital blood supply is always preserved by a complete deep palmar arch. Preprocedural patency tests have thus no added benefit to prevent ischemic complications of the hand. Finally, incompleteness of the SPA is not associated with a loss of upper-extremity function after transradial catheterization.
Assuntos
Cateterismo Cardíaco/métodos , Cateterismo Periférico/métodos , Avaliação da Deficiência , Dedos/irrigação sanguínea , Intervenção Coronária Percutânea/métodos , Artéria Radial , Atividades Cotidianas , Idoso , Angiografia , Cateterismo Cardíaco/efeitos adversos , Cateterismo Periférico/efeitos adversos , Feminino , Humanos , Isquemia/diagnóstico , Isquemia/etiologia , Isquemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Punções , Artéria Radial/diagnóstico por imagem , Artéria Radial/fisiopatologia , Fluxo Sanguíneo Regional , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
Galectins are an ancient family of ß-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis.
Assuntos
Doenças Cardiovasculares/metabolismo , Galectinas/metabolismo , Animais , Biomarcadores/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Humanos , Neovascularização Patológica , Neovascularização Fisiológica , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Transdução de SinaisRESUMO
OBJECTIVES: The aim of this study was to determine the effects of an acute myocardial infarction (AMI) on baseline and hyperemic flow in both culprit and nonculprit arteries. BACKGROUND: An impaired coronary flow reserve (CFR) after AMI is related to worse outcomes. The individual contribution of resting and hyperemic flow to the reduction of CFR is unknown. Furthermore, it is unclear whether currently used experimental models of AMI resemble the clinical situation with respect to coronary flow parameters. METHODS: Intracoronary Doppler flow velocity measurements were obtained in culprit and nonculprit arteries immediately after successfully revascularized ST-segment elevation myocardial infarction (n = 40). Stable patients without obstructive coronary artery disease served as control subjects and were selected by propensity-score matching (n = 40). Similar measurements in an AMI porcine model were taken both before and immediately after 75-min balloon occlusion of the left circumflex artery (n = 11). RESULTS: In the culprit artery, CFR was 36% lower than in matched control subjects (Δ = -0.9; 1.8 ± 0.9 vs. 2.8 ± 0.7; p < 0.001) with consistent observations in swine (Δ = -0.9; 1.5 ± 0.4 vs. 2.4 ± 0.9 for after and before AMI, respectively; p = 0.04). An increased baseline and a decreased hyperemic flow contributed to the reduction in CFR in both patients (baseline flow: Δ = +5 and hyperemic flow: Δ = -7 cm/s) and swine (baseline flow: Δ = +8 and hyperemic flow: Δ = -6 cm/s). Similar changes were observed in nonculprit arteries (CFR: 2.8 ± 0.7 vs. 2.0 ± 0.7 for STEMI patients and control subjects; p < 0.001). CFR significantly correlated with infarct size as a percentage of the left ventricle in both patients (r = -0.48; p = 0.001) and swine (r = -0.61; p = 0.047). CONCLUSIONS: CFR in both culprit and nonculprit coronary arteries decreases after AMI with contributions from both an increased baseline flow and a decreased hyperemic flow. The decreased CFR after AMI in culprit and nonculprit vessels is not a result of pre-existing microvascular dysfunction, but represents a combination of post-occlusive hyperemia, myocardial necrosis, hemorrhagic microvascular injury, compensatory hyperkinesis, and neurohumoral vasoconstriction.
Assuntos
Circulação Coronária , Vasos Coronários/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Idoso , Animais , Biópsia , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Modelos Animais de Doenças , Ecocardiografia Doppler , Feminino , Humanos , Hiperemia/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Pontuação de Propensão , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Suínos , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a metalloprotease that cleaves von Willebrand factor (VWF). There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in ST-elevation myocardial infarction (STEMI) patients. It is unclear whether this contributes to no reflow, infarct size, and intramyocardial haemorrhage (IMH). We aimed to determine the role of ADAMTS13 in STEMI patients and to investigate the benefits of recombinant ADAMTS13 (rADAMTS13) in a porcine model of myocardial ischaemia-reperfusion. METHODS AND RESULTS: In 49 consecutive percutaneous coronary intervention (PCI)-treated STEMI patients, blood samples were collected directly after through 7 days following PCI. Cardiac magnetic resonance was performed 4-6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 min. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI, in comparison with patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. In rADAMTS13-treated animals, no differences in infarct size, IMH, or formation of microthrombi were witnessed compared with controls. CONCLUSIONS: No correlation was found between VWF/ADAMTS13 and infarct size in patients. However, patients suffering from IMH had significantly higher VWF activity and lower ADAMTS13 activity. Intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischaemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow.
Assuntos
Proteína ADAMTS13/administração & dosagem , Proteína ADAMTS13/sangue , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/enzimologia , Idoso , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intra-Arteriais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Intervenção Coronária Percutânea , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Sus scrofa , Fatores de Tempo , Resultado do Tratamento , Fator de von Willebrand/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0157233.].
RESUMO
BACKGROUND: Microvascular injury (MVI) after coronary ischemia-reperfusion is associated with high morbidity and mortality. Both ischemia and reperfusion are involved in MVI, but to what degree these phases contribute is unknown. Understanding the etiology is essential for the development of new potential therapies. METHODS AND FINDINGS: Rats were divided into 3 groups receiving either 30 minutes ischemia, 90 minutes ischemia or 30 minutes ischemia followed by 60 minutes reperfusion. Subsequently hearts were ex-vivo perfused in a Langendorff-model. Fluorescence and electron microscopy was used for analysis of capillary density, vascular permeability and ultrastructure. Most MVI was observed after 30 minutes ischemia followed by 60 minutes reperfusion. In comparison to the 30' and 90' ischemia group, wall thickness decreased (207.0±74 vs 407.8±75 and 407.5±71, p = 0.02). Endothelial nuclei in the 30'-60' group showed irreversible damage and decreased chromatin density variation (50.5±9.4, 35.4±7.1 and 23.7±3.8, p = 0.03). Cell junction density was lowest in the 30'-60' group (0.15±0.02 vs 2.5±0.6 and 1.8±0.7, p<0.01). Microsphere extravasation was increased in both the 90' ischemia and 30'-60' group. CONCLUSIONS: Ischemia alone for 90 minutes induces mild morphological changes to the coronary microcirculation, with increased vascular permeability. Ischemia for 30 minutes, followed by 60 minutes of reperfusion, induces massive MVI. This shows the direct consequences of reperfusion on the coronary microcirculation. These data imply that a therapeutic window exists to protect the microcirculation directly upon coronary revascularization.
Assuntos
Circulação Coronária , Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Animais , Capilares , Comunicação Celular , Núcleo Celular/metabolismo , Cromatina/química , Modelos Animais de Doenças , Isquemia/fisiopatologia , Masculino , Microesferas , Reperfusão Miocárdica , Perfusão , Permeabilidade , Ratos , Ratos WistarRESUMO
AIMS: IFN-beta (IFNß) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNß hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNß treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNß signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS: In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/ß receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNß were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION: Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico , Artéria Femoral/imunologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/imunologia , Isquemia/tratamento farmacológico , Receptor de Interferon alfa e beta/imunologia , Animais , Anticorpos Monoclonais/imunologia , Aterosclerose/metabolismo , Circulação Colateral/efeitos dos fármacos , Modelos Animais de Doenças , Artéria Femoral/fisiologia , Membro Posterior/irrigação sanguínea , Isquemia/imunologia , Isquemia/metabolismo , Macrófagos/imunologia , Camundongos Knockout , Monócitos/metabolismoRESUMO
Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR)-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1). In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1) and reduced numbers of CD206-positive (M2) macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular patients.
Assuntos
Circulação Colateral/fisiologia , Galectina 2/fisiologia , Inflamação/fisiopatologia , Macrófagos/fisiologia , Monócitos/fisiologia , Animais , Antígenos CD40/biossíntese , Diferenciação Celular , Células Cultivadas , Circulação Colateral/efeitos dos fármacos , Células Dendríticas/metabolismo , Galectina 2/deficiência , Galectina 2/genética , Galectina 2/farmacologia , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/biossíntese , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/fisiologia , Macrófagos/classificação , Macrófagos/efeitos dos fármacos , Receptor de Manose , Lectinas de Ligação a Manose/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Fenótipo , Ligação Proteica/efeitos dos fármacos , Células RAW 264.7 , Receptores de Superfície Celular/biossíntese , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais , Linfócitos T/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: A total of 40% to 50% of patients with ST-segment-elevation myocardial infarction develop microvascular injury (MVI) despite angiographically successful primary percutaneous coronary intervention (PCI). We investigated whether hyperemic microvascular resistance (HMR) immediately after angiographically successful PCI predicts MVI at cardiovascular magnetic resonance and reduced myocardial blood flow at positron emission tomography (PET). METHODS AND RESULTS: Sixty patients with ST-segment-elevation myocardial infarction were included in this prospective study. Immediately after successful PCI, intracoronary pressure-flow measurements were performed and analyzed off-line to calculate HMR and indices derived from the pressure-velocity loops, including pressure at zero flow. Cardiovascular magnetic resonance and H2 (15)O PET imaging were performed 4 to 6 days after PCI. Using cardiovascular magnetic resonance, MVI was defined as a subendocardial recess of myocardium with low signal intensity within a gadolinium-enhanced area. Myocardial perfusion was quantified using H2 (15)O PET. Reference HMR values were obtained in 16 stable patients undergoing coronary angiography. Complete data sets were available in 48 patients of which 24 developed MVI. Adequate pressure-velocity loops were obtained in 29 patients. HMR in the culprit artery in patients with MVI was significantly higher than in patients without MVI (MVI, 3.33±1.50 mm Hg/cm per second versus no MVI, 2.41±1.26 mm Hg/cm per second; P=0.03). MVI was associated with higher pressure at zero flow (45.68±13.16 versus 32.01±14.98 mm Hg; P=0.015). Multivariable analysis showed HMR to independently predict MVI (P=0.04). The optimal cutoff value for HMR was 2.5 mm Hg/cm per second. High HMR was associated with decreased myocardial blood flow on PET (myocardial perfusion reserve <2.0, 3.18±1.42 mm Hg/cm per second versus myocardial perfusion reserve ≥2.0, 2.24±1.19 mm Hg/cm per second; P=0.04). CONCLUSIONS: Doppler-flow-derived physiological indices of coronary resistance (HMR) and extravascular compression (pressure at zero flow) obtained immediately after successful primary PCI predict MVI and decreased PET myocardial blood flow. CLINICAL TRIAL REGISTRATION URL: http://www.trialregister.nl. Unique identifier: NTR3164.