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Posts Tagged ‘Age’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) is used to reconstitute flow into post-stenotic, chronically underperfused myocardium. This post-stenotic myocardium consists of connective tissue scars, dying cardiomyocytes, and hypo-active or chronically hibernating myocardium with microvascular disturbances due to microthrombi and decreased capillary density. When bulk flow is successfully reconstituted by CABG or PTCA, the gradual recovery of microcirculation is considered as decisive for the recovery of mechanical function of surviving post-stenotic myocardium. Traditionally, neovascularization of disturbed microcirculation was considered to result exclusively from the proliferation, migration, and remodeling of fully differentiated endothelial cells (ECs) derived from pre-existing blood vessels. Recently, however, it was demonstrated that circulating, bone marrow-derived endothelial progenitor cells (EPCs) may home to sites of postnatal neovascularization and differentiate into ECs in situ, which is called “vasculogenesis”. Vascular trauma, as it occurs during surgical procedures, or inflammation leads to a cascade of events that result in the chemoattraction of inflammatory cells or other cell types to the site of injury. These blood-borne cells produce pro-angiogenic factors that, in turn, attract other cell types such as circulating EPCs. Systemic inflammatory responses have been described after cardiac surgery with cardiopulmonary bypass (CPB). Contact of the blood components with the artificial surface of the extracorporeal circuit, ischemia-reperfusion injury, endotoxemia, and operative trauma are possible causes for this phenomenon. Trauma has been considered as the critical stimulus for the mobilization of EPCs and proangiogenic vascular endothelial growth factor (VEGF) during CABG. It has been speculated that this mobilization may contribute to the revascularization of injured tissue, which would be of great clinical relevance for a successful outcome of CABG. Presently, there is a strong trend to perform CABG in patients of advanced age. However, experimental data indicate impaired neoangiogenesis in ischemic tissues and impaired re-endothelialization of vascular lesions as a function of advanced age. The mechanisms for this age-dependent impairment of vascular repair are largely unknown. Therefore, we analyzed the influence of age on CABG-induced mobilization of EPCs and cytochemokines with angiogenesis-modulating potential in a cohort of consecutive patients with stable coronary artery disease (CAD) scheduled for elective CABG. Probably, several types of endothelial precursor or progenitor cells have angiogenic potential after homing into traumatic tissue. Therefore, we used two phenotypic markers (CD34 and AC133 or CD133), which are expressed in all EPC types, but in the case of AC133, not in differentiated ECs. This was done to exclude from our analysis any mature or dying ECs with doubtful angiogenic capacity, potentially released from damaged vessels in old patients. In this analysis, we demonstrate that the preoperative number of circulating EPCs in patients with stable CAD is reduced with increasing age, together with decreased plasma VEGF levels. During CABG, mobilization of circulating EPCs could be detected in all patients, but this mobilization remained on a persistently lower level in the older patient group, suggesting that the responsiveness for mobilization of EPCs is impaired with age. Optimized strategies for ex-vivo expansion of those cells might be especially required in the elderly, if transplantation of these cells into poststenotic tissue will develop as a future co-therapy to existing interventions of revascularization.

This study demonstrated that the basal number of circulating EPCs in patients with stable CAD is decreased with increasing age. Furthermore, plasma VEGF levels are reduced with increasing age. This age-associated decrease could not be explained by higher prevalences of other risk factors, such as male gender, diabetes mellitus, hypertension, or hyperlipoproteinemia at older ages nor by any differences in left ventricular function or New York Heart Association classes. The operative trauma of complex cardiac surgery with CPB induced a mobilization in EPCs/ lymphocytes and EPCs/blood in all patients, but this mobilization remained on a persistently lower level in the older patient group, which could not be explained by any differences in the operative procedure (time on CPB, cross-clamping time, or number of grafts) or in the operation-induced increase in cytochemokines with a reported potency for modulation of angiogenesis (IL-6, IL-8, and IL-10). Similar age-associated losses in the number of circulating endothelial-related progenitor cells in patients undergoing CABG have not been reported so far. In 45 male subjects without a history of cardiovascular disease, the Framingham risk score and impairment of endothelium-mediated, flow-dependent brachial artery dilation were strong predictors of depressed numbers in circulating progenitor cells with colony-forming capacity. In a mixed group of healthy probands and CAD patients, Vasa et al. reported age-associated losses in circulating cells positive for CD34_ and KDR_, which may include progenitor cells and mobilized ECs. In their cohort, smoking was a strong predictor of lowered values in CD34_/KDR_ cells, independent of age. In the patients, self-reported smoking status, which is notoriously unreliable before cardiac surgery, could not be verified by interrogations of spouses or relatives. This may explain why we could not detect an effect of smoking on circulating EPCs. The reasons for the age-associated losses in circulating EPCs remain unknown at present. In this study, there was an age-independent correlation of circulating EPCs with plasma VEGF levels. Circulating or transplanted EPCs contribute to post-ischemic neovascularization in animal experiments and patients, and angiogenic factors like VEGF and PlGF are involved in this neovascularization. In animals, advanced age is associated with attenuated post-ischemic neovascularization and attenuated local induction of VEGF. Similarly, arterial re-endothelialization after vascular trauma is attenuated in old animals in which trauma-induced local VEGF expression is lower and local VEGF supplementation rescues vascular healing. Experimental elevation of plasma VEGF in mice by inoculation with adenoviral vectors induced rapid mobilization of endothelial precursor cells. Therefore, it is tempting to propose that lowered VEGF levels in the elderly patients are the reason for lowered circulating EPCs. However, this causality remains to be proven for basal steady-state levels, and the cause of depressed circulating VEGF levels in elderly patients remains unknown. In experimental studies, hypoxia-inducible factor-1 stabilization by hypoxia, which mediates hypoxic VEGF expression, is attenuated in cells from old animals. This might be relevant for the attenuated and retarded CABG-induced activation of plasma VEGF in older patients. However, this may be less relevant for the age-associated lowering in basal VEGF levels before surgery. Local and systemic inflammation by vascular trauma is considered an important contributor of post-ischemic neovascularization. In the patients, the operative trauma resulted in a substantial mobilization of cytochemokines with angiogenesis-modulating potential, except for IL-18 and PlGF. These observations are in agreement with previous reports. Although none of these activated factors could be directly correlated with the individual increase in EPCs during and after the operation in the patients, it is reasonable to assume that the complex spectrum of inflammatory activation is contributing to the mobilization of surgery-induced EPCs. Similar conclusions have been derived from observations on transient mobilization of KDR_/AC133_ cells in patients after burns or CABG. The kinetics of mobilization in that study differed somewhat from our observations, but the two studies are not directly comparable owing to differences in progenitor cell analysis. It is remarkable that the substantial inflammatory activation during surgery in our study could not abolish age-associated differences in EPC levels. The decline in the fraction of lymphocytes/leukocytes after CPB down to one-quarter that of the baseline value at 12 h after CPB most likely reflects substantial homing of lymphocytes into tissues in response to the systemic inflammatory activation induced by CPB. Homing must also contribute to the decline of circulating EPCs/ blood during this time. Therefore, circulating EPC levels underestimate the amount of EPC mobilization. However, quantification of lymphocyte or EPC homing could not be obtained in our patients. Application of different populations of EPCs or other mononuclear bone marrow cells improves postischemic organ function and microcirculation in animals and patients. However, it is not clear whether the surgery-induced mobilization of EPCs is sufficient for such a contribution. Furthermore, it is unclear whether the EPCs in elderly patients have the same angiogenic potential compared with those of younger patients. The EPCs collected from the circulation can be amplified in vitro. The co-application of amplified EPCs, together with native artery recanalization or bypass grafting, probably will develop as a therapeutic option in the future. The experimental data suggested that such co-therapy is especially desirable in elderly patients. The data suggested that mobilization of such cells for therapeutic application might be more difficult with an increasing age of patients. The inflammatory activation by complex CABG does not offset this age-associated lowering. Therefore, further studies are required for a better understanding of optimized strategies for recruitment, ex-vivo expansion, and retransplantation strategies involving EPCs in aging patients.

Abbreviations and Acronyms:

APC _ allophycocyanin

CABG _ coronary artery bypass grafting

CAD _ coronary artery disease

CPB _ cardiopulmonary bypass

EC _ endothelial cell

EPC _ endothelial progenitor cell

KDR _ kinase insert domain containing receptor

IL _ interleukin

PlGF _ placental growth factor

PTCA _ percutaneous transluminal coronary angioplasty

VEGF _ vascular endothelial growth factor

Source reference:

http://www.sciencedirect.com/science/article/pii/S0735109703012725

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