Endogenous G-CSF and CD34+ cell mobilization after acute myocardial infarction

BACKGROUND: Several reports showed an increase of CD34(+) stem/progenitor cell count early after an acute myocardial infarction (AMI), suggesting a contribution of bone marrow cells in myocardial regeneration after the acute event. Nevertheless, at present plasma mediators of CD34(+) cell mobilization from bone marrow to peripheral blood in patients with AMI are poorly understood. Aim of our study was to establish the impact of different well-known mobilizing cytokines on spontaneous stem cell mobilization in patients with different ischemic heart syndromes, such as the AMI and the chronic stable angina (CSA), compared to healthy controls. METHODS: In 16 patients with AMI, 18 with CSA and 22 healthy blood donors the concentration of CD34(+) cells, and mobilizing cyokines (G-CSF, SCF, VEGF, SDF1-alpha) were assessed. RESULTS: The peak number of circulating CD34(+) cells in AMI patients (8.58+/-2.08 cells/microl) was higher than that observed in patients with CSA (3.41+/-0.56 cells/microl, p=0.0061) or in healthy controls (2.18+/-0.35 cells/microl, p<0.001). However endogenous G-CSF was significantly higher in the serum of patients with AMI compared to CSA patients and to controls and in CSA patients compared to controls. Interestingly, as regards VEGF, while this cytokine was increased in AMI with respect to control and CSA group, the latter showed a significantly lower concentration with respect to controls. Finally SDF-1 alpha was higher in AMI patients with respect to controls. CD34(+) cells were significantly correlated to G-CSF (directly) and to SCF (inversely) in patients with AMI. CONCLUSION: In the present study, we have demonstrated for the first time that the spontaneous mobilization of CD34(+) cells into the peripheral blood of patients with AMI is significantly correlated to endogenous G-CSF. Considering recent data suggesting a potential favourable effect of circulating CD34(+) cells on left ventricular function, the present evidence of a correlation between endogenous G-CSF and CD34(+) cell levels supports the pharmacological administration of G-CSF as a non-invasive option for regeneration of myocardial tissue after AMI.     

Alloantigen presenting function of normal human CD34+ hematopoietic cells

The identification of the CD34 molecule, expressed almost exclusively on human hematopoietic stem cells and committed progenitors, and the development of CD34-specific monoclonal antibodies have made procurement of relatively pure populations of CD34+ marrow cells for autologous transplantation feasible. Characterization of the immunogenicity of CD34+ marrow cells may facilitate the design of successful strategies to use these cells for allogeneic transplantation. CD34+ marrow cells from normal volunteers were enriched to greater than 98% purity by immunoaffinity chromatography on column followed by fluorescence-activated cell sorting. Purified CD34+ cells were tested for expression of HLA-DR and other accessory molecules, and function in hematopoietic colony growth and mixed leukocyte culture (MLC) assays. Greater than 95% CD34+ cells were positive for HLA-DR and 74% +/- 10% were highly positive for CD18, the common beta-chain of a leukointegrin family. CD34+/CD18- cells were small, agranular lymphocytes which contained the majority of precursors for colony-forming cells detected in long-term cultures. They produced almost no stimulation of purified T cells from HLA-DR-incompatible individuals in bulk MLC or in limiting dilution assay. In contrast, CD34+/CD18+ cells were large, were enriched for cells forming mixed colonies in short- but not long-term assays, and were capable of stimulating allogeneic T cells. CD86, a natural ligand for the T-cell activation molecule CD28, was coexpressed with CD18 in 6% +/- 3% of CD34+ cells. CD34+/CD86+ cells, but not CD34+/CD86- cells, exhibited strong alloantigen presenting function. Thus, pluripotent hematopoietic activity and alloantigen presenting function are attributes of distinct subsets of CD34+ marrow cells. CD34+/CD18- or CD34+/CD86- cells may be more effective than either the whole CD34+ population or unseparated marrow in engrafting allogeneic recipients and may also facilitate induction of tolerance.     

外周血CD34+细胞数在有危险因素的急性心肌梗死患者中的变化

目的:健康人外周血中前体CD34+细胞数目很少,但在急性缺血时,这些细胞可以从骨髓动员到外周血。研究发现,有心血管危险因素的患者,外周血CD34+细胞数目是减少的。然而,有心血管事件危险因素的患者,急性心肌梗死是否能促进CD34+细胞的动员,目前尚不完全清楚。方法:42例心血管事件危险因素患者被分成两组:急性心肌梗死组20例,无冠状动脉粥样硬化性心脏病组22例。同时,没有冠心病及任何心血管病危险因素的16例自愿者入选为健康对照组。流式细胞仪分析外周血CD34+细胞数目。结果:急性心肌梗死组,外周血CD34+细胞的数目为（1.915±0.667）/μl,与健康对照组（1.925±0.629）/μl值比较,P=0.963。无冠状动脉粥样硬化性心脏病组,外周血CD34+细胞的数目为（1.804±0.605）/μl。在心肌梗死组与无冠心病组间比较,外周血CD34+细胞的数目无明显不同（P=0.575）。而且,患者并存心血管危险因素的多少与外周血中CD34+细胞水平似乎成反向相关。结论:有心血管事件危险因素患者,发生急性心肌梗死后外周血前体CD34+细胞未发现增加。由此提示心血管病危险因素可能抑制急性缺血诱导的前体CD34+细胞的动员,且与危险因素多少相关。     

Implantation of cardiac progenitor cells using self-assembling peptide improves cardiac function after myocardial infarction

Implantation of various types of cells into the heart has been reported to be effective for heart failure, however, it is unknown what kinds of cells are most suitable for myocardial repair. To examine which types of cells are most effective, we injected cell–Puramatrix™ (PM) complex into the border area and overlaid the cell–PM patch on the myocardial infarction (MI) area. We compared cardiac morphology and function at 2 weeks after transplantation. Among clonal stem cell antigen-1 positive cardiac progenitors with PM (cSca-1/PM), bone marrow mononuclear cells with PM (BM/PM), skeletal myoblasts with PM (SM/PM), adipose tissue-derived mesenchymal cells with PM (AMC/PM), PM alone (PM), and non-treated MI group (MI), the infarct area of cSca-1/PM was smaller than that of BM/PM, SM/PM, PM and MI. cSca-1/PM and AMC/PM attenuated ventricular enlargement and restored cardiac function in comparison with MI. Capillary density in the infarct area of cSca-1/PM was higher than that of other five groups. The percentage of TUNEL positive cardiomyocytes in the infarct area of cSca-1/PM was lower than that of MI and PM. cSca-1 secreted VEGF and some of them differentiated into cardiomyocytes and vascular smooth muscle cells. These results suggest that transplantation of cSca-1/PM most effectively prevents cardiac remodeling and dysfunction through angiogenesis, inhibition of apoptosis and myocardial regeneration.     

Enhanced functional response of CD133+ circulating progenitor cells in patients early after acute myocardial infarction

Aims: Circulating progenitor cells (PC) may contribute to myocardialrecovery following infarction. Growth factors including VEGFare produced during ischaemia and stimulate PC release and activation.In this study, we focused on the functional chemotactic responseof PC to VEGF in subjects early after myocardial ischaemia. Methods and results: Number and phenotype of PC were characterized using flow-cytometry.CD133⁺PC were isolated from peripheral blood using positiveMACS isolation. The chemotactic response towards members ofthe VEGF family (VEGF-A, PlGF-1, and VEGF-E) was analysed inthree groups: (i) early period following acute myocardial infarction(days 2–4) treated with primary PCI (AMI) (n = 35), (ii)stable coronary artery disease (CAD) (n = 35), and (iii) controls(CTR) (n = 20). CD133⁺PC number was 2-fold higher in AMI whencompared with CAD and CTR (P = 0.0001), whereas CAD was notdifferent from CTR. The chemotactic response of CD133⁺PC toVEGF-A, PlGF-1, and VEGF-E was significantly enhanced (2-fold)in AMI when compared with CAD (P = 0.0001). While the increaseof the VEGFR-1-mediated/PlGF-triggered response was rapid (2days following infarction), the VEGFR-2-mediated/VEGF-E-triggeredresponse was maximally increased on day 4 post-AMI, thus correlatingwith the kinetics of maximal inflammatory activation reflectedby increased CRP levels (P = 0.019). Conclusion: The enhanced chemotactic response of CD133⁺PC following myocardialinfarction represents a novel principle potentially involvedin cardiovascular repair early after myocardial infarction.Acute inflammatory processes are closely associated with thisincreased cellular function.     

Outcome after cardiac arrest during acute myocardial infarction

A community-wide study of acute myocardial infarction (AMI) was conducted in all 16 acute-care general hospitals in the Worcester, Massachusetts, metropolitan area during the years 1975, 1978, 1981 and 1984. The in-hospital and long-term prognoses of 667 patients with AMI complicated by cardiac arrest (CA) was compared with that of 2,596 AMI patients without CA. The incidence of CA complicating AMI was similar (21%) during each of the 4 study years. Among patients with AMI who had CA, 36% had CA within the first day of hospitalization and 48% within the first 2 days. The in-hospital case-fatality rate was much higher for AMI patients with CA (78%) than for those without CA (4%) (p less than 0.001). For patients discharged alive from the hospital, a trend toward a higher mortality rate was seen at 1 and 2 years after hospital discharge for patients with CA; however, long-term survival rates were not significantly different between AMI patients with and without CA. When time of occurrence of CA relative to in-hospital survival was examined, patients with early CA (within 1 day or within 2 days of hospital admission) had a significantly greater in-hospital survival (39% and 34%) than did those with late CA (after 1 day or after 2 days) (13% and 12%). Similarly, patients discharged from the hospital after early CA had a significantly better chance of long-term survival than patients discharged after late CA.     

Relationship between cardiac sympathetic function and baroreceptor sensitivity after acute myocardial infarction.

The relationship between baroreceptor sensitivity (BRS) and cardiac sympathetic nerve function after acute myocardial infarction (AMI) was investigated in 34 patients. BRS was measured during the Valsalva maneuver and cardiac sympathetic function was assessed by the washout rate (WR) of I-123 meta-iodo-benzyl guanidine (123I-MIBG) with planar image (global WR) and polar map analysis (regional WR). Gated left ventricular ejection fraction (LVEF) measured by left ventriculography as a parameter of ventricular function was measured with quantitative gated SPECT (QGS). The gated LVEF correlated with global WR (r=-0.36, p=0.034) and regional WR of normal area (r=-0.46, p=0.006), but not with BRS, although BRS correlated with global WR (r=-0.43, p=0.015) and regional WR of normal area (r=-0.72, p<0.0001). After AMI, baroreceptor function is linked to sympathetic activation, as elucidated by the regional WR of normal area, which suggests that separation of the infarcted area from the non-infarcted myocardium is necessary for evaluating sympathetic activation after AMI and that the regional kinetics of 123I-MIBG in the normal area are a more suitable marker of activated cardiac nerve function than global 123I-MIBG kinetics.     

福辛普利对急性心肌梗死患者左心功能及重塑过程的影响

目的 评价福辛普利对急性心肌梗死（AMI）患者左心功能和左心室重塑的影响。方法 对30例初次前壁AMI患得,发病12h内开始应用福辛普利治疗,分别于AMI 性期和恢复期进行Killip心功能评价和二维超声心动图（2DE）检查。结果 不伴有明显血流动力学障碍的AMI患者,早期应用福辛普利可减轻左心室扩张,改善患者左心功能。     

急性心肌梗死急诊介入治疗对心功能的影响

目的：探讨急性心肌梗死（AMI）后行急诊经皮冠状动脉成形术（PCI）和行择期PCI治疗的近期疗效和安全性。方法：248例AMI患者被分为两组,急诊PCI组19例,择期PCI组229例。对两组患者住院期间用药情况及PCI后心功能进行分析。结果：两组患者术后心功能各项指标均明显改善,与择期PCI组相比,急诊PCI组左室射血分数明显提高[（52.7±6.3）%比（54.1±2.7）%],左室舒张末内径明显减小[（48.8±1.7）mm比（47.8±2.4）mm],P均〈0.05。结论：急性心肌梗死后行急诊经皮冠状动脉成形术是一种安全有效的介入性治疗手段,可以防止再梗死和心肌缺血,进一步改善心功能。     

自体骨髓间充质干细胞移植对急性心肌梗死后心功能的影响

目的观察骨髓间充质干细胞（MSCs）经冠脉移植对急性心肌梗死后心功能的影响。方法24只日本大耳白兔,随机分为MSCs移植组（n=12）和培养液对照组（n=12）。从兔股骨抽取骨髓,体外培养MSCs。通过结扎左冠前降支建立急性心肌梗死模型。冠脉结扎后7d,细胞移植组和对照组直接经冠脉注入MSCs和培养液。于心肌梗死前、细胞移植前、细胞移植后1、2和4周对兔进行超声心动图检查。移植后4周处死动物,进行BrdU和第Ⅷ因子相关抗原免疫组化检测。结果移植后2周,MSCs移植组在射血分数（LVEF）和左室收缩末直径（LVESD）方面与移植前和对照组相比有显著改善（P<0.05）;移植4周后,LVEF、LVESD和左室舒张末直径（LVEDD）在MSCs移植组与移植前及对照组相比均有显著改善（P<0.05）。免疫组化检测发现,MSCs移植组BrdU染色阳性,血管计数较对照组明显增多（P<0.01）。结论经冠脉移植的MSCs可在梗死区心肌内存活并逐渐分化成心肌样细胞,促进毛细血管生成,显著改善心功能。     

急性脑梗死后内源性G-CSF和CD34+细胞动员关系的研究

目的研究急性脑梗死患者发病后自身干细胞（外周血CD34^＋细胞）及其相关的粒细胞集落刺激因子（G-CSF）水平变化。方法采用对照研究,用流式细胞仪检测健康对照组和急性脑梗死组发病后第1天和第7天中造血干细胞（外周血CD34^＋细胞）,同时用ELISA法检测内源性G-CSF的水平变化。结果急性脑梗死后的第1天和第7天,患者体内外周血CD34^＋细胞和内源性G-CSF的水平有不同程度的升高,并且患者中外周血CD34^＋细胞与血清内源性G-CSF水平升高存在正相关（r=0.320）。结论急性脑梗死早期,患者体内外周血CD34^＋细胞水平和内源性G-CSF水平均升高,并且存在正相关。     

Apelin enhances cardiac neovascularization after myocardial infarction by recruiting aplnr+ circulating cells

Rationale: Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development. However, the role of apelin signaling in stem cell recruitment after ischemia is unknown. Objective: To investigate the role of apelin signaling in recruitment after ischemia. Methods and Results: Aplnr was specifically expressed in circulating cKit+/Flk1+ cells but not in circulating Sca1+/Flk1+ and Lin+ cells. cKit+/Flk1+/Aplnr+ cells increased significantly early after myocardial ischemia but not after hind limb ischemia, indicative of an important role for apelin/Aplnr in cell recruitment during the nascent biological repair response after myocardial damage. In line with this finding, apelin expression was upregulated in the infarcted myocardium. Injection of apelin into the ischemic myocardium resulted in accelerated and increased recruitment of cKit+/Flk1+/Aplnr+ cells to the heart. Recruited Aplnr+/cKit+/Flk1+ cells promoted neovascularization in the peri-infarct area by paracrine activity rather than active transdifferentiation, resulting into cardioprotection as indicated by diminished scar formation and improved residual cardiac function. Aplnr knockdown in the bone marrow resulted in aggravation of myocardial ischemia-associated damage, which could not be rescued by apelin. Conclusions: We conclude that apelin functions as a new and potent chemoattractant for circulating cKit+/Flk1+/Aplnr+ cells during early myocardial repair, providing myocardial protection against ischemic damage by improving neovascularization via paracine action.     

Daily exercise and bone marrow-derived CD34+/133+ cells after myocardial infarction treated by bare metal stent implantation.

BACKGROUND: The aims of the present study were to explore the mobilization of bone marrow-derived CD34(+)/133(+) cells in patients with acute myocardial infarction (AMI) and bare metal stent implantation who participated in daily exercise training, and associations with exercise capacity and restenosis. METHODS AND RESULTS: Participants comprised 23 Japanese men with AMI (Killip 1) who had been treated with a bare metal stent. All patients were advised to walk for 30-60 min/day, at least 4 times per week starting at 11 days after AMI, and were instructed to record the amount of time spent walking each day. At 10 days and then at 3 months after onset of AMI, symptom-limited cardiopulmonary exercise tests were performed and the number of CD34(+)/133(+) cells in the peripheral blood were measured by fluorescence-activated cell sorter analysis. At 3 months after AMI, the number of CD34(+)/133(+) cells and oxygen consumption at anaerobic threshold were higher in the high exercise group (ie, exercise duration >4 h/week) than the low exercise group (ie, exercise duration <2 h/week). At 3 months after AMI, the number of CD34(+)/133(+) cells significantly correlated with oxygen consumption at the anaerobic threshold (p=0.002). CONCLUSION: Moderate daily exercise of >4 h/week increases exercise capacity and the number of circulating CD34(+)/133(+) cells at 3 months after AMI.     

Regional cardiac adrenergic function using I-123 meta-iodobenzylguanidine tomographic imaging after acute myocardial infarction

The effect of acute myocardial infarction (AMI) on regional cardiac adrenergic function was studied in 27 patients mean +/- standard deviation 10 +/- 4 days after AMI. Regional adrenergic function was evaluated noninvasively with I-123 meta-iodobenzylguanidine (MIBG) using a dedicated 3-detector tomograph. Four hours after its administration, there was reduced MIBG uptake in the region of infarction, 0.38 +/- 0.31 counts/pixel/mCi x 103 compared with 0.60 +/- 0.30 counts/pixel/mCi x 103 and 0.92 +/- 0.35 counts/pixel/mCi x 103 in the zones bordering and distant from the infarct area, respectively, p less than 0.001. In all patients, the area of reduced MIBG uptake after 4 hours was more extensive that the associated thallium-201 perfusion defect with defect scores of 52 +/- 22 and 23 +/- 18%, respectively, p less than 0.001. After anterior wall AMI, the 4-hour MIBG defect score was 70 +/- 13% and the degree of mismatch between myocardial perfusion and MIBG uptake was 30 +/- 9% compared with 39 +/- 17 and 21 +/- 17% after inferior AMI, p less than 0.001 and p = 0.016, respectively. The 4-hour MIBG defect score correlated inversely with the predischarge left ventricular ejection fraction, r = -0.73, p less than 0.001. Patients with ventricular arrhythmia of greater than or equal to 1 ventricular premature complexes per hour, paired ventricular premature complexes or ventricular tachycardia detected during the late hospital phase had higher 4-hour MIBG defect scores, 62.5 +/- 15.0%, than patients with no detectable complex ventricular ectopic activity and a ventricular premature complex frequency of less than 1 per hour, 44.6 +/- 23.4%, p = 0.036.(ABSTRACT TRUNCATED AT 250 WORDS)