Circulating CD34⁺ progenitor cells and growth factors in patients treated with PCI for acute myocardial infarction or stable angina pectoris.

OBJECTIVE: To differentiate the effect of myocardial infarction from the effect of percutaneous coronary intervention (PCI) on the circulatory profiles of CD34(+) cells and growth factors in patients with ST-elevation myocardial infarction (STEMI). METHODS: Twenty patients with STEMI and 10 with angina pectoris (AP) were included. All were treated with PCI. Blood was drawn before PCI in the AP group, and after 3 and 12 hours, and 1, 3, 5, 7 and 14 days after PCI in both groups. In STEMI patients, correlation analyses between TIMI myocardial perfusion grade (TMP-grade) and circulating CD34(+) cells were also assessed. RESULTS: Circulating CD34(+) cells increased from day 1 to days 5 and 7 after PCI only in STEMI patients (p < 0.05). Between-group analyses revealed a borderline significant difference in change in SDF-1α concentrations from 3 h to 14 days after PCI (p = 0.05), and SDF-1α was significantly higher in STEMI patients 14 days after PCI (p < 0.05). In both groups, peak HGF concentrations were observed 3 h after PCI, whereas IGF-1 increased in AP patients only, 3 h after PCI (p < 0.005). TIMI perfusion grade was negatively correlated to the circulating number of CD34(+) cells 5 days after PCI (r =-0.69, p < 0.005). CONCLUSION: After PCI, STEMI patients have significantly higher numbers of circulating CD34(+) progenitor cells compared to patients with AP. STEMI results in a significant increase in SDF-1α after 14 days, and the increase at this time may indicate a favorable environment for progenitor cell therapy.

Cell treatment after acute myocardial infarction prevents early decline in circulating IGF-1.

OBJECTIVES: To examine the influence of intracoronary autologous bone marrow cell transplantation after acute myocardial infarction on circulating growth factors and their relationship to left ventricular function. METHODS: Circulating insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), stromal derived factor-1-alpha (SDF-1α), and transforming growth factor beta (TGF-ß) were measured in patients randomized to cell treatment or control, in the ASTAMI study. Autologous cells were injected intracoronary on day 6; blood was sampled on days 5, 9, and at three months. Left ventricular ejection fraction was recorded by electrocardiogram-gated single photon emission computed tomography at six months. RESULTS: Only change in IGF-1 from baseline to three months differed between groups (p = 0.024). A weak but significant correlation was found between left ventricular ejection fraction and the averaged IGF-1 concentrations of all patients (r = 0.24, p = 0.02). Patients with IGF-1 above or below median (102 ng/ml) had a left ventricular ejection fraction of 52.3% (±11.4) versus 46.4% (±12.2) respectively (p = 0.017). CONCLUSIONS: Intracoronary bone marrow cell treatment after myocardial infarction attenuates a reduction in circulating IGF-1. IGF-1 levels over time were weakly, but significantly correlated to left ventricular ejection fraction.

The profile of circulating metalloproteinases after PCI in patients with acute myocardial infarction or stable angina.

UNLABELLED: The objective of this study was to investigate the time profiles of plasma matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases (TIMP-1 and -2), and pregnancy associated plasma protein A (PAPP-A) in patients with acute myocardial infarction (AMI), compared to patients with stable angina pectoris (AP), all treated with percutaneous coronary intervention (PCI) with stent. METHODS: Twenty patients with ST-elevation AMI and 10 patients with AP were included. Serum levels of the selected markers were measured before (only in the AP group) PCI, and 3 and 12 hours, 1,3,5,7 and 14 days after PCI in all patients. RESULTS: The levels of MMP-9 and MMP-9/TIMP-1 ratio, being higher in the AMI group compared to the AP group at 3 hours, were significantly reduced 1 day after PCI (p<0.01 for both), sustaining during the study period. A similar pattern was observed in PAPP-A levels with significant reduction after 12 hours (p<0.01). In the AP group only smaller changes were observed, except from an increase in PAPP-A levels from before PCI to 3 hours (p<0.001), followed by significant reduction. No significant correlations were found between any of the measured biomarkers and the infarct size, either evaluated in the acute phase or after 6 weeks. CONCLUSION: AMI patients treated with PCI had an early significant reduction in MMP-9, MMP-9/TIMP-1 ratio and PAPP-A when compared to patients with stable angina pectoris treated with PCI. This indicates that the metalloproteinases may be involved in the early phase of the plaque rupture process, with limited influence of the PCI procedure.

Age and stress related phenotypical changes in bone marrow CD34+ cells.

OBJECTIVE: Phenotypical changes in the human bone marrow (BM) due to age and stress have not so far been properly addressed in the literature. In the present study, we compared CD34(+) BM cells between older and young volunteers. The influence of stress on CD34(+) cell phenotype in older patients was investigated in an age-matched group with acute myocardial infarction (AMI). Cytokines thought to influence BM CD34(+) cell homeostasis were also analysed. MATERIAL AND METHODS: BM mononuclear cells of 10 older volunteers and of 7 young volunteers (18-25 years), as well as 22 AMI patients, were analysed by flow cytometry for the following markers: CD34, CD38, CD117 (c-kit) and CD133. Blood samples were analysed for CRP, IL-6, MCP-1, IL-8, MMP-9, TIMP-1 and TNFalpha by ELISA methods. RESULTS: Significantly higher numbers of CD34(+) CD38(-) cells (both absolute and relative) were observed in older volunteers than in young volunteers and AMI patients. Higher numbers of immature progenitors, namely CD34(+)CD38(-) cells and CD34(+)CD38(-)CD117(+)CD133(+) cells, were observed among older volunteers compared to the other groups. However, the relative number of CD34(+) cells lacking CD38 expression or expressing CD133 was higher in the old volunteers and AMI patients. None of the circulating factors investigated correlated with any of the cell population yields. CONCLUSION: In this study, we found that the absolute and relative numbers of BM CD34(+)CD38(-) progenitor cells increase with age. The increment is attenuated in patients with AMI.

Cardiac accumulation of bone marrow mononuclear progenitor cells after intracoronary or intravenous injection in pigs subjected to acute myocardial infarction with subsequent reperfusion.

OBJECTIVE: The purpose of the present study was to compare the efficacy of intracoronary and intravenous injection of autologous progenitor cells for homing to the acutely infarcted but reperfused myocardium in pigs. METHODS: Myocardial infarction was induced in 11 anesthetized pigs by 60-min balloon inflation in the mid LAD. After balloon deflation, reperfusion was verified and autologous CD31(+) progenitor cells, or bone marrow mononuclear cells, labeled with PKH67, were injected either intracoronarily (n=6) or intravenously (n=3). By autopsy, 4-5 days after induction of infarction, tissue from the heart and other organs was obtained for fluorescence microscopy. RESULTS: In the heart, PKH(+) cells were detected throughout the reperfused infarcted myocardium, and the number of PKH(+) cells was significantly higher after intracoronary than after intravenous injection (3.2+/-0.55 vs. 0.33+/-0.17 cells/high-power field/10(6) cells injected, P=.01). Few PKH(+) cells were detected in the spleen, lung, mesenteric lymph node, and bone marrow. In an additional animal with a coil placed in the mid LAD, progenitor cells were not detected in the infarcted myocardium or in the normal myocardium. CONCLUSION: Autologous mononuclear and CD31(+) cells from bone marrow accumulated in the infarcted myocardium when injected intracoronarily or intravenously after established reperfusion, and the accumulation of cells was significantly greater after intracoronary injection than after intravenous injection. Accumulation of PKH(+) cells did not appear in the normal myocardium or in the nonreperfused infarcted myocardium. PKH(+) cells were detected in spleen, lung, and bone marrow but to a lesser degree than in the infarcted myocardium.

Endothelin receptor antagonism attenuates cardiomyocyte apoptosis after induction of ischemia in rats.

OBJECTIVE: Apoptosis has recently been implicated as a process that may contribute to loss of cardiomyocytes and to adverse myocardial remodeling in congestive heart failure (CHF). We investigated to what extent myocardial ischemia and CHF lead to induction of apoptotic gene programs and loss of cardiomyocytes through apoptosis, and subsequently to what extent the beneficial effects of endothelin (ET) receptor antagonism after myocardial infarction (MI) could be attributed to reduction of apoptotic cell loss in the myocardium. DESIGN: Northern blot analysis, analysis of DNA fragmentation, and immunohistochemical analysis were performed after induction of MI in rats. RESULTS: After induction of MI, the mRNA levels of the pro-apoptotic genes FAS, BAX, P53, and CASPASE-1 were significantly increased in the non-ischemic region of the left ventricle (LV) with highest levels of expression in the peri-infarct area. High levels of FAS, BAX, P53, and CASPASE-1 mRNA were also observed in the infarcted region. Concomitantly, numerous TUNEL-positive cells and internucleosomal degradation of DNA were found in tissue from the peri-infarct area and in the infarcted zone, indicating apoptotic cell death. Treatment with bosentan, a mixed ET(A)/ET(B) receptor antagonist, during the first 24 h after induction of MI significantly reduced the area of TUNEL-positive myocardium in the ischemic region (64 +/- 2% of LV circumference in the vehicle group vs 55 +/- 2% of LV circumference in the bosentan group, p < 0.05). Consistently, bosentan also caused a similar reduction of infarct size. CONCLUSION: Our data demonstrate activation of pro-apoptotic genes and provide evidence of cardiomyocyte apoptosis in the viable peri-infarct area and in the infarcted region after MI in rats. Intervention with bosentan may attenuate cardiomyocyte cell loss through apoptosis in the area at risk after induction of ischemia.