Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy: the REGENERATE-DCM clinical trial

Objective: The application of autologous bone marrow cells has emerged as an investigational cell-based therapy for ischemic stroke. Previous animal studies have reported that stroke affects leukocytes in the bone marrow. In addition, older age and presence of comorbidities raise concerns about the variability in yield of bone marrow stem cells. These issues may potentially impact autologous applications of bone marrow cell therapies in stroke patients. We examined whether acute ischemic stroke (AIS) affects the bone marrow in patients by assessing various cell subpopulations within the mononuclear fraction of bone marrow harvested from healthy donors and study patients in our clinical trial testing mononuclear cells (MNCs) in patients with AIS. Methods: This study examined the bone marrow composition of 22 consecutive patients with AIS enrolled into our clinical trial testing the safety of autologous bone marrow MNCs administered intravenously within 24 to 72 hours after symptom onset. After bone marrow harvest, MNCs are isolated, separated, and characterized at a GMP facility. The bone marrow from 15 healthy donors was also processed at the same GMP facility. Descriptive analysis comprised calculation of means for absolute cell counts and determination of proportions for subtypes of different cell subpopulations. Samples of healthy bone marrow donors were compared with that of AIS patients. Results: AIS patients had a median age of 61 (IQR 50-73), had CAD (5%), Afib (14%), diabetes (32%), hypertension (50%), hyperlipidemia (32%), or were actively smoking (27%). Onset time to harvest was 48 ±11 hours after stroke onset. Figure 1 shows no significant differences among the proportions of cell populations including lineage negative, CD34+ cells (a marker of hematopoietic stem cells - HSCs). There was no significant difference in the variance of the cell subpopulations between healthy donors and stroke patients, except for NK cells which were significantly higher among the stroke patients (p = 0.0074). Age, history of DM, or the location of the infarct depending on vascular territory did not affect the proportion of the different cell populations. Conclusions: AIS does not cause significant changes in the proportions of different cell types in the MNCs of bone marrow including the HSCs. We found no evidence that autologous MNCs are different, in terms of cell composition, from study patients who are older and have vascular comorbidities compared with healthy donors.

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Abstract 3419: Positive Effect of Bone Marrow Progenitor Cell Transfer on Regional Post Infarction Ventricular Remodeling by Magnetic Resonance Imaging. Insights from the REPAIR AMI Trial.

Circulation ◽

10.1161/circ.116.suppl_16.ii_772-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Andreas Rolf ◽

Susanne Mollmann ◽

Johannes Rixe ◽

Guido Conradi ◽

Volker Schachinger ◽

...

Keyword(s):

Bone Marrow ◽

Placebo Group ◽

Progenitor Cell ◽

Ventricular Remodeling ◽

Wall Thickening ◽

Bone Marrow Progenitor Cell ◽

Bone Marrow Progenitor ◽

Functional Benefit ◽

Adverse Remodeling ◽

Positive Effect

Objective : The acute loss of myocytes during infarction increases loading conditions, which in turn triggers adverse remodeling of infarcted, adjacent and remote regions. Late Gadolinium Enhancement (LGE) cardiac MRI (CMR) can distinguish these regions and thus determine the effect of bone marrow progenitor cell (BMC) therapy on regional remodeling and function. Methods : 47 patients from the REPAIR AMI trial who underwent CMR at baseline and 12 month were evaluated in a segment by segment fashion according to the AHAs 17 segment model, defining LGE positive segments as infarcted and LGE negative segments as adjacent or remote. We measured enddiastolic wall diameters (WD) and wall thickening (WT) at 0 and 12 month by serial MRI. Results : WD decreased in all patients and all segments with a tendency to smaller diameters in BMC treated patients. In the prespecified subgroup of patients with larger infarcts (EF below the median of 48.9%) we observed a positive effect on adverse remodeling in BMC patients not only in infarcted but also in the remote areas. Infarcted segments showed a decrease in WD of 21.9% ± 4.0 SE in the BMC group vs. 8.5% ± 3.4 in the Placebo Group p=0.02. In BMC patients WD decreased in remote segments by 8.1% ± 4.4 SE compared to 4.9% ± 3.3 SE in the Placebo group, p=0.03. This effect on remodeling translates into a functional benefit. In remote segments WT decreases in both gropus but significantly so only in Placebo patients (BMC-7.8% ± 5.4 p= 0.2 vs. Placebo −13.9% ± 4.4 p=0.002, p for interaction 0.4). The largest effect was observed in the infarcted segments where BMC therapy led to an increase in WT of 26.6% ± 5.1 SE compared to Placebo 0.7% ± 4.6 SE p= 0.0001. The positive effect is mediated by wall diameters, regression analysis shows a significant inverse relationship between WD and WT, p = 0.0001 Conclusion : BMC therapy effectively prevents adverse remodeling not only in the infarct zone but also in remote segments for patients with large infarcts resulting in increased contractility. This seems to be mediated by a positive effect on enddiastolic wall geometry yielding smaller wall diameters.

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