Detailed Analysis of Bone Marrow From Patients With Ischemic Heart Disease and Left Ventricular Dysfunction

Abstract

Rationale Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI). Objective To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD). Methods & Results BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p< 0.05). BM-derived endothelial colonies were significantly decreased (p< 0.05). Increased BM CD11b+ cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p< 0.05). While increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34+ percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355). Conclusions In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.

Bone Good to the Heart

“…It is noteworthy that Circulation Research has recently published another report from the Cardiovascular Cell Therapy Research Network (CCTRN) comparing composition and functionality of BMC collected from patients with ST-segment-elevation myocardial infarction at different times after MI (in TIME and LateTIME trials) and from patients with chronic ischemic heart failure (in the Effectiveness of Stem Cell Treatment for Adults With Ischemic Cardiomyopathy, the FOCUS Study). 22 Interestingly, in that study, the same authors of the present work showed a positive correlation of BM CD34 + precursors and a negative correlation of CD11b + cells with recovery of cardiac function as assessed by left ventricular ejection fraction. The discrepancy between those findings and data presented in this issue can be attributed, at least in part, to the distinct end point chosen and to the extended cohort used to generate the former.…”

A Look at the Bone Marrow Predicts the Global Outcome

“…2 There is a growing interest in the BM status in patients with cardiovascular disease or risk factors. 11,12 For instance, acute myocardial infarction induces BM metabolic activation, 13 and failure of the BM to mobilize CD34 + cells post-acute myocardial infarction is associated with a poor outcome. 14 In diabetes mellitus, especially with vascular disease, the BM undergoes extensive remodeling and stem cell mobilization is impaired.…”

Stem Cell in the Rough

“…9 A series of larger trials performed under the auspices of the CCTRN had suggested the absence of therapeutic benefit of bone marrow-derived mononuclear cells after myocardial infarction. 10 Human bone marrow is a desirable source because of accessibility for harvest, favorable biological profile, and extensive clinical experience.…”

“…13 In consideration of more favorable outcomes reported in European trials predating the CCTRN effort, 14,15 the present analysis was undertaken to evaluate whether the material content of bone marrow mononuclear cells may underpin disparate results. 9 To this end, flow-cytometry and colony assays mined for regenerative propensity within heterogeneous mixtures of bone marrow cellular compartments. Bone marrows exhibiting increased CD34 + and decreased CD11b + cell content were found to confer an ejection fraction benefit both in the setting of acute and chronic left ventricular dysfunction.…”

“…Bone marrows exhibiting increased CD34 + and decreased CD11b + cell content were found to confer an ejection fraction benefit both in the setting of acute and chronic left ventricular dysfunction. 9 The clinical use of this subpopulation is independently supported by separate trials with CD34 + cells delivered in purified form, as CD34 + -based therapy has been shown to yield signals of improvement in refractory angina 16 and in ischemic cardiomyopathy. 17 Collectively these results point to the importance of particular stem cell niches within the bone marrow that are associated with the capability to direct cell repair behavior, serving thereby as putative predictors of myocardial restoration.…”