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The bone marrow harbors a heterogeneous population of progenitor cells that give rise to mainly hematopoietic or endothelial cells. This is essentially a mixture of multiple stem cell lineages, and many of these populations were later isolated and investigated separately. Interest in bone marrow–derived mononuclear cells (BMMNCs) for cardiac repair was sparked by observations in animal studies that a subpopulation of bone marrow cells mobilize to the heart after myocardial infarction (MI), express early cardiac markers, and improve cardiac function.1,2 Some animal studies indicated possible improvements after injecting BMMNCs in postinfarct animals.1,2 These observations supported a hypothesis that bone marrow–derived cells might participate in myocardial recovery or regeneration. The unsorted population of BMMNCs was particularly attractive during the early cell therapy experience because of their relative accessibility via bone marrow biopsy, minimal sorting and processing, and experience utilizing the cells in bone marrow transplantation. With the realization that these progenitor cells mobilize in peripheral blood, some investigators attempted to harvest the progenitor cells from peripheral blood or unprocessed bone marrow extract, but most studies relied on bone marrow biopsy–derived mononuclear cells. The majority of clinical experience in cardiac stem cell trials to date remains with BMMNCs.
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Acute Myocardial Infarction
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Some of the earliest studies investigating the efficacy of BMMNCs in improving cardiovascular outcomes targeted patients with AMI. This was an attractive indication because of the acute and dramatic nature of cell loss and damage that occurs in the postinfarct period and the potential attenuation benefits of this response.42 The trials largely targeted patients with ST-segment elevation MI and treated them with intracoronary infusion of BMMNCs. The initial clinical experience was largely limited to single arm or nonrandomized trials.43,44,45,46,47,48 These studies reported an improvement in LV systolic function and/or infarct size 3 to 6 months after cell therapy infusion and few safety issues.
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These relatively positive early results led to a series of randomized controlled studies testing the safety and efficacy of BMMNCs (Table 10–3). Given the known risks associated with the coronary infusion process and bone marrow biopsy, these trials were not blinded, and they compared two arms of cell therapy or utilized a nonplacebo control. In other words, control patients underwent optimal standard of care without undergoing bone marrow biopsy or sham intracoronary infusion procedures. This nonuniform exposure to risk in the cell therapy group sometimes resulted in a higher number of periprocedural complications such as increases in cardiac biomarkers of injury or stent thrombosis. Nevertheless, these events did not translate into a significant difference in overall incidence of major serious adverse events. However, in terms of efficacy, the trials provided mixed results with respect to improvement in LVEF, LV volumes, and infarct or scar size. Even positive results were inconsistent as to the specific parameters that were improved among these studies.49,50,51,52,53,54,55,56,57,58,59,60,61,62,63
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The third generation studies included randomized placebo-controlled studies that aimed to strengthen blinding and to add a placebo control arm as an alternative to the optimal medical therapy control arm that was utilized previously. These studies validated the safe nature of the bone marrow harvest and intracoronary infusion procedure but unfortunately have not provided a conclusive answer to the efficacy question.64,65,66,67,68,69,70 Several meta-analyses have attempted to combine data to determine efficacy but have likewise yielded mixed results.41,71,72
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Several hypotheses have been generated to explain the conflicting results of the trials: the relatively small number of patients, variation in timing of cell infusion, differences in number of cells infused, and different modalities of measuring LV function and dimensions. Another important criticism of the studies is the appropriateness of the surrogate end point used to test for efficacy, namely LV size or function. For example, although angiotensin-converting enzyme (ACE) inhibitors provide superior survival benefit over hydralazine-nitrate in patients with heart failure and reduced LVEF, hydralazine-nitrates provide a greater improvement in LVEF, highlighting the limitation of using surrogate end points.73 Thus, the more relevant question is whether BMMNC therapy provides a hard outcome improvement in AMI that would justify the associated risks and resources committed, similar to other approved therapies such as percutaneous coronary intervention or use of thiopyridine antagonists. To answer this question conclusively, a 3000-patient multicenter randomized clinical trial, the Effect of Intracoronary Reinfusion of BMMNC on All Cause Mortality in Acute Myocardial Infarction (BAMI), is being conducted by European Union scientists, with an expected completion date in the spring of 2018 (retrieved from http://clinicaltrials.gov/ct2, identification NCT01569178).
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Chronic Heart Failure
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The use of BMMNCs for the treatment of chronic heart failure began with pilot studies that aimed to determine their safety, similar to studies for AMI indication.74,75,76,77,78,79,80,81,82,83,84 The studies were mostly positive, showing a mix of symptomatic, contractile, and perfusion improvements regardless of the method of injection at follow-up intervals of 3 to 12 months. This led to multiple randomized trials to confirm efficacy, but the results thus far have been mixed (Table 10–4).85,86,87,88,89,90,91,92,93,94,95
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In contrast to the AMI trials, in which cell delivery was largely intracoronary, the method of delivery in chronic heart failure trials included both intracoronary infusion and intramyocardial injections. A number of trials randomized ischemic cardiomyopathy patients undergoing CABG to receive injections of BMMNCs versus standard surgery. No single delivery method seemed to predict a consistent response or lack of response to delivered BMMNCs. The trials primarily targeted ischemic cardiomyopathy, and those that showed positive results found a small improvement in end points such as LVEF and New York Heart Association (NYHA) class. Interestingly, a randomized controlled study of nonischemic patients showed improvement in imaging parameters and functional status.96 The safety profile of these studies collectively was once again reassuring. Meta-analysis of chronic heart failure studies did not yield a definitive answer to the question of efficacy.97,98 Thus, the main conclusion that can be drawn from these studies is that treatment is largely safe and well tolerated, but larger studies will be needed to answer the question of efficacy of BMMNCs in cardiomyopathy patients.
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Peripheral Arterial Disease
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BMMNCs are the most tested cell therapy for the treatment of PAD (Table 10-5). The first pilot study to investigate the safety and efficacy of cell therapy in PAD examined the injection of BMMNCs versus peripheral blood mononuclear cells (PBMCs) into the gastrocnemius muscle of patients with chronic limb ischemia (CLI). The limbs injected with BMMNCs showed significant improvement in ankle brachial index (ABI), transcutaneous oxygen pressure (TcPO2), rest pain, and pain-free walking time.99 Subsequently, multiple randomized trials tested the safety and efficacy of BMMNCs in patients with PAD, with conflicting results (Table 10–5).100,101,102,103,104,105,106,107,108,109 Collectively, the data appear to point toward a small favorable response of measures such as ABI or TcPO2, but end points such as amputation-free survival did not differ between groups. Two meta-analyses that used rigorous methodological standards concluded there is insufficient evidence for benefit of BMMNCs for the treatment of PAD.110,111
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The majority of studies utilized intramuscular (IM) injection of cell therapy with a minority using intra-arterial (IA) injection. Klepanec et al randomized PAD patients to IM versus IA injection of BMMNCs and observed comparable improvements in quality-of-life questionnaire, TcPO2 and pain scale in both groups.107 Terra et al tested the effect of repeated IA infusion of BMMNCs against placebo in 161 patients with critical limb ischemia. After 6 months there was no difference in the primary end point of amputation-free survival or all-cause mortality.109 There was no increased risk of adverse events associated with BMMNCs in randomized trials.