Intramyocardial Bone Marrow Cell Injection for Chronic Myocardial Ischemia - Intramyocardial Bone Marrow Cell Injection for Chronic Myocardial Ischemia

Aug 13, 2009
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Date Published:
01/01/2009
Date Updated:
08/13/2009
Original Posted Date:
08/13/2009
References

Description:

Two small randomized controlled trials have shown conflicting results regarding the beneficial effect of intramyocardial bone marrow cell injection on myocardial function in patients with chronic myocardial ischemia. Accordingly, this trial sought to study the efficacy of intramyocardial bone marrow cell injection on myocardial function and left ventricular (LV) function in patients with chronic ischemia, who were not candidates for conventional treatment.

Hypothesis:

Intramyocardial bone marrow injection would be efficacious in improving myocardial perfusion and LV function in patients with chronic myocardial ischemia, as compared with placebo.

Study Design

Study Design:

Patients Screened: 69
Patients Enrolled: 50
Mean Follow Up: 3 months
Mean Patient Age: 63 years
Female: 14
Mean Ejection Fraction: 55%

Patient Populations:

  • Severe angina (CCS class III/IV) despite optimal medical therapy
  • Myocardial ischemia in at least one myocardial segment on Tc-99m tetrofosmin single-photon emission computed tomography
  • Ineligible for percutaneous or surgical revascularization

Exclusions:

  • LVEF <35%
  • Acute myocardial infarction within 6 months of enrollment
  • History of malignancy
  • Renal dysfunction (glomerular filtration rate <30 ml/min)
  • Unexplained hematologic abnormalities

Primary Endpoints:

  • Difference in SSS

Secondary Endpoints:

  • Improvement in LVEF, as determined by cardiac MRI
  • Change in CCS angina class
  • Change in Seattle Angina Questionnaire quality-of-life score

Drug/Procedures Used:

On the day of the injection procedure, 80 ml of bone marrow was harvested from each patient. Mononuclear cells were isolated, washed, and resuspended to a final concentration of 40 x 106/ml.

Following randomization, a blinded syringe with either bone marrow cell suspension or placebo solution (NaCl 0.9% with 0.5% human serum albumin) was brought to the catheterization laboratory. Eight to ten intramyocardial injections of 0.2-0.3 ml each were delivered into the ischemic regions, as identified by 3-D electromechanical mapping of the LV (using the NOGA system).

Concomitant Medications:

Beta-blockers (96%), statins (100%), aspirin (82%), clopidogrel (42%), and nitrates (84%)

Principal Findings:

A total of 50 patients were randomized, 25 to the bone marrow cell group, and 25 to placebo. Baseline characteristics were fairly similar between the two arms. Prior myocardial infarction was noted in 64% of the patients, with prior coronary artery bypass grafting in 86% and prior percutaneous coronary intervention (PCI) in 58%. About 42% had diabetes, 54% had dyslipidemia, and the mean body mass index was 28.5 kg/m2.

In the bone marrow cell group, the SSS improved from 23.5 at baseline to 20.1 at 3 months (p < 0.001). In the placebo group, the SSS also improved from 24.8 at baseline to 23.7 at 3 months (p = 0.004). On comparing the two groups, SSS was significantly better in the bone marrow cell group compared with placebo (treatment effect, -2.44; 95% confidence interval, -3.58 to -1.30; p < 0.001). There was no difference in the summed rest score between the two groups at 3 months (p = 0.25). The mean number of ischemic segments decreased from 3.9 to 1.5 in the bone marrow cell group, and from 3.1 to 2.4 in the placebo group (p < 0.05 for both). However, this was greater in the bone marrow cell group at 3 months (p < 0.001). The percentage of injected segments with an improved perfusion was significantly higher in the bone marrow cell group than in the placebo group (57% vs. 20%; p < 0.001). The percentage of noninjected segments with an improved perfusion was similar in both groups (5% vs. 6%; p = 0.48).

The bone marrow cell therapy arm was noted to have a significant increase in LV ejection fraction (EF) compared with the placebo arm on cardiac magnetic resonance imaging (MRI) (change, 3%; p = 0.03). No differences in LV volumes were noted between the two groups. Clinical status improvement according to Canadian Cardiovascular Society (CCS) angina class was also significantly better in the bone marrow cell therapy arm compared to placebo at 6 months (-0.79 vs. -0.39, p = 0.03). Quality-of-life score was also significantly higher in the bone marrow cell therapy arm at 6 months (p = 0.04). Bicycle exercise testing demonstrated increased maximal achieved workload in the bone marrow cell therapy arm at 6 months compared with placebo. Similarly, time to significant ST-segment depression also improved in the treated arm compared with placebo (treatment effect, 1.3 minutes; 95% confidence interval, 0.6-2.0; p = 0.001).

Adverse events from the therapy were rare, and included one death and one PCI in the bone marrow cell therapy arm, and one pericardial effusion, one cerebrovascular accident, and one Staph aureus infection in the placebo arm. No arrhythmias were noted in either arm.

Interpretation:

Although this is a small trial, its results are encouraging, and indicate that intramyocardial bone marrow cell injection is associated with an improvement in myocardial perfusion, mildly improved LVEF, reduced angina, improved quality of life, and improved exercise capacity in patients with chronic myocardial ischemia, who were not candidates for conventional treatment, as compared with placebo. Further clinical trials will help elucidate the evolving role of stem cell therapy in patients with chronic ischemia and ischemic cardiomyopathy.

References:

van Ramshorst J, Bax JJ, Beeres SL, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA 2009;301:1997-2004.

Keywords: Depression, Myocardial Infarction, Stroke, Tomography, Emission-Computed, Magnetic Resonance Imaging, Percutaneous Coronary Intervention, Cell- and Tissue-Based Therapy, Dyslipidemias, Bone Marrow Cells, Serum Albumin, Body Mass Index, Quality of Life, Cardiomyopathies, Catheterization, Confidence Intervals, Coronary Artery Bypass, Diabetes Mellitus, Pericardial Effusion


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