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How to measure the effects of the intracoronary stem cell therapy?

Michał Tendera , Wojciech Wojakowski
DOI: http://dx.doi.org/10.1093/ejechocard/jeq025 438-439 First published online: 22 March 2010

Abstract

The results of clinical studies showed that there is a moderate increase in left ventricular (LV) ejection fraction (EF) at 4–6 months after stem cell therapy. So far, the endpoint of such trials was the change of LVEF and volumes measured by LV angiography or MRI; however, these parameters might not be optimal to assess the effects of BMC therapy. BOOST trial was one of the first studies addressing the effect of bone marrow cell transfer in patients with acute ST-elevation myocardial infarction. The results of 5-year follow-up were reported, showed no sustained effect on the LV systolic function in the whole group, but some beneficial effects on diastolic function were found. Other study showed using tissue-Doppler that after implantation of selected CD133+ and CD133–CD34+ bone marrow-derived cells in patients with history of anterior MI and severely reduced LVEF the indices of regional LV systolic function improved. Clinical significance of these findings remains to be established; however, the assessment of diastolic function and tissue-Doppler imaging might be valuable parameters in stem cell-based trials.

After several years of intensive research on the effect of bone marrow (BM)-derived cell injection in patients with recent myocardial infarction (MI), we are still lacking definitive answers about the usefulness of this treatment. Overall, the results of clinical studies showed that there is a moderate increase in left ventricular (LV) ejection fraction (EF) at 3–6 months,1 and there is some indication that this moderate effect can translate into clinical benefit.2 Two major questions remain to be answered to make further progress in stem cell-based trials. First of all, it seems that the primary end-point of all published studies—LVEF and volumes are not the ultimate outcome measures. Also, the optimal population of patients for enrollment in such trials needs to be identified, because it seems unlikely that in the era of timely myocardial reperfusion inclusion of patients with recent MI on all-comers basis is indicated. Most of these patients undergoing primary PCI have preserved LVEF and good outcome. The primary reason is that improvement of LV contractility after stem cell infusion is confined to acute MI patients with severely reduced LVEF that are not common in current clinical practice because of the availability of primary PCI and modern antithrombotic treatment. Therefore, the data from long-term follow-up of stem cell trials are very important because it helps identify additional parameters that might be used for the assessment of the efficiency of BM-derived cells in acute MI.

BOOST trial was one of the first studies addressing the effect of BM cell transfer in patients with acute ST-elevation myocardial infarction (STEMI).3 While after 6 months there was a significant difference in LVEF in favour of cell treatment, this effect was no longer present after 18-month follow-up, mainly due to the improvement of the EF in the control group.4 In 2009 the results of 5-year follow-up were reported, showing no sustained effect on the LV systolic function in the whole group, but suggesting a long-term improvement in patients with large infarctions.5 Major adverse cardiac events occurred with similar frequency in both groups, but the study was not powered to address clinical outcomes.

It is obvious that after acute myocardial ischaemia not only the systolic, but also the diastolic function is impaired. Moreover, after reperfusion, diastolic function may remain impaired for a longer time.6 In addition, post MI diastolic wall motion abnormalities were found to be associated with neurohormonal activation, and with angiographic severity of coronary artery disease, and to provide independent prognostic information.7 In patients undergoing surgical revascularization, improvement of diastolic function was related to the extent of viable myocardium at baseline and to reverse remodelling after revascularization.8

However, most stem cell studies focused on the EF and LV remodelling, and there was no report on the effect of cell therapy on diastolic function until the publication of Schaefer et al.,9 the part of a comprehensive work-up of the BOOST trial patients. The same group was studied after 5 years of follow-up.10 To assess LV diastolic function, the authors measured transmitral flow velocities (E/A ratio), diastolic myocardial velocities (Ea/Aa ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). They found a beneficial effect of BMC transfer on E/A ratio up to 18 months of follow-up, but it did not last up to 5 years. In addition, there was no persistent effect on other parameters (Ea/Aa, IVRT, DT, and E/Ea) in long-term follow-up. In addition, analysis of tissue-Doppler parameters [early diastolic (Ea), late diastolic (Aa) velocities] showed no significant differences between the treatment and control groups. Patients with the infarct transmurality above the median showed higher overall treatment effect on one of the parameters (E/A); however, the subgroup analysis in such a moderate-sized trial should be interpreted with caution.

Clinical significance of these findings remains to be established. The results of the present study suggest that the improvement of diastolic function is limited to the first 1–2 years after treatment. Duration of this improvement may therefore be as long as that of the systolic function. It is likely that a combined analysis of systolic and diastolic LV function could serve as a predictor of clinical outcome. It is not impossible that, with a progressive nature of coronary atherosclerosis, any improvement in LV function, even if not sustained, may be a reflection of better vascularization of the border zone, which may improve prognosis long-term.

Karatasakis et al. measured the longitudinal systolic myocardial strain and strain rate using by tissue-Doppler imaging to evaluate the effects of selected CD133+ and CD133− CD34+ BM-derived cells on the regional LV function.11 Authors enrolled 10 patients with history of anterior MI and severely reduced LVEF. All patients had patent infarct-related (IRA) left anterior descending artery; however, they had no recent percutaneous coronary intervention in this territory. Investigators carried out Thalium 201 scintigraphy and low-dose dobutamine stress echocardiography to document the non-viable anteroapical LV segments. Interestingly, the 2D echocardiography was also used for the baseline assessment of the IRA patency prior to enrolment of patients and intracoronary stem cell infusion, which is a novel approach in stem cell trials. Although the study cohort was limited in size, the study yielded some interesting results. Authors showed that 6 months after cell infusion there was no effect on global LV systolic function but the indices of regional LV systolic function measured as systolic longitudinal deformation (ejection time strain, maximum strain during the cardiac cycle, peak systolic strain rate) significantly improved in the anteroapical segments. The most evident effect of stem cell infusion was 67–76% increase of peak systolic stain rate, which was observed both at rest and following dobutamine infusion.11

Both stem cell studies expand the knowledge on the effects of BM cells on LV systolic function. The most important message is that endpoints previously used in such studies, primarily LVEF and volumes, were not optimal for full assessment of the effect of BMC on LV function. It seems that the measurement of diastolic function and regional contractility using tissue-Doppler imaging should be included into outcome measures of future stem cell trials.

We still do not have a definitive answer not only as to the clinical effect of stem cell therapy, but also as to the type and number of cells, their preparation, timing of the treatment, and patient population that can benefit from it. The fact that improvement of LV function after intracoronary administration of unselected mononuclear BM-derived cells is limited both in magnitude and in time, points out to the necessity to study different other cell populations, like very small embryonic-like cells,12 cells expressing CD133 antigen, or mesenchymal cells. So far, the intracoronary infusion of immunomagnetically selected CD34+CXCR4+ cells failed to improve the LV function as demonstrated by the REGENT trial. All of them may require ex vivo pre-treatment to enhance their potential to differentiate into functional myocardium. So far, we have no proof that cell administration in patients can result in true myocardial regeneration. To achieve this goal, there is a need to better understand stem cell biology, and also to find the most appropriate surrogate endpoints for clinical studies. Assessment of diastolic function may potentially serve this latter purpose.

The study was supported by the European Union structural funds, Innovative Economy Operational Programme, grant No. POIG 01.02-00-109/09 ‘Innovative methods of stem cells applications in medicine’ and Polish Ministry of Science and Higher Education grants 0651/P01/2007/32, 2422/P01/2007/32.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of the EJECHO or of the European Society of Cardiology.

References

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