CORRESPONDENCE: LETTER TO THE EDITOR
Testing Regeneration of Human Myocardium Without Knowing the Identity and the Number of Effective Bone Marrow Cells Transplanted: Are the Results Meaningful?
Daniele Torella, MD*,
Georgina M. Ellison, PhD and
Santo Dellegrottaglie, MD
* Department of Experimental and Clinical Medicine, Laboratory of Molecular and Cellular Cardiology, Magna Graecia University, Campus Germaneto, Catanzaro 88100, Italy (Email: dtorella{at}unicz.it).
We read with great interest and attention the intriguing IACT study by Strauer et al. in a recent issue of the Journal (1). We wish to highlight a few points that might be crucial for the correct interpretation of the results.
The method used to derive the ejection fraction by ventriculography is not specified in the study. If it was the biplane Simpson’s method the conclusions might be questionable. This method, also when applied to echocardiographic images, requires significant geometric assumptions and suffers from limited accuracy and reproducibility (2). Both ventriculography and echocardiography do not represent the optimal modalities (especially when compared to cardiac magnetic resonance imaging) for repeated measurements in small-sized follow-up studies (3). The sample size of the IACT study seems inadequate to confer sufficient statistical power for intergroup comparisons.
Regional systolic functional analysis was used to detect changes in infarct size. However, significant differences in the amount of viable myocardium and the transmural extent of the necrosis in the treated versus untreated dysfunctional myocardial segments may have potentially influenced the degree as well as the time-course of functional recovery in the two study groups (4).
Because the nature of the trial was nonrandomized, this study has no control/placebo group. Therefore, the placebo effect and/or additional balloon expansion during cell administration cannot be ruled out.
The bone marrow cells (BMCs) used in the IACT study were obtained from a noncloned cell preparation, and, therefore, it is impossible to ascertain the number and nature of the putative regenerating cells administered. Because of that, it cannot be determined whether the protocol used in this study does in fact test the regenerative potential of the BMCs (5). Indeed, the amount of myocardial regeneration in the treated patients, if any, cannot be measured owing to technical and ethical reasons.
Even if we believe in the myocardial regenerative potential of BMCs, it has to be pointed out that the controversy surrounding this topic has yet to be properly addressed (5). Strauer et al. (1) have further documented the safety and feasibility of BMC injection in patients with chronic heart failure; however, their data do not address some of the most controversial issues facing this therapy.
In particular, because they could not reasonably deal with the issue of myocardial regeneration, Strauer et al. (1) offer an alternative explanation for their results. This paracrine interpretation argues that the injected BMCs release angiogenic ligands, enhance cardiomyocyte survival, and may recruit resident cardiac stem cells (CSCs) (5), but it is equally lacking in real data. Recently, it has also been proposed that apoptosis of transplanted cells modulates local tissue reactions, leading to improved cardiac outcome (6). Whether these putative cell-related effects play any significant role or whether they are specific to BMCs or just the consequence of any cell transplantation await the proper experiments.
What does remain clear is that at present there is no documented mechanistic explanation for the reported improvement in cardiac function in postinfarct patients treated with autologous BMCs.
Overall, we are persuaded that the relative contributions of the transplanted BMCs and/or the recruited CSCs on de novo myogenesis and vasculogenesis will be unlikely resolved by small clinical trials. The identity of the therapeutic cells present in the bone marrow must be established and their biological properties defined before planning large clinical trials.
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1. Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery diseasethe IACT study. J Am Coll Cardiol 2005;46:1651-1658.[Abstract/Free Full Text]2. Hoffmann R, von Bardeleben S, ten Cate F, et al. Assessment of systolic left ventricular functiona multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J 2005;26:607-616.[Abstract/Free Full Text] 3. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy Am J Cardiol 2002;90:29-34.[CrossRef][Web of Science][Medline] 4. Knuesel PR, Nanz D, Wyss C, et al. Characterization of dysfunctional myocardium by positron emission tomography and magnetic resonancerelation to functional outcome after revascularization. Circulation 2003;108:1095-1100.[Abstract/Free Full Text] 5. Torella D, Ellison GM, Nadal-Ginard B, Indolfi C. Cardiac stem-progenitor cell biology and regenerative potential Trends Cardiovasc Med 2005;15:229-236.[CrossRef][Medline] 6. Thum T, Bauersachs J, Poole-Wilson PA, et al. The dying stem cell hypothesisimmune modulation as a novel mechanism for progenitor cell therapy in cardiac muscle. J Am Coll Cardiol 2005;46:1799-1802.[Abstract/Free Full Text]
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