Copyright © 2006, European Society of Cardiology
ACE inhibitors and statins for bone marrow failure following myocardial infarction?
aDepartment of Physiology, Maastricht University, CARIM, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
bDepartment of Cardiology, University Hospital Maastricht, CARIM, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands
* Corresponding author. Tel.: +31 43 3881200; fax: +31 43 3884166. Email address: m.post{at}fys.unimaas.nl
Received 6 February 2006; accepted 7 February 2006
See article by Thum et al. [4] (pages 50–60) in this issue.
Since their initial description a decade ago, endothelial precursor cells (EPCs) have been intensively studied, especially in relation to vascular injury or pathology and their clinical consequences. However, there is no consensus on the precise phenotypic definition of EPCs. Nonetheless, it has been established that these EPCs contribute to neovascularization in a variety of tissues [1] and they may even play a role in tissue regeneration if they transdifferentiate and integrate into functional tissue, for instance myocardium. The latter, however, is highly controversial.
Recruitment of EPCs from the bone marrow appears to be a natural mechanism to restore vascular function or even tissue function. Many acute tissue injuries, including myocardial infarction (MI), lead to a transient rise in circulating EPCs [2]. The functional importance of this rise in EPCs after MI is suggested by a correlation with better prognosis through reduced incidence of cardiac failure or death from cardiac cause. Multiple mechanisms have been described for this presumed interaction between peripheral organs and the bone marrow, mostly involving circulating factors such as VEGF [2] and perhaps CSFs [3]. It is therefore surprising that Thum and colleagues [4], in a study reported in this issue, observed diminished EPC recruitment after experimental MI in a rat model. They further found that ACE inhibition as well as statin treatment restores and activates EPC recruitment beyond pre-MI levels, which they offer as an explanation for the increased post-MI levels of EPCs in patients: these patients almost universally use ACE inhibitors and statins. Although they technically did not test a combination of the two drugs, which would have reflected the usual clinical situation, this is unlikely to lower EPC levels.
Alternative explanations for their findings, however, can be considered. First, the timing of EPC assessment may be crucial. In clinical as well as some experimental studies, the early rise in EPCs after MI or other injuries peaks at 48h with normalization at around 3days [2,5], the earliest time point studied by Thum et al. Thus, it is conceivable that they missed a rise in EPCs in the first 2days.
Second and more likely, the severity of injury may be critical. A 50% infarct is a severe injury and these animals invariably develop heart failure as attested by appreciable rise in end diastolic pressure 7days post-MI. With such a level of necrosis and associated inflammation, the pool of EPCs may have become exhausted. Furthermore, it is likely that massive tissue injury is accompanied by persistent high levels of TNF
. In heart failure patients, EPC levels are negatively correlated with TNF levels, suggesting a myelosuppressive activity of this cytokine [6].
Finally, as the authors exhaustively discuss, there is no uniform description or analysis of EPCs, and therefore different cells may be the star actor in each study. The confusion with EPCs can be related to (1) the necessity to distinguish precursor cells from circulating mature endothelial cells and (2) the absence of a uniquely identifying marker of endothelial phenotype. The single characteristic that distinguishes a precursor cell from a mature endothelial cell is the number of replications of which it is capable. For a mature endothelial cell this is approximately 50times, and for circulating cells that presumably have been sloughed off from the vascular wall, it is 20times or less. Up to 90 replication cycles have been described in so-called late outgrowth precursor cells [7]. This obviously requires extremely laborious and tedious protocols, so short-cuts have been developed. Among these, CD133 (AC133) serves as an indicator of precursor cell phenotype. More stringent analysis requires showing and quantifying the formation of endothelial cell colonies 6–8weeks after plating, usually after one or several preplating steps that identify and discard early adherent cells [8]. Being more stringent than most investigators in this field, Thum and coworkers chose a middle ground. They also went to great length to phenotype "their cells". The only step that was not taken was to demonstrate in vivo that these EPCs incorporate into the endothelium of neovasculature. Thus, it remains possible that these cells are diminished after MI, whereas other cells that may be more mature or not of endothelial origin are increased.
The good news is that established therapies with ACE inhibitors or statins increase the level of EPCs and therefore seem to be myelotropic. This study provides independent confirmation of the findings by Comte et al. on ACE inhibitors [9] and by several groups on statins [10]. Observations regarding the different molecular mechanisms associated with each drug open the way to specifically address the question whether enhanced recruitment of EPCs contributes to their beneficial effects on cardiac function. Systemic MMP-9 inhibition should abrogate the EPC increase by ACE inhibition and reveal EPC-independent effects on cardiac function. Likewise, the dependency of statins on precursor cell recruitment might be shown in mice where the VEGF pathway is interrupted, as has been described for id1+/–id3–/– mice [11]. A very recent study comparing the functional effects of EPC therapy with that of ACE inhibitors and β-blockers as well as the combination of the three suggests that cells act through a different mechanism [12], but further studies are certainly indicated to establish these mechanisms.
An interesting result from the study by Thum et al. is that statins may have a stronger effect on EPC levels than ACE inhibitors. Not only recruitment but also the function of EPCs may be improved by statins. The enhanced eNOS activity measured in EPC under statin treatment may be an indicator [13]. On the basis of this mechanism, one may even hypothesize that ACE inhibition and statin treatment post-MI have an additive effect on EPC function.
With these incremental steps, the extremely complex question regarding the functional significance of the natural EPC response after tissue injury will eventually be resolved and will provide a sound fundament for therapeutic intervention.
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