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Circulating progenitor cells as predictor of mortality in cardiovascular disease: Could physical activity change the global outcome?

      Predicting the risk of all-cause mortality, but in particular a cardiovascular (CV) cause, has been extensively researched within different patient populations suffering from endothelial dysfunction due to cardiovascular disease (CVD). Constantly, new blood biomarkers with clinical and prognostic relevance are emerging. For instance, within the last 20 years circulating progenitor cells (CPCs) have come into focus as an independent predictor of all-cause or CV mortality [
      • Fadini G.P.
      • Mehta A.
      • Dhindsa D.S.
      • et al.
      Circulating stem cells and cardiovascular outcomes: from basic science to the clinic.
      ]. In a healthy state, progenitor cells are being mobilized from bone marrow to the peripheral blood when needed and circulate in very low quantity. Only ~3 cells/μl of blood are usually CPCs expressing the typical hematopoietic surface marker CD34, while those additionally expressing CD133 or also endothelial markers such as KDR are even rarer (~1 cell/μl or 0.03 cell/μl, respectively) [
      • Cimato T.R.
      • Conway A.
      • Nichols J.
      • et al.
      CD133 expression in circulating hematopoietic progenitor cells.
      ,
      • Fadini G.P.
      • Baesso I.
      • Albiero M.
      • et al.
      Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau.
      ]. In patients with elevated risk experiencing CV events, CPCs are even less numerous [
      • Fadini G.P.
      • Rigato M.
      • Cappellari R.
      • et al.
      Long-term prediction of cardiovascular outcomes by circulating CD34+ and CD34+CD133+ stem cells in patients with type 2 diabetes.
      ], possibly explained by an exhaustion of the progenitor cell reserve in bone marrow [
      • Gremmels H.
      • van Rhijn-Brouwer F.C.C.
      • Papazova D.A.
      • et al.
      Exhaustion of the bone marrow progenitor cell reserve is associated with major events in severe limb ischemia.
      ]. Despite their scarcity, these cells have the ability to renew the CV system proven by higher numbers of CPC colony-forming units being associated with enhanced endothelial function [
      • Hill J.M.
      • Zalos G.
      • Halcox J.P.
      • et al.
      Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.
      ]. As a logical consequence with less CPCs present for regeneration, a long-term deterioration of health or even death could be probable. However, when interpreting risk or hazard ratios of mortality based on CPC levels, conclusions should be drawn with caution because methodological standards such as cell isolation, acquisition of rare events by flow cytometry, and reporting of outcomes differ between studies [
      • Fadini G.P.
      • Mehta A.
      • Dhindsa D.S.
      • et al.
      Circulating stem cells and cardiovascular outcomes: from basic science to the clinic.
      ] and could introduce data variability [
      • Kropfl J.M.
      • Schmid M.
      • Di Marzio Y.
      • et al.
      Circulating adult stem and progenitor cell numbers-can results be trusted?.
      ]. Both studies reporting continuous CD34+ proportions and concentrations found negative associations with all-cause and CV mortality [
      • Patel R.S.
      • Li Q.
      • Ghasemzadeh N.
      • et al.
      Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease.
      ,
      • Fadini G.P.
      • de Kreutzenberg S.
      • Agostini C.
      • et al.
      Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes.
      ]. However, the interpretation of a diminished likelihood of CV death per unit increase in log-transformed CD34+ data very much depends on the unit description of CPCs. A one-unit increase in CD34+ as proportion of nucleated cells in terms of risk reduction is an ambitious goal, if you consider that CD34+ cells fall within a healthy range of only ~0.05% and are even further reduced in CVD. Therefore, reporting CPC concentrations using a single-platform flow cytometry approach instead would seem appropriate to make studies predicting all-cause or CV mortality by CPCs more comparable and results more applicable. Nonetheless, it has to be noted that using a volume-based flow cytometric method, instead of expressing cells as part of total acquired events, bias could be introduced by disease-specific hemodilution or unidentified leucocytosis [
      • Fadini G.P.
      • Baesso I.
      • Albiero M.
      • et al.
      Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau.
      ]. Only intervention studies assessing CPC changes could apply necessary corrections using differential blood cell counts [
      • Matomaki P.
      • Kainulainen H.
      • Kyrolainen H.
      Corrected whole blood biomarkers - the equation of Dill and Costill revisited.
      ]. Furthermore, cell subsets under investigation should be clearly defined and detrimental aspects of each cell type should be considered. Against the common notion of the usually detected negative association between CPCs and mortality in CVD, a recent study found that low levels of a subgroup of CD34+/KDR+ cells were associated with longer incident-free survival in coronary artery disease (CAD) patients. These results were explained by a mechanism of defense in an attempt to compensate for more aggressive pathogenetic factors of atherosclerosis [
      • Pelliccia F.
      • Pasceri V.
      • Moretti A.
      • et al.
      Endothelial progenitor cells predict long-term outcome in patients with coronary artery disease: ten-year follow-up of the PROCREATION extended study.
      ], but could also indicate intra-plaque angiogenesis driven by their elevated cell level [
      • Hristov M.
      • Weber C.
      Ambivalence of progenitor cells in vascular repair and plaque stability.
      ].

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