In this controlled study we examined the correlation between the diseased coronary arteries and the frequency of CD34/45+ BM-CPCs in patients with IHD.
Coronary artery disease results from a chronic inflammatory disease of the vascular wall and leads to vessel occlusion and organ damage [
11]. Despite intense efforts to determine the pathogenesis of atherosclerosis, this process remains poorly understood. Reports suggest that risk factors and a genetic predisposition together induce inflammatory processes that leads to cell damage and impairs regeneration within the vessel wall [
12,
13]. Since resident endothelial cells infrequently proliferate, [
14] it has been postulated that there are other sources of vascular replenishment in response to continuous damage [
15]. Circulating progenitor cells derived from bone marrow circulate in the peripheral blood and have been implicated in neoangiogenesis after tissue ischemia has occurred [
16‐
19]. BM-CPCs are capable of proliferating and differentiating into endothelial cells and are therefore ideal candidates for vascular regeneration [
20,
21]. Experiments in animals show that the systemic application or mobilization of stem cells and progenitor cells beneficially influences the repair of endothelial cells after injury and the progression of atherosclerosis [
22‐
28]. Clinical trials indicated a beneficial effect of intracoronary infusion of BMCs, or circulating progenitor cells (CPCs), on myocardial function in patients with acute myocardial infarction (AMI) [
29,
30]. Previous studies demonstrated, that the mobilization and functional activity of CD34/45
+ and CD133/45
+ BM-CPCs significantly increased after an intracoronary infusion of BMCs in patients with ischemic heart disease [
31,
32]. BM-CPCs can also be used as a predictive biomarker for cardiovascular risk, vascular function and the extent of cardiac repair [
33]. Moreover, smoking is associated with depletion of CD34+ and CD133+ endothelial progenitor cells in patients with coronary artery disease [
34]. In a large clinical study, Hill et al [
35] reported that high-risk individuals have fewer BM-CPCs compared with to their low-risk counterparts. In contrast, Werner et al [
11] identified a significant association between increased numbers of BM-CPCs and a decreased risk of major cardiovascular events and hospitalization in patients with coronary artery disease. BM-CPCs mobilization can also predict severe endothelial dysfunction in patients with coronary heart disease [
36]. Moreover, the transient increase in CD34/45
+ and CD133/45
+ BM-CPCs reached a maximum after three weeks of regular symptom-limited (ischemic and/or subischemic) exercise training, but did not persist until 3 months after the regular training after acute myocardial infarction [
37,
38]. However, it is unknown whether the frequency of CD34
+ BM-CPCs relates to the number of diseased coronary arteries in patients with IHD. We demonstrated in our study that the frequency of BM-CPCs was significantly impaired in patients with IHD3 compared to IHD2 and IHD1. In patients with heart failure and preserved LVEF, diabetes is associated with a significantly increased risk of developing adverse HF outcomes [
39]. Diabetes mellitus is associated with both an increased risk of atherosclerotic disease and poor outcomes after vascular occlusion. The clinical severity of vascular occlusive disease in diabetics has in part been attributed to impaired collateral vessel development [
40] Extensive studies have shown that the numbers of circulating angiogenic cells are significantly lower in type II diabetes and their angiogenic potential is also dramatically diminished. These cells display defective adhesion to the endothelium, reduce proliferation rate, and impaire ability to create new vascular structures [
41,
42]. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells and their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Similarly, insulin resistance impairs circulating angiogenic progenitor cell function. On the other hand, increases in fractalkine level and the number and functional changes of blood dendritic cells might contribute to diabetic coronary atherosclerosis and plaque destabilization [
43‐
45]. On the basis of these findings, it is tempting to speculate that the decreased frequency of CD34
+ BM-CPCs by DM lead to a progression of atherosclerosis and increase the number of diseased coronary arteries in patients with IHD. In line with this hypothesis we observed in our study a significant higher incidence of DM in patients with IHD3 compared to IHD2 and IHD1. Furthermore, we demonstrated that the frequency of BM-CPCs negatively correlated with the level of HbA1c in IHD patients with DM. The CD34
+ BM-CPCs frequency in DM patients with HbA1c > 7% was significantly reduced compared to DM patients with HbA1c < 7%. Recent studies have shown that the PPARϒ agonist pioglitazone treatment increases the number and function of BM-CPCs in type 2 DM patients with coronary artery disease [
46,
47]. Improved levels of HbA1c by pharmacological therapy may lead to an increase of BM-CPCs frequency and functional activity and thereby may enhance the vascular regeneration in IHD patients with DM.