Ischemia-related changes in circulating stem and progenitor cells and associated clinical characteristics in peripheral artery disease

Abstract

AIMS The extent and clinical significance of stem and progenitor cell (SPC) increases in response to lower extremity ischemia in people with peripheral artery disease (PAD) are unclear. We compared changes in SPC levels immediately following a treadmill exercise test between individuals with and without PAD. Among participants with PAD, we determined whether more severe PAD was associated with greater increases in SPCs following treadmill exercise induced lower extremity ischemia. APPROACH AND RESULTS We measured SPC levels in 25 participants with PAD and 20 without PAD before and immediately after a treadmill exercise test. Participants with PAD, compared to participants without PAD, had greater increases in CD34+CD45dim (+0.08±0.03 vs. −0.06±0.04, p=0.008), CD34+CD45dimCD133+ (+0.08±0.05 vs. −0.08±0.04, p=0.014), CD34+CD45dimCD31+ (+0.10±0.03 vs. −0.07±0.04, p=0.002), and CD34+CD45dimALDH+ SPCs (+0.18±0.07 vs. −0.05±0.08, p=0.054) measured as a percentage of all white blood cells. Among participants with PAD, those with any increases in the percent of SPCs immediately after the treadmill exercise test compared to those with no change or a decrease in SPCs had lower baseline ABI values (0.65±0.17 vs. 0.90±0.19, p=0.004) and shorter treadmill times to onset of ischemic leg symptoms (2.17±1.54 vs. 5.25±3.72 minutes, p=0.012). CONCLUSIONS In conclusion, treadmill exercise-induced lower extremity ischemia is associated with acute increases in circulating SPCs among people with PAD. More severe PAD is associated with a higher prevalence of SPC increases in response to lower extremity ischemia. Further prospective study is needed to establish the prognostic significance of ischemia related increases in SPCs among patients with PAD.

Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease

“…By promoting lower extremity ischemia, a stimulus for endothelial progenitor cell release, treadmill exercise could potentially stimulate circulating endothelial cell increases and migration to ischemic lower extremity muscles in patients with PAD. 2,3,10 Combining ischemia-inducing treadmill exercise with GM-CSF had potential to enhance therapeutic benefits of GM-CSF. However, combining exercise with GM-CSF was not better than exercise alone, and GM-CSF alone did not significantly improve any outcome more than placebo.…”

“…Progenitor cells were measured in peripheral blood using standard methods. 10 Detailed methods are reported as eMethods in Supplement 2.…”

Circulating Progenitor Cells Identify Peripheral Arterial Disease in Patients With Coronary Artery Disease

“…Several measures have been found to increase mobilization of PCs, such as lifestyle modification, intensifying statin therapy, cilostazol, and exercise. 31, 50,25, 26 Thus, identifying subjects at risk for PAD may allow for earlier interventions, and potentially abrogation of that risk. A low CD34+/VEGF2R+ PC cell count is indicative of worse long term prognosis, especially from vascular events.…”

Circulating stem cells and cardiovascular outcomes: from basic science to the clinic

“…35 Peripheral blood levels of CD34 þ HSPCs and CD34 þ VEGFR2 þ EPCs were found to be reduced in patients with evidence of both CAD and PAD compared to subjects with CAD alone, 80 findings that were confirmed by other studies. 35,81,82 Subjects with low levels of both CD34 þ and CD34 þ VEGFR2 þ counts had a 65% higher odds of having PAD and CAD compared to those with CAD, indicating that reduction in EPC populations, in particular, is associated with more extensive multi-site atherosclerosis. 80 There have been conflicting reports on the relationships between CSC numbers and presence of HF or its severity in small populations.…”