Abstract
Recently, a clinical study on patients with stable coronary artery disease (CAD) showed that external counterpulsation therapy (ECP) at high (300 mmHg) but not at low inflation pressure (80 mmHg) promoted coronary collateral growth, most likely due to shear stress-induced arteriogenesis. The exact molecular mechanisms behind shear stress-induced arteriogenesis are still obscure. We therefore characterized plasma levels of circulating microparticles (MPs) from these CAD patients because of their ambivalent nature as a known cardiovascular risk factor and as a promoter of neovascularization in the case of platelet-derived MPs. MPs positive for Annexin V and CD31CD41 were increased, albeit statistically significant (P<0.05, vs. baseline) only in patients receiving high inflation pressure ECP as determined by flow cytometry. MPs positive for CD62E, CD146, and CD14 were unaffected. In high, but not in low, inflation pressure treatment, change of CD31CD41 was inversely correlated to the change in collateral flow index (CFI), a measure for collateral growth. MPs from the high inflation pressure group had a more sustained pro-angiogenic effect than the ones from the low inflation pressure group, with the exception of one patient showing also an increased CFI after treatment. A total of 1005 proteins were identified by a label-free proteomics approach from MPs of three patients of each group applying stringent acceptance criteria. Based on semi-quantitative protein abundance measurements, MPs after ECP therapy contained more cellular proteins and increased CD31, corroborating the increase in MPs. Furthermore, we show that MP-associated factors of the innate immune system were decreased, many membrane-associated signaling proteins, and the known arteriogenesis stimulating protein transforming growth factor beta-1 were increased after ECP therapy. In conclusion, our data show that ECP therapy increases platelet-derived MPs in patients with CAD and that the change in protein cargo of MPs is likely in favor of a pro angiogenic/arteriogenic property.Trial RegistrationClinicalTrials.gov NCT00414297
Highlights
In patients with coronary artery disease (CAD), therapeutic promotion of coronary collateral growth is an attractive option for re-vascularizing myocardial tissue aside from percutaneous coronary intervention (PCI) and surgical bypass grafting
We provide evidence that patients with stable CAD undergoing external counterpulsation (ECP) therapy exhibit, on average, increased plasma levels of platelet-derived microparticles (PMPs) stained positive for CD31 and CD41 antigens
The increase in MP numbers was not due to an increase of cells carrying CD31 antigen or CD41, and the increase of MPs was confirmed by semiquantitative proteomics data revealing an increase in CD31 (PECA1) and cellular proteins
Summary
In patients with coronary artery disease (CAD), therapeutic promotion of coronary collateral growth is an attractive option for re-vascularizing myocardial tissue aside from percutaneous coronary intervention (PCI) and surgical bypass grafting. Aside from increased collateral growth [5,6], an improvement of myocardial perfusion [7], endothelial function, and/or nitric oxide bioavailability [5,8,9,10] have been demonstrated after ECP treatment. In a recent study where chronic stable CAD patients were randomly assigned to low (80 mmHg) or high (300 mmHg) pressure ECP for a total of 30 hours, a significant increase of collateral function was demonstrated in the 300 mmHg group [5]. Similar results on collateral function have been obtained in an open, non-randomized trial of patients with chronic CAD undergoing 35 hours of ECP [6]
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