Role of Angiopoietic Coronary Endothelial Dysfunction in the Pathogenesis of Ischemic Cardiomyopathy

Abstract

Background: The angiopoietic endothelial dysfunction in ischemic cardiomyopathy (ICMP) remains unexplored.

Aim: The identification of the imbalance of endothelial dysfunction mediators and the number of endothelial progenitor (EPC) and desquamated (EDC) cells in patients with coronary heart disease (CHD) with and without ICMP.

Methods: A total of 87 patients (47 with ICMP and 40 without ICMP) were observed. The content of EPCs (CD14⁺CD34⁺VEGFR2⁺) in vein blood and EDCs (CD45^-CD146⁺) in the blood from the coronary sinus and cubital vein was determined by flow cytometry. The contents of HIF-1α and HIF-2α in vein blood as well as that of ADMA and endothelin-1 in sinus plasma and angiopoietin-2, MMP-9 and galectin-3 in both samples were assessed using ELISA, and VEGF, PDGF, SDF-1 and MCP-1 contents using immunofluorescence.

Results: ADMA and endothelin-1 levels in the sinus blood were comparable between the patient groups; a deficiency of HIF-1α and excess of HIF-2α were detected in the vein blood of ICMP patients. The EDC content in the vein blood increased in CHD patients regardless of ICMP, and the concentrations of VEGF-A, VEGF-B, PDGF, MCP-1, angiopoietin-2, and MMP-9 were normal. In ICMP patients, vein blood was characterized by an excess of galectin-3 and sinus blood by an excess of EDCs, angiopoietin-2, MMP-9 and galectin-3.

Conclusion: ICMP is accompanied by angiopoietic endothelial dysfunction.

Keywords: angiogenesis; coronary heart disease; endothelial progenitor cells; growth factors; heart failure.

Figure 1

The content of endothelial dysfunction mediators in the sinus blood and hypoxia-inducible factors in the peripheral blood of CHD patients, suffering and not suffering from ICMP. (A) The concentration of asymmetric dimethylarginine and endothelin-1 in the sinus blood of CHD patients, suffering from ICMP (n = 21) and not suffering from ICMP (n = 18), assessed through a Mann–Whitney test. (B) The content of hypoxia-inducible factor (HIF)-1α in the peripheral blood of CHD patients, suffering from ICMP (n = 17) and not suffering from ICMP (n = 16), assessed through a Mann–Whitney test. (C) The content of HIF-2α in the peripheral blood of CHD patients, suffering from ICMP (n = 20) and not suffering from ICMP (n = 17), assessed through a chi-squared test with Yates’ correction. The results are presented as Me [Pe 25; Pe 75], for HIF-2α, as a sample of the proportion of patients showing values above zero. p is the level of statistical significance of differences. Notes: ADMA, asymmetric dimethylarginine; HIF, hypoxia-induced factor. The use of color is essential.

Figure 2

Integral map of the interrelationships between the concentration of angiopoietic and vasomotor endothelial dysfunction mediators and the content of endothelial progenitor cells and endothelial desquamated cells in CHD patients in the pooled sample (regardless of the presence of ICMP) in peripheral (A) and sinus (B) blood. Notes: ADMA, asymmetric dimethylarginine (n = 36); Ang, angiopoietin (n = 21 and n = 39); EPC, endothelial progenitor cells (n = 25); EDC, endothelial desquamated cells (n = 21 and n = 16); Gal, galectin (n = 33 and n = 40); MCP, monocytic chemotactic factor (n = 59 and n = 58); MMP, matrix metalloproteinase (n = 32 and n = 36); PDGF, platelet growth factor (n = 19 and n = 17); SDF, stromal cell-derived factor (n = 26 and n = 21); sin, the parameter was determined in the blood from the coronary sinus; VEGF, vascular endothelial growth factor (VEGF-A: n = 53 and n = 48; VEGF-B: n = 26 and n = 20).

Figure 3

Integral map of the interrelationship between the concentration of angiopoietic and vasomotor endothelial dysfunction mediators and the content of endothelial progenitor and desquamated cells in peripheral and sinus blood in CHD patients, not suffering from ICMP (A) and suffering from ICMP (B). Notes: ADMA, asymmetric dimethylarginine (n = 16 and n = 20); Ang, angiopoietin (n = 18 and n = 23); EPC, endothelial progenitor cells (n = 14 and n = 11); EDC, endothelial desquamated cells (n = 11 and n = 11); Gal, galectin (n = 19 and n = 24); MCP, macrophage chemotactic factor (n = 33 and n = 36); MMP, matrix metalloproteinase (n = 18 and n = 24); PDGF, platelet growth factor (n = 10 and n = 10); SDF, stromal cell-derived factor (n = 14 and n = 13); sin, the parameter was determined in the blood from the coronary sinus; VEGF, vascular endothelial growth factor (n = 26 and n = 29).