Ischemic cardiomyopathy is characterized by insufficient proinflammatory and proangiogenic myocardial response associated with a blood HIF‑1/2 imbalance

Aim. To identify the role of impaired production of hypoxia-inducible factors (HIF) 1 and 2 in determining the balance of angiogenesis mediators, pro- and antiinflammatory cytokines in peripheral and coronary sinus blood in patients with coronary artery disease (CAD), with and without ischemic cardiomyopathy (ICM).

Material and methods. The study included 30 patients with coronary artery disease (CAD) and non-cardiomyopathy, 22 patients with CAD without cardiomyopathy, and 20 healthy donors. Patients with non-cardiomyopathy had a lower left ventricular ejection fraction (LVEF) compared to CAD patients without cardiomyopathy (30,00 [22,00; 36,00]% and 59,50 [50,25; 67,00]%, p<0,001). Peripheral (cubital vein) and coronary sinus blood was used as the sample material. The plasma concentrations of TNF-α, TGF-β1, IL-10, VEGF-A, PDGF, and SCF were assessed in both blood samples using a multiplex assay, while HIF-1α, HIF-2α, and IL-6 — an enzyme-linked immunosorbent assay.

Results. In the peripheral blood of patients with CAD, regardless of ICM, the concentration of TNF-α, IL-6, VEGF-A, PDGF was normal, while the SCF level showed a tendency to increase (p=0,054), and TGF-β1 — to decrease (p=0,059); excess IL-10 and HIF-2α was determined only in patients with ICM (respectively, 2,80 [2,00; 3,30] pg/ml versus 1,78 [0,50; 2,40] pg/ml, p=0,018; 40,0% vs 0% of positive cases, p=0,047), excess HIF-1α — only in CAD patients without cardiomyopathy (6,00 [5,00; 6,20] ng/ml and 4,60 [3,28; 5,11] ng/ml, p=0,049). In the coronary flow relative to the peripheral flow in CAD patients without ICM, the concentration of TNF-α, IL-6, PDGF was higher (1,09 [0,68; 2,47] pg/ml, p=0,004; 5,85 [3,12; 7,15] pg/ml, p=0,011; 7,60 [3,70; 9,94] pg/ml, p=0,036), which was not determined in patients with ICM, who had a higher content of TGF-β1 (4,42 [3,38; 5,69] pg/ml, p=0,022). Regardless of ICM type, the VEGF-A content in sinus blood exceeded the systemic level (7,80 [3,25; 9,75] pg/ml, p=0,041), while the concentration of HIF-1α, IL-10, and SCF corresponded to them.

Conclusion. Insufficient cardiac angiogenesis in ICM is largely associated with the anergy of the myocardial proinflammatory response with atherogenesis, rather than with reduced response to hypoxia. This, on the contrary, is more significant at the systemic level in ICM pathogenesis and is characterized by the predominance of HIF-2 over HIF-1.

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