Cardiovascular Risk in Patients With Takayasu Arteritis Directly Correlates With Diastolic Dysfunction and Inflammatory Cell Infiltration in the Vessel Wall: A Clinical, ex vivo and in vitro Analysis

Abstract

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Atherosclerosis leads to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression.

Methods: Patients with active TAK arteritis were compared with age- and sex-matched atherosclerotic patients (Controls). In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical changes of the vessel wall were evaluated as well.

Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. The degree of dysfunction appears associated with uric acid levels. A significant increase in aortic stiffness was also observed and associated with levels of peripheral T lymphocytes. CD3⁺ CD4⁺ cell infiltrates were detected in the vessel wall samples of TAK patients, whose mean percentage of Tregs was lower than Controls at T0, but increased significantly at T18. Opposite behavior was observed for Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD).

Conclusion: Our data suggest that different pathogenic mechanisms underlie vessel damage, including atherosclerosis, in TAK patients compared with Controls. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

Keywords: Regulatory T Lymphocytes (Tregs); T helper-like cells; Takayasu arteritis (TAK); echocardiography; immune cell infiltration; vascular stiffness.

Figure 1

Uric acid levels in TAK patients increase according to the severity of heart diastolic dysfunction (A) and aortic valve regurgitation (B).

Figure 2

Values of aortic vascular stiffness (ASI) in TAK patients compared with Controls (atherosclerotic patients) (A). ASI values are directly related to the degree of LV diastolic dysfunction (B) and uric acid (UA) levels (C) in TAK patients. Common carotid intima-media thickness (IMT) shows an inverse correlation with aortic diameter indexed by body surface area (BSA) (Aoi) (D) and aortic wall thickness (E), and a direct correlation with ASCVD 10-year risk rate (F) in TAK patients. Evaluation was performed excluding already known cardiovascular disease (B,C) and those who underwent to surgical treatment (D-F).

Figure 3

Immune cell infiltration (CD3⁺, CD4⁺, CD8⁺, and CD15⁺) and expression level of inflammation-associated cytokines of vascular injury HMGB1 in biopsy samples from blood vessels of TAK patients (A-E) and Controls (F-L). Representative immunohistochemistry (original magnification: 20X) is shown in the top and middle panels. The lower panel shows the results as mean ± S.D. of three independent experiments for each field.

Figure 4

Frequency of Treg and Th17 cells in TAK patients and atherosclerotic Controls. (A) Flow cytometry analysis: gating was performed on live CD3⁺CD4⁺ cells to identify Foxp3+Treg and IL-17⁺ cells. Representative plots from one patient for each group. (B) Results are presented as mean ± S.D. of CD3⁺CD4⁺Foxp3⁺ percentages and CD3⁺CD4⁺IL-17⁺ T cells (C) in TAK patients before (T0) and after 18 months (T18) of infliximab treatment and in matched Controls (Wilcoxon signed-rank test and unpaired t-test, Mann-Whitney test).