Atherosclerosis severity in patients with familial hypercholesterolemia: The role of T and B lymphocytes

Waleria T Fonzar; Francisco A Fonseca; Henrique A Fonseca; Tuany P Silva; Alfredo A Rodrigues; Daniela Teixeira; Mayari E Ishimura; Maria E Coste; Carolina N França; Henrique T Bianco; Magnus Gidlund; Rafael L Morais; Clarissa A Bittencourt; Carlos A Fonzar; Viviane A Sant'Anna; Ieda L Maugeri; Joao B Pesquero; Maria C Izar

doi:10.1016/j.athplu.2022.03.002

Atherosclerosis severity in patients with familial hypercholesterolemia: The role of T and B lymphocytes

Atheroscler Plus. 2022 Mar 18:48:27-36. doi: 10.1016/j.athplu.2022.03.002. eCollection 2022 Apr.

Authors

Waleria T Fonzar¹, Francisco A Fonseca¹, Henrique A Fonseca^{1

2}, Tuany P Silva¹, Alfredo A Rodrigues¹, Daniela Teixeira³, Mayari E Ishimura³, Maria E Coste¹, Carolina N França^{1

4}, Henrique T Bianco¹, Magnus Gidlund⁵, Rafael L Morais⁶, Clarissa A Bittencourt⁶, Carlos A Fonzar¹, Viviane A Sant'Anna¹, Ieda L Maugeri³, Joao B Pesquero⁶, Maria C Izar¹

Affiliations

¹ Department of Medicine, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
² Academic Research Organization - Hospital Albert Einstein, São Paulo, SP, Brazil.
³ Department of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
⁴ Universidade Santo Amaro, São Paulo, SP, Brazil.
⁵ Department of Immunology, Universidade de São Paulo, São Paulo, SP, Brazil.
⁶ Department of Biophysics, Universidade Federal de São Paulo, São Paulo, SP, Brazil.

Abstract

Background and aims: Familial hypercholesterolemia (FH) is characterized by lifelong exposure to high LDL-c concentrations and premature atherosclerotic cardiovascular disease; nevertheless, disease severity can be heterogeneous.We aimed at evaluating if the immune-inflammatory system could modulate atherosclerosis burden in FH.

Methods: From a cohort of subjects with confirmed FH (Dutch Lipid Clinic Network and genotype), 92 patients receiving high-intensity lipid-lowering therapy (statin ± ezetimibe) were included. The extension and severity of coronary atherosclerosis was assessed by standardized reporting systems (CAD-RADS) for coronary computed tomography angiography (CCTA) and coronary artery calcium (CAC) scores. Lipids, apolipoproteins, anti-oxLDL and anti-apolipoprotein B-D peptide (anti-ApoB-D) autoantibodies (IgM and IgG), lymphocytes subtypes, platelet, monocyte and endothelial microparticles (MP), IgM levels (circulating or produced by B1 cells) and cytokines in the supernatant of cultured cells were determined. Multiple linear regression models evaluated associations of these biomarkers with CAC and CAD-RADS scores.

Results: In univariate analysis CAC correlated with age, systolic blood pressure, TCD4+ cells, and titers of IgM anti-ApoB-D. In multiple linear regression [ANOVA F = 2.976; p = 0.024; R² = 0.082), CD4+T lymphocytes (B = 35.289; beta = 0.277; p = 0.010; 95%CI for B 8.727 to 61.851), was independently associated with CAC. CAD-RADS correlated with age, systolic blood pressure, titers of IgM anti-ApoB-D, and endothelial MP in univariate analysis. In multiple linear regression, [ANOVA F = 2.790; p = 0.032; R² = 0.119), only age (B = 0.027; beta = 0.234; p = 0.049; 95% CI for B 0.000 to 0.053) was independent predictor.

Conclusions: In subjects with FH, under high-intensity lipid-lowering therapy, age and CD4+T cells were associated to atherosclerosis burden.

Keywords: Apolipoprotein B-D peptide; CD4+T cells; Coronary computed tomography angiography; Familial hypercholesterolemia; Immune system.