Autor:innen:
H. Fischer (Heidelberg, DE)
I. Hemmerling (Heidelberg, DE)
M. Scheller (Heidelberg, DE)
C. Müller-Tidow (Heidelberg, DE)
N. Frey (Heidelberg, DE)
F. Leuschner (Heidelberg, DE)
Introduction: Driver gene mutations of clonal hematopoesis of indeterminate potential (CHIP), as the DNMT3A loss of function mutation R882H, are frequent in cardiovascular diseases as they can lead to an elevated inflammatory status and altered functions of lymphoid and myeloid immune cells. Previous work within the working group has shown elevated blood pressure levels in mice and patients with DNMT3a mutations, suggesting a possible role in the development of arterial hypertension.
Methods: Using a MxCre model, the immunological profile of R882H-KI mice was characterized by FACS analysis of peripheral blood, cardiac and renal tissue. In order to assess hypertension-associated end organ damage, histological analysis of cardiac and renal tissue was performed evaluating both morphological changes and the extent of fibrosis. Furthermore, clinical parameters were determined to exclude a secondary genesis of hypertension and the presence of a metabolic syndrome.
Results: The proportion of B cells (19,22 % ± 7,29 % vs. 41,73 % ± 11,61 %, p = 0,0002) and natural killer cells (1,25 % ± 1,06 % vs. 2,61 % ± 0,39 %, p = 0,0458) in peripheral blood of D3a-mutant mice was significantly higher compared to wildtype controls. Besides, the proportion of naive T cells (CTL: 5,91 % ± 3,66 % vs. 17,76 % ± 7,94 %, p = 0,0199, Th: 21,80 % ± 8,83 % vs. 54,05 % ± 11,11 %, p = 0,0018) and effector memory T cells (CTL: 47,94 % ± 12,04 % vs. 27,15 % ± 5,96 %, p = 0,0166, Th: 55,32 % ± 13,75 % vs. 23,88 % ± 3,72 %, p = 0,0032) within the population of cytotoxic T cells and Th cells differed significantly. Within the leucocyte population of renal tissue, higher proportions of neutrophils (6,82 % ± 2,36 % vs. 14,03 % ± 4,58 %, p = 0,0233) and natural killer cells (0,56 % ± 0,15 % vs. 1,21 % ± 0,24 %, p = 0,0014) and lower proportions of resident monocytes (1,69 % ± 0,47 % vs. 0,81 % ± 0,44 %, p = 0,0389) and M2 macrophages (5,15 % ± 2,0 % vs. 1,56 % ± 0,54 %, p = 0,0254) were observed. However, the extent of fibrosis in kidney samples did not differ significantly. Analysis of heart slices presented a significantly higher degree of fibrosis in D3a-mutant mice (0,60 % ± 0,08 % vs. 0,71 % ± 0,06 %, p = 0,0481) and a tendency towards hypertrophy of the left ventricular lateral wall (1,34 ± 0,24 mm vs. 1,51 ± 0,06 mm, p = 0,2210) and septum (1,35 ± 0,15 mm vs. 1,55 ± 0,14, p = 0,0899). Clinical parameters (sodium, potassium, creatinine, uric acid, nor-/metanephrine, glucose, HbA1c, cholesterol, triglycerides, LDL, HDL) did not indicate the presence of a metabolic syndrome or a pathology causing secondary hypertension. Data presented as mean ± SD, WT vs. D3a-mut
Conclusions: The distribution of immune cells in peripheral blood and kidneys varied between mutation carriers and wildtype controls, possibly suggesting a higher inflammatory status and renal inflammation. Also, the higher degree of fibrosis and cardiac hypertrophy constitute important signs of hypertensive heart disease.