Perivascular inflammation is critically involved in the progression of aortic aneurysms in Marfan syndrome

Abstract Background Perivascular inflammation is implicated in the development of vascular diseases, but its contribution to the structural abnormalities within the aorta in Marfan syndrome (MFS) remains unclear. Objectives The aim of this study is to elucidate the pathophysiological role of perivascular inflammation in aortic dilatation in MFS. Methods Periaortic tissue inflammation in patients with MFS and Fbn1C1041G/+ mice was assessed through immunohistochemical staining for immune cells and qRT-PCR analysis of inflammatory cytokines. The impact of perivascular inflammation on aortic dilatation was examined using a high-fat diet (HFD) to induce metabolic stress in perivascular adipose tissue (PVAT) in Fbn1C1041G/+ mice. These mice were also treated with low-dose pitavastatin (0.3 mg/kg/day) which exerts anti-inflammatory effects on adipose tissues. For clinical assessment of perivascular inflammation, we developed a machine learning-based automated analysis program to calculate the perivascular fat attenuation index of the ascending aorta (AA-FAI), correlating with periaortic fat inflammation. The AA-FAI was calculated in 159 non-hereditary connective tissue disorders (HCTDs) patients, 36 MFS patients, and 9 Loeys–Dietz syndrome (LDS) patients. The correlation between aortic diameter expansion rate measured by ultrasound imaging and the AA-FAI was examined. Results Both MFS patients and Fbn1C1041G/+ mice showed a marked accumulation of macrophages in the periaortic tissue, along with elevated inflammatory cytokines (respectively; p 0.05). In Fbn1C1041G/+ mice, HFD feeding promoted periaortic inflammation and aortic dilatation resulting in elastic fiber fragmentation, fibrosis, proteoglycan accumulation, and activation of MMP and TGF-b downstream targets in the tunica media. These pathological changes were inhibited by low-dose pitavastatin without altering blood lipid parameters (respectively; p 0.05). The AA-FAI was significantly higher in HCTDs patients, including MFS and LDS, compared to non-HCTDs patients (-52.90 ± 12.69 HU, -51.70 ± 7.99 HU vs -62.02 ± 8.54 HU, respectively; p 0.0001). An elevated AA-FAI was associated with accelerated aortic enlargement in MFS patients (R2 = 0.332, p = 0.039). The AA-FAI was lower in the statin group (non-statin use, -60.46 ± 8.76 HU vs statin use, -65.37 ± 6.84 HU; p = 0.039). Conclusions These findings underscore the contribution of perivascular inflammation to aneurysm formation in MFS and its therapeutic implications for managing MFS-associated vascular events.