Perivascular inflammation in the progression of aortic aneurysms in Marfan syndrome
Hiroyuki Sowa, … , Hiroshi Akazawa, Issei Komuro
Hiroyuki Sowa, … , Hiroshi Akazawa, Issei Komuro
Published August 28, 2025
Citation Information: JCI Insight. 2025;10(19):e184329. https://doi.org/10.1172/jci.insight.184329.
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Research Article Cardiology Inflammation

Perivascular inflammation in the progression of aortic aneurysms in Marfan syndrome

Abstract

Inflammation plays important roles in the pathogenesis of vascular diseases. We here show the involvement of perivascular inflammation in aortic dilatation of Marfan syndrome (MFS). In the aorta of patients with MFS and Fbn1C1041G/+ mice, macrophages markedly accumulated in periaortic tissues with increased inflammatory cytokine expression. Metabolic inflammatory stress induced by a high-fat diet (HFD) enhanced vascular inflammation predominantly in periaortic tissues and accelerated aortic dilatation in Fbn1C1041G/+ mice, both of which were inhibited by low-dose pitavastatin. HFD feeding also intensifies structural disorganization of the tunica media in Fbn1C1041G/+ mice, including elastic fiber fragmentation, fibrosis, and proteoglycan accumulation, along with increased activation of TGF-β downstream targets. Pitavastatin treatment mitigated these alterations. For noninvasive assessment of perivascular adipose tissues (PVAT) inflammation in a clinical setting, we developed an automated analysis program for CT images using machine learning techniques to calculate the perivascular fat attenuation index of the ascending aorta (AA-FAI), correlating with periaortic fat inflammation. The AA-FAI was significantly higher in patients with MFS compared with patients without hereditary connective tissue disorders. These results suggest that perivascular inflammation contributes to aneurysm formation in MFS and might be a target for preventing and treating vascular events in MFS.

Authors

Hiroyuki Sowa, Hiroki Yagi, Kazutaka Ueda, Masaki Hashimoto, Kohei Karasaki, Qing Liu, Atsumasa Kurozumi, Yusuke Adachi, Tomonobu Yanase, Shun Okamura, Bowen Zhai, Norifumi Takeda, Masahiko Ando, Haruo Yamauchi, Nobuhiko Ito, Minoru Ono, Hiroshi Akazawa, Issei Komuro

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Figure 6

Effect of background factors on AA-FAI.

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Effect of background factors on AA-FAI. (A) Scatterplots showing the cor...
(A) Scatterplots showing the correlation between the expansion speed of the aortic diameter and the AA-FAI in the 2 years leading to prophylactic aortic surgery (n = 13). Patients with at least 2 follow-ups for echo cardiography within the last 2 years of imaging the analyzed CT were recruited. (B–D) Scatterplots showing the correlation between age, BMI, total cholesterol (T-chol), and the fat attenuation index to the ascending aorta (AA-FAI) in patients without enlargement of ascending aorta (age and BMI, n = 69; T-chol, n = 61). (E–G) Among the patients without enlargement of ascending aorta, the AA-FAI was compared in 2 groups according to the absence or presence of hypertension (HTN) [(–), n = 37; (+), n = 32], dyslipidemia (DLp) [(–), n = 32; (+), n = 37], and chronic kidney disease (CKD) [(–), n = 44; (+), n = 25]. The data are presented as mean ± SD. Unpaired 2-tailed t test with Welch’s correction. (H and I) Among the patients without enlargement of ascending aorta, the AA-FAI and ct-PVAT area were compared in 2 groups according to the absence or presence of statin treatment [(–), n = 52; (+), n = 17]. The data are presented as mean ± SD. *P < 0.05, unpaired 2-tailed t test with Welch’s correction. (J) The AA-FAI was compared in patients with non-HCTDs and MFS who were not taking statins (non-HCTDs, n = 121; MFS, n = 34). The data are presented as mean ± SD. ****P < 0.0001, unpaired 2-tailed t test with Welch’s correction. (K) The scheme of MFS pathology suggested by this study. Perivascular adipose tissue (PVAT) inflammation enhances TGF-β signaling in the tunica media and leads to aortic dilatation. Immune cells including macrophages that migrate into perivascular tissues due to signals of inflammatory adipokines may secret TGF-β that further enhances signaling in the tunica media. ERKs, extracellular signal-regulated kinases; HCTDs, hereditary connective tissue disorders; HFD, high-fat diet; LDS, Loeys-Dietz Syndrome; MFS, Marfan syndrome; MMPs, matrix metalloproteinases; VSMC, vascular smooth muscle cell.