Exploiting the anti-fibrotic effects of statins on thoracic aortic aneurysm progression: results from a meta-analysis and experimental data

Abstract

Aims: Thoracic aortic aneurysm (TAA) that progress to acute aortic dissection is often fatal and there is no pharmacological treatment that can reduce TAA progression. We aim to evaluate statins' effects on TAA growth rate and outcomes using a meta-analysis approach.

Methods and results: A detailed search related to the effects of statins on TAA was conducted according to PRISMA guidelines. The analyses of statins' effects on TAA growth rate were performed on 4 studies (n = 1850), while the impact on outcomes was evaluated on 3 studies (n = 2,867). Patients under statin treatment showed a reduced TAA growth rate (difference in means = -0.36 cm/year; 95%CI: -0.64, -0.08; p = 0.013) when compared to controls, patients not taking statins. Regarding the outcomes (death, dissection, or rupture of the aorta, and the need for operative repair), statins exhibited a protective effect reducing the number of events (log odds ratio = -0.56; 95%CI: -1.06, -0.05; p = 0.030). In vitro, the anti-fibrotic effect of atorvastatin was tested on vascular smooth muscle cells (VMSC) isolated from patients with TAA. Our results highlighted that, in transforming growth factor beta 1 (TGF-β1) pro-fibrotic condition, VSMC expressed a significant lower amount of collagen type I alpha 1 chain (COL1A1) when treated with atorvastatin (untreated = +2.66 ± 0.23 fold-change vs. treated = +1.63 ± 0.09 fold-change; p = 0.014).

Conclusion: Statins show a protective effect on TAA growth rate and adverse outcomes in patients with TAA, possibly via their anti-fibrotic properties on VSMC. Given the current lack of effective drug treatments for TAA, we believe our findings highlight the need for more in-depth research to explore the potential benefits of statins in this context.

Keywords: fibrosis; outcomes; statins; thoracic aortic aneurysm; vascular smooth muscle cells.

FIGURE 1

Prisma Flow Chart. The flow chart represents the number of studies evaluated according to PRISMA guidelines.

FIGURE 2

Forest plots of the statin effect on thoracic aorta aneurism (TAA) growth rate and outcomes in TAA patients. (A) TAA grown rate was evaluated with the standardized difference in means (SMD) between baseline and follow-up, (B) while the effect of statins on outcomes was evaluated with log odds ratio (logOR). The diamond represents the estimated overall effect, while the squares represent each study with its 95% CI.

FIGURE 3

In vitro atorvastatin treatment of human aortic VSMC limits collagen I expression in pro-fibrotic conditions. (A) Representative images of immunofluorescence assay for COL1A1 (green) on human aortic VSMC in presence or absence of TGF-β1. The nuclei have been stained with Hoechst (in blue). Scale bar = 200 µm. Magnification = ×20. (B) Immunofluorescence densitometric quantification of VSMC treated with vehicle (white bar), atorvastatin (Atorva, yellow bar), TGF-β1 (blue bar), and TGF-β1 + atorvastatin (green bar). Collagen I quantification data are shown as mean ± SEM, n = 3 (without atorvastatin) and n = 6 (with atorvastatin). One-way ANOVA: ***p = 0.0001 (red line). Tukey’s multiple comparison post-test: **p < 0.01; ***p = 0.0001. (C) Western blot images of COL1A1 expression levels in total protein extracts of human aortic VSMC. GAPDH has been used as loading control. (D) Western blot relative densitometric quantification of VSMC treated with vehicle (white bar), atorvastatin (Atorva, yellow bar), TGF-β1 (blue bar), and TGF-β1 + atorvastatin (green bar). Data are shown as mean ± SEM, n = 5. One-way ANOVA: **p < 0.01 (red line). Tukey’s multiple comparison post-test: *p < 0.05.