ACE inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm

Abstract

Background: Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors.

Methods and results: Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2-4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-[Formula: see text], and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: -0.24 mm (95% CI: -0.90-0.45, P = NS).

Conclusions: ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth.

Trial registration: Nederlands Trial Register 1345.

Figure 1. Aneurysm wall protein interleukin-6, interleukin-8, and monocyte chemoattractant protein 1 content.

(*) levels significantly lower in Ramipril-treated individuals (P<0.014 and P<0.008 for IL-8 and MCP-1 respectively). Non-treated controls (white bars); Ramipril-treated patients (grey bars).

Figure 2. Effect of ramipril on aneurysm wall leucocyte content.

Semi-quantitative analysis of aortic wall monocyte/macrophage (CD68), neutrophil (myeloperoxidase (MPO)), B-cell (CD20), plasma cell (CD138), T-cell (CD3), T-helper cell (CD4), and cytotoxic T-cells (CD8). Cell counts are based on reflect the number of double positive cells per 6 medium power fields. Cell content is expressed as the number of cells per mm². Non-treated controls (white bars); ramipril-treated patients (grey bars). *P<0.009.

Figure 3. Ramipril reduces (P<0.004) macrophage activation as assessed by CD68/HLA-Dr double staining and increases aortic wall M2 content (CD68/CD163 double positive cells, P<0.006) content, thus resulting in a shift in the M1/M2 balance (P<0.002).

Cell counts are based on the number of double positive cells per 6 medium power fields. Cell content is expressed as the number of cells per mm². Non-treated controls (white bars); ramipril-treated patients (grey bars).

Figure 4. Similar aneurysm progression in AAA patients using an ACE inhibitor (dashed line, n = 82) and those not using an ACE-inhibitor (solid line, n = 204) (data from the PHAST study¹⁷).

The mean 18 month difference between AAA patients on an ACE inhibitor and those not was −0.24 mm (95% CI: −0.90–0.45 mm).