Link between plasminogen activator inhibitor-1 and cardiovascular risk in chronic hepatitis C after viral clearance

Abstract

The pathophysiological implications of plasminogen activator inhibitor-1 (PAI-1) in HCV infection remain obscure. This prospective study evaluated 669 HCV patients, of whom 536 had completed a course of anti-HCV therapy and had pre-, peri- and post-therapy measurements of various profiles, including PAI-1 levels. Multivariate analysis demonstrated, before anti-HCV-therapy, platelet count and PAI-1-rs1799889 genotype were associated with PAI-1 levels. Among patients with a sustained virological response (SVR, n = 445), platelet count was associated with PAI-1 level at 24 weeks post-therapy. GEE analysis showed that PAI-1-rs-1799889 and interferon-λ3-rs12979860 genotypes affected PAI-1 levels early and late in therapy, respectively. At 24 weeks post-therapy, higher lipid, brain natriuretic peptide, homocysteine and PAI-1 levels and PAI-1 activity were noted only in SVR patients compared with pre-therapy levels. Within 24 weeks post-therapy, 2.2% of the SVR (mean age: 57.8 yr; 8 smoking males; the 2 females had pre-therapy hypercholesteremia or cardiovascular family history of disease) and 0% of the non-SVR patients experienced a new cardiovascular event. Platelet counts consistently correlated with PAI-1 levels regardless of HCV infection. PAI-1-rs-1799889 and interferon-λ3-rs12979860 genotypes mainly affected PAI-1 levels longitudinally. Within 24 weeks post-anti-HCV therapy, the SVR patients showed increasing PAI-1 levels with accelerating cardiovascular risk, especially the vulnerable cases.

Figure 1. Longitudinal trends in plasminogen activator inhibitor-1 (PAI-1) levels.

The included patients with chronic hepatitis C were stratified according to (A) sex (male: 1; female: 0), (B) PAI-1-rs-1799889 genotype (4 G/4 G genotype: 1; non-4G/4 G genotype: 0) and (C) IFNL3-rs-12979860 genotype (CC genotype: 1; non-CC genotype: 0). The blood-drawing time points were as follows: 1, 2 weeks before therapy; 2, after 4 weeks of therapy; 3, after 12 weeks of therapy; 4, after 24 weeks of therapy; 5, after 36 weeks of therapy; 6, after 48 weeks of therapy; 7, after 60 weeks of therapy; and 8, after 72 weeks of therapy.

Figure 2. Associations between independent factors and plasminogen activator inhibitor-1 (PAI-1) levels in pre-, peri- and post-anti-hepatitis C virus therapy stages.

The tips of the black arrowheads indicate dependent factors, and the bases of the black arrowheads indicate independent factors. BMI: body mass index; TGs: triglycerides; Plt: platelet; PAI-1 SNP: PAI-1-rs-1799889 genotype; TC: total cholesterol; Tx: anti-HCV therapy; eGFR: estimated glomerular filtration rate; Sex: male sex; APRI: aspartate aminotransferase to platelet ratio index; HOMA-IR: homeostasis model assessment-estimated insulin resistance; IFNL3: interferon λ3; TC: total cholesterol.

Figure 3. Immunohistochemical studies of hepatic plasminogen activator inhibitor-1 (PAI-1) levels.

Representative livers from a chronic hepatitis C (CHC) patient with severe fibrosis and some inflammation (A, 100X; B, 200X) and another CHC patient with severe inflammation, steatosis and mild fibrosis (C, 100X; D, 200X) before the initiation of anti-hepatitis C virus therapy. A liver specimen from a normal subject was stained for PAI-1 (E, 100X; F, 200X) and served as a negative control (without HCV infection). A hepatocellular carcinoma specimen served as a positive control for PAI-1 staining (G, 100X; H, 200X). The arrows indicate PAI-1-positive stained cells. Black arrows: biliary and endothelial cells; red arrows: malignant hepatocytes.