HCV infection increases CVD risk through several mechanisms, including insulin resistance, hepatic steatosis, and increased chronic inflammation and immune activation [15].
There are countless risk score calculators and charts that aim to predict 10-year CVD risk in the general population. However, serum lipids, which are incorporated in most CVD risk scores, including the Framingham risk score, are reduced in the setting of chronic liver disease and may therefore underestimate CVD risk in infected persons [16]. This highlights the need for alternative means to estimate CVD risk in chronic HCV-infected patients and the validation of non-hepatically produced CVD biomarkers for this purpose.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel inflammatory marker that has been found to be a CVD risk marker independent of traditional risk factors, including LDL and hsCRP [17]. It is characterized by high vascular endothelial specificity and low biovariability [18].
Regarding changes in serum lipids, this study illustrates low or optimal levels of baseline total cholesterol, LDL, and HDL with a statistically significant increase after SVR achievement (p < 0.001), regardless of fibrosis, compared to non-SVR patients, who experienced an insignificant change in their lipid profile parameters 12 weeks after the end of treatment. It is apparent that successful eradication of HCV promotes normalization of the cellular function of hepatocytes improving hepatic lipid production. This highlights the strong association between HCV and lipid levels. A limitation associated with this finding is that the present study did not assess the diet, physical activity level, waist circumference, and family history of patients, which are crucial factors that influence lipid metabolism.
Notably, lipid profile components were found to be significantly lower in cirrhotic patients, a finding which is in accordance with several other studies that demonstrated similar results [19,20,21,22]. It is apparent that successful eradication of HCV promotes normalization of the cellular function of hepatocytes improving hepatic lipid production, reflecting the strong association and interaction between HCV and lipid levels. A limitation associated with this finding is that the present study did not assess the dietary habits, physical activity, waist circumference, and family history of patients, which are crucial factors that influence lipid metabolism.
On the other hand, the current study demonstrated a significant decrease in Lp-PLA2 concentration after DAA therapy in patients who experienced SVR, while patients who did not achieve SVR experienced a rise in Lp-PLA2, yet this increase was of no statistical significance. This finding is in accordance with a study conducted by Chew et al. [23]. It is a distinct finding that might be explained by the ongoing HCV viremia, which in turn augments hepatic inflammation, and promotes further systemic immune activation and inflammation.
As per the Framingham risk score, 70% of patients were defined as low risk, with only 30% classified as moderate/high risk at baseline. Furthermore, there was no significant difference in calculated risk scores and risk stratification into each group after treatment as compared to baseline, indicating a lack of any correlation between HCV clearance and this score.
On the contrary, using a cut-off value of >235 ng/ml for Lp-PLA2 mass, 17.78% of patients were found to be low risk, with 82.2% of patients identified as high risk at baseline. A significant decline in the number of patients classified as high risk was observed after treatment with DAAs, from 82.2 to 60%, with a consequent rise in the number of low-risk patients to 40% post-treatment (p = 0.002). Comparable results were demonstrated by Chew et al., who conducted a study comprising 54 HCV/HIV co-infected patients administered peginterferon (PEG)/ribavirin (RBV) for 72 weeks. At baseline, there was no difference in CVD risk class by Lp-PLA2 level, whereas, after treatment, Lp-PLA2 levels decreased, although not statistically significantly, amongst SVRs (median change = −17.5 ng/ml [IQR, −67.0 to 47.0]) but not non-SVRs (median change = 9.50 ng/ml [IQR, −49.0 to 67.0]). There was a statistically significant difference in CVD risk class distribution by Lp-PLA2 level at 24 weeks after the end of treatment, with 25 of 27 (93%) of the non-SVR group in the high-risk category compared with 17 of 27 (63%) of the SVR group (p = 0.021) [23]. Another study conducted by Chew et al. aimed to predict CVD risk in HCV-infected and HCV non-infected patients using the Framingham risk score. In unadjusted analyses, the Framingham risk score was similar between both groups (p = 0.192), while adjusting for CVD risk factors overlooked by the Framingham risk score (age, race, BMI, chronic kidney disease, drug and alcohol use, and HIV status), HCV infection was associated with minimally lower risk score (p < 0.001) [24]. This suggests that the Framingham risk score may underestimate CVD risk in these patients, which is in accordance with our study.
A lack of association of Lp-PLA2 with the degree of liver disease was evident in the present study as the difference in Lp-PLA2 concentration between cirrhotic and non-cirrhotic patients was statistically insignificant (S = 0.463), suggesting that it may be less confounded by hepatic dysfunction as opposed to hepatically produced CVD biomarkers.
Lp-PLA2 concentration was found to show a significant positive correlation with age, smoking, BMI, hypertension, diabetes, FBG, and HbA1c level. Gender differences in Lp-PLA2 levels were also found; men had significantly higher levels than women (358.018 ± 77.133 vs. 271.8 ± 51.467 ng/ml; p < 0.001). Lower Lp-PLA2 levels in women could be explained by the fact that estrogen hormone causes down-regulation of Lp-PLA2 expression due to lower concentrations of LDL cholesterol in women or estrogen-related decrease in platelet-activating factor acetylhydrolase activity [25]. Of note, estrogen replacement therapy could significantly reduce Lp-PLA2 activity in healthy post-menopausal women [26], while administration of steroids with progesterone-like activity increases Lp-PLA2 activity [27]. Additionally, smoking may increase the carrier (LDL) and the substrate (oxidized LDL) for Lp-PLA2 [28].
Finally, our study demonstrates the diagnostic performance of the best cut-off values of baseline AST, ALT, serum albumin, platelet count, and liver stiffness score in the prediction of cardiovascular disease risk in chronic HCV-infected patients. A cut-off value of >28 IU/l for ALT yielded the highest sensitivity (82.43%) in predicting CVD risk, while an albumin level ≤3.7 g/dl was most specific (93.75%) with the highest positive predictive value (96.6%).
We have to declare that the interpretation of the favorable changes in Lp-PLA2 mass was hindered by the lack of validation of the biomarker for CVD risk prediction in the context of HCV infection and the inability to correlate biomarker levels with hard outcomes such as CVD events or valid alternative means. Despite these limitations, our data remain informative, and further investigation that aims to test the predictive utility of both non-hepatic and hepatic CVD biomarkers and quantifying the potential benefit of HCV treatment on CVD is warranted.