Human epididymal protein 4 reflects extracellular matrix accumulation and predicts the outcome of post-operative patients with severe aortic stenosis after transcatheter aortic valve implantation

Background/Introduction Left ventricular fibrosis is one of the features of severe aortic stenosis (AS), and it is related to prognosis after transcatheter aortic valve implantation (TAVI). It is also said that the degree of LV fibrosis can be evaluated using CT-ECV (Ref 1), but contrast-enhanced CT cannot be repeated due to the use of contrast media and cost considerations. Human epididymis protein 4 (HE4), novel fibrosis marker, is expressed only in activated fibroblast and is expected to reflect ongoing LV fibrosis. In our prior research involving AS patients undergoing surgical aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI), we revealed that HE4 is associated with residual left ventricular hypertrophy and adverse cardiac events postoperatively (Ref 2). Purpose In this study, we aimed to evaluate the association between serum HE4 levels and CT-ECV values, as well as the prognostic value of combining these parameters, in patients undergoing routine preoperative contrast-enhanced CT for TAVI. Methods We measured serum HE4 levels and CT-ECV in 85 consecutive patients who underwent TAVI at Kumamoto University Hospital from 2020 to 2022. After TAVI, the patients were followed up for 578 days (interquartile range, 364-831). We divided our subjects into the high and low HE4 groups using median value (125.0 pmol/L). The endpoint of this study was a composite of cardiovascular death and heart failure hospitalization. Results There were 29 men (34%), and the mean patient age was 85.0±4.8 years. the circulating levels of BNP, hsTnT and the serum creatinine level were significantly higher in the high HE4 group. HE4 was positively correlated with CT-ECV (r=0.39, p <0.0001) (Fig.1A), and CT-ECV was significantly higher in the high HE4 group. Linear regression analysis of factors associated with CT-ECV value demonstrated that HE4 was significantly and independently associated with CT-ECV value in a positive manner. All 85 patients had available data for analysis of mortality and cardiovascular events. During follow up period, 12 (14.1%) of the 85 patients died or were hospitalized for cardiovascular diseases. The following events were registered: cardiovascular death (n=7), and hospitalization for HF decompensation (n=5).The Kaplan-Meier curve demonstrated a significantly higher probability of the adverse events in the high HE4 group compared with the low HE4 group (log-rank p=0.02) (Fig.1B). Multivariate COX proportional hazard analysis proved HE4 to be an independent prognostic factor (hazard ratio [HR]: 7.85; 95 % confidence interval [CI]: 1.44-42.76, p = 0.017). The combination of high HE4 and high CT-ECV (cutoff value: 30.0%) identified patients with a significantly higher probability of adverse cardiovascular events (log-rank test: p=0.013) (Fig.2). Conclusions HE4 is a novel biomarker reflected cardiac fibrosis, and worth evaluating as a predictor of severe AS patients after TAVI.