Circulating SerpinA3 as a novel indicator of cardiovascular dysfunction after anthracycline chemotherapy
Authors: Boen H , Bosman M , Delrue L , Heggermont W , Guns P J , Van Den Heyning C , Heidbuchel H , Van Craenenbroeck E M , Franssen C 
Published: November 2023

Abstract

Background
Close monitoring of development of cardiovascular toxicity during anthracycline (AC) chemotherapy is crucial for early diagnosis and guidance of therapy. SerpinA3, a serine protease inhibitor, was recently described as prognostic marker for heart failure and elevated plasma levels are associated with increased mortality. The effect of AC on SERPINA3 levels in a cancer population has not been studied yet

Purpose
To investigate whether SERPINA3 plasma levels could serve as a marker for cancer therapy-related cardiac dysfunction and whether its levels are influenced by AC chemotherapy

Methods
Adult cancer patients requiring AC chemotherapy were enrolled between January 2020 and June 2022. Patients with a history of heart failure or prior cardiotoxicity were excluded. Measurement of cTnI and NT-proBNP and echocardiography (LVEF and GLS) were performed at four timepoints: before the start of AC (V1), directly after completion of chemotherapy (V2), 3 months thereafter (V3) and 1 year after V2 (V4). CTRCD was diagnosed according to the recent ESC guidelines.

Results
Fifty-one patients fulfilled inclusion criteria and agreed to participate in the study. Patients were on average 54 years old and the majority were female (80.4%).
After anthracyclines, 38 patients developed asymptomatic CTRCD, graded as mild in 29 patients and moderate (LVEF 40-49%) in patients.
SerpinA3 plasma levels at V3 were significantly higher in patients with moderate CTRCD (247.7; [196.4-428.9]) compared to patients with no CTRCD (142.7; [126.5-170.2]; p=0.004).
In patients developing moderate CTRCD, a significant increase in SerpinA3 from baseline to V2 ( 209.0 [162.025-2.7]; 313.3 [212.6- 387.1, p=0.028) and remained elevated till V3 (247.7 [196.4-428.9], p=0.038). In patients with no CTRCD SerpinA3 showed an opposite trend with no significant difference at V2 compared to V1 (190.1 [165.2-230.5] vs 196.3 [170.8-297.1]; p= 0.972), but a subsequent significant decline from V2 to V3 (142.7 [126.5-170.2]; p=0.003). In patients with mild CTRCD a similar, but non-significant trend as in no CTRCD patients was seen(211.4 [167.8-302.6] vs 218.3 [171.9-277.7]; p=0.346 vs 167.5 [140.5-286.8]; p=0.122).
These findings were confirmed by the absolute change in SerpinA3 from baseline to V4 which differed significantly in moderate CTRCD (+51.3; [7.1-176.4]) compared to both patients with no CTRCD (-47.5;[ -78.0- -35.4]; p=0.019) and patients with mild CTRCD (-52.0;[ -78.6- 32.8]; p=0.043).
In patients with moderate CTRCD SerpinA3 values at V4 remained significantly elevated in patients without full cardiac recovery 1 year after the end of chemotherapy (4/5 patients; p=0.050).

Conclusion
SerpinA3 is increased after anthracycline chemotherapy in patients with moderate CTRCD. A lasting increase of serpinA3 was observed in in patients who did not show a complete recovery of cardiac function, potentially indicative of a worse cardiac prognosis.Figure 1Figure 2