Circulating SerpinA3 as a novel indicator of cardiovascular dysfunction after anthracycline chemotherapy

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