Background:Endothelial dysfunction commonly co-exists with chronic heart failure (CHF). However, its impact on CHF patients remains unclear. The “Endothelial activation and stress index” (EASIX)-Score is an easy to calculate score based on the routinely available laboratory parameters lactate dehydrogenase (LDH), creatinine and platelets. It has been linked to Endothelial dysfunction. Furthermore, it has been shown to predict survival in allogeneic stem cell transplantation patients as well as in COVID-19 patients.

Methods:A total of 4243 CHF patients from the outpatients CHF registry of the University of Heidelberg, Germany with all necessary laboratory parameters were identified. EASIX was calculated using the formula LDH (U/L) x creatinine (mg/dl) / platelets (nl). Statistical analysis was performed using Microsoft Excel 2019 and Python Version 3.11.0. A p-value of <0.05 was regarded as statistically significant.

Results:The median age of the cohort was 62,4 years (IQR 53,0-70,9), 72 % were male. At baseline 63,7% of the patients were in NYHA functional classes I and II, whereas 36,3% of patients were in New York Heart Association (NYHA) functional classes III and IV. The median NTproBNP was 542 pg/ml (IQR 177- 1668) and median EASIX at baseline was 1,09 (IQR 0,75-1,65). 797 of the 4243 patients reported an EASIX >2 at baseline which has been previously validated as a cut-off. In the overall cohort, patients with an EASIX score >2 at baseline had an overall five-year survival rate of 91.2% whereas patients with an EASIX score <= 2 had an overall five-year survival rate of 95.2% (p<0,0001) (Figure 1). Subgroup analyses revealed that EASIX >2 was associated with statistically significant five-year survival rate differences for Heart Failure with reduced Ejection Fraction (HFrEF) (90.8% for EASIX <2 vs 93.6% for EASIX <=2, p<0.01) and for Heart Failure with mildy reduced and preserved Ejection Fraction (HFmrEF/HFpEF) (92.9% for EASIX >2 vs 97.4% for EASIX <=2, p=0.014). However, no statistically difference in five-year survival rates between EASIX >2 and EASIX <= 2 could be observed when patients were in NYHA functional classes III and IV at baseline (91.0% versus 91.0%, p=0.40)(Figure 2). In contrary, when patients where in NYHA functional classes I and II at baseline, a statistically significant difference for EASIX >2 in five-year survival rate was observed (92.6% versus 97.2%, p<0.0001)(Figure 2). The same phenomena could be observed when left ventricular systolic ejection fraction (LVEF) was severely reduced at baseline (LVEF <30%)(91.4% five-year survival rate for EASIX >2 vs. 91.7% for EASIX <=2, p=0.24) and when NTproBNP at baseline was >1000pg/ml (90.8% versus 90.0%, p=0.48).


Figure 1: Five-year survival rate of patients with EASIX >2 and <= 2.                      Figure 2: Five-year surival rate of patients with EASIX >2 and <=2 seperated by NYHA classes at baseline.

Conclusions:Endothelial dysfunction characterized by EASIX is associated with lower survival in a cohort of CHF patients. However, while it is associated with differences in survival rates for the different heart failure classifications (HFrEF/HFmrEF and HFpEF), no association between EASIX and survival rate was observed when patients where in advanced NYHA classes, had severely reduced LVEF or high NTproBNP values at baseline.