Abstract Body: Hypothesis: Endothelin (ET)-1 is upregulated in hypertension and especially resistant forms of hypertension. As ET-1 is a paracrine hormone involved in renal organ damage, we investigated the correlation between eGFR and activity of the ET system in the resistant hypertensive population of the PRECISION trial (NCT03541174), in which aprocitentan, a dual endothelin ET_A/ET_B receptor antagonist, significantly reduced blood pressure and UACR. To assess activity of the ET system, ET-1 and CT-proET-1, a stable peptide and biomarker for ET-1 production, were measured in plasma.
Methods: From plasma collected at screening from the future randomized patients in PRECISION, ET-1 (n=688) and CT-proET-1 (n=100, randomly selected) were measured by ELISA and LC-MS-based assays respectively. Baseline levels of CT-proET-1 were determined on pooled plasma from healthy adults (n=70). Pearson correlation coefficient was determined between biomarkers of the ET system and eGFR.
Results: CT-proET-1 concentrations measured in patients with resistant hypertension were higher than concentrations from healthy subjects (83 vs 55 pM). In patients with an eGFR≥60 mL/min/1.73m², mean CT-proET-1 concentration was 75 pM [95% CI 70-81; n=77] as compared to 116 pM [95% CI 95-140 n=23] in patients with eGFR<60 mL/min/1.73m². In these two subgroups, mean ET-1 concentrations were 1.90 ng/L [95% CI 1.85-1.95; n=531] and 2.10 ng/L [95% CI 1.99-2.22; n=157] for patients with an eGFR≥60 and eGFR<60 mL/min/1.73m² respectively. There was an inverse correlation between CT-proET-1 and eGFR (r=-0.61, p<0.0001) and a less pronounced correlation between ET-1 and eGFR (r=-0.11, p=0.0027) (see Figure).
Conclusions: In patients with resistant hypertension, there was a strong inverse correlation between plasma CT-proET-1 and renal function, suggesting the role of the ET system not only in hypertension but also in renal damage. These data demonstrate that CT-proET-1 is a sensitive biomarker of the ET system, reflecting the production of ET-1.