MO747: Endotrophin Levels are Extremely Elevated in Dialysis Patients with Heart Failure with Preserved Ejection Fraction (HFPEF) and are Influenced by Background Treatment with Diuretics and ARBS/ACEI
Authors: Genovese Federica , Reese-Petersen Alexander , Karsdal Morten A , López Begoña , García Fernández Nuria , Diez Javier , González Arantxa 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Endotrophin, a bioactive molecule derived from the cleavage of the collagen type VI pro-peptide, released during collagen maturation, has been associated with multiple pathogenic processes, including inflammation and fibrosis.
PRO-C6, a biomarker reflecting circulating endotrophin levels, has been associated with an adverse prognosis in multiple disease settings, including chronic kidney disease and heart failure with preserved ejection fraction (HFpEF).
Here, we assessed levels of PRO-C6 in a population of dialysis patients with and without heart failure, and we observed an association of PRO-C6 with imaging and soluble biomarkers of heart disease, presence of co-morbidities and medications.

METHOD
PRO-C6 was measured with the enzyme-linked immunosorbent assay developed by Nordic Bioscience (Denmark) in serum of 46 patients undergoing dialysis (mean age 70 years, 37% female) and with HFpEF (61%), HFmrEF (7%), HFrEF (2%) or no HF (30%) collected at the Clínica Universidad de Navarra (Spain). The samples were collected pre-dialysis. PRO-C6 was also measured in serum of 50 healthy individuals (mean age 61 years, 50% female) collected at the same site. Differences between groups were estimated with the Kruskal–Wallis test, correlations were estimated with Spearman’s rank correlation coefficient.

RESULTS
Levels of PRO-C6 were extremely elevated in the serum of dialysis patients compared with healthy individuals (81 ng/mL versus 6.3 ng/mL; P &lt; 0.0001), and also compared with previously seen levels in HFpEF patients (patients with levels above 16 ng/mL were at increased risk of worse outcome in the TOPCAT cohort).
Among the dialysis patients, patients with HFpEF had significantly increased PRO-C6 levels compared with patients with no HF (90.2 ng/mL versus 61.8 ng/mL; P = 0.03). Due to the low number of events, the numerical increase in PRO-C6 levels in patients that died, had myocardial infarction and pulmonary hypertension did not reach statistical significance.
PRO-C6 showed modest direct correlations with age, NT-proBNP, hsTNT and collagen type I C-terminal telopeptide (CITP), and a modest inverse correlation with eGFR. When looking at echo parameters, PRO-C6 was modestly directly correlated with left ventricular posterior wall thickness and relative wall thickness and modestly inversely correlated with left ventricular end diastolic volume.
Interestingly, patients treated with ARB/ACEi and diuretics presented significantly lower levels of PRO-C6 compared with those that were not receiving these drugs (64.4 ng/mL versus 90.2 ng/mL; P = 0.01 and 59.0 ng/mL versus 87.1 ng/mL; P = 0.008, respectively). Patients treated with antiplatelets on the contrary had higher levels of PRO-C6 (88.9 ng/mL versus 67.7 ng/mL; P = 0.04).

CONCLUSION
Even in a population of kidney failure patients, presenting very high levels of circulating endotrophin, the presence of HFpEF was associated with further increased levels of endotrophin. Moreover, endotrophin levels were associated with echo parameters and biomarkers reflecting diastolic disfunction and left ventricular stress and damage. We have shown here for the first time that patients treated with ARB/ACEi and diuretics present lower levels of circulating endotrophin.
PRO-C6 measuring endotrophin confirms being a biomarker of interest in HFpEF patients, even in the presence of kidney failure.