Abstract Body (Do not enter title and authors here): Background:
Natriuretic peptides (NPs) have been reported to have beneficial effects on adipose tissue, as well as the cardiovascular system and kidneys. Epicardial adipose tissue (EAT) has been recognized as an important target for the treatment of heart failure. Sacubitril/valsartan (ARNI) increases NPs by inhibiting neprilysin, but its effect on EAT has not been reported. We evaluated the impact of ARNI on EAT in patients with heart failure and compared this impact in patients with ischemic cardiomyopathy (ICM) to patients with non-ischemic cardiomyopathy (NICM).

Methods:
This study was a secondary analysis of patients enrolled in the open-label, standard treatment-controlled, randomized clinical trial (SAVE-HF) investigating the effect of ARNI in 59 stable patients with chronic heart failure and reduced left ventricular ejection fraction. Cardiovascular magnetic resonance (CMR) was performed at baseline and after 9 months. EAT was measured as the thickness of adipose tissue situated between the outer wall of the right ventricular myocardium and the visceral layer of the pericardium at a mid-ventricular level on end-diastolic short-axis cine images.

Results:
We identified 36 ICM patients and 19 NICM. There was a trend of higher prevalence of diabetes mellitus in the ICM cohort (p=0.08). Baseline EAT was similar in ICM patients (4.9 ± 1.7 mm) and NICM patients (5.1 ± 1.9 mm). In the ICM cohort, EAT was significantly reduced in the ARNI group compared with the standard treatment group (p=0.04), with an EAT reduction of 7.1%. There was an inverse relationship between the changes in EAT and atrial NP (ANP) (r=-0.39, p=0.02). After accounting for the usage of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i), the benefit of ARNI on reducing EAT remained unchanged. In contrast, ARNI was not associated with EAT reduction in the NICM cohort (p=0.9).

Conclusion:
ARNI reduced epicardial adiposity by significantly increasing circulating ANP in ICM patients, even after accounting for the usage of SGLT2-i, but it did not reduce EAT in NICM patients. These findings may suggest differential pathophysiological mechanisms of EAT adipocytes depending on the cause and pathology of heart failure.