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. 2022 Aug:182:106303.
doi: 10.1016/j.phrs.2022.106303. Epub 2022 Jun 10.

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside

Celestino Sardu  1 , Massimo Massetti  2 , Lucia Scisciola  3 , Maria Consiglia Trotta  4 , Matteo Santamaria  5 , Mario Volpicelli  6 , Valentino Ducceschi  7 , Giuseppe Signoriello  8 , Nunzia D'Onofrio  9 , Ludovica Marfella  10 , Flavia Casolaro  11 , Michele D ' Amico  12 , Antonio Ruocco  13 , Maria Luisa Balestrieri  14 , Ciro Mauro  15 , Concetta Rafaniello  16 , Annalisa Capuano  17 , Giuseppe Paolisso  18 , Raffaele Marfella  19
Affiliations
Free article

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside

Celestino Sardu et al. Pharmacol Res. 2022 Aug.
Free article

Abstract

Objectives: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling.

Background: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy.

Methods: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users.

Results: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users.

Conclusions: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Keywords: CRTd non-responders; Clinical outcomes; HFrEF; MiRs regulation.

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