血管紧张素受体/脑啡肽酶抑制剂在 CRTd 无反应者中的作用：从表观遗传学到临床旁支。
Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside.
机构信息
Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Cardiovascular and Arrhythmias Department "Gemelli Molise", Campobasso, Italy; Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Rome, Italy.
出版信息
Pharmacol Res. 2022 Aug;182:106303. doi: 10.1016/j.phrs.2022.106303. Epub 2022 Jun 10.
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.
目的
我们评估了血管紧张素受体/脑啡肽酶抑制剂（ARNI）是否可以降低心脏再同步治疗除颤器（CRTd）无反应者 12 个月随访时的心力衰竭（HF）住院和死亡风险，同时调节与 CRTd 无反应者不良心脏重构相关的微小 RNA（miRs）。
背景
以左心室射血分数（LVEF）降低、左心室收缩末期容积（LVESv）增加和 6 分钟步行试验（6MWT）减少为特征的不良心脏重构是 CRTd 无反应者的重要病理机制，并且可能与 miRNA（miRs）的变化有关，miRs 可调节心脏纤维化、细胞凋亡和肥大。
方法
在 CRTd 无反应者中，根据是否使用 ARNI 将患者分为 ARNI 使用者和非 ARNI 使用者，在基线和 1 年随访时评估 miR 水平和临床结局（LVEF、心脏死亡和 6MWT）。
结果
在基线时，非 ARNI 使用者（n=106）和 ARNI 使用者（n=312）之间的炎症标志物、miR-18、miR-145 和 miR-181 水平无差异（p>0.05）。在 1 年随访时，ARNI 使用者与非 ARNI 使用者相比炎症标志物（p<0.01）和 miR-181 水平（p<0.01）最低，miR-18（p<0.01）和 miR-145（p<0.01）水平最高。在 1 年随访时，ARNI 使用者与非 ARNI 使用者相比，LVEF（p<0.01）和 6MWT（p<0.01）的增加更大，LVESv（p<0.01）的减少更显著。Cox 回归分析表明，基于 ARNI 的治疗可增加 CRTd 抗重构作用的可能性。根据症状改善、超声心动图和功能分类改善，ARNI 使用者中有 37 例（34.9%）成为应答者，而非 ARNI 使用者中仅有 20 例（6.4%）成为应答者。
结论
ARNI 可能影响调节与 CRTd 不良心脏重构反应相关的微小 RNA（miRs）的表观遗传机制。
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