Targeted Ganglionated Plexi Ablation With Nanoformulated Calcium Suppresses Postoperative AF Via Vagosympatholytic and Anti-Inflammatory Effects

IF 8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC. Clinical electrophysiology Pub Date : 2025-01-01 DOI:10.1016/j.jacep.2024.09.035

Ehsan Jafree MD , Michael O’Quinn MD, PhD , Pouria Shoureshi MD , Brianna Rose BA , Li Wang PhD , Na Nguyen BS , Tam Nguyen MD, PhD , Kenneth J. Dormer PhD , Kytai T. Nguyen PhD , Anindita Das PhD , Mohammed Quader MD, PhD , Vigneshwar Kasirajan MD , Karoly Kaszala MD, PhD , Kenneth A. Ellenbogen MD , Jose F. Huizar MD , Alex Y. Tan MD

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引用次数: 0

Abstract

Background

The mechanisms underlying postoperative atrial fibrillation (POAF) remain unclear.

Objectives

The aim of this study was to test the hypothesis that targeted chemical ganglionated plexi (GP) modulation of all major left atrial–pulmonary vein GP using novel nanoformulated calcium chloride (nCaCl₂) can reverse postoperative neuroelectrical remodeling by suppressing vagosympathetic nerve activity and the localized inflammatory process, both critical substrates of POAF.

Methods

In a novel canine model of POAF with serial thoracopericardiotomies, sympathetic nerve activity (SNA), vagal nerve activity (VNA) and GP nerve activity (GPNA) were recorded; spontaneous and in vivo AF vulnerability were assessed; and atrial and circulating inflammatory markers and norepinephrine (NE) were measured to determine the neuroelectrical remodeling that promotes POAF and its subsequent modulation with nCaCl₂ GP treatment (n = 6) vs saline sham controls (n = 6).

Results

The first 3 postpericardiotomy weeks demonstrated increased plasma C-reactive protein (P = 0.034) and NE (P = 0.033), decreased atrial effective refractory period (P = 0.002), and increased AF vulnerability (P = 0.0008). Subsequent nCaCl₂ GP treatment reversed atrial effective refractory period remodeling 6 weeks later (P < 0.001) and decreased AF vulnerability (P = 0.0002) and spontaneous AF burden (P = 0.03). nCaCl₂ GP treatment acutely (3 days) and chronically (6 weeks) suppressed GPNA (P = 0.008 and P = 0.04), SNA (P = 0.048 and P = 0.041), and VNA (P = 0.041 and P = 0.046) and increased mean RR interval (P = 0.046 and P = 0.034). In sham controls, the opposite changes occurred (increased GPNA [P = 0.035 and P = 0.02], SNA [P = 0.048 and P = 0.042], and VNA [P = 0.041 and P = 0.042] and decreased mean RR interval [P = 0.041 and P = 0.046]). Plasma NE (P = 0.044), left atrial interleukin-6 (P = 0.008), nerve growth factor (P < 0.001), and sympathetic nerve levels (P < 0.001) were reduced, along with apoptosis of GP neurons in the nCaCl₂ GP group.

Conclusions

Targeted GP modulation with nCaCl₂ durably suppresses POAF by inducing apoptosis of GP neurons and inhibiting GP and vagosympathetic nerve activity. This exerts a localized anti-inflammatory effect to reverse the proarrhythmic neural-electrical remodeling following thoracopericardiotomy without myocardial damage or compensatory neural regrowth.

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纳米钙靶向神经节丛消融通过迷走交感神经溶解和抗炎作用抑制术后房颤。

背景：术后心房颤动（POAF）的发生机制尚不清楚。目的：本研究的目的是验证一种假设，即使用新型纳米配方氯化钙（nacl2）靶向化学神经节丛（GP）调节所有主要的左心房-肺静脉GP，可以通过抑制迷走交感神经活动和局部炎症过程逆转术后神经电重构，这两个都是POAF的关键底物。方法：在连续胸心包切开术的新型犬POAF模型中，记录交感神经活动（SNA）、迷走神经活动（VNA）和GP神经活动（GPNA）；评估自发性和体内心房颤动脆弱性；测量心房和循环炎症标志物和去甲肾上腺素（NE），以确定神经电重构促进POAF及其随后的nCaCl2 GP治疗（n = 6）与生理盐水假对照（n = 6）。结果：心包切开术后的前3周显示血浆c反应蛋白（P = 0.034）和NE （P = 0.033）增加，心房有效不应期缩短（P = 0.002）， AF易损增加（P = 0.0008）。随后的nCaCl2 GP治疗逆转了6周后心房有效不应期重构（P < 0.001），降低了房颤易损性（P = 0.0002）和自发性房颤负担（P = 0.03）。nCaCl2 GP急性治疗（3天）和慢性治疗（6周）抑制GPNA （P = 0.008和P = 0.04）、SNA （P = 0.048和P = 0.041）和VNA (P = 0.041和P = 0.046)，增加平均RR间隔（P = 0.046和P = 0.034）。在假对照组中，发生相反的变化（GPNA [P = 0.035和P = 0.02], SNA [P = 0.048和P = 0.042], VNA [P = 0.041和P = 0.042]升高，平均RR间隔缩短[P = 0.041和P = 0.046]）。nCaCl2 GP组血浆NE （P = 0.044）、左房白细胞介素-6 （P = 0.008）、神经生长因子（P < 0.001）、交感神经水平（P < 0.001）降低，GP神经元凋亡。结论：nCaCl2靶向调节GP可通过诱导GP神经元凋亡、抑制GP和迷走交感神经活性来持续抑制POAF。这具有局部抗炎作用，可逆转胸心包切开术后的非心律失常神经电重构，且无心肌损伤或代偿性神经再生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JACC. Clinical electrophysiology CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

10.30

自引率

5.70%

发文量

250

期刊介绍： JACC: Clinical Electrophysiology is one of a family of specialist journals launched by the renowned Journal of the American College of Cardiology (JACC). It encompasses all aspects of the epidemiology, pathogenesis, diagnosis and treatment of cardiac arrhythmias. Submissions of original research and state-of-the-art reviews from cardiology, cardiovascular surgery, neurology, outcomes research, and related fields are encouraged. Experimental and preclinical work that directly relates to diagnostic or therapeutic interventions are also encouraged. In general, case reports will not be considered for publication.