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

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.