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 (nCaCl) 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&#xa0;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 nCaClGP treatment (n&#xa0;=&#xa0;6) vs saline sham controls (n&#xa0;=&#xa0;6). RESULTS: The first 3 postpericardiotomy weeks demonstrated increased plasma C-reactive protein (P&#xa0;=&#xa0;0.034) and NE (P&#xa0;=&#xa0;0.033), decreased atrial effective refractory period (P&#xa0;=&#xa0;0.002), and increased AF vulnerability (P&#xa0;=&#xa0;0.0008). Subsequent nCaClGP treatment reversed atrial effective refractory period remodeling 6&#xa0;weeks later (P&#xa0;< 0.001) and decreased AF vulnerability (P&#xa0;=&#xa0;0.0002) and spontaneous AF burden (P&#xa0;=&#xa0;0.03). nCaClGP treatment acutely (3&#xa0;days) and chronically (6&#xa0;weeks) suppressed GPNA (P&#xa0;=&#xa0;0.008 and P&#xa0;=&#xa0;0.04), SNA (P&#xa0;=&#xa0;0.048 and P&#xa0;=&#xa0;0.041), and VNA (P&#xa0;=&#xa0;0.041 and P&#xa0;=&#xa0;0.046) and increased mean RR interval (P&#xa0;=&#xa0;0.046 and P&#xa0;=&#xa0;0.034). In sham controls, the opposite changes occurred (increased GPNA [P&#xa0;=&#xa0;0.035 and P&#xa0;=&#xa0;0.02], SNA [P&#xa0;=&#xa0;0.048 and P&#xa0;=&#xa0;0.042], and VNA [P&#xa0;=&#xa0;0.041 and P&#xa0;=&#xa0;0.042] and decreased mean RR interval [P&#xa0;=&#xa0;0.041 and P&#xa0;=&#xa0;0.046]). Plasma NE (P&#xa0;=&#xa0;0.044), left atrial interleukin-6 (P&#xa0;=&#xa0;0.008), nerve growth factor (P&#xa0;< 0.001), and sympathetic nerve levels (P&#xa0;< 0.001) were reduced, along with apoptosis of GP neurons in the nCaClGP group. CONCLUSIONS: Targeted GP modulation with nCaCldurably 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.