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

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.