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Targeted Ganglionated Plexi Ablation With Nanoformulated Calcium Suppresses Postoperative AF Via Vagosympatholytic
Ehsan Jafree1, Michael O'Quinn1, Pouria Shoureshi1
1Electrophysiology Section, Division of Cardiology, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia, USA; Pauley Heart Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
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.
Insights
Targeted modulation of ganglionated plexi (GP) with nanoformulated calcium chloride (nCaCl2) suppressed nerve activity and inflammation, effectively preventing postoperative atrial fibrillation (POAF) in a canine model.
Area of Science:
- Cardiovascular Surgery
- Neuroscience
- Pharmacology
Background:
- The mechanisms driving postoperative atrial fibrillation (POAF) are not fully understood.
- Identifying targets to prevent POAF is crucial for improving patient outcomes after cardiac surgery.
Purpose of the Study:
- To investigate if targeted chemical modulation of the ganglionated plexi (GP) using nanoformulated calcium chloride (nCaCl2) can prevent POAF.
- To determine if nCaCl2 treatment can reverse neuroelectrical remodeling by suppressing vagosympathetic nerve activity and local inflammation.
Main Methods:
- A canine model of POAF was established using serial thoracopericardiotomies.
- Measurements included sympathetic nerve activity (SNA), vagal nerve activity (VNA), GP nerve activity (GPNA), atrial effective refractory period, and in vivo AF vulnerability.
- Inflammatory markers and norepinephrine (NE) levels were assessed in atrial tissue and circulation.
Main Results:
- Post-thoracopericardiotomy, increased C-reactive protein, NE, GPNA, SNA, VNA, and AF vulnerability were observed.
- nCaCl2 treatment reversed these changes, reducing AF vulnerability and burden, suppressing nerve activity, and decreasing inflammatory markers.
- nCaCl2 induced apoptosis of GP neurons, inhibiting pro-arrhythmic remodeling without causing myocardial damage.
Conclusions:
- Targeted GP modulation with nCaCl2 offers a durable strategy to suppress POAF.
- This approach works by inducing GP neuron apoptosis and inhibiting GP and vagosympathetic nerve activity, alongside a localized anti-inflammatory effect.
- nCaCl2 effectively reverses pro-arrhythmic neural-electrical remodeling post-thoracopericardiotomy.
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