Abstract 18679: Sympathetic Nerve Blocks Promote an Anti-Inflammatory Response by Activating the Jak2-stat3-Mediated Signaling Cascade: A Novel Mechanism With Clinical Implications
Introduction: Myocarditis is a major risk factor for heart failure and sudden death. The cholinergic anti-inflammatory pathway (CAIP) is a complex immune mechanism that regulates peripheral inflammatory responses and can be triggered by the central nervous system.
Hypothesis: Sympathectomy’s ability to attenuate inflammation and its potential mechanism of action are unknown.
Methods: Experimental autoimmune myocarditis (EAM) was produced by injecting 2 mg of porcine cardiac myosin into footpads. Fifty-two rats were assigned to the normal control group (control, n=10), the EAM group (Myo, n=15), the sympathectomy plus EAM group (MyoNB, n=15), the β-blocker pus EAM group (MyoBB, n=9), and the only sympathectomy group (NB, n=8). Relevant signaling pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, electrophysiological changes, and cytokine levels.
Results: In the Myo group, 4 (27%) rats died suddenly at 14 ± 4 days after acute myocarditis and 7 (47%) surviving rats had arrhythmia. However, no rat died and had arrhythmia in the control or MyoNB groups (p=0.02). Compared with control, left ventricular dysfunction and higher levels of inflammation such as Cox2, iNOS, TNF-α, IL-6, and HMGB1 increase (P<0.05 versus control) and increased fibrosis with slower conduction velocity (CV; P<0.01 versus control) were observed in Myo, but not in MyoNB. Compared with control (100%), the Myo group showed reduced phosphate/total STAT3 (0.5±0.1 times, p=0.001) and JAK2 (0.5±0.0 times, p=0.01). However, MyoNB showed significantly enhanced JAK2 activation (2.2±0.1 times, p=1.00) followed by STAT3 phosphorylation (2.2 ± 0.2 times, p=1.00) with the increased secretion of acetylcholine (105±1%, p=0.03). α7nAChR expression was increased in Myo groups. In addition, the same trends in levels of protein expression were observed in the lungs, liver and spleen containing innate immune cells.
Conclusions: Sympathectomy increased survival and showed antiarrhythmic effects along with the reduction of inflammation in EAM models via activation of the JAK2-STAT3-mediated signaling cascade. It represents an exciting opportunity to develop new and novel therapeutics to attenuate cardiac inflammation.
Author Disclosures: H. Park: None. H. Park: None. H. Kim: None. M. Kim: None. N. Kim: None. H. Pak: None. M. Lee: None. B. Joung: None.
- © 2016 by American Heart Association, Inc.