Abstract 17087: VNS Induced Early Suppression of the Excessive Inflammatory Response May Contribute to its Beneficial Effects on Chronic Heart Failure
Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF, the central mechanism remains unclear. Since VNS exerts powerful anti-inflammatory effects, we investigated how VNS impacts on the inflammatory regulation and the development of CHF.
Methods: In 8 weeks old Sprague-Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI. We adjusted the intensity of VNS below the threshold of bradycardia (20 Hz, 1.5±0.9 volts, 10 sec on, 50 sec off). In the first group (EARLY) (CHF: n=8, VNS: n=13), we continued VNS for 3 days and evaluated the early impact of VNS on inflammation on the 3rd day. In the second group (LATE) (CHF: n=13, VNS: n=13), we continued VNS for 4 weeks and evaluated cardiac remodeling and function on the last day.
Results: In EARLY, hemodynamic parameters or plasma BNP as an index of CHF did not change significantly. In contrast, VNS halved the invasion of CD 68 positive cells in the left ventricle (LV) (CHF: 295.1±142.1, VNS: 110.7±59.6 counts/mm2, p<0.01), and markedly reduced interleukin-1β (IL-1β) not only in plasma (CHF: 75.7±27.6, VNS: 32.9±6.8 pg/mL, p<0.01) but also in the heart (CHF: 13.2±4.6, VNS: 9.3±2.4 pg/mg, p<0.05) and spleen (CHF: 170.2±65, VNS: 115.4±58.8 pg/mg, p<0.05). TNF-α, IL-6, HMGB-1 and CRP remained unchanged. In addition, VNS significantly reduced the expression of TGF-β in LV which is a key mediator of fibroblast activation (CHF: 31±4.0, VNS: 16.6±2.0 %, p<0.01). In LATE, VNS significantly decreased cardiac fibrosis (Masson’s trichrome stain) (CHF: 4.4±0.7, VNS: 2.9±1.1 %, p<0.01), heart weight (CHF: 3.7±0.5, VNS: 3.2±0.5 g/kg, p<0.01) and LVEDP (CHF: 24.2±5.0, VNS: 17.5±7.1 mmHg, p<0.01), suggesting that VNS prevented cardiac remodeling and preserved LV function.
Conclusion: VNS significantly decreased the invasion of macrophage, IL-1β and TGF-β production from the beginning of VNS initiation, and resulted in the decrease of cardiac fibrosis and the improvement of cardiac remodeling as well as cardiac function. VNS induced early suppression of the excessive inflammatory response may lead to its late beneficial effects on CHF.
Author Disclosures: A. Nishizaki: None. K. Saku: None. T. Kishi: None. T. Ide: None. K. Sunagawa: None.
- © 2015 by American Heart Association, Inc.