Abstract 17556: The Symptom Limited Up-titration of VNS May Result in Neural Damage, Thus Too Strong to Benefit Chronic Heart Failure
Background: Vagal nerve stimulation (VNS) improves chronic heart failure (CHF) in animals and in human. Although the stimulus intensity was up-titrated to the symptomatic threshold such as twitching and cough, whether such symptom-limited threshold exerts maximum benefits for CHF remains unknown. In this study we investigated the dose response of VNS for CHF after large myocardial infarction (MI) in rats.
Methods: In 8 weeks Sprague-Dawley rats, we created large MI. We implanted a device for VNS and started stimulation from 2 weeks after MI (Sham: n=21, C-VNS: n=15, H-VNS: n=16). In the conventional stimulation group (C-VNS), we up-titrated VNS until it reached the symptom limits. In the second group, we halved VNS intensity (H-VNS). To evaluate the early impact of VNS on inflammatory responses, we compared the macrophage invasion and plasma inflammatory cytokines at 3 days after VNS. 4 weeks after VNS, we evaluated its chronic effects on hemodynamics and CHF parameters.
Results: At 3 days after VNS, both C-VNS and H-VNS significantly reduced the number of inflammatory macrophages in the left ventricle (Sham: 433±84, C-VNS: 95±41, H-VNS: 135±61 pg/mL, p<0.05) and plasma interleukin 1β(Sham: 78.5±44.5, C-VNS: 36.7±21.9, Half: 32.9±6.8 pg/mL, p<0.05) without changing hemodynamics. 4 weeks after VNS, both H-VNS and C-VNS notably reduced biventricular weight (Sham: 3.8±0.3, C-VNS: 3.4±0.3, H-VNS: 3.2±0.5 mmHg, p<0.05), LV end-diastolic pressure (Sham: 24.5±1.1, C-VNS: 21.3±1.7, H-VNS: 17.5±2.3 mmHg, p<0.05) and brain natriuretic peptide (Sham: 432±165, C-VNS: 233±123, H-VNS: 129±55 pg/mL, p<0.05). The impacts of VNS on those parameters were stronger in H-VNS than in C-VNS. Histological studies showed that C-VNS halved the number of myelinated vagal fibers (Sham: 244±43, C-VNS: 104±60, H-VNS: 187±63/mm2, p<0.01), indicating that the C-VNS induced the significant neural damage.
Conclusion: In the early phase, both C-VNS and H-VNS equally suppressed the inflammatory responses. In contrast, in the late phase, H-VNS outperformed C-VNS in improving CHF suggesting that the neural damage in C-VNS attenuated the benefits of VNS. The symptom limited up-titration of VNS may result in overdose of VNS, thus too strong to maximally benefit patient with heart failure.
Author Disclosures: A. Nishizaki: None. K. Saku: None. K. Sakamoto: None. T. Kishi: None. T. Akashi: None. T. Takehara: None. Y. Oga: None. K. Fujii: None. T. Ide: None. K. Sunagawa: None.
- © 2014 by American Heart Association, Inc.