A fully degradable triboelectric vagus nerve stimulator for attenuating cardiac remodeling and heart failure at different stages

1. Bozkurt, B. et al. Heart failure epidemiology and outcomes statistics: a report of the heart failure society of America. J. Card. Fail 29, 1412–1451 (2023).

   Google Scholar 

2. Khan, M. S. et al. Global epidemiology of heart failure. Nat. Rev. Cardiol. 21, 717–734 (2024).

   Google Scholar 

3. Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).

   Google Scholar 

4. Pesce, M. et al. Cardiac fibroblasts and mechanosensation in heart development, health and disease. Nat. Rev. Cardiol. 20, 309–324 (2023).

   Google Scholar 

5. Savarese, G. et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 118, 3272–3287 (2023).

   Google Scholar 

6. Burchfield, J. S., Xie, M. & Hill, J. A. Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation 128, 388–400 (2013).

   Google Scholar 

7. Gentile, F. et al. Treating heart failure by targeting the vagus nerve. Heart Fail Rev. 29, 1201–1215 (2024).

   Google Scholar 

8. Konstam, M. A. et al. Advances in our clinical understanding of autonomic regulation therapy using vagal nerve stimulation in patients living with heart failure. Front Physiol. 13, 857538 (2022).

   Google Scholar 

9. Bazoukis, G., Stavrakis, S. & Armoundas, A. A. Vagus nerve stimulation and inflammation in cardiovascular disease: a state-of-the-art review. J. Am. Heart Assoc. 12, e030539 (2023).

   Google Scholar 

10. Verrier, R. L., Libbus, I., Nearing, B. D. & KenKnight, B. H. Multifactorial benefits of chronic vagus nerve stimulation on autonomic function and cardiac electrical stability in heart failure patients with reduced ejection fraction. Front Physiol. 13, 855756 (2022).

    Google Scholar 

11. Gold, M. R. et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF Trial. J. Am. Coll. Cardiol. 68, 149–158 (2016).

    Google Scholar 

12. Zannad, F. et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur. Heart J. 36, 425–433 (2015).

13. Nearing, B. D., Libbus, I., Amurthur, B., KenKnight, B. H. & Verrier, R. L. Acute autonomic engagement assessed by heart rate dynamics during vagus nerve stimulation in patients with heart failure in the ANTHEM-HF trial. J. Cardiovasc. Electrophysiol. 27, 1072–1077 (2016).

14. Stavrakis, S. et al. Neuromodulation of inflammation to treat heart failure with preserved ejection fraction: a pilot randomized clinical trial. J. Am. Heart Assoc. 11, e023582 (2022).

    Google Scholar 

15. Jiang, Y., Po, S. S., Amil, F. & Dasari, T. W. Non-invasive low-level tragus stimulation in cardiovascular diseases. Arrhythm. Electrophysiol. Rev. 9, 40–46 (2020).

    Google Scholar 

16. Booth, L. C., Saseetharan, B., May, C. N. & Yao, S. T. Selective efferent vagal stimulation in heart failure. Exp. Physiol. 109, 2001–2005 (2024).

    Google Scholar 

17. Tat, T., Libanori, A., Au, C., Yau, A. & Chen, J. Advances in triboelectric nanogenerators for biomedical sensing. Biosens. Bioelectron. 171, 112714 (2021).

    Google Scholar 

18. Wang, Z. L. & Song, J. Piezoelectric nanogenerators based on zinc oxide nanowire arrays. Science 312, 242–246 (2006).

    Google Scholar 

19. Omar, R. et al. Biodegradable, biocompatible, and implantable multifunctional sensing platform for cardiac monitoring. ACS Sens 9, 126–138 (2024).

    Google Scholar 

20. Kim, Y.-J. et al. High-performing and capacitive-matched triboelectric implants driven by ultrasound. Adv. Mater. 36, 2307194 (2024).

    Google Scholar 

21. Olofsson, L. P. et al. alpha7 nicotinic acetylcholine receptor and cAMP response element binding protein are essential for prolonged monocyte deactivation by vagus nerve signaling (116.37). J. Immunol. 186, 116.37 (2011).

    Google Scholar 

22. Olofsson, P. S. et al. Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces tumor necrosis factor in endotoxemia. Bioelectron. Med. 2, 37–42 (2015).

    Google Scholar 

23. Tanaka, S. et al. Vagus nerve stimulation activates two distinct neuroimmune circuits converging in the spleen to protect mice from kidney injury. Proc. Natl. Acad. Sci. USA 118, e2021758118 (2021).

    Google Scholar 

24. Kakinuma, Y. et al. Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1α. FEBS Lett. 579, 2111–2118 (2005).

    Google Scholar 

25. Resende, R. R. & Adhikari, A. Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation. Cell Commun. Signal 7, 20 (2009).

    Google Scholar 

26. Ponikowski, P. et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (ESC)developed with the special contribution of the heart failure association (HFA) of the ESC. Eur. Heart J. 37, 2129–2200 (2016).

    Google Scholar 

27. van der Wal, M. H. L., Jaarsma, T. & van Veldhuisen, D. J. Non-compliance in patients with heart failure; how can we manage it?. Eur. J. Heart Fail 7, 5–17 (2005).

    Google Scholar 

28. Heidenreich, P. A. et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ. Heart Fail 6, 606–619 (2013).

    Google Scholar 

29. Miller, L., Birks, E., Guglin, M., Lamba, H. & Frazier, O.H. Use of ventricular assist devices and heart transplantation for advanced heart failure. Circ. Res. 124, 1658–1678 (2019).

    Google Scholar 

30. Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J. Am. Coll. Cardiol. 79, e263–e421 (2022).

    Google Scholar 

31. Borlaug, B. A. Evaluation and management of heart failure with preserved ejection fraction. Nat. Rev. Cardiol. 17, 559–573 (2020).

    Google Scholar 

32. Leopold, J. A. & Loscalzo, J. The emerging role of precision medicine in cardiovascular disease. Circ. Res. 122, 1302–1315 (2018).

    Google Scholar 

33. Roy, A. et al. Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions. FASEB J. 30, 688–701 (2016).

    Google Scholar 

34. Zhao, L. et al. Choline attenuates cardiac fibrosis by inhibiting p38MAPK signaling possibly by acting on M3 muscarinic acetylcholine receptor. Front Pharm. 10, 1386 (2019).

    Google Scholar 

35. Leib, C. et al. Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. Circ. Res 109, 130–140 (2011).

    Google Scholar 

36. Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    Google Scholar 

37. Báez-Pagán, C. A., Delgado-Vélez, M. & Lasalde-Dominicci, J. A. Activation of the macrophage α7 nicotinic acetylcholine receptor and control of inflammation. J. Neuroimmun. Pharm. 10, 468–476 (2015).

    Google Scholar 

38. Frangogiannis, N. G. The extracellular matrix in ischemic and nonischemic heart failure. Circ. Res. 125, 117–146 (2019).

    Google Scholar 

39. Floras, J. S. & Ponikowski, P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur. Heart J. 36, 1974–1982 (2015).

    Google Scholar 

40. Olshansky, B., Sabbah, H. N., Hauptman, P. J. & Colucci, W. S. Parasympathetic nervous system and heart failure. Circulation 118, 863–871 (2008).

    Google Scholar 

41. Guo, Z. et al. Neuraminidase 1 deficiency attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory via AMPK-SIRT3 pathway in diabetic cardiomyopathy mice. Int J. Biol. Sci. 18, 826–840 (2022).

    Google Scholar 

42. Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).

    Google Scholar 

Download references

Author notes

1. These authors contributed equally: Zhen Guo, Sheng-Yu Chao, Chun-Yan Kong, Ling-Ling Xu, Xi Cui.

Authors and Affiliations

1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P. R. China

   Zhen Guo, Chun-Yan Kong, Ming-Yu Wang, Yu-Lan Ma, Xiu-Jun Dai & Qi-Zhu Tang

2. Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, P. R. China

   Zhen Guo, Sheng-Yu Chao, Ling-Ling Xu, Xi Cui & Yi-Chang Quan

3. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, P. R. China

   Zhen Guo, Chun-Yan Kong, Ming-Yu Wang, Yu-Lan Ma, Xiu-Jun Dai & Qi-Zhu Tang

4. School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China

   Sheng-Yu Chao & Ling-Ling Xu

5. Vita Tech Innovation Center, Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, P. R. China

   Xi Cui & Zhou Li

6. School of Biomedical Engineering, Tsinghua University, Beijing, P. R. China

   Xi Cui & Zhou Li

7. Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, School of Engineering Medicine, Beihang University, Beijing, P. R. China

   Yuan Xi

Contributions

Z.G., S.Y.C., C.Y.K., L.L.X., and X.C. contributed equally to this work. Z.G. performed animal experiments, surgical procedures, echocardiography, and data analysis. S.Y.C. designed and fabricated the BTENG device and conducted device characterization. C.Y.K. performed histological and molecular analyses. L.L.X. optimized device fabrication and characterization. X.C. conducted electrical measurements. Y.X. performed RNA-sequencing and bioinformatics analyses. Y.C.Q., M.Y.W., Y.L.M., and X.J.D. assisted with experiments and data collection. Z.L. and Q.Z.T. conceived and supervised the project, designed experiments, secured funding, and wrote the manuscript. All authors discussed results and approved the final manuscript.

Corresponding authors

Correspondence to Zhou Li or Qi-Zhu Tang.

Competing interests

All authors declare no competing interests.

Peer review information

Nature Communications thanks Stavros Stavrakis, who co-reviewed with Maria Toumpourleka, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions