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Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI

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Abstract

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.

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The datasets are available on reasonable request to the corresponding author.

References

  1. Abumandour MMA, Hanafy BG, Morsy K, El-Kott A, Shati A, Salah El-Din E, Bassuoni NF (2022) Cervicothoracic sympathetic system in the dog: new insights by the gross morphological description of each ganglion with its branches on each side. Folia Morphol (Warsz) 81:20–30. https://doi.org/10.5603/FM.a2021.0009

    Article  CAS  PubMed  Google Scholar 

  2. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL (2018) 2017 AHA/ACC/HRS Guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart rhythm society. Circulation 138:e210–e271. https://doi.org/10.1161/cir.0000000000000548

    Article  PubMed  Google Scholar 

  3. Albani S, Fabris E, Doimo S, Barbati G, Perkan A, Merlo M, Gatti G, Di Lenarda A, Van’t Hof AWJ, Maras P, Sinagra G (2018) Early occurrence of drug intolerance as risk factor during follow-up in patients with acute coronary syndrome or coronary revascularization. Eur Heart J Cardiovasc Pharmacother 4:195–201. https://doi.org/10.1093/ehjcvp/pvy017

    Article  PubMed  Google Scholar 

  4. Ali R, Ciccone J, Tseng V (2017) Cervical sympathetic blockade for the management of electrical storm. J Clin Anesth 36:47–50. https://doi.org/10.1016/j.jclinane.2016.07.037

    Article  PubMed  Google Scholar 

  5. Amgalan D, Pekson R, Kitsis RN (2017) Troponin release following brief myocardial ischemia: apoptosis versus necrosis. JACC Basic Transl Sci 2:118–121. https://doi.org/10.1016/j.jacbts.2017.03.008

    Article  PubMed  PubMed Central  Google Scholar 

  6. Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN (2019) Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev 99:1765–1817. https://doi.org/10.1152/physrev.00022.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S (2018) Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev 98:1627–1738. https://doi.org/10.1152/physrev.00038.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Frangogiannis NG (2015) Pathophysiology of Myocardial Infarction. Compr Physiol 5:1841–1875. https://doi.org/10.1002/cphy.c150006

    Article  PubMed  Google Scholar 

  9. Goldberger JJ, Arora R, Buckley U, Shivkumar K (2019) Autonomic nervous system dysfunction: JACC focus seminar. J Am Coll Cardiol 73:1189–1206. https://doi.org/10.1016/j.jacc.2018.12.064

    Article  PubMed  PubMed Central  Google Scholar 

  10. Herring N, Kalla M, Paterson DJ (2019) The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies. Nat Rev Cardiol 16:707–726. https://doi.org/10.1038/s41569-019-0221-2

    Article  PubMed  Google Scholar 

  11. Heusch G (1990) Alpha-adrenergic mechanisms in myocardial ischemia. Circulation 81:1–13. https://doi.org/10.1161/01.cir.81.1.1

    Article  CAS  PubMed  Google Scholar 

  12. Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, Indolfi C, Rimoldi O (2000) alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101:689–694. https://doi.org/10.1161/01.cir.101.6.689

    Article  CAS  PubMed  Google Scholar 

  13. Heusch G, Deussen A, Thamer V (1985) Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 13:311–326. https://doi.org/10.1016/0165-1838(85)90020-7

    Article  CAS  PubMed  Google Scholar 

  14. Hopf HB, Skyschally A, Heusch G, Peters J (1995) Low-frequency spectral power of heart rate variability is not a specific marker of cardiac sympathetic modulation. Anesthesiology 82:609–619. https://doi.org/10.1097/00000542-199503000-00002

    Article  CAS  PubMed  Google Scholar 

  15. Irie T, Yamakawa K, Hamon D, Nakamura K, Shivkumar K, Vaseghi M (2017) Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy. Am J Physiol Heart Circ Physiol 312:H392–H405. https://doi.org/10.1152/ajpheart.00644.2016

    Article  PubMed  Google Scholar 

  16. Jia XF, Liang FG, Kitsis RN (2021) Multiple Cell Death Programs Contribute to Myocardial Infarction. Circ Res 129:397–399. https://doi.org/10.1161/CIRCRESAHA.121.319584

    Article  CAS  PubMed  Google Scholar 

  17. Kawashima T (2005) The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution. Anat Embryol (Berl) 209:425–438. https://doi.org/10.1007/s00429-005-0462-1

    Article  PubMed  Google Scholar 

  18. Kokubun S, Sato T, Yajima T, Ichikawa H (2019) Distribution of postganglionic neurons which contain dopamine beta-hydroxylase, tyrosine hydroxylase, neuropeptide Y and vasoactive intestinal polypeptide in the human middle cervical ganglion. Tissue Cell 58:42–50. https://doi.org/10.1016/j.tice.2019.04.006

    Article  CAS  PubMed  Google Scholar 

  19. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233–270. https://doi.org/10.1093/ehjci/jev014

    Article  PubMed  Google Scholar 

  20. Liu S, Yu X, Luo D, Qin Z, Wang X, He W, Ma R, Hu H, Xie J, He B, Lu Z, Jiang H (2018) Ablation of the ligament of marshall and left stellate ganglion similarly reduces ventricular arrhythmias during acute myocardial infarction. Circ Arrhythm Electrophysiol 11:e005945. https://doi.org/10.1161/CIRCEP.117.005945

    Article  PubMed  Google Scholar 

  21. Manolis AA, Manolis TA, Apostolopoulos EJ, Apostolaki NE, Melita H, Manolis AS (2021) The role of the autonomic nervous system in cardiac arrhythmias: the neuro-cardiac axis, more foe than friend? Trends Cardiovasc Med 31:290–302. https://doi.org/10.1016/j.tcm.2020.04.011

    Article  CAS  PubMed  Google Scholar 

  22. Markman TM, Gugger D, Arkles J, Riley MP, Dixit S, Guandalini GS, Frankel DS, Epstein AE, Callans DJ, Singhal S, Marchlinski FE, Nazarian S (2023) Neuromodulation for the treatment of refractory ventricular arrhythmias. JACC Clin Electrophysiol 9:161–169. https://doi.org/10.1016/j.jacep.2022.08.031

    Article  PubMed  Google Scholar 

  23. Meng L, Tseng CH, Shivkumar K, Ajijola O (2017) Efficacy of Stellate ganglion blockade in managing electrical storm: a systematic review. JACC Clin Electrophysiol 3:942–949. https://doi.org/10.1016/j.jacep.2017.06.006

    Article  PubMed  PubMed Central  Google Scholar 

  24. Okninska M, Maczewski M, Mackiewicz U (2022) Ventricular arrhythmias in acute myocardial ischaemia-Focus on the ageing and sex. Ageing Res Rev 81:101722. https://doi.org/10.1016/j.arr.2022.101722

    Article  PubMed  Google Scholar 

  25. Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Ter Maaten JM, Ng LL, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Metra M, Zwinderman AH (2017) Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J 38:1883–1890. https://doi.org/10.1093/eurheartj/ehx026

    Article  CAS  PubMed  Google Scholar 

  26. Papa A, Kushner J, Marx SO (2022) Adrenergic Regulation of Calcium Channels in the Heart. Annu Rev Physiol 84:285–306. https://doi.org/10.1146/annurev-physiol-060121-041653

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez-Sinovas A, Sanchez JA, Valls-Lacalle L, Consegal M, Ferreira-Gonzalez I (2021) Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease. Int J Mol Sci 22:4413. https://doi.org/10.3390/ijms22094413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ruiz-Meana M, Rodríguez-Sinovas A, Cabestrero A, Boengler K, Heusch G, Garcia-Dorado D (2008) Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury. Cardiovasc Res 77:325–333. https://doi.org/10.1093/cvr/cvm062

    Article  CAS  PubMed  Google Scholar 

  29. Schwartz PJ, Ackerman MJ (2022) Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias. Eur Heart J 43:2096–2102. https://doi.org/10.1093/eurheartj/ehac134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shivkumar K, Ajijola OA, Anand I, Armour JA, Chen PS, Esler M, De Ferrari GM, Fishbein MC, Goldberger JJ, Harper RM, Joyner MJ, Khalsa SS, Kumar R, Lane R, Mahajan A, Po S, Schwartz PJ, Somers VK, Valderrabano M, Vaseghi M, Zipes DP (2016) Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 594:3911–3954. https://doi.org/10.1113/jp271870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Singh K, Communal C, Sawyer DB, Colucci WS (2000) Adrenergic regulation of myocardial apoptosis. Cardiovasc Res 45:713–719. https://doi.org/10.1016/s0008-6363(99)00370-3

    Article  CAS  PubMed  Google Scholar 

  32. Sorbets E, Steg PG, Young R, Danchin N, Greenlaw N, Ford I, Tendera M, Ferrari R, Merkely B, Parkhomenko A, Reid C, Tardif JC, Fox KM (2019) β-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study. Eur Heart J 40:1399–1407. https://doi.org/10.1093/eurheartj/ehy811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Van Weperen VYH, Vos MA, Ajijola OA (2021) Autonomic modulation of ventricular electrical activity: recent developments and clinical implications. Clin Auton Res 31:659–676. https://doi.org/10.1007/s10286-021-00823-4

    Article  PubMed  PubMed Central  Google Scholar 

  34. Vaseghi M, Barwad P, Malavassi Corrales FJ, Tandri H, Mathuria N, Shah R, Sorg JM, Gima J, Mandal K, Saenz Morales LC, Lokhandwala Y, Shivkumar K (2017) Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 69:3070–3080. https://doi.org/10.1016/j.jacc.2017.04.035

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yoshie K, Rajendran PS, Massoud L, Mistry J, Swid MA, Wu X, Sallam T, Zhang R, Goldhaber JI, Salavatian S, Ajijola OA (2020) Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction. JCI Insight 5:e124477. https://doi.org/10.1172/jci.insight.124477

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yu L, Zhou L, Cao G, Po SS, Huang B, Zhou X, Wang M, Yuan S, Wang Z, Wang S, Jiang H (2017) Optogenetic modulation of cardiac sympathetic nerve activity to prevent ventricular arrhythmias. J Am Coll Cardiol 70:2778–2790. https://doi.org/10.1016/j.jacc.2017.09.1107

    Article  PubMed  Google Scholar 

  37. Yu X, He W, Xie J, He B, Luo D, Wang X, Jiang H, Lu Z (2019) Selective ablation of ligament of Marshall inhibits ventricular arrhythmias during acute myocardial infarction: possible mechanisms. J Cardiovasc Electrophysiol 30:374–382. https://doi.org/10.1111/jce.13802

    Article  PubMed  Google Scholar 

  38. Zhang S, Wang M, Jiao L, Liu C, Chen H, Zhou L, Wang Y, Wang Y, Liu Z, Liu Z, Zhou Y, Zhou H, Xu X, Li Z, Liu Z, Yu Z, Nie L, Yu L, Jiang H (2022) Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction. Heart Rhythm 19:2095–2104. https://doi.org/10.1016/j.hrthm.2022.08.002

    Article  PubMed  Google Scholar 

  39. Zhou Z, Liu C, Xu S, Wang J, Guo F, Duan S, Deng Q, Sun J, Yu F, Zhou Y, Wang M, Wang Y, Zhou L, Jiang H, Yu L (2022) Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model. Basic Res Cardiol 117:34. https://doi.org/10.1007/s00395-022-00939-2

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge Tuantuan Tan, Yan-hong Tang and Xi Wang for their kind support. We thank Figdraw for providing scientific drawing materials.

Funding

This work was supported by the National Natural Science Foundation of China (82070425 and 82270402 to Zhibing Lu, 82000386 to Ke-Qiong Deng, 82100403 to Chen-Ze Li, and 81900455 to Xiaomei Yu).

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Author notes

  1. Meng Zheng, Siyu Chen and Ziyue Zeng contributed equally to this work and share the first authorship.

  2. Ke-Qiong Deng and Zhibing Lu contributed equally to this work and share the corresponding authorship.

Authors and Affiliations

  1. Department of Cardiology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430000, Hubei, China

    Meng Zheng, Siyu Chen, Ziyue Zeng, Huanhuan Cai, Hanyu Zhang, Weina Wang, Xianqing Li, Chen-Ze Li, Bo He, Ke-Qiong Deng & Zhibing Lu

  2. Cardiovascular Institute, Zhongnan Hospital of Wuhan University, Wuhan, China

    Meng Zheng, Siyu Chen, Ziyue Zeng, Huanhuan Cai, Hanyu Zhang, Weina Wang, Xianqing Li, Chen-Ze Li, Bo He, Ke-Qiong Deng & Zhibing Lu

  3. Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China

    Meng Zheng, Siyu Chen, Ziyue Zeng, Huanhuan Cai, Hanyu Zhang, Weina Wang, Xianqing Li, Chen-Ze Li, Bo He, Ke-Qiong Deng & Zhibing Lu

  4. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Xiaomei Yu

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  1. Meng Zheng
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Zheng, M., Chen, S., Zeng, Z. et al. Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI. Basic Res Cardiol 119, 57–74 (2024). https://doi.org/10.1007/s00395-023-01026-w

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