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Mapping Renal Innervations by Renal Nerve Stimulation and Characterizations of Blood Pressure Response Patterns

Abstract

Increased sympathetic nervous activity is one of main contributors to pathogenesis and progression of hypertension. Renal denervation (RDN) has been demonstrated as a potential therapy for treatment of hypertension; however, lack of indicators of intra-/post-procedure results in inconsistent clinical outcomes. Renal nerve stimulation (RNS), a simple and promising method, could evoke elevated blood pressure as an intraoperative indicator for RDN. But related researches on patterns of blood pressure responses to RNS are still incomplete. To investigate and categorize the phenotypes of blood pressure response to RNS and heart rate alteration before and after RNS, 24 Chinese Kunming dogs were used to perform RNS from bifurcation to ostium of renal arteries after angiography, and a total of 483 stimulated sites were complete. We identified five different patterns of blood pressure response to RNS in 483 stimulated sites, (1) continuous ascending and finally keeping steady above baseline (26.9%), (2) declining and then rising over baseline (11.8%), (3) declining and then rising but below baseline (14.5%), (4) fluctuating in the vicinity of baseline (39.5%), and (5) continuous declining and finally keeping steady below baseline (7.2%), and found no difference in RR intervals among five blood pressure responses before and after renal nerve stimulation. Renal nerve stimulation could elicit different patterns of blood pressure response, which could potentially assist in distinguishing sympathetic-excitatory sites and sympathetic-inhibitory sites from mixed nerve components, which might help to improve the efficacy of RDN.

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References

  1. 1.

    Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P. A., Sadowski, J., Bartus, K., et al. (2009). Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet., 373(9671), 1275–1281.

    Article  Google Scholar 

  2. 2.

    Kandzari, D. E., Böhm, M., Mahfoud, F., Townsend, R. R., Weber, M. A., Pocock, S., et al. (2018). Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet., 391(10137), 2346–2355.

    Article  Google Scholar 

  3. 3.

    Azizi, M., Sapoval, M., Gosse, P., Monge, M., Bobrie, G., Delsart, P., et al. (2015). Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): A multicentre, open-label, randomised controlled trial. Lancet., 385(9981), 1957–1965.

    Article  Google Scholar 

  4. 4.

    Fengler, K., Rommel, K. P., Blazek, S., Besler, C., Hartung, P., von Roeder, M., et al. (2019). A three-arm randomized trial of different renal denervation devices and techniques in patients with resistant hypertension (RADIOSOUND-HTN). Circulation., 139(5), 590–600.

    Article  Google Scholar 

  5. 5.

    Townsend, R. R., Mahfoud, F., Kandzari, D. E., Kario, K., Pocock, S., Weber, M. A., et al. (2017). Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): A randomised, sham-controlled, proof-of-concept trial. Lancet., 390(10108), 2160–2170.

    Article  Google Scholar 

  6. 6.

    Bhatt, D. L., Kandzari, D. E., O'Neill, W. W., D'Agostino, R., Flack, J. M., Katzen, B. T., et al. (2014). A controlled trial of renal denervation for resistant hypertension. The New England Journal of Medicine, 370(15), 1393–1401.

    CAS  Article  Google Scholar 

  7. 7.

    Mahfoud, F., Renkin, J., Sievert, H., Bertog, S., Ewen, S., Böhm, M., et al. (2020). Alcohol-mediated renal denervation using the peregrine system infusion catheter for treatment of hypertension. JACC. Cardiovascular Interventions, 13(4), 471–484.

    Article  Google Scholar 

  8. 8.

    Townsend, R. R., & Sobotka, P. A. (2018). Catheter-based renal denervation for hypertension. Current Hypertension Reports, 20(11), 93.

    Article  Google Scholar 

  9. 9.

    Tan, K., Lai, Y., Chen, W., Liu, H., Xu, Y., Li, Y., et al. (2019). Selective renal denervation guided by renal nerve stimulation: Mapping renal nerves for unmet clinical needs. Journal of Human Hypertension, 33(10), 716–724.

    Article  Google Scholar 

  10. 10.

    Chinushi, M., Suzuki, K., Saitoh, O., Furushima, H., Iijima, K., Izumi, D., et al. (2016). Electrical stimulation-based evaluation for functional modification of renal autonomic nerve activities induced by catheter ablation. Heart Rhythm, 13(8), 1707–1715.

    Article  Google Scholar 

  11. 11.

    Hilbert, S., Kosiuk, J., Hindricks, G., & Bollmann, A. (2014). Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. International Journal of Cardiology, 177(2), 669–671.

    Article  Google Scholar 

  12. 12.

    Lu, J., Wang, Z., Zhou, T., Chen, S., Chen, W., Du, H., et al. (2015). Selective proximal renal denervation guided by autonomic responses evoked via high-frequency stimulation in a preclinical canine model. Circulation. Cardiovascular Interventions, 8(6).

  13. 13.

    Liu, H., Chen, W., Lai, Y., Du, H., Wang, Z., Xu, Y., et al. (2019). Selective renal denervation guided by renal nerve stimulation in canine. Hypertension., 74(3), 536–545.

    CAS  Article  Google Scholar 

  14. 14.

    Sakakura, K., Ladich, E., Cheng, Q., Otsuka, F., Yahagi, K., Fowler, D. R., et al. (2014). Anatomic assessment of sympathetic peri-arterial renal nerves in man. Journal of the American College of Cardiology, 64(7), 635–643.

    Article  Google Scholar 

  15. 15.

    Fudim, M., Sobotka, A. A., Yin, Y. H., Wang, J. W., Levin, H., Esler, M., et al. (2018). Selective vs. global renal denervation: A case for less is more. Current Hypertension Reports, 20(5), 37.

    Article  Google Scholar 

  16. 16.

    van Amsterdam, W. A., Blankestijn, P. J., Goldschmeding, R., & Bleys, R. L. (2016). The morphological substrate for renal denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study. Annals of Anatomy, 204, 71–79.

    Article  Google Scholar 

  17. 17.

    Kiuchi, M. G., Esler, M. D., Fink, G. D., Osborn, J. W., Banek, C. T., Böhm, M., et al. (2019). Renal denervation update from the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 73(23), 3006–3017.

    Article  Google Scholar 

  18. 18.

    Tsioufis, C., Dimitriadis, K., Tsioufis, P., Patras, R., Papadoliopoulou, M., Petropoulou, Z., et al. (2018). ConfidenHT™ system for diagnostic mapping of renal nerves. Current Hypertension Reports, 20(6), 49.

    Article  Google Scholar 

  19. 19.

    Chen, W., Du, H., Lu, J., Ling, Z., Long, Y., Xu, Y., et al. (2016). Renal artery vasodilation may be an indicator of successful sympathetic nerve damage during renal denervation procedure. Scientific Reports, 6, 37218.

    CAS  Article  Google Scholar 

  20. 20.

    Xu, Y., Xiao, P., Fan, J., Chen, W., Du, H., Ling, Z., et al. (2018). Blood pressure elevation response to radiofrequency energy delivery: one novel predictive marker to long-term success of renal denervation. Journal of Hypertension, 36(12), 2460–2470.

    CAS  Article  Google Scholar 

  21. 21.

    Zuern, C. S., Eick, C., Rizas, K. D., Bauer, S., Langer, H., Gawaz, M., et al. (2013). Impaired cardiac baroreflex sensitivity predicts response to renal sympathetic denervation in patients with resistant hypertension. Journal of the American College of Cardiology, 62(22), 2124–2130.

    Article  Google Scholar 

  22. 22.

    Sata, Y., Hering, D., Head, G. A., Walton, A. S., Peter, K., Marusic, P., et al. (2018). Ambulatory arterial stiffness index as a predictor of blood pressure response to renal denervation. Journal of Hypertension, 36(6), 1414–1422.

    CAS  Article  Google Scholar 

  23. 23.

    Veiga, A. C., Milanez, M., Ferreira, G. R., Lopes, N. R., Santos, C. P., De Angelis, K., et al. (2020). Selective afferent renal denervation mitigates renal and splanchnic sympathetic nerve overactivity and renal function in chronic kidney disease-induced hypertension. Journal of Hypertension, 38(4), 765–773.

    CAS  Article  Google Scholar 

  24. 24.

    Ong, J., Kinsman, B. J., Sved, A. F., Rush, B. M., Tan, R. J., Carattino, M. D., et al. (2019). Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice. Journal of Neurophysiology, 122(1), 358–367.

    CAS  Article  Google Scholar 

  25. 25.

    Wehrwein, E. A., Orer, H. S., & Barman, S. M. (2016). Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Comprehensive Physiology, 6(3), 1239–1278.

    Article  Google Scholar 

  26. 26.

    Tsai, W. C., Chan, Y. H., Chinda, K., Chen, Z., Patel, J., Shen, C., et al. (2017). Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs. Heart Rhythm, 14(2), 255–262.

    Article  Google Scholar 

  27. 27.

    Esler, M., Lambert, G., Esler, D., Ika, S. C., Guo, L., & Jennings, G. (2020). Evaluation of elevated heart rate as a sympathetic nervous system biomarker in essential hypertension. Journal of Hypertension, 38(8), 1488–1495.

    CAS  Article  Google Scholar 

  28. 28.

    Gal, P., de Jong, M. R., Smit, J. J., Adiyaman, A., Staessen, J. A., & Elvan, A. (2015). Blood pressure response to renal nerve stimulation in patients undergoing renal denervation: A feasibility study. Journal of Human Hypertension, 29(5), 292–295.

    CAS  Article  Google Scholar 

  29. 29.

    Kandzari, D. E., Bhatt, D. L., Brar, S., Devireddy, C. M., Esler, M., Fahy, M., et al. (2015). Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. European Heart Journal, 36(4), 219–227.

    Article  Google Scholar 

  30. 30.

    Murai, H., Okuyama, Y., Sakata, Y., Kaneko, S., Hamaoka, T., Okabe, Y., et al. (2015). Different responses of arterial blood pressure to electrical stimulation of the renal artery in patients with resistant hypertension. International Journal of Cardiology, 190, 296–298.

    Article  Google Scholar 

  31. 31.

    de Jong, M. R., Hoogerwaard, A. F., Adiyaman, A., Smit, J. J. J., Heeg, J. E., van Hasselt, B. A. A. M., et al. (2018). Renal nerve stimulation identifies aorticorenal innervation and prevents inadvertent ablation of vagal nerves during renal denervation. Blood Pressure, 27(5), 271–279.

    Article  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Changzhi Zhang and Jie Yang for their help in intervention procedures.

Funding

This work was supported by the General Project of the National Natural Science Foundation of China under Grant No.82000471 and General Project from Chongqing Municipal Health Bureau under Grant No.2016MSXM023.

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Authors

Contributions

HZ, YL, YX, HL, WC, LS, ZL, and YY designed this experiment. YL, YX, KT, and XL prepared and recorded the intervention procedure. HZ, HL, YL, ZO, and WC performed the intervention procedure. HZ, YL, YX, HL, and ZO collected the data, and all authors participated in data analysis. HZ, YL, and YY composed this paper. All authors reviewed and approved for the final version of manuscript.

Corresponding author

Correspondence to Yuehui Yin.

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Ethics Approval

The experimental protocol was approved by the Animal Experimentation Ethics Committee of Chongqing Medical University, in accordance with the guidelines of National Institutes of Health for the care and use of laboratory animals.

Conflict of Interest

The authors declare no competing interests.

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Associate Editor Marat Fudim oversaw the review of this article

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Zhou, H., Li, Y., Xu, Y. et al. Mapping Renal Innervations by Renal Nerve Stimulation and Characterizations of Blood Pressure Response Patterns. J. of Cardiovasc. Trans. Res. (2021). https://doi.org/10.1007/s12265-021-10149-1

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Keywords

  • Hypertension
  • Renal denervation
  • Renal nerve stimulation
  • Blood pressure response