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Renal sympathetic denervation resurrected; or NOT?
700
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
in completing ongoing clinical trials of RDT both in untreated hypertension and in resistant hypertension. We also need additional trials to be designed, or completed, as soon as possible to help us assess the important clinical questions raised by these data, including the true magnitude of the BP lowering effect in different populations, the durability of the BP lowering effect, identification of potential biomarkers that can predict subpopulations in whom outcomes will be best, and the long-term safety of the various procedures. In terms of long term safety, based on previous work in animal models,4 we should be particularly interested in ensuring the patients who have received RDT are able to safely handle hemodynamic stressors like hypovolemia or systemic inflammatory response syndrome (SIRS). As a community, those of us interested in hypertension should remain open minded to data as it is presented. For example, if the ongoing SPYRAL HTN OFF-MED study continues to provide favorable results and the similarly designed RADIANCE SOLO study (using the Paradise ultrasound catheter system)5 also demonstrate a favorable BP effect, we may want to consider whether RDT is a potential treatment for more mild forms of hypertension, rather than just resistant hypertension as was originally postulated. Of course, this determination will require careful consideration of the data in the context of what we know clinically about the challenges of managing hypertension in this country, including issues with medication adherence and patient preferences. No one is in a better position to offer the ‘big picture’ interpretation of these data than the clinical hypertension specialist. As a community, we should demand continued research into RDT in different clinical scenarios and maintain a stance of inquisitive equipoise until more data are available. Michael J. Bloch, MD, FACP, FASH, FNLA, FSVM Department of Medicine University of Nevada School of Medicine Reno, NV, USA Department of Vascular Care Renown Institute of Heart and Vascular Health Reno, NV, USA https://doi.org/10.1016/j.jash.2017.10.001
References 1. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903–9.
2. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Eng J Med 2014;370:1393–401. 3. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheterbased renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, shamcontrolled, proof of concept. Lancet 2016. epub ahead of print, https://doi.org/10.1016/S0140-6736(17)32281-X. 4. Singh RR, Sajeesh V, Booth LC, et al. Catheter based renal denervation exacerbates blood pressure fall during hemorrhage. J Am Col Cardiol 2017;69(8):951–64. 5. MB wishes to disclose that he receives research support as a principal investigator for the RADIANCE Study from Recor, manufacturer of the Paradise Catheter Based Renal Denervation System. Available at: www.clinicaltrials.gov/ t2/show/NCT02649426. Accessed September 24, 2017.
RENAL SYMPATHETIC RESURRECTED; OR NOT?
DENERVATION
Percutaneous renal denervation appeared in our medical life in recent years, created a lot of noise and then disappeared without any residual sign. The concept was that ablating the renal nerves would interrupt the signals from and to the kidneys (Figure 1) and thus eliminate the unnecessary production of renal hormones, the unnecessary sodium and fluid retention on one hand and the harmful effects of sympathetic overflow on target organs on the other. The early simplicity1,2 and other subsequent studies3,4 addressed patients with drug resistant hypertension, a group of patients with unmet medical need. These patients were poorly controlled and suffered high rates of cardiovascular events. The hope was that percutaneous renal denervation would lower and control hypertension in these patients and perhaps decrease the need for antihypertensive medication. Most of these studies demonstrated impressive BP reduction with renal denervation, but they were criticized for been poorly designed with no controls.5,6 Then results of Symplicity HTN-3 came and ‘‘ugly facts disproved beautiful hypotheses’’. A well designed and well executed randomized trial, simplicity 3,7 showed that the effect of renal denervation were similar to sham control. Results were disappointing to almost everyone, including the writer of this article. Many ideas and opinions were offered and many speculative assumptions were made ie, patient selection, drug carry over, medication titration, etc., but the most realistic explanation was that ‘‘the method used to deliver renal denervation was ineffective’’. Thermal energy delivered in the form of radiofrequency energy, was inadequate, because too few lesions were delivered per renal artery, not enough to achieve
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
701
Figure 1. Diagram depicting the influence of efferent and afferent sympathetic fibers in modulating sympathetic responses of the kidney, the heart, the vasculature, and other target organs. (Papademetriou et al. Circulation. 2014;129:1440-51)
circumferential ablation, and the depth achieved not adequate to reach most sympathetic fibers in the adventitia of the renal artery. In the mid and proximal segment of the main renal artery the fibers travel at a depth, that is up to 12 mm from the lumen, whereas RF energy only penetrates to 2.5–4.0 mm. Obviously the thought leaders went back to the drawing board and (we) came up with a new protocol: Recruit patients with uncontrolled hypertension on 1–3 medications and elevated systolic and diastolic BP (not resistant to drug therapy), or patients with hypertension but not taking any medication: Change the ablation procedure so to achieve as complete as possible renal denervation: and place as many ablation lesions as possible distally and into the branches. Most of the sympathetic fibers to and from the kidney course close to the lumen in the distal part of the renal artery and in the large branches, thus are amenable to thermal ablation. The recent paper in Lancet describes the first 80 patients recruited for the Spyral Off-med study.8 The objective of the study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. It was a multicenter, international, single-blind, randomized, sham-controlled, proof of-concept trial enrolled patients in 21 centers in the
USA, Europe, Japan, and Australia. Patients were eligible if they were drug-naive or had discontinued their antihypertensive medications for any reason. Eligible patients were those with an office systolic blood pressure (SBP) of 150 -180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at the second screening. All patients underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomization assignments. The primary endpoint, a change in 24-h blood pressure at 3 months, was compared between groups. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. A total of 353 patients were screened for this part of the study. Eighty patients were randomly assigned to renal denervation (n ¼ 38) or sham control (n ¼ 42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: The 24-h SBP decreased by 5$5 mm Hg and diastolic by 4$8 mm Hg, the office SBP decreased by 10$0 mm Hg and office DBP by 5$3 mm Hg. No significant changes were seen in the shamcontrol group: The mean difference between the groups
702
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
Figure 2. Responders and non-responders in the renal denervation and sham control groups. Changes at 3 months for individual patients in renal denervation and sham control groups (A) 24-h ambulatory SBP and DBP. (B) Office SBP and DBP. BP, blood pressure. SBP, systolic blood pressure. DBP, diastolic blood pressure. (Townsend RR et al. Lancet. 2017 Aug 25. pii: S0140-6736(17)32281)
favored renal denervation for 3-month change in both office and 24-h blood pressure from baseline. There were no major adverse events in either group. The study results were interpreted as providing biological proof of principle for the blood-pressure lowering efficacy of renal denervation. This may be true, but the study results by no means prove that renal denervation works on everyone. In fact the individual patient responses printed in the paper indicate
variable response. As shown in Figure 2, more patient in the renal denervation group demonstrated reduction in systolic and diastolic BP compared to sham control (by 24-hr BP: 25 and 28 vs. 17 and 18 or by office BP: 29 and 27 pts in the renal denervation group, vs. 23 and 20 pts in the sham group). Although this data strongly suggest that renal denervation works in more patients than the sham procedure, by no means it proves that renal denervation is for everyone. Furthermore it is of concern that more than one
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
in five patients who had the real renal denervation demonstrated increase in both 24-hr ambulatory pressures and office BPs. The authors correctly point out that this was a proof of concept study for the new catheter and more data are needed in the context of a larger pivotal trial. Yet data from this study are more believable that data from previous trials. The design of the study deferred from previous studies in several critical ways: a) it required at least two baseline BP measurements and validation of BP criteria by ABPM, thus avoiding the possibility of unintended baseline BP exacerbation, b) recruited patients on no medication, thus avoiding the pitfalls of medication non-compliance or carryover effect and c) incorporated knowledge and data relevant to nerve anatomy, acquired from recent trials. Data from recent histology studies indicate that sympathetic fibers course close to the lumen in the distal segment of the renal artery and into the branches.9 Thus this study mandated placing the radiofrequency lesions distally and into the branches, d) approximately 4 times more lesions were placed in both renal arteries in the current study as compared to simplicity HTN-3 (43.8 vs. 11.2). Thus it is more likely that more complete renal denervation was achieved in the current study as compared to previous studies. The question then is why the variable response? Why as many patients in the renal denervation group showed increase in BP? The answer is not so simple and a lot more work is needed to understand the role of renal nerves in hypertension and how to best modulate them in order to achieve blood pressure control. I will not even attempt here to explain the complex role of renal nerves on the kidney and hypertension. Suffices to say for now that hypertension is multifactorial and sympathetic renal nerves are only one factor that influences hypertension. We still need to understand; a) who are the patients with sympathetically mediated hypertension, b) how much denervation is necessary to have an effect on blood pressure control and c) what is the best way to achieve almost complete renal denervation? Agree with the authors that more work is needed before renal denervation becomes prime time procedure. Until then renal denervation will remain in the domain of research. Vasilios Papademetriou, MD, DSc Professor of Medicine (Cardiology) Georgetown University Hypertension and Vascular Medicine program VA Medical Center Washington DC
703
https://doi.org/10.1016/j.jash.2017.10.006
References 1. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicenter safety and proof-of-principle cohort study (The Symplicity HTN-1 trial). Lancet 2009;373:1275–81. 2. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, B€ohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 trial): a randomized controlled trial. Lancet 2010;376:1903–9. 3. Papademetriou V, Tsioufis CP, Sinhal A, Chew DP, Meredith IT, Malaiapan Y, et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension 2014;64(3): 565–72. 4. Ott C, Mahfoud F, Schmid A, Ditting T, Sobotka PA, Veelken R, et al. Renal denervation in moderate treatment-resistant hypertension. J Am Coll Cardiol 2013;62(20):1880–6. 5. Papademetriou V, Rashidi AA, Tsioufis C, Doumas M. Renal nerve ablation for resistant hypertension: how did we get here, present status and future directions. Circulation 2014;129:1440–51. 6. Papademetriou V, Tsioufis C, Doumas M. Renal denervation and SYMPLICITY HTN-3: ‘Dubium sapientiae initium’ (Doubt is the beginning of wisdom). Circ Res 2014;115:211–4. 7. Bhatt D, Kandzari D, O’Neill W, D’Agostino R, Flack J, Katzen B, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370: 1393–401. 8. Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, et al., SPYRAL HTN-OFF MED trial investigators*. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial. Lancet 2017. 9. Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler D, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64(7):635–43.
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
in completing ongoing clinical trials of RDT both in untreated hypertension and in resistant hypertension. We also need additional trials to be designed, or completed, as soon as possible to help us assess the important clinical questions raised by these data, including the true magnitude of the BP lowering effect in different populations, the durability of the BP lowering effect, identification of potential biomarkers that can predict subpopulations in whom outcomes will be best, and the long-term safety of the various procedures. In terms of long term safety, based on previous work in animal models,4 we should be particularly interested in ensuring the patients who have received RDT are able to safely handle hemodynamic stressors like hypovolemia or systemic inflammatory response syndrome (SIRS). As a community, those of us interested in hypertension should remain open minded to data as it is presented. For example, if the ongoing SPYRAL HTN OFF-MED study continues to provide favorable results and the similarly designed RADIANCE SOLO study (using the Paradise ultrasound catheter system)5 also demonstrate a favorable BP effect, we may want to consider whether RDT is a potential treatment for more mild forms of hypertension, rather than just resistant hypertension as was originally postulated. Of course, this determination will require careful consideration of the data in the context of what we know clinically about the challenges of managing hypertension in this country, including issues with medication adherence and patient preferences. No one is in a better position to offer the ‘big picture’ interpretation of these data than the clinical hypertension specialist. As a community, we should demand continued research into RDT in different clinical scenarios and maintain a stance of inquisitive equipoise until more data are available. Michael J. Bloch, MD, FACP, FASH, FNLA, FSVM Department of Medicine University of Nevada School of Medicine Reno, NV, USA Department of Vascular Care Renown Institute of Heart and Vascular Health Reno, NV, USA https://doi.org/10.1016/j.jash.2017.10.001
References 1. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903–9.
2. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Eng J Med 2014;370:1393–401. 3. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheterbased renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, shamcontrolled, proof of concept. Lancet 2016. epub ahead of print, https://doi.org/10.1016/S0140-6736(17)32281-X. 4. Singh RR, Sajeesh V, Booth LC, et al. Catheter based renal denervation exacerbates blood pressure fall during hemorrhage. J Am Col Cardiol 2017;69(8):951–64. 5. MB wishes to disclose that he receives research support as a principal investigator for the RADIANCE Study from Recor, manufacturer of the Paradise Catheter Based Renal Denervation System. Available at: www.clinicaltrials.gov/ t2/show/NCT02649426. Accessed September 24, 2017.
RENAL SYMPATHETIC RESURRECTED; OR NOT?
DENERVATION
Percutaneous renal denervation appeared in our medical life in recent years, created a lot of noise and then disappeared without any residual sign. The concept was that ablating the renal nerves would interrupt the signals from and to the kidneys (Figure 1) and thus eliminate the unnecessary production of renal hormones, the unnecessary sodium and fluid retention on one hand and the harmful effects of sympathetic overflow on target organs on the other. The early simplicity1,2 and other subsequent studies3,4 addressed patients with drug resistant hypertension, a group of patients with unmet medical need. These patients were poorly controlled and suffered high rates of cardiovascular events. The hope was that percutaneous renal denervation would lower and control hypertension in these patients and perhaps decrease the need for antihypertensive medication. Most of these studies demonstrated impressive BP reduction with renal denervation, but they were criticized for been poorly designed with no controls.5,6 Then results of Symplicity HTN-3 came and ‘‘ugly facts disproved beautiful hypotheses’’. A well designed and well executed randomized trial, simplicity 3,7 showed that the effect of renal denervation were similar to sham control. Results were disappointing to almost everyone, including the writer of this article. Many ideas and opinions were offered and many speculative assumptions were made ie, patient selection, drug carry over, medication titration, etc., but the most realistic explanation was that ‘‘the method used to deliver renal denervation was ineffective’’. Thermal energy delivered in the form of radiofrequency energy, was inadequate, because too few lesions were delivered per renal artery, not enough to achieve
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
701
Figure 1. Diagram depicting the influence of efferent and afferent sympathetic fibers in modulating sympathetic responses of the kidney, the heart, the vasculature, and other target organs. (Papademetriou et al. Circulation. 2014;129:1440-51)
circumferential ablation, and the depth achieved not adequate to reach most sympathetic fibers in the adventitia of the renal artery. In the mid and proximal segment of the main renal artery the fibers travel at a depth, that is up to 12 mm from the lumen, whereas RF energy only penetrates to 2.5–4.0 mm. Obviously the thought leaders went back to the drawing board and (we) came up with a new protocol: Recruit patients with uncontrolled hypertension on 1–3 medications and elevated systolic and diastolic BP (not resistant to drug therapy), or patients with hypertension but not taking any medication: Change the ablation procedure so to achieve as complete as possible renal denervation: and place as many ablation lesions as possible distally and into the branches. Most of the sympathetic fibers to and from the kidney course close to the lumen in the distal part of the renal artery and in the large branches, thus are amenable to thermal ablation. The recent paper in Lancet describes the first 80 patients recruited for the Spyral Off-med study.8 The objective of the study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. It was a multicenter, international, single-blind, randomized, sham-controlled, proof of-concept trial enrolled patients in 21 centers in the
USA, Europe, Japan, and Australia. Patients were eligible if they were drug-naive or had discontinued their antihypertensive medications for any reason. Eligible patients were those with an office systolic blood pressure (SBP) of 150 -180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at the second screening. All patients underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomization assignments. The primary endpoint, a change in 24-h blood pressure at 3 months, was compared between groups. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. A total of 353 patients were screened for this part of the study. Eighty patients were randomly assigned to renal denervation (n ¼ 38) or sham control (n ¼ 42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: The 24-h SBP decreased by 5$5 mm Hg and diastolic by 4$8 mm Hg, the office SBP decreased by 10$0 mm Hg and office DBP by 5$3 mm Hg. No significant changes were seen in the shamcontrol group: The mean difference between the groups
702
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
Figure 2. Responders and non-responders in the renal denervation and sham control groups. Changes at 3 months for individual patients in renal denervation and sham control groups (A) 24-h ambulatory SBP and DBP. (B) Office SBP and DBP. BP, blood pressure. SBP, systolic blood pressure. DBP, diastolic blood pressure. (Townsend RR et al. Lancet. 2017 Aug 25. pii: S0140-6736(17)32281)
favored renal denervation for 3-month change in both office and 24-h blood pressure from baseline. There were no major adverse events in either group. The study results were interpreted as providing biological proof of principle for the blood-pressure lowering efficacy of renal denervation. This may be true, but the study results by no means prove that renal denervation works on everyone. In fact the individual patient responses printed in the paper indicate
variable response. As shown in Figure 2, more patient in the renal denervation group demonstrated reduction in systolic and diastolic BP compared to sham control (by 24-hr BP: 25 and 28 vs. 17 and 18 or by office BP: 29 and 27 pts in the renal denervation group, vs. 23 and 20 pts in the sham group). Although this data strongly suggest that renal denervation works in more patients than the sham procedure, by no means it proves that renal denervation is for everyone. Furthermore it is of concern that more than one
Hypertension Highlights / Journal of the American Society of Hypertension 11(11) (2017) 699–703
in five patients who had the real renal denervation demonstrated increase in both 24-hr ambulatory pressures and office BPs. The authors correctly point out that this was a proof of concept study for the new catheter and more data are needed in the context of a larger pivotal trial. Yet data from this study are more believable that data from previous trials. The design of the study deferred from previous studies in several critical ways: a) it required at least two baseline BP measurements and validation of BP criteria by ABPM, thus avoiding the possibility of unintended baseline BP exacerbation, b) recruited patients on no medication, thus avoiding the pitfalls of medication non-compliance or carryover effect and c) incorporated knowledge and data relevant to nerve anatomy, acquired from recent trials. Data from recent histology studies indicate that sympathetic fibers course close to the lumen in the distal segment of the renal artery and into the branches.9 Thus this study mandated placing the radiofrequency lesions distally and into the branches, d) approximately 4 times more lesions were placed in both renal arteries in the current study as compared to simplicity HTN-3 (43.8 vs. 11.2). Thus it is more likely that more complete renal denervation was achieved in the current study as compared to previous studies. The question then is why the variable response? Why as many patients in the renal denervation group showed increase in BP? The answer is not so simple and a lot more work is needed to understand the role of renal nerves in hypertension and how to best modulate them in order to achieve blood pressure control. I will not even attempt here to explain the complex role of renal nerves on the kidney and hypertension. Suffices to say for now that hypertension is multifactorial and sympathetic renal nerves are only one factor that influences hypertension. We still need to understand; a) who are the patients with sympathetically mediated hypertension, b) how much denervation is necessary to have an effect on blood pressure control and c) what is the best way to achieve almost complete renal denervation? Agree with the authors that more work is needed before renal denervation becomes prime time procedure. Until then renal denervation will remain in the domain of research. Vasilios Papademetriou, MD, DSc Professor of Medicine (Cardiology) Georgetown University Hypertension and Vascular Medicine program VA Medical Center Washington DC
703
https://doi.org/10.1016/j.jash.2017.10.006
References 1. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicenter safety and proof-of-principle cohort study (The Symplicity HTN-1 trial). Lancet 2009;373:1275–81. 2. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, B€ohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 trial): a randomized controlled trial. Lancet 2010;376:1903–9. 3. Papademetriou V, Tsioufis CP, Sinhal A, Chew DP, Meredith IT, Malaiapan Y, et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension 2014;64(3): 565–72. 4. Ott C, Mahfoud F, Schmid A, Ditting T, Sobotka PA, Veelken R, et al. Renal denervation in moderate treatment-resistant hypertension. J Am Coll Cardiol 2013;62(20):1880–6. 5. Papademetriou V, Rashidi AA, Tsioufis C, Doumas M. Renal nerve ablation for resistant hypertension: how did we get here, present status and future directions. Circulation 2014;129:1440–51. 6. Papademetriou V, Tsioufis C, Doumas M. Renal denervation and SYMPLICITY HTN-3: ‘Dubium sapientiae initium’ (Doubt is the beginning of wisdom). Circ Res 2014;115:211–4. 7. Bhatt D, Kandzari D, O’Neill W, D’Agostino R, Flack J, Katzen B, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370: 1393–401. 8. Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, et al., SPYRAL HTN-OFF MED trial investigators*. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial. Lancet 2017. 9. Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler D, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64(7):635–43.