HYPERTENSION
Renal denervation: Not as easy as it looks Murray Esler
CREDIT: H. MCDONALD/SCIENCE TRANSLATIONAL MEDICINE
Renal sympathetic denervation with intravascular radiofrequency catheters in hypertensive patients is less efective than anticipated, owing to radio frequency energy being applied to a part of the renal artery where the nerves are at the greatest distance from the aortic lumen and to distortion of energy distribution and temperature gradients by regional tissue anatomical variations (Tzafriri et al., this issue).
Baker IDI Heart and Diabetes Institute, Post Ofce Box 6492, St. Kilda Road Central, Melbourne , Victoria, Australia. E-mail: [email protected]
failure, including those revealed by Tzafriri et al. in this issue of Science Translational Medicine (8). SOURCES OF ERROR Tzafriri et al. (8) demonstrate that previously unexpected denervation technical failures can arise when administered intraluminal radio frequency (RF) energy does not reach its target—the periarterial sympathetic nerves—owing to energy conductivity, power distribution, and temperature gradients being distorted by regional tissue microanaA
B
Superior
100 Vein
Lymph node
E Tendon Anterior
E
Renal artery E
E
Posterior
Renal denervation (%)
Despite the widespread prescribing of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, diuretics, and calcium channel blockers, target blood pressures are not achieved in about 10% of patients. In these drug-resistant hypertensives, a new strategy was devised: a device-based therapy targeting the sympathetic nervous system, called catheter-based renal denervation (1, 2). In renal denervation therapy, radiofrequency or ultrasonic energy is delivered into the lumen of both renal arteries so as to ablate the renal sympathetic nerves. Tree facts provided the knowledge base for the development of this revolutionary therapy: (i) Te renal sympathetic outfow is commonly activated in patients with essential hypertension, particularly those who are drug-resistant (3); (ii) surgical renal denervation in experimental models of hypertension usually lowers arterial pressure or prevents the development of the hypertension (4); and (iii) the anatomy of the renal postganglionic sympathetic nerves is favorable for denervation, with the nerves passing to the kidneys close to the renal artery walls (5, 6), potentially within reach of ablating energy delivered via a catheter in the artery lumen. Te earlier Symplicity trials in endovascular renal nerve ablation, HTN-1 (1) and HTN-2 (2), ushered in a new era in the treatment of drug-resistant hypertension. Te denervation procedure was commonly powerfully antihypertensive and almost invariably safe. But there were disappointments in individual nonresponding patients and in some negative trials, most notably the infuential pivotal U.S. trial Symplicity HTN-3 (7). It is now evident that catheterbased renal denervation is not as easy as originally believed, with technical shortcomings being the reason for therapeutic
tomical variations (Fig. 1A). Diferent tissues near the renal arteries can act as barriers to energy dissipation or as conductive “sinks”; thus, the existence of a symmetrical cone of energy passage beyond the arterial wall, to a predictable depth, is a myth. Te authors determined the sources of error of renal denervation by reproducing the approach in pigs and using computational modeling (8). Anatomical analysis demonstrated complex periarterial anatomy, typically with muscle and fbrous tissue dorsally, and peritoneum and large veins ventrally. Tis nonhomogeneous anatomy infuenced ablation zone orientation, shape, and dimensions. Fibrous muscle sheaths were found to draw the electric feld and substantially increase the lateral and circumferential extent of the ablation geometry. Lymph nodes and skeletal muscle were both predicted and observed to draw the ablation zone, whereas blood vessels acted as an energy sink, tending to limit ablation depth (Fig. 1A). In the renal denervation procedure in patients, interventionalists fo-
80 60 40 20 0
Sympathetic nerves Inferior
Fig. 1. Failure to denervate. (A) Diferent positions of the ablating electrode (“E”) in the renal artery lumen are shown. Veins act as energy sinks, preventing RF energy from reaching the nerve target. Lymph nodes and tendons draw the energy but can redirect it. The outfow of energy toward the targeted nerves is not a symmetrical cone. (B) The efectiveness of endovascular radiofrequency renal nerve ablation assessed with renal norepinephrine spillover measurements made before and 30 days after the procedure. [Data reproduced with permission of (3)] Symplicity Arch and Flex catheters were used in approximately equal numbers. The denervation was incomplete, sometimes markedly so, with pronounced nonuniformity between individual patients. These results contradict the cliche that achieving sympathetic denervation is technically “easy.” The inability to lower blood pressure after renal denervation may be due to suboptimal denervation, not only to the absence of sympathetic nervous activation in individual patients. www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
1
Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
cus on delivering energy to “quadrants” of the renal artery wall, to superior, inferior, anterior (ventral), and posterior (dorsal) felds. Tzafriri et al. now emphasize the tissue diferences in these quadrants and how the microanatomy in each will likely infuence energy conductivity and thermal ablation diferently. Further concerning the “quadrants” into which energy is delivered, a second lesson for interventionalists might derive from another aspect of anatomy: the sympathetic nerves. Overall, the nerves are closer to the artery lumen distally, but this is much more evident in the anterior and posterior quadrants. Te degree of ablation achieved in anterior and posterior quadrants will be particularly sensitive to whether RF energy is applied proximally or distally in the artery, but less so for other quadrants. With single-electrode Symplicity RF catheters in hypertensive patients, denervation is incomplete and nonuniform between patients (Fig. 1B) (3). Denervation can be less than 25%, which is inadequate for a full therapeutic efect. Histological analyses of sympathetic nerves by Tzafriri and colleagues in pigs produced similar results, with distortion of the energy path providing one explanation (8). Another important cause of failure to achieve adequate renal sympathetic denervation is the common procedural practice of delivering energy in the lumen of the proximal part of the renal arteries, near their origin from the aorta (3, 7). Te renal sympathetic nerves are more distant from the artery lumen proximally and are closer and more easily accessed by administered energy in the distal renal artery and the renal artery divisions (5, 6). Failure to achieve denervation can also result from procedural inexperience and incompetence, which was recently documented as one source of the failure for blood pressure to be lowered in the Symplicity HTN-3 trial (3, 9, 10). THE SYMPLICITY TRIALS Te Symplicity HTN-3 trial (7) resulted in a negative outcome that cast a pall over the renal denervation feld. Although it was a comprehensive, rigorously designed study, whether renal denervation was actually achieved in individual patients was not evaluated in Symplicity HTN-3. Tis is a noteworthy defciency in trial design, especially because the majority of participating interventionists, although experienced in other procedures, had never performed a percutaneous renal denervation (6). Te
less-than-complete denervation in the hands of experienced proceduralists evident in Symplicity HTN-1 (2) was therefore exacerbated in Symplicity HTN-3 by operator inexperience and lack of training (3). It is now a matter of record that the denervation procedure fared badly in Symplicity HTN-3 (9). Energy was applied preferentially in the proximal part of the renal arteries, which was theoretically unsound (5, 6). Additionally, retrospective analysis of the procedural records of all patients demonstrated that in 74%, not even one fully circumferential renal artery application of RF energy was achieved, when it was a protocol prerequisite that this be done bilaterally; thus, efective nerve ablation was impossible. It is noteworthy that in the minority of patients in whom energy was applied circumferentially in both renal arteries (approximately 5%), blood pressure lowering was similar in degree to that noted in the earlier Symplicity trials (9). Further, as expected from the study of Tzafriri et al. (8), given that energy penetration to sympathetic nerves outside the renal arteries is unpredictable, in Symplicity HTN3 blood pressure lowering was observed if there were numerous energy applications, bilaterally exceeding 14 (9). On the basis of the data from Tzafriri et al. concerning the number of RF energy applications, “the more the merrier.” RENAL DENERVATION IN THE FUTURE Te Symplicity HTN-3 trial shook the renal denervation feld, but not too violently; the trial is now seen to have failed in its procedural execution rather than in concept (3, 8). Why should renal denervation lower blood pressure, in four mammalian species (rats, dogs, rabbits, and pigs) (4), but not in the humans (7, 9)? In the words of Dr. George Bakris, Symplicity HTN-3 trial co-chief investigator, “Given procedural uncertainty and the virtual inability to know with precision where within a vessel a burn was delivered, it is highly likely that RDN as it was performed in the HTN-3 was technically inconsistent at best, but technically inadequate at worst” (10). Te feld of renal denervation for experimental hypertension is active, energized by these clinical studies. Blood pressure lowering was demonstrated with catheter-based renal denervation by Tzafriri et al. (8), even in pigs with normal blood pressure. It is now time to refect on what future science is needed. Some ideas fow from Tzafriri et al. (8). One idea is that multiple applica-
tions of RF energy—more than are currently made, which is typically 8 to 12 in total bilaterally—should be applied to the renal artery walls. Te authors demonstrated that an individual dose of RF energy may not reach its target (periarterial nerves) owing to local anatomy variations distorting energy conductivity and temperature gradients. Supporting this recommendation is the fnding in Symplicity HTN-3 (9) that blood pressure fall with renal denervation was only seen with numerous energy applications. Further, these fndings support the use of multielectrode RF catheters in the future. A second important recommendation, deriving from other sources (5, 6), is that RF and ultrasonic energy must be delivered into the distal renal arteries and even into the renal artery divisions. It has been a critical failing in many studies that this has not been done (9). Te evidence from experimental studies on this point is that RF energy delivery into the proximal renal arteries produces suboptimal denervation, whereas energy delivery into the distal renal arteries and renal artery divisions produces nearcomplete denervation, uniform between animals (6). Te experience in patients in whom RF energy has been administered more proximally parallels this (Fig. 1B) (3). Te “quadrants” (felds) into which clinical interventionalists deliver energy— anterior (ventral), posterior (dorsal), superior, and inferior—up to now have not been diferentiated in terms of energy dosing; in short, the requirement has been that each quadrant should receive at least one energy dose, this dose being the same in all quadrants. But perhaps procedural discrimination between the quadrants is desirable. For example, Tzafriri et al. (8) demonstrate the infuence of regional anatomy on energy fow, suggesting that in the anterior quadrant, energy sinks provided by large veins may perhaps prevent energy penetration to the neural target. Should a higher energy dose be given in this feld? Or more doses? Te regional anatomy of sympathetic nerves also difers according to quadrant. Te convergence of sympathetic nerves on the renal arteries, in their course toward the kidneys, is much more pronounced in the anterior and posterior quadrants and less obvious in superior and inferior quadrants (6). Te degree of ablation achieved in anterior and posterior quadrants will be particularly sensitive to whether RF energy is applied proximally or distally in the artery, but less so for other quadrants.
www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
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Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
Tere will be other specifc questions for the future. Does unilateral renal denervation lower pressure? Tis becomes a relevant clinical question in patients in whom a bilateral renal denervation procedure is not possible, such as in the presence of multiple renal arteries on one side. Although there are some misgivings on this point, Tzafriri et al. suggest “yes” (8). Should RF catheters be irrigated, to minimize renal artery wall damage, rather than just relying on renal blood fow to dissipate energy from the vessel wall? Another contentious matter, with Tzafriri et al. again suggesting “yes.” A more general question is whether renal denervation antihypertensive trials in the future will be in patients with severe, drugresistant hypertension? Te Symplicity HTN3 trial did emphasize the particular difculty of securing and monitoring drug adherence in this patient group (9). Te pivotal renal denervation antihypertensive trial of the future may perhaps be in younger, untreated hypertensive patients, with less severe disease. Tese patients have high renal sympathetic
activity to target (3), drug adherence interpretation problems will be avoided as patient groups will be unmedicated, and the ethics of such a trial could be justifed on the grounds that the denervation procedure is safer than it was at frst anticipated. REFERENCES 1. H. Krum, M. Schlaich, R. Whitbourn, P. A. Sobotka, J. Sadowski, K. Bartus, B. Kapelak, A. Walton, H. Sievert, S. Thambar, W. T. Abraham, M. Esler, Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 373, 1275–1281 (2009). 2. M. D. Esler, H. Krum, P. A. Sobotka, M. P. Schlaich, R. E. Schmieder, M. Böhm, Symplicity HTN-2 Investigators, Renal sympathetic denervation in patients with treatmentresistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet 376, 1903–1909 (2010). 3. M. Esler, Illusions of truths in the Symplicity HTN-3 trial: Generic design strengths but neuroscience failings. J. Am. Soc. Hypertens. 8, 593–598 (2014). 4. G. F. DiBona, M. Esler, Translational medicine: The antihypertensive efect of renal denervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R245–R253 (2010). 5. K. Sakakura, E. Ladich, Q. Cheng, F. Otsuka, K. Yahagi, F. Kolodgie, M. Joner, R. Virmani, Anatomical distribution of
6. 7.
8.
9.
10.
human renal sympathetic nerves: Pathological study. J. Am. Coll. Cardiol. 63, A2151 (2014). F. Mahfoud, T. L. Luscher, Renal denervation: Simply trapped by complexity. Eur. Heart J. 36, 199–202 (2015). D. L. Bhatt, D. E. Kandzari, W. W. O’Neill, R. D’Agostino, J. M. Flack, B. T. Katzen, M. B. Leon, M. Liu, L. Mauri, M. Negoita, S. A. Cohen, S. Oparil, K. Rocha-Singh, R. R. Townsend, G. L. Bakris, SYMPLICITY HTN-3 Investigators, A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 370, 1393–1401 (2014). A. R. Tzafriri, J. H. Keating, P. M. Markham, A.-M. Spognardi, J. R. L. Stanley, G. Wong, B. G. Zani, D. Highsmith, P. O’Fallon, K. Fuimaono, F. Mahfoud, E. R. Edelman, Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci. Transl. Med. 7, 285ra65 (2015). D. E. Kandzari, D. L. Bhatt, S. Brar, C. M. Devireddy, M. Esler, M. Fahy, J. M. Flack, B. T. Katzen, J. Lea, D. P. Lee, M. B. Leon, A. Ma, J. Massaro, L. Mauri, S. Oparil, W. W. O’Neill, M. R. Patel, K. Rocha-Singh, P. A. Sobotka, L. Svetkey, R. R. Townsend, G. L. Bakris, Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur. Heart J. 36, 219–227 (2014). S. Nathan, G. L. Bakris, The future of renal denervation in resistant hypertension. Curr. Hypertens. Rep. 16, 494 (2014).
10.1126/scitranslmed.aaa5457 Citation: M. Esler, Renal denervation: Not as easy as it looks. Sci. Transl. Med. 7, 285fs18 (2015).
www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
3
Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
Renal denervation: Not as easy as it looks Murray Esler
CREDIT: H. MCDONALD/SCIENCE TRANSLATIONAL MEDICINE
Renal sympathetic denervation with intravascular radiofrequency catheters in hypertensive patients is less efective than anticipated, owing to radio frequency energy being applied to a part of the renal artery where the nerves are at the greatest distance from the aortic lumen and to distortion of energy distribution and temperature gradients by regional tissue anatomical variations (Tzafriri et al., this issue).
Baker IDI Heart and Diabetes Institute, Post Ofce Box 6492, St. Kilda Road Central, Melbourne , Victoria, Australia. E-mail: [email protected]
failure, including those revealed by Tzafriri et al. in this issue of Science Translational Medicine (8). SOURCES OF ERROR Tzafriri et al. (8) demonstrate that previously unexpected denervation technical failures can arise when administered intraluminal radio frequency (RF) energy does not reach its target—the periarterial sympathetic nerves—owing to energy conductivity, power distribution, and temperature gradients being distorted by regional tissue microanaA
B
Superior
100 Vein
Lymph node
E Tendon Anterior
E
Renal artery E
E
Posterior
Renal denervation (%)
Despite the widespread prescribing of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, diuretics, and calcium channel blockers, target blood pressures are not achieved in about 10% of patients. In these drug-resistant hypertensives, a new strategy was devised: a device-based therapy targeting the sympathetic nervous system, called catheter-based renal denervation (1, 2). In renal denervation therapy, radiofrequency or ultrasonic energy is delivered into the lumen of both renal arteries so as to ablate the renal sympathetic nerves. Tree facts provided the knowledge base for the development of this revolutionary therapy: (i) Te renal sympathetic outfow is commonly activated in patients with essential hypertension, particularly those who are drug-resistant (3); (ii) surgical renal denervation in experimental models of hypertension usually lowers arterial pressure or prevents the development of the hypertension (4); and (iii) the anatomy of the renal postganglionic sympathetic nerves is favorable for denervation, with the nerves passing to the kidneys close to the renal artery walls (5, 6), potentially within reach of ablating energy delivered via a catheter in the artery lumen. Te earlier Symplicity trials in endovascular renal nerve ablation, HTN-1 (1) and HTN-2 (2), ushered in a new era in the treatment of drug-resistant hypertension. Te denervation procedure was commonly powerfully antihypertensive and almost invariably safe. But there were disappointments in individual nonresponding patients and in some negative trials, most notably the infuential pivotal U.S. trial Symplicity HTN-3 (7). It is now evident that catheterbased renal denervation is not as easy as originally believed, with technical shortcomings being the reason for therapeutic
tomical variations (Fig. 1A). Diferent tissues near the renal arteries can act as barriers to energy dissipation or as conductive “sinks”; thus, the existence of a symmetrical cone of energy passage beyond the arterial wall, to a predictable depth, is a myth. Te authors determined the sources of error of renal denervation by reproducing the approach in pigs and using computational modeling (8). Anatomical analysis demonstrated complex periarterial anatomy, typically with muscle and fbrous tissue dorsally, and peritoneum and large veins ventrally. Tis nonhomogeneous anatomy infuenced ablation zone orientation, shape, and dimensions. Fibrous muscle sheaths were found to draw the electric feld and substantially increase the lateral and circumferential extent of the ablation geometry. Lymph nodes and skeletal muscle were both predicted and observed to draw the ablation zone, whereas blood vessels acted as an energy sink, tending to limit ablation depth (Fig. 1A). In the renal denervation procedure in patients, interventionalists fo-
80 60 40 20 0
Sympathetic nerves Inferior
Fig. 1. Failure to denervate. (A) Diferent positions of the ablating electrode (“E”) in the renal artery lumen are shown. Veins act as energy sinks, preventing RF energy from reaching the nerve target. Lymph nodes and tendons draw the energy but can redirect it. The outfow of energy toward the targeted nerves is not a symmetrical cone. (B) The efectiveness of endovascular radiofrequency renal nerve ablation assessed with renal norepinephrine spillover measurements made before and 30 days after the procedure. [Data reproduced with permission of (3)] Symplicity Arch and Flex catheters were used in approximately equal numbers. The denervation was incomplete, sometimes markedly so, with pronounced nonuniformity between individual patients. These results contradict the cliche that achieving sympathetic denervation is technically “easy.” The inability to lower blood pressure after renal denervation may be due to suboptimal denervation, not only to the absence of sympathetic nervous activation in individual patients. www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
1
Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
cus on delivering energy to “quadrants” of the renal artery wall, to superior, inferior, anterior (ventral), and posterior (dorsal) felds. Tzafriri et al. now emphasize the tissue diferences in these quadrants and how the microanatomy in each will likely infuence energy conductivity and thermal ablation diferently. Further concerning the “quadrants” into which energy is delivered, a second lesson for interventionalists might derive from another aspect of anatomy: the sympathetic nerves. Overall, the nerves are closer to the artery lumen distally, but this is much more evident in the anterior and posterior quadrants. Te degree of ablation achieved in anterior and posterior quadrants will be particularly sensitive to whether RF energy is applied proximally or distally in the artery, but less so for other quadrants. With single-electrode Symplicity RF catheters in hypertensive patients, denervation is incomplete and nonuniform between patients (Fig. 1B) (3). Denervation can be less than 25%, which is inadequate for a full therapeutic efect. Histological analyses of sympathetic nerves by Tzafriri and colleagues in pigs produced similar results, with distortion of the energy path providing one explanation (8). Another important cause of failure to achieve adequate renal sympathetic denervation is the common procedural practice of delivering energy in the lumen of the proximal part of the renal arteries, near their origin from the aorta (3, 7). Te renal sympathetic nerves are more distant from the artery lumen proximally and are closer and more easily accessed by administered energy in the distal renal artery and the renal artery divisions (5, 6). Failure to achieve denervation can also result from procedural inexperience and incompetence, which was recently documented as one source of the failure for blood pressure to be lowered in the Symplicity HTN-3 trial (3, 9, 10). THE SYMPLICITY TRIALS Te Symplicity HTN-3 trial (7) resulted in a negative outcome that cast a pall over the renal denervation feld. Although it was a comprehensive, rigorously designed study, whether renal denervation was actually achieved in individual patients was not evaluated in Symplicity HTN-3. Tis is a noteworthy defciency in trial design, especially because the majority of participating interventionists, although experienced in other procedures, had never performed a percutaneous renal denervation (6). Te
less-than-complete denervation in the hands of experienced proceduralists evident in Symplicity HTN-1 (2) was therefore exacerbated in Symplicity HTN-3 by operator inexperience and lack of training (3). It is now a matter of record that the denervation procedure fared badly in Symplicity HTN-3 (9). Energy was applied preferentially in the proximal part of the renal arteries, which was theoretically unsound (5, 6). Additionally, retrospective analysis of the procedural records of all patients demonstrated that in 74%, not even one fully circumferential renal artery application of RF energy was achieved, when it was a protocol prerequisite that this be done bilaterally; thus, efective nerve ablation was impossible. It is noteworthy that in the minority of patients in whom energy was applied circumferentially in both renal arteries (approximately 5%), blood pressure lowering was similar in degree to that noted in the earlier Symplicity trials (9). Further, as expected from the study of Tzafriri et al. (8), given that energy penetration to sympathetic nerves outside the renal arteries is unpredictable, in Symplicity HTN3 blood pressure lowering was observed if there were numerous energy applications, bilaterally exceeding 14 (9). On the basis of the data from Tzafriri et al. concerning the number of RF energy applications, “the more the merrier.” RENAL DENERVATION IN THE FUTURE Te Symplicity HTN-3 trial shook the renal denervation feld, but not too violently; the trial is now seen to have failed in its procedural execution rather than in concept (3, 8). Why should renal denervation lower blood pressure, in four mammalian species (rats, dogs, rabbits, and pigs) (4), but not in the humans (7, 9)? In the words of Dr. George Bakris, Symplicity HTN-3 trial co-chief investigator, “Given procedural uncertainty and the virtual inability to know with precision where within a vessel a burn was delivered, it is highly likely that RDN as it was performed in the HTN-3 was technically inconsistent at best, but technically inadequate at worst” (10). Te feld of renal denervation for experimental hypertension is active, energized by these clinical studies. Blood pressure lowering was demonstrated with catheter-based renal denervation by Tzafriri et al. (8), even in pigs with normal blood pressure. It is now time to refect on what future science is needed. Some ideas fow from Tzafriri et al. (8). One idea is that multiple applica-
tions of RF energy—more than are currently made, which is typically 8 to 12 in total bilaterally—should be applied to the renal artery walls. Te authors demonstrated that an individual dose of RF energy may not reach its target (periarterial nerves) owing to local anatomy variations distorting energy conductivity and temperature gradients. Supporting this recommendation is the fnding in Symplicity HTN-3 (9) that blood pressure fall with renal denervation was only seen with numerous energy applications. Further, these fndings support the use of multielectrode RF catheters in the future. A second important recommendation, deriving from other sources (5, 6), is that RF and ultrasonic energy must be delivered into the distal renal arteries and even into the renal artery divisions. It has been a critical failing in many studies that this has not been done (9). Te evidence from experimental studies on this point is that RF energy delivery into the proximal renal arteries produces suboptimal denervation, whereas energy delivery into the distal renal arteries and renal artery divisions produces nearcomplete denervation, uniform between animals (6). Te experience in patients in whom RF energy has been administered more proximally parallels this (Fig. 1B) (3). Te “quadrants” (felds) into which clinical interventionalists deliver energy— anterior (ventral), posterior (dorsal), superior, and inferior—up to now have not been diferentiated in terms of energy dosing; in short, the requirement has been that each quadrant should receive at least one energy dose, this dose being the same in all quadrants. But perhaps procedural discrimination between the quadrants is desirable. For example, Tzafriri et al. (8) demonstrate the infuence of regional anatomy on energy fow, suggesting that in the anterior quadrant, energy sinks provided by large veins may perhaps prevent energy penetration to the neural target. Should a higher energy dose be given in this feld? Or more doses? Te regional anatomy of sympathetic nerves also difers according to quadrant. Te convergence of sympathetic nerves on the renal arteries, in their course toward the kidneys, is much more pronounced in the anterior and posterior quadrants and less obvious in superior and inferior quadrants (6). Te degree of ablation achieved in anterior and posterior quadrants will be particularly sensitive to whether RF energy is applied proximally or distally in the artery, but less so for other quadrants.
www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
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Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
Tere will be other specifc questions for the future. Does unilateral renal denervation lower pressure? Tis becomes a relevant clinical question in patients in whom a bilateral renal denervation procedure is not possible, such as in the presence of multiple renal arteries on one side. Although there are some misgivings on this point, Tzafriri et al. suggest “yes” (8). Should RF catheters be irrigated, to minimize renal artery wall damage, rather than just relying on renal blood fow to dissipate energy from the vessel wall? Another contentious matter, with Tzafriri et al. again suggesting “yes.” A more general question is whether renal denervation antihypertensive trials in the future will be in patients with severe, drugresistant hypertension? Te Symplicity HTN3 trial did emphasize the particular difculty of securing and monitoring drug adherence in this patient group (9). Te pivotal renal denervation antihypertensive trial of the future may perhaps be in younger, untreated hypertensive patients, with less severe disease. Tese patients have high renal sympathetic
activity to target (3), drug adherence interpretation problems will be avoided as patient groups will be unmedicated, and the ethics of such a trial could be justifed on the grounds that the denervation procedure is safer than it was at frst anticipated. REFERENCES 1. H. Krum, M. Schlaich, R. Whitbourn, P. A. Sobotka, J. Sadowski, K. Bartus, B. Kapelak, A. Walton, H. Sievert, S. Thambar, W. T. Abraham, M. Esler, Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 373, 1275–1281 (2009). 2. M. D. Esler, H. Krum, P. A. Sobotka, M. P. Schlaich, R. E. Schmieder, M. Böhm, Symplicity HTN-2 Investigators, Renal sympathetic denervation in patients with treatmentresistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet 376, 1903–1909 (2010). 3. M. Esler, Illusions of truths in the Symplicity HTN-3 trial: Generic design strengths but neuroscience failings. J. Am. Soc. Hypertens. 8, 593–598 (2014). 4. G. F. DiBona, M. Esler, Translational medicine: The antihypertensive efect of renal denervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R245–R253 (2010). 5. K. Sakakura, E. Ladich, Q. Cheng, F. Otsuka, K. Yahagi, F. Kolodgie, M. Joner, R. Virmani, Anatomical distribution of
6. 7.
8.
9.
10.
human renal sympathetic nerves: Pathological study. J. Am. Coll. Cardiol. 63, A2151 (2014). F. Mahfoud, T. L. Luscher, Renal denervation: Simply trapped by complexity. Eur. Heart J. 36, 199–202 (2015). D. L. Bhatt, D. E. Kandzari, W. W. O’Neill, R. D’Agostino, J. M. Flack, B. T. Katzen, M. B. Leon, M. Liu, L. Mauri, M. Negoita, S. A. Cohen, S. Oparil, K. Rocha-Singh, R. R. Townsend, G. L. Bakris, SYMPLICITY HTN-3 Investigators, A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 370, 1393–1401 (2014). A. R. Tzafriri, J. H. Keating, P. M. Markham, A.-M. Spognardi, J. R. L. Stanley, G. Wong, B. G. Zani, D. Highsmith, P. O’Fallon, K. Fuimaono, F. Mahfoud, E. R. Edelman, Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci. Transl. Med. 7, 285ra65 (2015). D. E. Kandzari, D. L. Bhatt, S. Brar, C. M. Devireddy, M. Esler, M. Fahy, J. M. Flack, B. T. Katzen, J. Lea, D. P. Lee, M. B. Leon, A. Ma, J. Massaro, L. Mauri, S. Oparil, W. W. O’Neill, M. R. Patel, K. Rocha-Singh, P. A. Sobotka, L. Svetkey, R. R. Townsend, G. L. Bakris, Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur. Heart J. 36, 219–227 (2014). S. Nathan, G. L. Bakris, The future of renal denervation in resistant hypertension. Curr. Hypertens. Rep. 16, 494 (2014).
10.1126/scitranslmed.aaa5457 Citation: M. Esler, Renal denervation: Not as easy as it looks. Sci. Transl. Med. 7, 285fs18 (2015).
www.ScienceTranslationalMedicine.org 29 April 2015 Vol 7 Issue 285 285fs18
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Downloaded from stm.sciencemag.org on May 6, 2015
FOCUS
