We are now looking back on 10 years of experience with catheter-based renal sympathetic denervation for treatment of human hypertension and it has been a long and winding road. Based on robust physiologic principles and convincing evidence from experimental models the concept of renal denervation (RDN) was introduced into clinical medicine and results from the initial proof-of-concept study [Symplicity Hypertension (HTN)-1]  and the subsequent first randomized controlled trial (Symplicity HTN-2)  were met with enthusiasm by most in the hypertension community. Findings from Symplicity HTN-3 , the largest and first study to include a sham control, failed to demonstrate a blood pressure (BP)-lowering effect beyond that observed in the sham control group  and brought the ‘RDN-express’ to a hold, albeit not derailing it. Concerted efforts to understand the neutral results of Symplicity HTN-3 provided relevant insights into the importance of operator experience, mode of delivery of ablation therapy, patient adherence with prescribed antihypertensive medication and others . Accounting for these factors, the very recently published SPYRAL HTN-OFF MED  trial was conducted as a renewed multicentre, randomised, controlled proof-of-concept trial, where eligible drug-naïve patients were randomly assigned to RDN or sham control. The trial clearly confirmed the BP-lowering efficacy of RDN with a significant difference in the primary endpoint of the change in 24-h BP at 3 months of –5.0 mmHg (95% confidence interval –9.9 to –0.2; P = 0.0414) for SBP and –4.4 mmHg (–7.2 to –1.6; P = 0.0024) for DBP. RDN therefore remains a viable option for treatment of hypertension .
Nevertheless, experience from all studies conducted thus far demonstrates that the BP response to RDN is variable. Identification of the most suitable patient cohort that may specifically benefit from RDN remains an important issue to be addressed, as is identification of those who may not benefit substantially from such an approach [6,7].
A number of potential predictors of the BP response to RDN have consistently been identified, including baseline SBP with higher baseline levels being associated with more pronounced BP-lowering efficacy . Several biomarkers have also been suggested in some studies to predict the BP response to RDN. Conversely, patients with isolated systolic hypertension or increased arterial stiffening have consistently been shown to respond less well to RDN in regards to its BP-lowering efficacy, most recently by means of ambulatory arterial stiffness index . Common to all these investigations was the definition of BP response or nonresponse to RDN, that is more or less than 10 mmHg with office SBP or more or less than 5 mmHg with ambulatory SBP measurement.
In this context, Fengler et al.  in the current issue of the Journal, present some interesting findings derived from applying a different approach to the definition of response by focusing on those patients with a very profound reduction in ambulatory daytime SBP of more than 20 mmHg at 3 months after RDN. Out of a reasonably large sample size of 190 patients from a single centre who underwent RDN with various devices, the authors identified 33 patients who fulfilled this criterion. In comparison to their counterparts with a less pronounced BP reduction, these patients were younger, had higher baseline ambulatory BP, were treated more frequently with ultrasound-based RDN, and were on combined diuretic therapy. Multivariate logistic regression analysis confirmed these factors as independent predictors for a profound BP response. Lower pulse wave velocity, measured invasively in a smaller subset of patients, was also found to be independently associated with a higher probability for a profound BP response.
The data provided are of relevance in the context of ongoing efforts to clinically identify patients who may respond most favorably to RDN. The association of a profound BP response with higher baseline ambulatory SBP does not come as a surprise [4,8]. Similarly, the association of a more pronounced BP reduction with younger age is somewhat expected, although not uniformly demonstrated in previous studies. Sympathetic activation is particularly elevated in early hypertension and hypertensive organ damage is more likely to be reversible in younger patients, thereby potentially facilitating a more favorable effect of sympatho-inhibition [4,6]. The absence of an association with age in other studies may well be due to the relatively limited spread of age groups within most study cohorts.
The interesting observation of a substantial BP reduction in patients treated with two different diuretics other than aldosterone-antagonists (typically thiazide and loop diuretics) may have a sound pathophysiologic basis. Thiazide  and loop diuretics  have been demonstrated to increase sympathetic nerve activity and more aggressive diuretic treatment may exaggerate the compensatory increase in sympathetic activity thereby potentially enhancing the sympatho-inhibitory and BP-lowering effect of RDN. Volume overload is a common feature of resistant hypertension and adequate diuretic therapy, including sequential nephron blockade if required, is a prerequisite for its diagnosis. It is conceivable that patients who are adherent to such diuretic regimens, and other prescribed antihypertensives including renin–angiotensin system blockers and calcium-channel blockers, but remain uncontrolled may be ideal candidates for RDN as it counteracts the mechanism not opposed by their pharmaco-therapy. Adequate diuretic therapy, if tolerated, should therefore be implemented prior to considering RDN.
It is puzzling that a trend towards significance was seen in regards to more pronounced BP lowering with radiofrequency unipolar treatment but not with multipolar radiofrequency treatment. This is most likely related to the relatively small numbers in respective groups and the variation in ablations performed, making comparison of different treatment modalities a challenging if not impossible task. Accordingly, these findings have to be interpreted with caution. Similarly, as appropriately acknowledged by the authors, comparison of efficacy of ultrasound vs. radiofrequency-based approaches is challenging within the context of this study and the findings should not be over-interpreted.
Continued thorough clinical observation paired with implementation of the lessons learned from available data into the design of future randomized controlled clinical trials will ultimately provide as with much needed information to offer RDN to those patients who are likely to benefit most.
M.P.S. is supported by an NHMRC Research Fellowship and has received consulting fees, and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer and Boehringer-Ingelheim. The other authors have no disclosures.
Conflicts of interest
There are no conflicts of interest.
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