Finding the best ablation strategy for renal denervation: A continuing saga

In this very interesting study, Beeftink and colleagues1 sought and successfully addressed an unmet need of current clinical practice: the estimation of the effect of distal renal denervation (RDN) on the safety and efficacy of blood pressure (BP) lowering in resistant hypertensive patients. They concluded that distal to the bifurcation, RDN is accompanied by a similar safety profile compared with proximal RDN, whereas there are no differences between the two strategies for BP lowering in resistant hypertension.1 This study improves our knowledge on the impact of targeting different renal arterial segments during RDN procedures. Aiming towards more effective RDN, we should increase our insight on periarterial renal nerve distribution in chronically hypertensive patients, which is currently very limited. In this context, it is not defined to what extent preclinical results can be applied to vessels subjected to atherosclerosis and hypertension. Pioneer studies have shown that the highest average number of nerves was observed in the proximal and middle segments of the renal artery and the lowest in the distal segments, while the mean distance from the lumen to the nerve was the longest in the proximal and the lowest in the distal segments.2, 3 Moreover, reports have suggested that RDN distally in the renal vasculature and more specifically in the branches results in greater noradrenaline reduction and BP lowering.4 This concept, however, should be tested in a wide clinical setting and issues regarding safety are not currently elucidated. Based on the above, there is a notion that proper location as well as increased number of ablation points during an RDN procedure can result in more complete interruption of the renal sympathetic nerves and thus in improved BP reduction. Along these lines, in the present study, the number of distal ablations were related to better ambulatory systolic BP reduction but not to office BP.1 In the SYMPLICITY HTN-3 trial, BP response increased with increasing number of ablations delivered and the successful delivery of circumferential quadrant ablations.5, 6 The difference in the mean number of ablations attempted (energy application) per artery between SYMPLICITY HTN-1 and SYMPLICITY HTN-3 was almost four, suggesting a “dose-response” dependency between the number of ablation attempts and the efficacy of RDN. Additionally, only a small proportion of patients in SYMPLICITY HTN-3 had successful ablation across all four quadrants of the renal artery. In these patients, complete four-quadrant ablation in both renal arteries was associated with a higher office systolic BP drop of 24.3 mm Hg. In the present study, there is a lack of data on four-quadrant ablation assessment and this limits the ability to address the confounding impact of incomplete ablation as it is perceived with a 360-degree interruption of nerves in the renal arteries.1 Consequently, the design of new studies addresses this issue by promoting a “more is better” approach to RDN ablation strategy in each renal artery.6, 7 As elegantly shown in histological studies, only a portion of the total nerves in each ablated artery segment is destroyed after RDN,8 and this is thought to have an impact on the RDN-induced BP lowering. From a pathophysiological point of view, although disruption of nerves is needed for neuromodulation and BP change, there are no data on whether complete denervation is either safe or needed for clinical efficacy. All published works on the norepinephrine level alterations after RDN and their association with percentages of nerve damage4 should be interpreted with caution since there is no solid evidence that norepinephrine reduction is translated to BP outcome, not even to sympathetic nervous system activation change.9 Moreover, when assessing a more accurate parameter of sympathetic drive, which is muscle sympathetic nerve activity, the latter is reduced after RDN but there is no correlation with the level of BP reduction.9, 10 All of the above may reset our approach to “incomplete” ablation and guide future studies for a more sophisticated search for the link between RDN-induced nerve damage, sympathetic activity alteration, and BP reduction. It is of paramount importance to identify clinical predictors of BP response to RDN.5, 7 Elevated office and ambulatory BP has been associated with greater reductions in BP and there are emerging data that obesity and younger age, along with absence of isolated systolic hypertension, are related to better BP control after RDN.11, 12 Regarding procedural parameters, acute changes in renal blood flow assessed by ultrasound or by pressure wires after RDN have also been proposed as predictors, but more data are needed.13 Additionally, electrical high-frequency stimulation of the renal arteries in animal and human settings causes an increase in BP that can be documented in the catheterization laboratory and there are important ongoing proof-of-principle studies in humans.14, 15 Regarding BP outcome, office as well as ambulatory BPs were estimated in the study by Beeftink and colleagues.1 This strengthens the validity of the results. It is proposed that ambulatory BP should be used as an end point for BP efficacy in RDN trials since it is less biased.7, 16 However, office BP reduction has strong evidence for cardiovascular protection17 and should not be neglected but included in RDN trials in tandem with ambulatory assessment of hemodynamic load.7 Most importantly, office BP should be carefully estimated and evidenced based on established methodology, which is a major point addressed in ongoing studies of RDN.16 The study adds to the established safety data of RDN, since there was no increased occurrence of vascular spasm in patients with distal ablations compared with the proximal therapies and renal function was not adversely affected.1 This is in line with previous reports showing a renal protective action of RDN during follow-up.3, 7, 11 Drug choice for uncontrolled hypertension accompanied or not by RDN is a difficult clinical task in terms of long-term persistence to therapy.6, 7 European experts on RDN suggest that in future RDN trials, it is crucial to standardize concomitant antihypertensive therapy. As a consensus, all patients should be treated with the combination of a renin angiotensin blocker, a calcium channel blocker, and a diuretic with a stable run-in period of at least 4 to 8 weeks. In addition, monitoring drug adherence as a potential confounder of BP response is crucial and can be done by pill counting, electronic pill dispenser, and by the more accurate toxicological drug analysis as in current trials.7, 16 Most significantly, the ongoing trials including patients not taking antihypertensive drugs will better inform us on the “true” efficacy of RDN in a nondrug-influenced patient setting.16 In the present study, the impact of changes of antihypertensive medication is addressed in which no significant changes were observed and the use of aldosterone antagonists did not change the outcome of the intervention.1 Distal ablation is safe and results in clinically meaningful reduction of BP in resistant hypertension but with no additional BP-lowering efficacy compared with standard main vessel therapy. The article provides important information on the influence of a procedural parameter of RDN but there are many other potent confounders. Only by integrating current data and addressing past misconceptions can we put an end to the saga of finding the best RDN therapeutic strategy.