Among all patients treated for arterial hypertension, about 10–15% do not reach the defined blood pressure (BP) targets and remain hypertensive despite the prescription of at least three antihypertensive medications at maximally tolerated doses (one of them being a diuretic) or require more than four drugs to obtain an adequate BP control. These patients are diagnosed as having apparent resistant hypertension but the prevalence of true resistant hypertension among treated and all hypertensive individuals appears to be about 10 and 7.9%, respectively .
As pharmacological treatments appear to be failing in patients with resistant hypertension, new therapeutic approaches have been developed for the management of resistant hypertension based on interventional procedures such as percutaneous renal sympathetic denervation, baroreflex activation, central iliac arteriovenous anastomosis or carotid body ablation . The renal sympathetic nervous system (SNS) plays a crucial role in the regulation of sodium excretion, renin secretion and renal hemodynamics . Hence, the SNS is critical for BP control and contributes to the development of several forms of hypertension [3,4]. This is the reason why renal sympathetic denervation has retained the greatest attention as a potential therapeutic target in resistant hypertension since the first description of a successful control of BP after a renal denervation performed using a catheter-based renal ablation with radiofrequency energy . Today, we have almost 10 years of experience with this procedure with close to 1900 publications on the topic since 2009.
The initial nonsham-controlled studies using renal sympathectomy demonstrated striking reductions in office BP (−30 mmHg SBP) in patients with apparent resistant hypertension, although the changes in ambulatory BP were less impressive (−11 mmHg SBP) but still significant [6,7]. Thereafter, many studies have confirmed these initial successes but one has to mention that several other follow-up publications did not report any significant decrease in BP using renal denervation whenever the procedure was compared with adjusted drug treatments [8–10]. The first large sham-controlled study was Symplicity HTN-3, which failed to demonstrate significant reductions in both office and ambulatory BP in patients treated with renal denervation whenever compared to the control group . However, several aspects of Simplicity HTN-3 have been criticized and potential confounding factors have been proposed to explain the disparate results, including major changes in medications and possibly drug adherence during the study period as well as technical problems regarding the quality of the renal denervation procedure, particularly the number of ablation points . Another small sham-controlled study failed to achieve significant reductions in BP with renal denervation . In contrast to Simplicity HTN-3, the data of several large uncontrolled national and international registries [14–16] tend to confirm the BP-lowering efficacy of renal denervation and a recently published well controlled study also reported a significant 6 mmHg reduction of ambulatory SBP, 6 months after renal denervation .
All together, the results of Simplicity HTN-3 and the disparate results of many smaller studies have finally called in question, the ability of renal sympathetic denervation to really lower BP in resistant hypertension. This is the reason why the SPYRAL HTN-OFF MED trial was performed in patients with hypertension and no antihypertensive medication to limit the impact of confounding factors. The results of this study have now proven that the concept of a BP reduction induced by renal denervation in untreated hypertensive patients is valid, but the results of this trial are still considered by some as rather modest (−5.0/−4.4 mmHg decrease in SBP/DBP) .
One characteristic feature of almost all renal denervation studies is not only the heterogeneity of the BP response with excellent responders who normalize their BP but also a large proportion of patients who are either partial or total nonresponders . In a way, this is not surprising considering the multiplicity of pathways implicated in the regulation of BP and hence, in the pathogenesis of hypertension . The SNS is a common pathway to some but definitively not all forms of hypertension. The prescription of antihypertensive drugs is associated with a similar heterogeneity of response with almost no possibility to predict which patient will respond to a given medication.
There are several possible ways to reduce the variability of the BP response to renal denervation. One approach may be to ameliorate the quality of the denervation per se and this has been done with the development of new catheters  and the more distal denervation of renal arteries. Another approach would be a better identification of the patients who might benefit from the procedure and in whom the renal sympathetic nerve system contributes to the maintenance of hypertension. In this respect, several investigators have analyzed factors that can predict a good or a poor response to renal denervation. Sex and obesity did not appear to influence the BP response to renal denervation . The strongest positive predictive factor that emerged was baseline office or ambulatory BP. Some factors were associated with a blunted response to renal denervation. This is the case, for example, of patients with isolated systolic hypertension or patients with accessory renal arteries [21,22].
The identification of isolated systolic hypertension (ISH) as a factor of poor response to sympathetic renal denervation is of particular interest. Indeed, ISH is the most common form of hypertension in the elderly. Yet, age has not always been associated with a reduced response to renal denervation [11,21]. The development of ISH in the elderly population is generally attributed to an increased arterial stiffness. In younger patients with ISH, the mechanism leading to the isolated increase in SBP is different and influenced primarily by an elevated peripheral vascular tone because of an increased sympathetic activity. Therefore, whereas former patients may not be proposed for renal denervation, the latter ones might be excellent candidates .
Laurent et al.  have demonstrated that arterial stiffness evaluated using the pulse wave velocity is a strong predictor of total and cardiovascular mortality whereas pulse pressure is not. Today well defined methodologies based on pulse wave velocity are recommended for the assessment of arterial stiffness . In patients with resistant hypertension, the presence or absence of arterial stiffness may be a good predictive factor of the response to renal denervation. Thus, in hypertensive patients treated by renal denervation, Okon et al.  reported that arterial stiffness, assessed by invasive pulse wave velocity, is the only significant predictor of BP reduction after denervation in a multivariate analysis. In this analysis, patients with increased stiffness were significantly older, had a higher prevalence of diabetes, had more often isolated systolic hypertension and had a higher pulse pressure and were less responsive to renal denervation.
Today, arterial stiffness can easily be measured using specific devices but these devices are not readily available and not yet used in all hypertension centers. In addition, invasive measurements of pulse wave velocity are not easy to perform. Therefore, an assessment of arterial stiffness using a simpler method would be welcome by physicians for all that it enables a reliable prediction of the BP response to renal denervation.
In the present issue of the Journal of Hypertension, Sata et al.  present the results of a post hoc analysis, in which they analyzed the impact of arterial stiffness, measured using the ambulatory arterial stiffness index (AASI) on the BP response produced by renal sympathetic denervation in patients with resistant hypertension. A good response to renal denervation was defined as a reduction of 24-h ambulatory SBP greater than 5% at 6 months. AASI was calculated as one minus the regression slope of diastolic on SBP in individual 24-h ambulatory recordings. This simple method to assess arterial stiffness was published in 2006 by Li et al.  and by Dolan et al.  and was based on large sets of ambulatory BP data obtained with oscillometric as well as auscultatory devices. In these large cohorts of normotensive participants and hypertensive patients, AASI was a good predictor of cardiovascular mortality and stroke. In Sata's article, the office and ambulatory BP response obtained 6 months after renal denervation in 111 patients with resistant hypertension were examined in the light of calculated AASI values stratified either as above or below the median or according to AASI quartiles. Results show that AASI calculated based on 24-h ambulatory BP measurements at baseline predict the ambulatory BP response 6 months after renal denervation. A low baseline AASI is associated with the best BP response to renal denervation. Whenever analyzed by quartiles, results were even more marked the rate of nonresponders rising with increasing AASI. In a multivariate analysis, an AASI below 0.51 is the only significant predictor of a reduction in 24-h ambulatory SBP of more than 5% after renal denervation. Beyond these observations, AASI was predictive of the BP response to renal denervation both among patients with ISH and non-ISH suggesting that AASI should not be considered as a marker of arterial stiffness only, but rather as a more integrative index of cardiovascular properties as discussed in the following.
The interest of Sata's findings is that AASI is obtained from a BP measurement (ABPM) that must be done anyway during the work up of patients with resistant hypertension before changing medical therapy or proposing an interventional procedure. In addition, ABPM should be available in all hypertension centers as it is strongly recommended to confirm the diagnosis of hypertension in many hypertension guidelines. Thus, AASI should be easy to calculate and available without buying any new device. Yet, the AASI is criticized essentially because of the potential impact of changes in nighttime BP . Indeed, although in the initial validation studies, AASI data were consistent in dippers and nondippers , it is now recognized that AASI is influenced not only by the BP levels but also by the degree of the nocturnal fall in BP . The impact of the day/night ratio of BP may cause a large variability of AASI values, for example, in cross-sectional studies. In addition, in some studies, the correlation with pulse wave velocity was found to be rather weak (0.28) . This may just confirm that AASI is reflecting more than arterial stiffness being a composite index integrating arterial stiffness, blood pressure variability and patients’ diurnal cycle . Interestingly, daytime or nighttime AASI based on daytime or night-time ambulatory BP correlated less well to 24-h pulse pressure than 24-h AASI . Whenever home BP values are used to calculate the index (called in that case HASI for home arterial stiffness index), HASI is inferior to AASI in terms of correlation with pulse pressure and pulse wave velocity even though it was predictive of stroke in men and normotensive individuals . One issue is the absence of well established cut-off values for AASI. In Sata's analyses, the cut-off value for the prediction of the BP response to renal denervation was 0.51. Whether the same cut off is applicable to other clinical conditions is not known.
As reviewed in 2012 by Kollias et al. , there is now accumulating clinical evidence that AASI is a good marker for the prediction of future cardiovascular events in individuals with or without hypertension. The fact that AASI is associated with several indices of arterial function and is not a pure marker of arterial stiffness does not represent a real problem as long as the index is used in the right clinical context. Today, the data presented by Sata et al. suggest that AASI may be a good index to preselect patients with resistant hypertension who may benefit from a renal denervation. The observation is undoubtedly of interest but it must be confirmed in a prospective clinical study and in a larger group of patients. Therefore, investigators may consider including AASI in future clinical trials exploring the place of renal sympathetic denervation in the management of patients with severe or resistant hypertension. If this measurement indeed increases the percentage of patients responding to renal denervation, it might well save the future of the technique.
Conflicts of interest
There are no conflicts of interest.
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