Renal nerve ablation as a tool for studying the interactions between arterial stiffness, blood pressure and sympathetic drive

In the past few years renal nerve ablation has gained growing clinical popularity and research interest, becoming one of the most ‘crowded’ areas of investigation, as documented by the large number of original articles, reviews, editorials, and official documents by scientific societies focused on this issue since 2008, when the Simplicity HTN-1 data were published in The Lancet[1]. This is justified by the importance afferent and efferent renal sympathetic nerves may have in favoring the development and progression of a high blood pressure state [2,3]. Also, sympathetic neural influences are deeply involved in the homeostatic control of cardiovascular and metabolic function and may participate, independently of the increase in blood pressure load, at the development and progression of cardiac and vascular end-organ damage [4,5]. This is additionally supported by the evidence that arterial stiffness, that is, a parameter closely correlated with the cardiovascular risk in hypertension as well as in other disease [6–8], is under tonic adrenergic neural influences [5]. The present issue of the Journal of Hypertension includes an intriguing article [9] reporting the results of a study focused on renal nerve ablation and aimed at addressing three major questions. First, whether renal denervation has favorable effects on arterial stiffness, known to be markedly altered in patients with resistant hypertension [10]. Second, whether these effects are related to the changes in sympathetic neural outflow, which appears to be remarkably activated in this clinical condition [11]. And third, whether the modifications in arterial stiffness might participate in the blood pressure-lowering effects of the procedure. The study has, thus, very ambitious goals, being aimed at providing numerous pieces of information of pathophysiological, clinical, and therapeutic relevance. As it will be discussed below, however, the study results, which are in part somewhat unexpected, also allow to critically discuss the pros and cons of the renal nerve ablation technique as a model for investigating the contribution of sympathetic neural factors to the vascular changes induced by the radiofrequency ablation of the renal nerves. They also allow to examine whether renal denervation is an adequate model for investigating the potential role of hemodynamic factors (reduction in blood pressure load) as determinants of and/or as contributors to the improvement in arterial stiffness detectable following the procedure. The results of the study by Hering et al.[9] from the Baker Institute of Melbourne (Australia) can be briefly summarized as follows. Radiofrequency ablation of renal nerves elicits, 3 months after the procedure, a significant reduction in both clinic blood pressure and in muscle sympathetic nerve firing rate (microneurographic technique) amounting to 16/8 mmHg and 9 bursts/100 heart beats, respectively. Concomitantly, there was a marked (−36% on average) reduction in the value of augmentation index, assessed via peripheral arterial tonometry at finger level and taken as a reliable measure of arterial stiffness. The magnitude of this reduction, however, was unrelated to the degree of the SBP and DBP decrease as well as to the amount of the concomitant sympathetic inhibition. On the basis of these findings, the authors conclude that the improvement in arterial stiffness detectable after renal denervation cannot be explained by the sympathomodulatory effects of the procedure, and is independent of the blood pressure lowering effects of the intervention. The study was based on the use of demanding techniques such as microneurographic recording of efferent postganglionic sympathetic nerve traffic to assess adrenergic function, as well as on peripheral artery tonometry via the Endopath device to assess augmentation index (a marker of peripheral arterial stiffness). It has two major merits. First, it provides for the first time evidence that the vascular functional alterations seen in resistant hypertension may be reversed in a short period of time following the renal nerve ablation procedure. Second, it represents one of the few available examples of the possibility that a given intervention (in the present case, renal denervation) is used as a model to investigate issues of pathophysiological relevance, such as the one concerning the relationships between arterial stiffness, adrenergic drive, and blood pressure load. How can the study conclusions be reconciled with what is already known on arterial stiffness and its relationships with sympathetic function and blood pressure load? As far as the interplay between sympathetic drive and arterial stiffness is concerned, the data of the present study do not seem to support previous findings claiming for a major role exerted by the adrenergic nervous system in the modulation of arterial stiffness and in determining its alterations in cardiovascular disease. Indeed, studies performed by our group and others in the past few years have shown that arterial stiffness and other vascular variables directly or indirectly related to stiffness are under a tonic sympathetic restraint [12–14]. This has been documented, for example, by the evidence that in heart failure, which is a condition characterized by a marked adrenergic overdrive and a concomitant impairment of arterial compliance [15], sympathetic nerve traffic is inversely related to arterial compliance values [13]. Furthermore, in a group of untreated essential hypertensive patients, pharmacological stimulation of adrenergic receptors located in the arterial wall was shown to affect arterial compliance, because the radial artery compliance index was markedly reduced during phenylephrine infusion in the brachial artery at doses devoid of any systemic blood pressure effect [13]. Finally, in two patients who had undergone hand allotransplantation (due to hand loss as a result of a car accident), loss of innervation of the radial artery was accompanied by elevated values of arterial distensibility, confirming the tonic inhibitory influence adrenergic drive exerts on this vascular parameter of a functional nature [14]. It is worth mentioning that in all the above referred studies arterial stiffness and other related parameters were assessed at the level of a medium size artery, such as the radial one. This kind of information is lacking for small arteries such as the finger ones. What can be reasons responsible for the discrepancy between the results obtained in previous studies and in the present one? It is hard to believe that this discrepancy was due to the effects of antihypertensive drugs, whose daily dosage and daily number was almost unchanged 3 months after the procedure. A more likely explanation is that the data of the present study were collected at the level of the finger circulation, whose sympathetic/vascular structure and function do not necessarily reflect qualitatively and/or quantitatitively those detectable in medium-size or large arteries. The data of the present study [9] cannot provide any conclusive answer to this question, considering that no information was provided on whether sympathetic burst incidence was related to arterial stiffness at baseline before renal denervation. There is another potential explanation for the above-mentioned discrepancy, namely that renal denervation might not represent a valuable model for studying the sympathetic/vascular interactions due to the interference of other circulating humoral and metabolic factors (such as angiotensin II, aldosterone, endothelin, nitric oxide, insulin, etc), which may exert divergent sympathetic and vascular effects. We believe, however, this possibility to be unlikely, given the fact that the assessment of the above-mentioned parameters was carried out in the study by Hering et al. 3 months after the procedure, that is, at a time period when many of the above-mentioned metabolic and humoral changes are still not occurring. Another intriguing study result relates to the possible determinants of the improvement in arterial stiffness reported after renal denervation. As already mentioned, the lack of correlation between vascular and sympathetic variables rules out any sympathetic component. The same conclusion can be drawn for the possibility that the functional vascular effects of renal denervation were due to a hemodynamic factor such as the reduction in the blood pressure load to the cardiovascular system. This because again no relationship was found by the Australian investigators between the changes in augmentation index and the blood pressure reduction seen in their patients [9]. In this context a study limitation is that only clinic blood pressure data were available for the analysis, no information being collected for 24-h ambulatory blood pressure values which reflect the ‘true’ hemodynamic load to the cardiovascular system [16]. Finally, as already mentioned, the data of the study are limited to a 3-month follow-up, a temporal window which does not allow a proper assessment of whether and to what extent what has been detected following 90 days from the procedure remains true also following a much longer observational period of time. Taking into account all the above-mentioned data and considerations it should be concluded that renal denervation may indeed represent a valuable ‘model’ for studying neural-vascular interactions. The validity of the model, however, should be strengthened by studies employing a demanding protocol, based on the assessment not only of small size but also of medium size and large artery stiffness as well as by repeated vascular and sympathetic evaluations during the follow-up period. This would allow some unavoidable ‘intrinsic’ limitations of the approach to be overcome. ACKNOWLEDGEMENTS Conflicts of interest The authors declare no conflicts of interest.