Rebuttal from L. E. K. Ratcliffe, W. Pijacka, F. D. McBryde, A. P. Abdala, D. J. Moraes, P. A. Sobotka, E. C. Hart, K. Narkiewicz, A. K. Nightingale and J. F. R. Paton

Renal denervation (RDN) and carotid sinus stimulation (CSS) reduce blood pressure in some patients with resistant hypertension (rHTN). Both Schlaich et al. (2014) and Jordan (2014) provide convincing arguments for their use. The key question is how do we clinically phenotype patients in order to offer the most effective anti-hypertensive treatment with minimal adverse effects? Schlaich et al. outline the importance of identifying patients characterised by sympathetic overactivity. However, recording muscle sympathetic nerve activity (MSNA) requires specialised equipment and highly skilled staff, limiting its use as a screening technique. In addition, response to RDN does not always correlate with baseline MSNA or change in MSNA (Brinkmann et al. 2012; Hart et al. 2013). An alternative may be to look at response to drugs targeting the autonomic nervous system or baroreflex sensitivity (Zuern et al. 2013). These may be particularly relevant in screening prior to CSS, perhaps targeting those with disrupted baroreflex response or the subset of rHTN patients with labile blood pressure. Given the need for clinical phenotyping prior to entry into well-conducted studies, it would seem appropriate to restrict these techniques to experienced and specialised hypertension research centres. There is no way to identify the location of the renal nerves prior to ablation, and no intra-procedural feedback to indicate successful RDN. Renal nerves rarely track the aorta to follow the origin of the renal artery coursing its entire length; they can join the artery close to the renal pelvis. Symplicity-HTN 3 (Bhatt et al. 2014) highlights the importance of operators with significant procedural experience, delivering a circumferential ablation pattern. A recent report presented histological assessment of nerve ablation post RDN. Despite a total of 11 ablations, histological sectioning suggested that RDN would not have resulted in complete denervation (Vink et al. 2014). The push for greater ablation numbers, with the aim of complete denervation, needs to be weighed up against the risk of complications such as renal artery stenosis (Chandra et al. 2014; Jaen Aguila et al. 2014). Jordan emphasised the relative invasive nature, high cost and adverse effect profile of CSS, with 7/42 experiencing a procedure-related significant adverse event (Scheffers et al. 2010). CSS has the advantage of being reversible allowing procedural success to be demonstrated. CSS would benefit from integration of blood pressure feedback and ECG entrainment to refine its action, making it more representative of the normal physiological system and preventing inappropriate blood pressure lowering which could cause cerebral hypoperfusion. With relatively short follow-up to date, the longer term effects of both RDN and/or CSS may not yet be apparent. This emphasises the importance of long-term (e.g. >10 years) patient follow-up, at least at a registry level. Carotid body (CB) modulation may offer patient phenotyping through relatively simple tests of CB activation and inactivation while measuring blood pressure and respiration. CB resection should provide clues as to the potential efficacy of this treatment in rHTN patients but the scientific challenge is to understanding the basis of the aberrant discharge and how to temper this without removing peripheral chemosensitivity. Interventional procedures are not a hypertension panacea and the rHTN population is a heterogeneous group requiring further clinical phenotyping. Interest in the sympathetic system as a target for HTN treatment seems renewed, and will perhaps stimulate further research into interventional and reversible pharmacological treatments targeting this system.