Effect of Renal deNervation on Arterial Stiffness and Haemodynamics in Patients With UncontRolled hypErtension (ENSURE)

Biomarkers to identify responder It is known that about one fifth of patients have a systolic BP reduction less than 10 mmHg after the renal denervation, and the failure of the HTN-3 study may be partly attributable to this point. Therefore, it is critical to identify a biomarker in order to screen patients who would benefit from this catheter-based therapy. Some investigators indicated that impaired cardiac baroreflex sensitivity may predict response to renal denervation therapy [13]. In addition, we also have several other candidates.

1. Arterial stiffness As indicated by Mitchell GF, it was proven that, in the Framingham study, arterial stiffness is a major contributor to the onset and development of high BP, but not the consequence [14]. Furthermore, from a physiological viewpoint, age-related arterial remodeling was closely associated with elevation in sympathetic activity [15], and it was reported that renal denervation lead to a decrease in patients' arterial stiffness [16]. However, it remains unclear whether patients with severe arterial stiffening would better benefit from this treatment.
2. Endocrinic biomarker Theoretically, renal denervation decreased patients' BP mainly through decreasing local and systematical sympathetic tone and renin-angiotensin-aldosterone (RAS) activity. However, it remains unclear if patients with high renin level or other biomarkers would have improved response from this novel therapy.

Other BP-related parameters Based on the published data from the HTN-1/2 and considering the worldwide marketing of this catheter-based device, clinical investigations need to be continued and not limited to efficacy on BP reduction or its safety. Several BP-related parameters are of great interest to be investigated with the novel denervation therapy.

1. Blood pressure variability In 2010, Rothwell and colleagues indicated that increased BP variability was significantly associated with cardiovascular mortality and stroke [17]. We found in the XCELLENT study that, rather than other antihypertensive agents, amlodipine was the only agent significantly decreasing patients' BP variability in both 24-hour and beat-to-beat settings, partly through ameliorating the autonomic nervous system (ANS) [18,19]. Renal denervation therapy is to denervate sympathetic nerve surrounding bilateral renal arteries by radiofrequency, so theoretically, this treatment many potentially have impact on patient's ANS, and further on patients' BP variability. With the development of 24-hour aortic ABPM named MOBIL-O-GRAPH, which is now commercially available and validated by invasive methods [20], we may investigate the impact of renal denervation not only on 24-hour brachial BP variability but also on 24-hour aortic BP variability.
2. Aortic blood pressure Several investigations indicated the superiority of central BP to brachial BP in the association with target organ damage [21,22], so it is interesting to investigate the efficacy of renal denervation not only on brachial BP but also on central BP. Some investigations indicated that renal denervation also reduced patients' aortic BP and augmentation index [15,23]. However, with the development of 24-hour aortic ABPM as mentioned before, it makes more sense to investigate the influence of renal denervation on ambulatory aortic BP.
3. Asymptomatic target organ damage As indicated by the HTN-1/2, even evaluated by 24-hour ABPM, the renal denervation therapy decreased patients' BP by 20/12 mmHg for systolic/diastolic BP, respectively [6]. Many asymptomatic target organ damages (TOD) were actually BP-related, so if this novel treatment would have impact on patients' TOD, including pulse wave velocity (PWV), echocardiograph-diagnosed and electrocardiograph-diagnosed left ventricular hypertrophy (LVH), carotid intima-media thickness (IMT) and plaque, and microalbuminuria, is still unknown, or even involving some not established target organ damage, such as cardiac remodeling or left ventricular diastolic dysfunction. Some investigators indicted the effect of renal denervation on PWV [16], left ventricular mass and diastolic dysfunction [24], but a systematic investigation on the efficacy of renal denervation on those BP-related target organ damage is still warranted.

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