History

Sympathectomy was one of the treatment options for essential hypertension in the early 1900s. Smithwick and Thompson [1] reported that splanchnicectomy reduced the mortality rate by half compared with the conventional medical therapy. However, the treatment was extinct because of its high complication rate and emerging antihypertensive medicines with robust clinical efficacy without serious side effects.

Less invasive treatment using catheters has been introduced for ischemic heart disease patients since 1977. Also, catheter ablation with promising effect and low complication is now an essential treatment for cases with arrhythmias. Therefore, the application of ablation to intervene sympathetic nerve was necessarily considered. RDN is the first catheter-based therapy used clinically for sympathetic nerve modulation. Although multiple single-center open-label studies have reported its beneficial effect, not all clinical trials, have shown the expected outcomes to lower the blood pressure as the author [2] reported.

Ogoyama et al. conducted a systematic review and updated meta-analysis to evaluate the effects of RDN on ambulatory and office blood pressures in patients with hypertension and concluded that RDN significantly reduced all blood pressure metrics in both medicated and unmedicated patients with hypertension, including uncontrolled and resistant hypertension [3].

However, the meta-analysis shows the benefit of RDN, it would be important to analyze why some clinical trials failed to demonstrate their effectiveness. Factors such as inclusion and exclusion criteria in the design of clinical trials may be one of the possible causes, this article will focus on the technical and device factors related to the efficacy of RDN.

Learning curve

There is always a learning curve in the development of physicians’ skills. This report presented by Weranuj et al. [2]. emphasized that RDN should be performed by a well-trained and experienced operator who should understand the indications, contra-indications, and its procedure in detail. However, as for the SYMPLICITY HTN-3, more than half of the operators had performed less than two cases during the trial, naturally raising a concern that the lack of operators’ experience might have given impact on the negative outcome of this trial [4].

In humans, the renal artery generally takes off downwardly from the aorta. Therefore, when the femoral artery approach is used for RDN, the tip of guiding catheter is engaged in the backward direction (acute angle) anatomically, requires more back up support for the intra-vascular intervention. The ParadiseTM system, which has a larger catheter size than that of the SpiralTM, requires more skills in delivering the catheter into the renal artery in some cases (Fig. 1).

Fig. 1
figure 1

Symplicity SpyralTM catheter (left) and ParadiseTM catheter (right). Symplicity SpyralTM catheter: The intended use is to deliver low-level radiofrequency energy through the wall of the renal artery to denervate the human sympathetic nerve. It consists of a distal, self-expanding array of four gold electrodes circumferentially attached by approximately 90° in a spiral configuration. The 6Fr. compatible catheter is advanced to the treatment site by tracking over a 0.014” guidewire using a rapid exchanged system. After the device is placed in a desired position for ablation, the guidewire is retracted proximally to allow the pre-shaped nitinol spiral electrode array to expand circumferentially and place the electrodes in contact with the arterial wall in a spiral pattern. ParadiseTM catheter: It emits a ring of ablative energy to interrupt renal sympathetic nerve traffic, while the arterial wall is protected by water circulation through a balloon. Ultrasound energy, which rises the temperature, that is cooled by circulating water in the balloon produces a donut-like thermal profile, which means the rise of temperature of renal artery surface is suppressed

Full size image

In coronary interventions, the radial artery is the primary site of catheter insertion as of today, and there are three possible advantages to use this site for RDN, too. First, as described earlier, the renal artery takes off downwardly from the aorta in humans, the radial artery approach allows the insertion of the device in the forward direction (obtuse angle) and is less technically challenging. Second, vascular complications such as aneurysms at the puncture site and retroperitoneal hemorrhage, which are widely known as problems for the femoral artery approach, do not occur with the radial. And thirdly, the patient can walk soon after the procedure is over, if the radial artery is punctured instead of the femoral.

The SpyralTM, which is already compatible with 6Fr. guiding catheters, can be converted to a radial artery approach applicable device by simply adjusting the total length of the catheter. Whereas the ParadiseTM, will face more challenges, since it requires significant modification, such as whole system downsizing including the balloon and its source of energy, ultrasound transducer.

Multiple ablation

The periarterial sympathetic nerves run in a web-like pattern around the renal artery. The density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations [5]. To obtain a substantial reduction in blood pressure by RDN, the total number of ablation sites must be increased to obstruct more sympathetic nerves. Then, risks may be pointed out that too many ablations may lead to increase complications. In other words, repeat ablation could cause perforation or stenosis, as described by Weranuj et al. [2]. However, as far as I know, there is no such report. Furthermore, multiple ablations might not be needed when using the ParadiseTM catheter because it emits a ring-shaped ablative energy and can circumferentially disturb the sympathetic nerve traffic around the renal artery.

Is ablation necessary for accessory arteries less than 3 mm in diameter? Lauder et al. reported that 22% out of 1000 hypertensive patients had adrenal accessory arteries as the result of angiography. Therefore, the ablations for the accessory arteries should be considered for effective treatment as the author reported. In clinical trials with the ParadiseTM system, patients with 2–4 mm diameter accessory arteries were excluded from the indication due to limitations imposed by the balloon outer diameter of the system. On the other hand, patients with small-diameter accessory arteries, the Spiral may be indicated to perform complete ablation of the sympathetic renal nerves due to relatively smaller system [6].

One of the shortcomings of RDN procedure is that the operator does not know for certain its endpoints at the end of the case. In coronary intervention, intra-coronary image provides accurate information on stent dilation and apposition status immediately after stenting, and this secures a good long-term prognosis. If accurate endpoints can be obtained immediately after the procedure of RDN, multiple ablations may be unnecessary because minimal ablation is enough to realize a substantial reduction of blood pressure. Qian et al. [7]. reported that trans-vascular pacing of aorticorenal ganglia elicited a change in mean arterial blood pressure of 22.2 mm Hg (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) and concluded it has the possibility to be used as a physiological procedural endpoint to guide transcatheter RDN.

Summary

Although several randomized clinical trials [8,9,10,11] have proved the effectiveness of RDN, RECUIRE [12], and the SPYRAL HTN-ON Med Expansion [13], the most recently announced studies did not meet its primary endpoint. The reason of those trials failed is explained by study design factors such as complicated inclusion and exclusion criteria, difficulty of consistent adherence to anti-hypertensive medicine during relatively longer follow-up period and having sham arm as control, etc. Also, technical factors such as the learning curve of operators, the capacity of devices, uncertain physiological procedural endpoint and the numbers and locations of the ablation site are to be taken into consideration.