Validation of a Novel Renal Denervation System With Cryoablation: A Preclinical Study and Case Series.

Recently, we designed a renal denervation with cryoablation (Cryo-RDN) system using liquid nitrogen and proved its short-term safety and effectiveness. In this study, we first conducted a 6-month follow-up in a swine model. Renal sympathetic nerve activity remained at a significantly lower level than that of the control group after 6 months. In patients with resistant hypertension, Cryo-RDN demonstrated preliminary safety. Renal function fluctuations and vascular-related complications were not detected. In addition, the average 24-hour systolic and diastolic blood pressure decreased by 12.17 ± 8.35 mm Hg and 8.50 ± 3.83 mm Hg at the 6-month follow-up, respectively, compared with their baseline values.

More than one billion people worldwide are living with hypertension, and the societal and economic burden of long-term medications and related complications are extremely high. Although drug treatment of hypertension has long been standardized and accepted, approximately 12%-18% of patients are either intolerant of or resistant to medical therapy, and drug adherence is far from satisfactory.2, 3, 4 These observations have brought attention to the importance of device-based antihypertensive therapy, which is a “one-time” treatment with long-term effectiveness.

Among these, renal denervation (RDN), which suppresses the overactivated sympathetic nerve system (SNS), is now the most studied and promising interventional antihypertensive treatment.5, 6, 7 Most of the existing studies are based on radiofrequency and ultrasound ablation and have confirmed the clinical and cost effectiveness of this treatment.8, 9, 10, 11 Therefore, we have gradually begun to explore other candidate energy sources suitable for RDN.

Cryoablation induces apoptosis by causing intracellular dehydration and has been widely used in the treatment of other diseases, such as cancer and arrhythmia. Thus, we originally used liquid nitrogen as a freezing energy source to ablate renal arteries and developed a cryoablation balloon catheter for RDN. Our previous study confirmed the short-term safety and efficacy of a prototype system applied in a swine model. Recently, we optimized the parameters and design of the cryoablation system. In this study, we aimed to verify the safety and efficacy of RDN with cryoablation (Cryo-RDN) in a longer-term swine model and to present the first human experience in patients with resistant hypertension (RH).

Methods

Cryo-RDN catheter

We used a modified Cryo-RDN balloon catheter specific for RDN with available balloon diameters of 4, 5, 6, and 7 mm. The internal structure of the balloon consists of a highly efficient, double-coiled freezing element and a rewarming system (Figure 1A). During cryoablation, ultra–low-temperature liquid nitrogen flows inside the coiled freezing element and absorbs heat from the surrounding area. The temperature outside the balloon decreases accordingly (Figure 1B). Warm nitrogen gas is used as the rewarming medium during thawing.

Figure 1

Schematic Diagram of the Cryo-RDN System

(A) Illustration of the Cryo-RDN catheter in the renal artery (lateral view, anterior view, and sectional axonometric view of the balloon during cryoablation). (B) Temperature change curve of the balloon surface and 3 mm outside the balloon after the start of cryoablation. The balloon consists of a double-coiled high-efficiency freezing and thawing element. During cryoablation, liquid nitrogen at ultralow temperature flows inside the coil freezing element and absorbs heat from surrounding tissues. Cryo-RDN = renal denervation with cryoablation.

General Cryo-RDN procedure

For the swine model, all swine were anesthetized using ketamine (0.3 mg/kg) and diazepam (5 mg/kg) to minimize suffering. Volatile anesthetic with isoflurane (1.5%-2%) was used to maintain general anesthesia. For patients, Cryo-RDN was conducted under conscious sedation. Intraprocedural anticoagulation consisting of heparin at 100 U/kg was administered to both swine and patients to prevent thrombosis.

The general operation procedure for both swine and patients was as follows: a 10-F dedicated sheath was inserted into the right femoral artery for the insertion of a 6-F Judkins right (JR4.0) catheter (Cordis, Johnson & Johnson) into the renal arteries. Bilateral renal angiography was first performed to confirm the anatomy and diameter of the main renal artery and the site of cryoablation. The 6-F catheter was replaced with an 8-F dedicated guiding catheter. A Cryo-RDN balloon catheter was placed as distal as possible in the main renal arteries. The balloon was inflated; after confirming that renal blood flow was totally blocked, cryoablation was conducted. Cryo-RDN was performed for 3 minutes in each artery, reducing the temperature to -95°C (ranging from -80°C to -115°C), followed by 1.5 minutes of rewarming. The balloon catheter was deflated and withdrawn, and renal angiography was again performed as a final check for renal artery obstruction, thrombus, perforation, or dissection.

Preclinical study design

The experimental scheme and the use of swine were approved by the Animal Use and Management Ethics Committee of Fudan University. The experimental design and implementation were in accordance with animal welfare guidelines.

Twenty-nine Shanghai White pigs (mean body weight: 45 ± 5 kg) were randomly assigned to 5 Cryo-RDN groups humanely killed at days 7, 14, 28, 90, and 180 after the operation, designated as the CR-7d (n = 5), CR-14d (n = 5), CR-28d (n = 5), CR-90d (n = 5), and CR-180d (n = 5) groups, respectively, or the control group (n = 4). Animals in the control group underwent renal angiography only; those in the Cryo-RDN groups underwent renal angiography plus bilateral Cryo-RDN. Standard lead II electrocardiography was continuously performed and recorded to determine the heart rate and rhythm.

Histologic assessment and norepinephrine detection in the swine model

At different points, the renal arteries were harvested and evenly divided into 5 parts each. Samples were embedded in paraffin, and slices from each part of the artery were stained with hematoxylin and eosin, Masson, and tyrosine hydroxylase (TH) antibody (ab137869) to assess neural injury via light microscopy. The depth of cryoablation and TH staining intensity were semiquantitatively measured as previously described to assess the effects of Cryo-RDN.

At the end of the follow-up period, the swine were anesthetized, and 6 pieces of renal cortical tissue and peripheral blood were collected; the norepinephrine (NE) concentration was measured using high-performance liquid chromatography.

First-in-human case series

This study was reviewed and approved by the ethics committees of Zhongshan Hospital Fudan University and Shanghai Tenth People’s Hospital ChiCTR1900020545.

Based on the requirement for the sample size from the Food and Drug Administration, a total of 6 patients (5 males and 1 female) with RH were recruited. Briefly, eligible patients were males or females aged 18-75 years old with a history of consecutive antihypertensive drug intake (≥3 types of antihypertensive drugs, including diuretics) with no alteration ≥2 weeks (average office systolic blood pressure [SBP] >140 mm Hg with 3 measurements and 24-hour SBP ≥135 mm Hg). Patients also needed to have an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and no history of cardiovascular or cerebrovascular events. Detailed inclusion and exclusion criteria are listed in Supplemental Table 1. Informed consent was obtained before enrollment. Medication intake, 24-hour ambulatory blood pressure monitoring (24-hour ABPM), office blood pressure (OBP), and eGFR at baseline and 1 and 6 months after Cryo-RDN were all recorded and compared. To monitor drug adherence, antihypertensive drugs were distributed to patients every 28 days during follow-up, and any excess medication from the previous distribution was collected at the next distribution. Renal angiography was performed at the 6-month follow-up. The occurrence of device-related adverse events in 6 patients was recorded to evaluate clinical safety.

Statistical analysis

All data were analyzed using GraphPad Prism 9.0 (GraphPad Software) and are presented as the mean ± SD for continuous variables. Categorical variables at baseline and during the follow-up period are presented as counts and percentages. The data from the animal study were compared with repeated-measures analysis of variance after testing for normal distribution. A value of P < 0.05 was considered statistically significant.

Results

Preclinical study

All animals in the cryoablation groups underwent bilateral Cryo-RDN and survived until necropsy without any procedure-related complications. The efficacy of cryoablation was comprehensively evaluated based on histologic and serologic indicators.

Histologic evaluation after Cryo-RDN

All 58 renal arteries from the 29 pigs were harvested at different times for histologic analysis. Pathological changes after cryoablation were observed in all vessels in the Cryo-RDN groups (Figure 2A). Persistent nerve fibrosis and atrophy lasted up to day 180. As a marker of SNS activity, TH staining intensity decreased after Cryo-RDN and remained at a significantly lower level than that of the control group (Figure 2B).

Figure 2

Nerve and Tissue Damage Around the Renal Artery

(A) Images of peripheral renal artery injury with hematoxylin & eosin, Masson, and TH staining at different time points. Successful Cryo-RDN was verified by persistent nerve fibrosis and atrophy for up to 180 days. (B) Decrease in TH staining intensity suggesting a decrease in sympathetic activity, scored on a scale from 0 to 3: 0 means no reaction, 1 means patchy/very weak reaction, 2 means weak to moderate reaction, and 3 means strong reaction. The minimum score that represents the most serious functional damage was adopted for each section. (C) Semiquantitative analysis of maximum ablation depth at different times. The maximum ablation depth stabilized at a high level for 180 days. (D) Semiquantitative analysis of maximum ablation circumference at different times. The maximum ablation circumference stabilized at a high level for 180 days. Values are expressed as the mean ± SD by repeated-measures analysis of variance (n = 8 for the control group, n = 10 for the CR-7d group, n = 10 for the CR-14d group, n = 10 for the CR-28d group, n = 10 for the CR-90d group, and n = 10 for the CR-180d group). ∗P < 0.05. TH = tyrosine hydroxylase; other abbreviation as in Figure 1.

The efficacy of Cryo-RDN with this device was evaluated by analyzing the maximal cryoablation depth between every follow-up, which comparatively ranged from 7.85 ± 1.41 mm to 8.89 ± 2.06 mm (P ≥ 0.05; Figure 2C). All pigs in the 5 Cryo-RDN groups showed >80% injury in terms of circumferential extension at the median level (Figure 2D). Consistent with this finding, the presence of at least 80% nerve damage was observed in all pigs (P ≥ 0.05) (Table 1). Limited muscle damage and lymph node necrosis were reported in 2 pigs but were not safety concerns. No appreciable adverse changes were observed in the renal parenchyma. There was no collateral damage to surrounding structures such as the adrenal gland or intestines.

Table 1

Evaluation of Circumferential Injury Induced by Cryo-RDN

	CR-7d (n = 10)	CR-14d (n = 10)	CR-28d (n = 10)	CR-90d (n = 10)	CR-180d (n = 10)
Injury circumferential extension (%)	83.4 ± 10.7	82.0 ± 11.4	86.4 ± 10.4	91.2 ± 11.0	90.9 ± 13.4
Injured nerve/total nerve (%)	84.0 ± 3.6	94.7 ± 4.7	93.0 ± 6.2	92.0 ± 3.6	89.3 ± 9.3

Values are mean ± SD. Injury circumferential extension (0%-100%) represents 0-360 degrees of injury in 1 cross-sectional image.

Cryo-RDN = renal denervation with cryoablation.

SNS activity assessment after Cryo-RDN

Cryo-RDN treatment resulted in a significant suppression of SNS activity in the swine model. Consistent with the decrease of TH staining intensity, on day 7, the renal NE concentration decreased 90% compared with that in the control group and remained significantly lower until day 180. The absolute values and changes in the renal NE concentration are shown in Figure 3A. In addition, the serum NE level decreased 10% compared with that in the control group after 7 days and remained stable in all groups after Cryo-RDN (Figure 3B).

Figure 3

Renal and Serum NE Concentration at Different Times

(A) NE concentration in the renal cortex at different times after Cryo-RDN. (B) NE concentration in serum at different times after Cryo-RDN. Values are expressed as the mean ± SD by repeated-measures of analysis of variance (n = 4 for the control group, n = 5 for the CR-7d group, n = 5 for the CR-14d group, n = 5 for the CR-28d group, n = 5 for the CR-90d group, and n = 5 for the CR-180d group). ∗P < 0.05. NE = norepinephrine; other abbreviations as in Figures 1 and 2.

Results of the first-in-human case series

After obtaining preclinical results in a swine model on device safety and efficacy, we conducted a first-in-human case series of 6 patients with RH. Their baseline and serologic parameters are shown in Table 2.

Table 2

Characteristics of Patients at Baseline (N = 6)

Age, y	55.83 ± 9.00
Females	1 (16.7)
Body mass index, kg/m2	26.92 ± 4.94
OBP, mm Hg
SBP	157.17 ± 15.05
DBP	102.00 ± 9.63
24-h average BP, mm Hg
SBP	145.83 ± 5.49
DBP	89.67 ± 9.93
Heart beats, beats/min	66.17 ± 7.96
Laboratory results
eGFR, mL/min/1.73 m2	78.52 ± 12.25
LDL cholesterol, mmol/L	2.30 ± 0.83
Methoxy norepinephrine, pg/mL	87.03 ± 47.58
Aldosterone, pg/mL	156.68 ± 55.27
Comorbidity
Diabetes mellitus	0 (0)
Coronary artery disease	1 (16.7)
Sleep apnea syndrome	1 (16.7)
Atrial fibrillation	2 (33.3)
Antihypertensive medication therapy
No. of antihypertensive medications	4.83 ± 0.57
ACEIs/ARBs	6 (100.0)
Calcium channel blockers	5 (83.3)
Diuretics	6 (100.0)
Beta-blockers	6 (100.0)
Centrally acting sympatholytics	1 (16.7)

Values are mean ± SD or n (%). The concentration of methoxy norepinephrine was measured using HPLC.

ACEIs = angiotensin-converting enzyme inhibitors; ARBs = angiotensin receptor blockers; BP = blood pressure; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; HPLC = high-performance liquid chromatography; LDL = low-density lipoprotein; OPB = office blood pressure; SBP = systolic blood pressure; other abbreviations as in Table 1.

Safety assessment of Cryo-RDN

Bilateral Cryo-RDN was successfully performed in all 6 participants and no serious adverse events occurred in the perioperative period. Based on renal angiography, no adverse complications, including endovascular thrombus and vascular injuries, were detected at any point and the vascular diameter of renal arteries was comparable with that in the preoperative period (Figure 4).

Figure 4

Representative Renal Angiograms of Patients Who Underwent Cryo-RDN at Different Times

(A) Preprocedure; (B) balloon inflation; (C) cryoablation; (D) postcryoablation; and (E) at the 6-month follow-up. Abbreviation as in Figure 1.

In addition, adverse nephrotoxic or systemic effects were not reported. The eGFR values remained stable throughout the 6-month follow-up period (baseline: 78.52 ± 12.25 mL/min/1.73 m2 vs. 6-month follow-up: 74.50 ± 10.65 mL/min/1.73 m2).

Blood pressure performance after Cryo-RDN

At the 1-month follow-up, 24-hour ABPM–related indices decreased slightly compared with baseline values. This tendency was more obvious until 6 months, when the average 24-hour SBP and diastolic blood pressure (DBP) in patients decreased dramatically by 12.17 ± 8.35 mm Hg and 8.50 ± 3.83 mm Hg, respectively (Figures 5A and 5B, Table 3). The declining trend in OBP was similar to that in 24-hour ABPM (Figures 5C and 5D, Table 3). Individual blood pressure (BP) monitoring data are shown in Figure 6.

Figure 5

BP at Different Times After Cryo-RDN

(A) Average 24-hour ABPM at baseline and 6 months after Cryo-RDN. (B) Average reduction in 24-hour ABPM at baseline and 6 months after Cryo-RDN. (C) Average OBP at baseline and 6 months after Cryo-RDN. (D) Average reduction in OBP at baseline and 6 months after Cryo-RDN. Values are expressed as the mean ± SD (n = 6). 24-hour ABPM = 24-hour ambulatory blood pressure monitoring; BP = blood pressure; DBP = diastolic blood pressure; OBP = office blood pressure; SBP = systolic blood pressure; other abbreviations as in Figure 1 and 2.

Table 3

BP Level, Heart Rate at Baseline and Follow-Ups

	Baseline	1 Mo	6 Mo
Ambulatory BP, mm Hg
24-h SBP	145.83 ± 5.49	142.83 ± 13.44	133.67 ± 11.41
24-h DBP	89.67 ± 9.93	85.50 ± 8.17	81.17 ± 11.18
Daytime SBP	147.83 ± 10.23	146.83 ± 14.82	135.17 ± 14.33
Daytime DBP	91.50 ± 10.88	86.67 ± 6.77	81.33 ± 11.66
Nighttime SBP	142.50 ± 9.44	135.00 ± 11.92	131.17 ± 11.20
Nighttime DBP	86.67 ± 11.57	82.83 ± 10.72	80.83 ± 12.07
Office BP, mm Hg
Office SBP	157.17 ± 15.05	141.33 ± 18.66	135.50 ± 12.99
Office DBP	102.00 ± 9.63	92.17 ± 11.02	86.50 ± 10.29
Heart rate, beats/min	66.17 ± 7.96	70.50 ± 8.22	72.67 ± 10.19

Values are mean ± SD.

Abbreviations as in Tables 1 and 2.

Figure 6

Changes in the BP Values of Individual Patients at the 6-Month Follow-Up Compared With Baseline

Abbreviations as in Figure 5.

We counted the antihypertensive drugs returned by our 6 patients and did not find any cases of missed doses or overdosing. Surprisingly, antihypertensive drug reduction was reported in 2 of 6 patients during the follow-up period, where 1 patient was able to reduce 1 type of antihypertensive drug and the other was able to reduce 2 types of antihypertensive drugs (Table 4).

Table 4

Antihypertensive Agents at Baseline and Follow-Ups

	Baseline	1 Mo	6 Mo
No. of antihypertensive medications	4.83 ± 0.57	3.83 ± 1.60	3.83 ± 1.72
ACEIs/ARBs	6 (100.0)	5 (83.3)	5 (83.3)
Calcium channel blockers	5 (83.3)	5 (83.3)	6 (100.0)
Diuretics	6 (100.0)	4 (66.7)	4 (66.7)
Beta-blockers	6 (100.0)	6 (100.0)	5 (83.3)
Centrally acting sympatholytics	1 (16.7)	1 (16.7)	1 (16.7)

Values are mean ± SD or n (%).

Abbreviations as in Tables 1 and 2.

Discussion

Based on previous studies, we speculated that cryoablation may also disrupt the over-activated SNS and could be used for RDN. Thus, we designed a new Cryo-RDN system and tested its safety and efficacy. In the long-term follow-up of the swine model, pathological analysis of renal arteries showed that Cryo-RDN effectively damaged sympathetic nerves with no vascular-related damage. Further sustained reduction in NE concentration confirmed the ablation efficiency for at least 6 months. For the following first-in-human case series, Cryo-RDN demonstrated preliminary safety. Patients’ average 24-hour SBP and DBP decreased by 12.17 ± 8.35 mm Hg and 8.50 ± 3.83 mm Hg, respectively, over a 6-month follow-up period. Office SBP and DBP decreased by 13.33 ± 12.27 mm Hg and 6.50 ± 19.52 mm Hg after 1 month and 21.67 ± 11.40 mm Hg and 15.50 ± 17.41 mm Hg after 6 months, respectively. No adverse events were reported based on renal function and angiography. This study preliminarily suggested the feasibility of the clinical application of this Cryo-RDN system.

In this study, we adopted liquid nitrogen as a freezing energy source and proved its effectiveness in a swine model. Based on our pathological analysis, Cryo-RDN with liquid nitrogen successfully induced neuronal apoptosis and nerve fibrosis and maintained an ablation depth of approximately 8 mm for 6 months. Previous autopsy reports have shown that 60%-80% of the peripheral SNS nerves around renal arteries are located within a distribution radius of <6.5 mm, which is within the coverage capacity of Cryo-RDN. This ablation depth is also equivalent to those of radiofrequency and ultrasound, which are 2 of the most studied and accepted ablation energy sources.15, 16, 17

With this sufficient ablation depth, Cryo-RDN was not associated with device-related adverse events. Both pathological analysis of the renal artery in swine and angiography of patients with RH showed no vascular complications (thrombosis, dissection, or stenosis). Furthermore, because the entire ablation process for each renal artery was completed in 5 minutes, the risk of kidney ischemia was minimal. Patients' renal function did not fluctuate during follow-up and they reported only mild intraoperative discomfort. For these reasons, the application of liquid nitrogen as a freezing energy source for Cryo-RDN has certain energy potential and implies a safe and effective clinical application in the future.

Additionally, because the ablation coverage percentage is another crucial factor in the efficiency of cryoablation, we designed a balloon catheter. Pathological results from the swine model showed that the effective ablation circumference reached 80% with a high ablation coverage percentage. As commonly used indicators of sympathetic activity in RDN, TH staining intensity and renal and serum NE concentrations were reduced significantly compared with those in the control group.18, 19, 20 Previous experience in the development of radiofrequency catheters tells us that the ablation efficiency and stability of the antihypertensive effect can be improved by increasing the ablation coverage percentage., Thus, in the new-generation, sham-controlled, randomized clinical trials, the SPYRAL HTN-ON MED and HTN-OFF MED studies, a multielectrode radiofrequency catheter was applied, in which RDN revealed its antihypertensive effect with or without medication and long-term persistence., This theory has also been supported by study of another balloon RDN catheter, the Paradise Renal Denervation System, which delivers ultrasound energy and was reported to perform better than radiofrequency ablation of the main renal arteries in a randomized, head-to-head trial. Using the same concept, our Cryo-RDN balloon catheter showed high ablation efficiency.

Consistent with the results from the preclinical animal study, the results from our 6 patients with RH demonstrated the preliminary safety of Cryo-RDN. In addition, the 24-hour SBP and DBP decreased by 12.17 ± 8.35 mm Hg and 8.50 ± 3.83 mm Hg, respectively, compared with baseline values. Similarly, the office SBP and DBP decreased by 13.33 ± 12.27 mm Hg and 6.50 ± 19.52 mm Hg, respectively, after 1 month and 21.67 ± 11.40 mm Hg and 15.50 ± 17.41 mm Hg, respectively, after 6 months compared with baseline values. These positive trends in BP reduction were similar to the latest SPYRAL and RADIANCE-HTN studies.8, 9, 10,, Because the sample size of patients was relatively small in this preliminary exploration of Cryo-RDN, comparison and interpretation with these studies cannot be made until further confirmation of the results in large randomized controlled trials.

Hypertension as a chronic disease requires long-term medication, and some patients have a certain degree of medication compliance and tolerance problems. These individuals remain at increased risk of target organ damage, morbidity, and mortality despite ongoing antihypertensive drug therapy. This gives rise to device-based interventional antihypertensive treatment. To date, few published articles have focused on cryoablation for RDN. In 2014, Prochnau et al reported a successful antihypertensive effect in 10 patients with RH who failed to show BP reduction after radiofrequency RDN. Although the authors suggested to some extent that cryoablation may be an energy option for RDN, atrial fibrillation cryoablation catheters were used in that study, and only 4 lesions were ablated on each side of the renal artery.

In our experiments, we originally designed a balloon ablation catheter and used liquid nitrogen as a freezing energy source for RDN. This method has several advantages. First, previous reports have indicated that cryoablation is endothelium friendly for arteries.27, 28, 29 Second, based on our results, Cryo-RDN of 1 renal artery took approximately 5 minutes; the overall procedure duration was relatively short. In addition, the operation is simple with a short learning curve, and the procedure is operator friendly.

Study limitations

Our study has several limitations. First, medication adherence has a dominant influence on BP control, but we did not test for blood concentrations of antihypertensive drugs. Standard antihypertensive drugs were distributed monthly, ensuring medication adherence to a large extent. In addition, a recent study suggested that medication adherence was high in patient follow-up after RDN, which suggests that, to some extent, the BP reduction in our patients after Cryo-RDN was less influenced by drug adherence than by the effect of Cryo-RDN itself. Second, the follow-up of patients with RH was relatively short considering that, thus far, the longest clinical follow-up of RDN in patients with RH was 36 months and demonstrated sustained antihypertensive efficacy, with even further reductions in BP over the follow-up period., In addition, as an early feasibility study, the sample size was limited. We have designed a multicenter randomized controlled trial to explore the long-term clinical efficacy of Cryo-RDN that is now ongoing.

Conclusions

Cryo-RDN with this dedicated cryoablation balloon catheter is safe and effective for sympathetic denervation in a swine model. Preliminary safety was demonstrated in the first-in-human case series, and an antihypertensive effect was reported in 6 patients with RH. Although further long-term randomized clinical trials with larger sample sizes are needed for confirmation, the results of this study indicate that this cryoablation technique with this new device could be a breakthrough in the clinical treatment of RH.

COMPETENCY IN MEDICAL KNOWLEDGE: RDN is performed by suppressing the overactive SNS. The results from recent clinical studies have suggested that RDN is the most promising interventional treatment for RH. Thus far, almost all studies have been based on radiofrequency and ultrasound ablation. Cryoablation induces apoptosis by causing intracellular dehydration and is widely used in the treatment of many other diseases. In this study, we innovatively adopted liquid nitrogen as a freezing energy source to perform Cryo-RDN. The long-term effectiveness of Cryo-RDN was demonstrated in a swine model with stable ablation depth and circumference. In the subsequent first-in-human case series, the safety of Cryo-RDN was preliminarily reported. In addition, 6 patients with RH showed a dramatic BP decrease at the 6-month follow-up, and 2 achieved antihypertensive drug reduction.

TRANSLATIONAL OUTLOOK: More than 1 billion people worldwide are living with hypertension, and approximately 12%-18% of them are either intolerant of or resistant to medical therapy; drug adherence is far from satisfactory. The societal and economic burden of long-term medication and related complications is extremely high. RDN is a “one-time” treatment with long-term effectiveness. Cryoablation has been suggested to have great safety and efficacy in Cryo-RDN; the operation procedure is operator friendly and takes little time. The results of this study indicate that this cryoablation technique with this new device could be a breakthrough in the clinical treatment of RH.

Funding Support and Author Disclosures

This work was supported by the National Natural Science Fund of China (81521001 to Dr Ge; 81670319 to Dr Shen), the Shanghai Municipal Science and Technology Commission (15441900100 to Dr Ge), the Chinese Academy of Medical Sciences (2019-I2M-5-060 to Dr Ge; 2020-JKCS-015 to Dr Shen), and the Shanghai Shenkang Hospital Development Center (SHDC2020CR3023B to Dr Shen). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.