Academic Editors: Stefano Omboni, Brian Tomlinson and Takatoshi Kasai
Background: Renal denervation (RDN)
is effective to lower systolic blood pressure (SBP) in essential hypertension.
However, patient selection under medications remains an important unmet clinical
need. Methods: This multicenter study aimed at observing whether
preprocedural features associated with increased renin-angiotensin-aldosterone
activity influence RDN response. This study enrolled the patients who underwent
RDN for uncontrolled hypertension. Medical records were reviewd and patients were
divided into 2 groups depending by meeting any of the following conditions prior
to RDN: (1)
Several prospective randomized sham-controlled trials have demonstrated that percutaneous renal denervation (RDN) lowers office and 24-hour blood pressure (BP) in patients with uncontrolled hypertension in both the presence and absence of antihypertensive drug therapy [1, 2, 3]. This procedure provides an opportunity to achieve BP goals with lower tablet burden . Current clinical interest fucusses on further increasing the RDN response rate. However, the latest evidence focusing on heart rate and renin-angiotensin-aldosterone system (RAAS) were all derived from a drug-free population [5, 6, 7]. Thus, distinguishing those hypertensive patients on medication who are best suited to the renal denervation procedure remains an unmet need.
A post-hoc analysis of the randomized sham-controlled Symplicity HTN-3 trial indicated that the use of an aldosterone antagonist at baseline was an independent predictor of the blood pressure response to RDN [8, 9]. However, patients with primary aldosteronism were excluded from the Symplicity HTN-3 trial. It is, therefore, possible that RDN is more effective in patients who tend to continue using an aldosterone antagonist for the underlying overactivity of RAAS . In a pilot proof of concept study, several preprocedural characteristics featuring overactive RAAS on medical treatment were associated with RDN response . The present analysis was aimed at increasing the sample size to compare blood pressure response among RDN recipients with vs. without the three features of overactive RAAS in a multi-center database.
We reviewed medical records of consecutive patients who received catheter-based
radiofrequency RDN (Symplicity Flex™ or Spyral™,
Medtronic, Minneapolis, MN, USA) for
uncontrolled hypertension in three medical centers between September 2013 and
August 2019 under approval of Institutional Review Boards, MacKay Memorial
Hospital (IRB No. 20MMHIS087e), which waived the requirement for informed consent
in this retrospective study. As of August 2019, patients meeting inclusion
criteria were consecutively identified by the same inclusion and exclusion
criteria from three hospitals, including the first 18 patients in the prior
single-center pilot study . Patient records were de-identified to preserve
patient privacy and the study was performed in accordance with the guidelines of
ICH-GCP (International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use–Good clinical practice). Patients
had no previous diagnosis of secondary hypertension, such as primary
aldosteronism, although some had a reported history of obstructive sleep apnea
and chronic kidney disease (CKD, defined as eGFR [estimated glomerular filtration
Patients were divided into two groups, including control patients (group A) and
those meeting at least one criteria in the predictive triad (group B). This
preprocedural triad consisted of the following characteristics prior to RDN: (1)
more than 10 mmHg of BP reduction after at least 14-day use of aldosterone
antagonist, (2) ratio of serum aldosterone concentration to plasma renin activity
Most patients had office BP measurement at 0, 1, 3, 6 and 12 months and 24-hour ABPM at 0, 1, 3–6 and 12 months after RDN. The medication was adjusted by the physicians’ decision for clinical needs. The number of medications prescribed was recorded at 0, 1, 3, 6, and 12 months by reviewing the electronic medical records.
Consistent with previous studies, RDN responders were defined by any of the
following criteria: (1) 24-hour systolic BP reduction
All data were analyzed using SPSS version 24.0 for Windows (IBM Corp., Chicago, IL, USA). Comparison of the baseline characteristics and blood pressure during times of follow-up between group A and B were examined using the Mann-Whitney U test for continuous variables, the Fisher’s exact test for categorical variables and analysis of covariance (ANCOVA) for baseline difference adjustment.
After excluding 3 cases with stage 5 CKD, 46 consecutive patients were enrolled in the study, of which 27 (59%) were in group A and 19 (41%) in group B. Five of 46 patients (11%) had two features of the triad and none had all three. The regimen of aldosterone antagonist was spironolactone 25 mg once daily. No significant differences between the groups in baseline patient demographics, BP, comorbidities, or neurohormones were observed. However, group A patients had a numerically higher mean 24-hour heart rate (70.7 bpm vs. 65.3 bpm, p = 0.071) and comparable 24-hour systolic (140.0 mmHg vs. 144.0 mmHg, p = 0.577) and diastolic BP (77.5 bpm vs. 76.6 bpm, p = 0.928). Group A subjects were prescribed fewer antihypertensive agents (4.0 vs. 4.9, p = 0.014) and fewer aldosterone antagonist (3.7% vs. 47.4%, p = 0.001). The proportion of CKD (55.6% vs. 80%, p = 0.350) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (66.7% vs. 89.5%, p = 0.092) was lower in group A, but without statistical significance (Table 1). The baseline ARR was 8.5 and 93.5 in group A and B (p = 0.012), respectively. Aldosterone antagonist was associated with a systolic BP reduction of 11 mmHg in those prescribed the drug. There were no procedure-related complications.
|Characteristic||Group A (n = 27)||Group B (n = 19)||p|
|Office SBP (mmHg)||154.4
|Office DBP (mmHg)||82.8
|Office pulse pressure (mmHg)||71.6
|Mean 24-hour SBP (mmHg)||140.0
|Mean 24-hour DBP (mmHg)||77.5
|Mean 24-hour pulse pressure (mmHg)||62.5
|Mean 24-hour HR (beat per min)||70.7
|eGFR (mL/min/1.73 m
|Chronic Kidney Disease||55.6%||80%||0.350|
|Number of medication class||4.0
|ACEi or ARB||66.7%||89.5%||0.092|
|Central alpha2 agonist||14.8%||5.3%||0.387|
|Loop diuretics or thiazide||55.6%||52.6%||1.000|
|Renin activity (ng/mL/hr)||16.6
|ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor
blockers; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration
rate; HR, heart rate; SBP, systolic blood pressure.|
Values are presented as the mean
On average, office systolic BP was 154.4
|Office SBP (mmHg)||24-hour SBP (mmHg)|
|Baseline||1 month||3 months||6 months||12 months||Baseline||1 month||3–6 months||12 months|
|Patient number||27 vs. 19||25 vs. 17||22 vs. 18||20 vs. 15||19 vs. 15||19 vs. 14||13 vs. 11||12 vs. 9||7 vs. 4|
|Group A vs. B|
|∆ Office SBP (mmHg)||∆ 24-hour SBP (mmHg)|
|1 month||3 months||6 months||12 months||1 month||3–6 months||12 months|
|p for model 1||0.465||0.256||0.495||0.048||0.373||0.961||0.707|
|p for model 2||0.421||0.052||0.459||0.025||0.900||0.629||0.430|
|SBP, systolic blood pressure. Group A: triad (–); Group B: triad (+).|
p for model 1: adjusting for baseline SBP, age and gender by analysis of covariance (ANCOVA).
p for model 2: adjusting for baseline office SBP, DBP, age, gender, number of medication class, aldosterone, and renin activity by analysis of covariance (ANCOVA).
The percentage of drug classes in use by each group is depicted in Fig. 1; the proportion of patients in group B prescribed at least four classes of drug decreased from 95% to 73% within three months and to 62% at 12 months. Compared to group A, the number of drug classes continued to decrease to 12 months in group B.
Percentage of drug class number distribution. Group A: triad (–); Group B: triad (+). The percentage of drug classes in use is depicted at baseline and 1, 3, 6, 12 months. The percentage of patients taking less than four classes of drug increases till 12 months only in group B.
Overall, nineteen patients (41%) had response to RDN in the first month. Thirty (65%) and thirty-one (67%) of all patients responded to the RDN procedure in six months and twelve months, respectively. The response rate was significantly greater in group B at 3 months (48.1% vs. 84.2%, p = 0.016); and (48.1% vs. 89.5%, p = 0.005) at 6 months. The proportion and timeline of response in two groups are depicted in Fig. 2.
Response rate to renal denervation (RDN) by groups. Group A: triad (–); Group B: triad (+). The change in proportion of responders in both groups during 12 months after RDN.
Sympathetic nerveous system activity is associated with RAAS overdrive in neurogenic hypertension . The RAAS may have a critical role in the activation of the sympathetic nervous system. Accumulated basic and clinical evidence supports the use of inhibitors of the RAAS, including aldosterone antagonists. These findings are consistent with the result that RDN significantly reduces the level of renin and aldosterone . This study demonstrated that RDN was associated with a greater response in group B patients, who had predictive features suggesting occult aldosterone overactivity. RDN may further inhibit pre-existing sympathetic activity in patients with relatively active RAAS, which was inadequately suppressed by concomitant antihypertensive medications.
Due to its complexity, the concept of aldosteronism remains incompletely
understood, and its true prevalence remains uncertain. Usually, the differential
diagnosis would be initiated when ARR
Impaired renal blood flow secondary to systemic disorders is a common etiology of RAAS overactivity [10, 20]. Therefore, decreased renal blood flow (TIMI-2) on the renal angiogram was another feature we chose to identify patients with overactive RAAS. Notably, the effect of BP lowering by angioplasty alone is disappointing . However, RDN has been shown to increase renal blood flow in animals , and investigating its impact on BP control is worthy of prospective investigation.
The patients in group B showed comparable BP effects at 1 month and more delayed response from 3 to 6 months. These findings might suggest a possible mechanism for to explain continuous BP decline for months in randomized control trials [1, 23]. Decreased spillover of norepinephrine could happen soon after RDN, but the process to modulate RAAS could last much longer. Notably, the SPYRAL HTN-ON MED trial also showed an apparent time effect of gradually decreasing systolic BP in the RDN treated group compared to the sham control group . However, the present 24-hour BP measurements at 1 month also seem to indicate that RDN could help to lower BP immediately within one month in nearly half of all RDN recipients.
This multi-center, retrospective post-hoc analysis has several limitations, including the relatively small sample size and imbalanced medication choices. The imbalanced RAAS inhibitors could also reflect the discriminative power of predictive triad. BP change may be attenuated by medication adjustment in the late period of follow-up; however, we still observed significant reduction of office BP at 12 months in group B compared with group A. Because our study cohort was not drug-naïve, the determinant ARR could be influenced by multiple drug interactions, leading to nonspecific diagnosis in both groups. So, the predictive triad should not be interpreted as criteria of diagnosis. It is possible that a small proportion of patients in group A may have unknowingly met one of the triad criteria due to missing data. However, the difference in proportion still led to a lower response rate in group A.
Patient selection under medications remains an important unmet clinical need. We observed a superior response rate following RDN in the group with the predictive triad at baseline. Our results warrant further investigation on its application and causality.
SIL and YHL contributed to the conception and design of the study. SIL, SHS, LYML, PLL, WRL, CLC, WRC, CTT, YJW, TDW, YHL collected the data. CCH and YHL performed and supervised statistical analysis. SIL drafted the manuscript. SIL, CCH, YHL critically reviewed the manuscript. All authors read and approved the final manuscript.
This study was approved by the Institutional Review Boards of MacKay Memorial Hospital (approval number: 20MMHIS087e), which waived the requirement for informed consent in this retrospective study.
We would like to express our gratitude to all those who have supported our work. Thanks to all the peer-reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest. Tzung-Dau Wang is serving as one of the Editorial Board members of this journal. We declare that Tzung-Dau Wang had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Stefano Omboni, Brian Tomlinson and Takatoshi Kasai.