2School of Medicine, ShaoXing University, Shaoxing, Zhejiang, China
Abstract
Background: Atrial fibrillation (AF) is the most common type of heart arrhythmia. Hypertension (HTN) is known as the most common risk factor for AF. The purpose of this study is to compare clinical results of combined renal denervation (RDN) and pulmonary vein isolation (PVI) in AF patients with HTN.
Methods: A systematic search was conducted on patients with AF and HTN, comparing the differences between RDN and PVI with PVI alone. The risk ratio (RR) of categorical variables and the mean difference of continuous variables with a 95% confidence interval were applied.
Results: This meta-analysis included 10 studies with a total of 875 patients. 420 patients were in the RDN + PVI group (48%) while 455 (52%) were in the PVI group. 694 patients had paroxysmal AF (79.3%) and 181 patients had persistent AF (20.7%). At 12 months follow-up, the treatment of RDN + PVI reduced the overall risk of AF recurrence in HTN patients
(RR = 0.64, P < .001, 95% confidence interval [CI]: 0.55-0.75). When pooled, the patients in the RDN + PVI group showed significant mean reductions in systolic blood pressure (BP)
(−13.39 mm Hg, P < .001) and diastolic BP (−7.14 mm Hg, P < .001) compared to PVI alone. Meanwhile, PVI + RDN significantly increased the estimated glomerular filtration rate
(+8.72 mL/min/1.73 m2, P < .001) compared with PVI alone. There was no significant difference in complications between the 2 groups.
Conclusion: Combined therapy of RDN + PVI seems more efficacious and superior to PVI alone in treating AF. Further and larger trials are needed to fully prove these outcomes.
Highlights
- The failure rate of atrial fibrillation (AF) recurrences after pulmonary vein isolation (PVI) remains unacceptably high and repeat operation are often needed.
- Renal denervation (RDN) intervenes in the contact between the kidney and autonomic nervous system to reduce blood pressure (BP).
- Renal denervation could be a safe and effective antihypertensive therapy option for patients with hypertension and chronic kidney disease.
- Combined RDN + PVI therapy significantly lowered AF recurrence and BP compared to PVI alone, without increasing complication rates.
Introduction
Atrial fibrillation (AF) is a common arrhythmia characterized by irregular and disordered atrial electrical activity, which inhibits normal sinus rhythm. It affects up to 1% of the general population worldwide.1 Hypertension (HTN) often accompanies many kinds of comorbidities and cardiac end-organ damage, such as arrhythmias caused by long-term exposure to elevated blood pressure (BP). Uncontrolled HTN plays an important role in the pathogenesis and prognosis of AF.2 Yet, HTN is the most important independent predictor of recurrent AF after catheter ablation.3,
Renal denervation (RDN) is a novel nonpharmacologic catheter-based intervention therapy that ablates the renal sympathetic nervous system, including both efferent fibers that regulates renin-angiotensin aldosterone axis and afferent fibers that adjusts systemic sympathetic nervous tone. Renal denervation has been demonstrated to suppress sympathetic activity and reduce BP in certain patients with HTN.6,
Methods
Search Strategy and Selection Criteria
We performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.8,
The studies were screened during the 3 stages (titles, abstracts, and full-text of papers) independently, duplicated, and assessed for risk of bias by 2 authors. Internal discussions were held on disagreements before entering the next stage of screening. Studies that met the following criteria were included: (1) the study assessed and compared RDN with PVI and PVI alone in patients, (2) the study involved adult human subjects aged ≥ 18 years, (3) the study reported at least 1 clinical result, (4) RCTs and prospective comparative studies. Exclusion criteria included: (1) studies with no control groups; (2) retrospective studies; (3) editorials; (4) case reports; (5) expert opinions; (6) reviews; and (7) studies with overlapping data. Non-English studies were searched but ultimately excluded due to the inability to analyze them. A PRISMA flowchart of the literature screening is shown in
A review protocol was not registered. Artificial intelligence-assisted technologies (such as large language models, chatbots, or image creators) were not used in the production of the submitted work.
Clinical Outcomes
The following clinical outcomes were collected: (1) AF recurrence, (2) changes in BP, (3) changes in estimated glomerular filtration rate (eGFR), and (4) complications including major adverse events. Atrial fibrillation recurrence (including atrial flutter or atrial tachycardia) was defined as episodes of atrial tachyarrhythmias lasting >30 seconds during the follow-up period. The first 3 months after ablation were considered a blanking period and excluded from the analysis. Major adverse events included vascular complications requiring intervention or surgery, pericardial tamponade requiring drainage, renal artery complications requiring intervention, phrenic nerve palsy, pneumothorax, stroke, and death.
The following information, if available, was extracted from the studies: primary author and year, study design and purpose, sample size, age and gender information, country of study, follow-up time frame, baseline study sample characteristics (number of HTN medications, eGFR, presence of type 2 diabetes, coronary artery disease (CAD), left-ventricular ejection fraction, left-atrial diameter (LAD), AF type, systolic blood pressure (SBP) and diastolic blood pressure (DBP)), follow-up data on AF recurrence, BP, eGFR, and safety complications.
Risk of Bias Assessments
The Cochrane risk of bias tool (The Cochrane Collaboration, Copenhagen, Denmark) was used to assess the quality and publication bias of the individual studies that were randomized. Studies that were non-randomized but prospective were assessed for quality and publication bias using The Methodological Index for Non-Randomized Studies (MINORS). The quality of the included studies was evaluated independently by 2 authors according to the Cochrane’s risk of bias 2.0. If there were disagreements, a third researcher was consulted. Each quality item was graded as low risk, high risk, or no clear risk. The evaluation content included 7 items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases.
Data Analysis
The main outcomes were AF recurrence, the antihypertensive effect of RDN, and the effect of RDN on eGFR. Secondarily, the analysis was to appraise the efficacy, safety, and durability of RDN. Statistical analysis was done with Review Manager (RevMan), version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark), and Stata 16. The DerSimonian Laird random-effects model was used to estimate the risk ratios and mean difference (MD) with the corresponding 95% confidence interval (CI). A bilateral
Results
Literature Screening Results and Literature Quality Evaluation
Baseline Study Characteristics
Effect of Renal Denervation on Atrial Fibrillation Recurrence
All the included studies reported AF recurrence rates during the follow-up period (
Effects of Renal Denervation on Blood Pressure
All included studies reported follow-up data on BP following the procedure (
Effect of Renal Denervation on Estimated Glomerular Filtration Rate
Every study reported eGFR at baseline. However, 1 study only reported eGFR changes for the PVI + RDN group and was therefore excluded.18 Only 5 studies reported eGFR during the follow-up period (
Complications
Nine trials reported data about complications following the procedure and during the follow-up period in the 2 groups.13-
Discussion
The results from 10 studies investigating the use of combined RDN and PVI in the treatment of paroxysmal and/or persistent AF in 876 patients with HTN and AF were examined. On the basis of the available evidence, the main findings of the study favoring the following favoring RDN and PVI treated group are the following: (1) the risk of AF recurrence is significantly reduced at follow-up; (2) SBP and DBP are significantly reduced at the 12-month follow-up; (3) eGFR is significantly increased at the 6-month follow-up; (4) the total rate of complications in the 2 groups, both during the procedures and during the follow-up period, is low; (4) there is no significant difference in complications.
Atrial fibrillation is related to an increased risk of cardiovascular events, mortality, and cognitive decline.22 Hypertension is one of the major modifiable and independent risk factors for the development and progression of AF.23 Atrial fibrillation increases BP beat-to-beat variability,24 which raises concerns about the potential risk of hypoperfusion and its influence on vascular and cognitive function. A recent meta-analysis of clinical trials showed that patients with AF had a reduced risk of dementia from BP-lowering treatment.25 There may be a synergistic effect between HTN and sympathetic overactivation, leading to abnormal atrial electrical conduction and promoting AF. A novel treatment regulating both BP and sympathetic activity in patients with AF and HTN is desirable and may be potentially beneficial.
Renal denervation has been proved to be effective in lowering BP in resistant HTN patients in multiple trials and network meta-analysis.26,
It remains unclear whether RDN improved AF outcomes by better BP control, a direct antiarrhythmic effect mediated by sympathetic inhibition, or both. Kirstein’s study provided evidence that among patients with multidrug-resistant arterial HTN and paroxysmal or persistent AF, concomitant RDN + AF ablation was not associated with better BP control or rhythm outcomes in comparison to AF-only ablation and medical therapy.13 In another single-center, randomized, sham-controlled pilot trial in patients with uncontrolled HTN at high risk of developing subclinical AF, RDN reduced subclinical AF events, subclinical AF burden, and fast AF compared to sham treatment.32 However, no significant change in 24-hour ambulatory systolic or diastolic BP from baseline to 6 months after the procedure in either the RDN or sham group was observed, suggesting that the antifibrillatory effect of RDN in this study appeared unrelated to the improvements in BP or changes in antihypertensive medication.32 A recently published study showed that RDN could represent an alternative therapy in AF by inhibiting atrial interstitial remodeling and atrial Receptor-for-Advanced-Glycation-End-products (RAGE)/soluble RAGE (sRAGE) dysbalance as well as inflammation in metabolic syndrome spontaneously hypertensive rats, not due to a decrease in BP.33 On the other hand, both persistent and paroxysmal AF patients are included in this meta-analysis. Impressively, the Evaluate Renal Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF) trial involved paroxysmal AF patients only and showed a recurrence rate of 28% in the RDN + PVI group vs. 43% in the PVI-only group, implying a lower recurrence in patients with paroxysmal AF as opposed to persistent AF.20 Larger-scale clinical trials focusing on normotensive patients are necessary to assess the antiarrhythmic mechanism of RDN.
Beyond the impact on BP, improvement of renal function is highlighted. HTN may cause chronic kidney disease (CKD) and contribute to its progression, whereas CKD induces HTN conversely. For any given cause of CKD, including HTN itself, the elevation in BP values amplifies the degree to which glomerular filtration rate worsens, making the high BP state an independent risk factor for end-stage renal disease.34,
On account of safety concerns, many previous studies have excluded patients with eGFR < 45 mL/min/1.73m2 or eGFR < 40 mL/min/1.75m2, respectively. In the study of Günes-Altan M, patients with eGFR ≥ 15 mL/min/1.73m2 were included, and no major cardiovascular or renal adverse events or sustained eGFR decline were observed after a follow-up of 12 months. This single-center experience showed a similar reduction in 24-hour, day and night-time ambulatory BP as well as in-office BP in patients with and without CKD at any time point up to 12 months after RDN.40 In the Global SYMPLICITY Registry, the largest dataset of patients treated with RDN (n = 1742), there was an insignificant difference in 24-hour ambulatory BP reduction between patients with and without CKD.39 A meta-analysis also showed the efficacy and safety of RDN for HTN in patients with CKD, with just an overall complication rate of 4.86%.41 These findings support the viewpoint that RDN could be a safe and effective antihypertensive therapy option for patients with HTN and CKD. Yet, patients with CKD have a high risk of contrast-induced nephropathy after RDN surgery. If RDN surgery can be carried out without or with only a small amount of contrast agent, CKD patients may benefit more from RDN.42 Furthermore, AF is highly prevalent among patients with CKD. An animal study suggested that CKD created a substrate for AF development in Nlrp3-/- and wildtype (WT) mice by activating the NLR-family pyrin domain-containing 3 (NLRP3) inflammasome in atria, which is associated with structural and electrical remodeling.43 Renal denervation may directly prevent CKD-induced AF, not by lowering the BP.
Regarding the safety of RDN, there was no significant difference in complications between the ren studies. Previous research on patients receiving RDN has reported similar safety results,35,
Study Limitations
The current meta-analysis has the following limitations. First, despite the inclusion of 10 clinical trials, small observational studies were included,17,
Conclusion
This meta-analysis revealed that adding RDN to PVI in patients with AF and HTN appears more effective and superior to using PVI alone to treat AF. Combination therapy showed improvement in BP and eGFR, and a reduced risk of AF recurrence. Moreover, the use of the technique proved to be safe. It is important to realize that while this novel and promising therapeutic modality shows potential as a treatment approach for AF, larger trials (including those enrolling patients with normal BP or different AF subtypes) are needed to confirm these findings and determine the patient groups that may benefit most from adjunctive RDN.
Footnotes
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