Renal Sympathetic Denervation
Hoogerwaard, Annemiek F.
DOI:10.33612/diss.157272672
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Publication date: 2021
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Hoogerwaard, A. F. (2021). Renal Sympathetic Denervation: From acute renal nerve stimulation induced hemodynamic changes to long-term clinical perspectives. University of Groningen.
https://doi.org/10.33612/diss.157272672
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chapter 1
1
GeneRal intRodUction
Renal sympathetic denervation (RDN) has been developed as a potential treatment modality for patients with hypertension, and the initial results of its blood pressure lowering effects were impressive (1). The underlying rationale of RDN is to disconnect the autonomic nervous intermodulation between the central nervous system and the kidneys, and consequently reducing sympathetic tone. Against this background, RDN seemed to be a plausible therapeutic option in patients with hypertension and other cardiovascular disease characterized by sympathetic overdrive. However, after the neutral results of the SYMPLICITY HTN-3 trial (2), RDN was characterized by a chequered past and experts stated “we have seen the rise and fall of RDN and we hope that we shall witness the resurrection” (3), to boost the moods of the researchers in this field. Since then, the hope for RDN as treatment option in cardiovascular disease has been translated into over 1,500 publications on the topic of RDN, including the articles in this thesis. All these publications aimed to improve patient selection, procedural techniques, and other related factors from previous RDN research. The introduction chapter of this thesis describes the rationale underlying the RDN approach, provides a brief overview of the most relevant RDN hypertension studies as well as its clinical impact in cardiovascular disease beyond hypertension, and related contemporary literature on the added value of renal nerve stimulation (RNS), followed by the aim and outline of this thesis.
Rationale underlying renal sympathetic denervation
The sympathetic efferent and afferent renal nerves in the vascular wall of the arteries form the connection between the kidney and autonomic nervous system, and constitute a crucial component of the autonomic crosstalk between the heart and the kidneys: the cardio-renal axis (4). Under physiological conditions the renal efferent nerves regulate the renal blood flow, sodium and water homeostasis, glomerular filtration rate, and renin release which regulates blood pressure and renal perfusion. However, under pathophysiological circumstances, (over)stimulation of the efferent renal sympathetic nerves leads to hypertension or volume overload in heart failure due to increased activation of the renin-angiotensin-aldosterone, and subsequently increased water retention, and sodium reabsorption, resulting in a higher intravascular volume. The afferent renal neural pathways including the sympathetic nerve fibres connect the kidneys to the dorsal roots and provide neural feedback to regions of the brainstem involved in the autonomic regulation of cardiovascular physiology. Activation of afferent sympathetic nerves can occur as a result of increased signalling from renal sensory fibres due to several pathophysiological stimuli such as ischemia, hypoxia and oxidative stress, resulting in enhanced sympathetic outflow to the kidneys. This increased renal afferent signalling directly influences sympathetic activity and affects among others
renal and cardiovascular systems, and results in increased systemic vascular resistance and hypertension (4–8). A schematic picture of the interaction between the renal aff erent signalling and eff erent sympathetic activity is illustrated in figure 1. Beyond the role in the development of hypertension, it is well known that the sympathetic nervous system is important in the initiation, progression, and maintenance of cardiac arrhythmias (9–13), and heart failure (14,15). The cardio-renal axis may trigger arrhythmias by stimulation of the mechano- and chemoreceptors in the renal wall and interstitium due to the previously described pathophysiological stimuli. Activation of these receptors in the kidneys may result in increased renal aff erent sympathetic signaling, subsequently leading to enhanced central sympathetic outflow and eff erent sympathetic eff ects to the heart, which leads subsequently to increased automaticity and triggered activity (4). Since RDN was initially developed for the treatment of hypertension and the main patient population of this thesis are hypertensive patients, the underlying pathophysiological mechanisms of sympathetic overdrive in other cardiovascular disease are not discussed in detail here.
Renal injury Renal ischemia
↑ Renin release → ↑ RAAS activation ↑ Sodium retention → hypervolaemia ↓ Renal blood flow
Proteinuria Glomerulosclerosis Hypertrophy Arrhythmia ↑ O2consumption Heart Failure Vasoconstriction Fluid shifts Atherosclerosis ↑ R en al a ffer ent sig na llin g ↑ E ffer ent sy m pa thet ic act iv ity
figure 1 - A global overview of the eff erent sympathetic activity to the kidney, aff erent sensory signaling
1
It is well known that patients with hypertension benefit from drugs that inhibit central release of catecholamines or inhibition of the catecholamine receptors (16). Furthermore, before the introduction of the current antihypertensive drugs, radical surgical methods for thoracic, abdominal, or pelvic sympathetic denervation had successful lowered blood pressure and mortality. However, these methods were associated with high perioperative morbidity and severe long-term complications, including autonomic system impairment (17,18). Once antihypertensive medications were available the use of surgical sympathectomy disappeared. However, intolerance and non-adherence to antihypertensive drugs is a major limitation of pharmacological therapy (19,20). In the search for novel strategies to offer non-drug treatment options for patients with resistant hypertension, endovascular RDN techniques were developed in the last decades.
Renal sympathetic denervation
Hypertension
The first patient with drug resistant hypertension was treated by RDN in 2009, and afterwards he had significant reduced blood pressure and norepinephrine serum concentrations, as parameters of decreased sympathetic activity (21). Thereafter, several non-blinded clinical studies reported tremendous reductions in office systolic blood pressure of > 30 mmHg compared to control (22,23). The ESC/ESH Management of Arterial Hypertension Guidelines of 2013 recommended to consider the use of RDN only in case of ineffectiveness of drug treatment in patients with resistant hypertension (class IIb, level of evidence C), and the guidelines stated that until more evidence is available on the long-term efficacy of RDN, these procedure should remain in the hands of experienced operators (class I, level of evidence C) (16). However, the first blinded, randomized, and sham-controlled SYMPLICITY HTN-3 trial failed to show a benefit of RDN on lowering 24-hour ambulatory blood pressure during follow-up in 535 patients with treatment resistant hypertension (2,24). Subsequently, both patient and procedural related factors have been intensively discussed as clarifications for the disappointing outcomes of the SYMPLICITY HTN-3 trial (25). This introduction will highlight a few of the most important factors that potentially contributed to the neutral results. First of all, the single monopolar electrode radiofrequency ablation catheter, Medtronic Symplicity Flex was designed to deliver point by point ablations and therefore required enhanced operator skills in catheter manipulation to achieve circumferential ablation. Of note, part of the participating centres in the trial were not experienced in performing RDN which may have resulted in unpredictable and incomplete RDN (26). Secondly, the role of the renal artery anatomy has been potentially underestimated in the first trials (27): non-denervated accessory arteries may result in residual sympathetic over-activity still causing hypertension at follow-up (28–30). Histological studies demonstrated that at the distal segments of the renal artery the nerves were closer to the lumen compared to the proximal segments,
so lesion depth has potentially not been sufficient at the proximal segments to ensure complete denervation (31–33). Moreover, side branches of the renal arteries were not treated with the first generation RDN catheters. And a procedural endpoint was not available. Thirdly, patient related factors, such as drug non-adherence (34), and a study population including patients with substantial vascular stiffness or isolated systolic hypertension may, at least in part, explain the negative results (35). Of note, after the neutral results of the SYMPLICITY HTN-trial, the current ESC/ESH Management of Arterial Hypertension Guidelines of 2018 states that the use of RDN is not recommended for routine treatment of hypertension (class III, level of evidence B), unless in the context of clinical studies and randomized controlled trials, until further evidence regarding their safety and efficacy becomes available (36). The manufacturers and clinical scientists responded to the physicians’ requests to address, at least part of the discussed issues, to improve outcome of RDN procedures. Further research showed that patients with ablations in the distal branches and higher number of ablations had better results after RDN (37). Furthermore, the design of the second-generation radiofrequency denervation catheters included multi-electrodes with a geometrical orientation aiming to obtain improved circumferential ablation of the renal artery wall without extensive catheter manipulation. Besides that, electrical high frequency renal nerve stimulation (RNS) has been developed as an eventual procedural endpoint for the RDN procedure. RNS is characterized by a functional approach, involving electrical RNS guided mapping and targeted ablation of the sympathetic nerve fibres, comparable to electro-anatomical guided mapping and ablation of cardiac arrhythmias (38). The RNS technique will be extensively described in the chapters of this thesis. Besides RNS-guided RDN, other denervation techniques have been tested. Ultrasound energy based ablation resulted in a more uniform, and full circumferential energy delivery creating ablation points with greater depth in the main arteries compared with ablation using radiofrequency energy (39–42). However, blood pressure lowering effects of ultrasound based RDN were similar to RDN with radiofrequency ablation of the main arteries, accessories, and side branches (43). In small studies RDN with cryo-balloon (44) or chemical RDN (45,46) have been successfully tested. Apart from the procedural improvements, patient related factors have also been studied. The prospective, open-label randomised controlled DENERHTN-trial, compared standardized antihypertensive drug therapy with or without RDN in patients with resistant hypertension to deal with the aspect of drug non-adherence. Both groups showed statistically and clinically significant blood pressure reductions at follow-up; mean change in daytime 24-h systolic blood pressure was -16 mmHg in the RDN group, and -10 mmHg in the antihypertensive treatment alone group. Moreover irrespective of drug adherence, RDN plus standardized antihypertensive drug therapy had a significantly better blood pressure lowering effect compared to standardized antihypertensive drug therapy alone (47). The SPYRAL HTN randomised, single-blind, sham-controlled trials focused also on the patient
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related issues, and included a different subset of patients, namely patients with mild to moderate hypertension instead of drug resistant hypertension, and moreover patients were medication-naïve or stopped their antihypertensive drugs (48). Both the SPYRAL HTN-OFF and the HTN-ON med studies provided clinical evidence supporting the clinical efficacy of RDN; i.e. significantly reduced blood pressure compared to sham-control at 6 months follow-up after RDN (49,50).
Clinical applications beyond hypertension
Initially, several clinical RDN case series and non-randomized trials reported that the included patients with resistant hypertension had improved blood pressure at follow-up, but were on top of that free of sympathetically induced (supra)ventricular arrhythmia (51). Up to know, a number of six randomized controlled studies, including 689 patients have investigated the effect of RDN as adjunctive treatment to pulmonary vein isolation in patients with hypertension and symptomatic atrial fibrillation. In a meta-analysis the mean odds ratio for atrial fibrillation recurrence for pulmonary vein isolation with RDN compared with pulmonary vein isolation alone was 0.43% (95% confidence interval 0.32-0.59) after 1 year, with also significant blood pressure reduction in the RDN group (52). Clinical evidence on RDN and the treatment of ventricular arrhythmias in both ischemic and non-ischemic cardiomyopathy is only based on small case series and case reports. Although in all these series, RDN seemed to be safe and effective in a selected subset of patients (53–56). Patients with heart failure are another group of patients with cardiovascular disease characterized by sympathetic overactivity (14,15). RDN in systolic heart failure resulted in improved hemodynamics, improved cardiac function and remodeling, increased natriuresis, and decreased neurohormonal activation in experimental animal studies (57). Up to now, only a few small clinical studies are available and demonstrated improved symptoms, exercise capacity, and biochemical and echocardiographic parameters at follow-up after RDN in patients with chronic systolic heart failure (58,59). Besides RDN, other approaches in treating heart failure through device-based autonomic modulation have been investigated, such as spinal cord stimulation, baroreflex activation therapy, and vagal nerve stimulation. In non-sham controlled studies these device-based therapies showed neutral or beneficial effects on heart failure symptoms (60–64), but advantage on cardiovascular mortality or heart failure hospitalizations has not been demonstrated yet. So, RDN looks promising in treating heart failure, however it remains to be seen and further investigations providing solid evidence are mandatory prerequisites before these new modalities can be recommended in the general practice.
Renal nerve stimulation
At the Isala Heart Centre in Zwolle, the RDN procedures are performed by cardiac electrophysiologists and these procedures are characterized by using RNS-guided
mapping and targeted ablation of the sympathetic nerve fibres. RNS was developed to potentially create a functional physiological intermediate endpoint for the RDN procedure. In animal models, RNS resulted in increased blood pressure, heart rate, and (nor) epinephrine concentrations before RDN. Whereas, after RDN these RNS-induced effects were significantly blunted (65–67). It has also been histologically demonstrated that the RDN induced suppressed effects on RNS-induced blood pressure increase may be related to the severity of tissue injury (68). In 2015, results on safety and proof of principle of the use of RNS in humans was reported (38). RNS induced a systolic blood pressure response of +43 mmHg before RDN compared to +9 mmHg after RDN. Later, we demonstrated in 14 patients that the acute RNS-induced blood pressure changes were positively correlated with 24-h ambulatory blood pressure decrease at a short-term follow-up compared to baseline (69), while the RNS-induced effects in non-denervated accessory arteries were both before and after RDN similar (28). Thus, there is proof from small clinical studies with short-term follow-up that RNS may be used to localize the optimal denervation points in the renal artery, in order to achieve complete denervation and adequate blood pressure lowering at follow-up in hypertension patients undergoing RDN.
aim and oUtline
The rationale of RDN remains attractive and reasonable based on the existing historical evidence, physiological knowledge and proof from animal models of sympathetic modulation. Moreover, since the publication of the first-in-man RDN procedure, the technique and patient selection has been improved in various ways as described in the general introduction. However, the added clinical value in treating hypertension on top of optimal medical therapy in drug-adherent hypertensive patients is disputable since it has not yet been proven in large randomized sham-controlled trials, the same restraints apply to clinical applications in cardiovascular disease beyond hypertension. Moreover, the exact underlying mechanisms of both RDN and RNS are not yet completely understood, and regarding RNS only small and short-term effects have been investigated. Of note, the latest randomized, sham-controlled SPYRAL HTN studies shined a new positive light on RDN as treatment option for hypertension. However, in the latest ESC/ ESH guidelines of arterial hypertension RDN is no longer recommended for the routine management of hypertension, and further research is still needed. Figure 2 represents a visual overview of the introduction on RDN; statements on existing evidence, topics still under debate and the aspects of this thesis are highlighted in the figure. The aim of the present thesis is firstly to further elucidate the acute underlying mechanisms of the RNS-induced cardiovascular effects during RDN, secondly to investigate the medium-term blood pressure lowering effects of RDN, and finally to discuss the future role of RDN in
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cardiovascular disease. The current thesis consists of six chapters which are divided in three parts. In part I, including chapter 2 and 3, the acute RNS-induced cardiovascular effects underlying RDN are investigated. Previous publications have only reported on blood pressure as acute cardiovascular effect of RNS. To further elucidate the underlying mechanism and induced effects both before and after RDN, we investigated the RNS-induced changes on arterial pressure hemodynamics (chapter 2), and heart rate variability
(chapter 3). After the acute RNS-induced cardiovascular effects in part I, the medium-term blood pressure lowering effects of RDN are described in part II of this thesis. In chapter 4, the blood pressure lowering effects of the use of RNS during RDN and its additional value for the RDN procedure in patients with treatment resistant hypertension are reported. Subsequently, we evaluated if patients with advanced vascular calcification should be excluded from RDN in chapter 5. From acute RNS-induced cardiovascular effects (part I), to medium-term blood pressure lowering effects (part II), to the final part III of this thesis, figure 2 – A visual overview of the brief introduction on RDN organized around four important topics:
hypertension, procedural aspects, clinical applications beyond hypertension, and RNS. The aspects discussed in the articles of this thesis are highlighted in orange. (RDN: renal sympathetic denervation, RNS: renal nerve stimulation).
in which the long-term future perspectives on RDN and RNS in cardiology are described. An invited review (chapter 6) discusses the question if RDN is still a treatment option in cardiovascular disease and the last chapter 7 could be considered as a concrete step towards the future, by presenting the background and rationale of the currently ongoing international multicenter ASAF trial in which patients with atrial fibrillation and signs of sympathetic overdrive are randomized to pulmonary vein isolation with or without RDN.
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