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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 58-65

Clinical benefits of renal denervation besides blood pressure reduction


1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
2 Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China

Date of Web Publication16-Jul-2018

Correspondence Address:
Junbo Ge
Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, 180 Fenglin Road, Shanghai 200032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_10_18

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  Abstract 


Hypertension (HTN) is currently one of the most common chronic diseases, among which some cases are poorly controlled and defined as resistant HTN (RH). Through years of exploration, it has been discovered that hyperactivity in the sympathetic nervous system and the renin–angiotensin system (RAS) initiates the development of RH, followed by other chain reactions in inflammation and oxidative injury. Attributed to their shared pathogenesis with communal cytokines and factors, other comorbidities of HTN, usually associated with cardiovascular and metabolic pathophysiology, often occur alongside primary symptoms, namely, atherosclerosis, heart failure, arrhythmia, and glucose metabolic disorder. Renal denervation (RDN) was first introduced as an alternative measure to help alleviate RH. Renal denervation's clinical relevance comes from directly cutting down afferent and efferent renal nerves, resulting in fewer nerve impulses transmitted to central nervous system and peripheral target organs, and less RAS activation, resulting in lower blood pressure. However, the practical effects of RDN have extended beyond lowering blood pressure and and and plays a role in anti-inflammation and antioxidation pathways. In this review, we briefly summarize the possible mechanism and beneficial clinical effect of RDN treatment in atherosclerosis improvement, cardioprotection, and diabetes remission.

Keywords: Arrhythmia, atherosclerosis, diabetes, heart failure, renal denervation


How to cite this article:
Chen H, Shen L, Ge J. Clinical benefits of renal denervation besides blood pressure reduction. Cardiol Plus 2018;3:58-65

How to cite this URL:
Chen H, Shen L, Ge J. Clinical benefits of renal denervation besides blood pressure reduction. Cardiol Plus [serial online] 2018 [cited 2018 Oct 19];3:58-65. Available from: http://www.cardiologyplus.org/text.asp?2018/3/2/58/236815




  Introduction Top


Sympathetic nervous system (SNS) and renin–angiotensin system (RAS) hyperactivity are considered pivotal in the development and maintenance of hypertension (HTN) and associated comorbidities.[1],[2],[3],[4] Disruption of renal sympathetic nerves is increasingly recognized as a potential method to alleviate adverse consequences of chronic sympathetic overactivity.[5] For more than a decade, renal denervation (RDN) has been used as an alternative treatment for patients with resistant HTN (RH). The efficacy of RDN in lowering blood pressure (BP) in hypertension remains controversial, with confounded sham-arms and Hawthorne effect, and the concrete clinical evidence in RH patients has not been definitively replicated, as various of studies worldwide have contradicted one another. The outcomes from symplicity series are not consistent. The studies HTN-1[6] and HTN-2[7] concluded that RDN played a role in BP decline, however these results were opposed by HTN-3[8], where the results were inconclusive, but coincided with the HTN-OFF-MED [9] study. The DENERHTN study, INSPiRED study, and another before-after single group trial also also claimed to find lower BP after RDN treatment.[10],[11],[12] Six-month, 1-, and 2-year data feedback from the Prague-15 serial trials demonstrated no difference comparing RDN and spironolactone.[13],[14],[15] Similarly, the ReSET trial also found RDN had no better reduction in BP than conventional drug therapy.[16] Oslo-RDN even came up with results that RDN was inferior to adjusted drug treatment.[17] Numerous meta-analyses have only elaborated the safety of RDN but not efficacy.[18],[19],[20]

With ongoing clinical and animal experiments, research groups are exploring more about the mechanisms of RDN on HTN. They have gradually realized that independent from BP reduction, RDN also improves other comorbidities of HTN due to intricate interactions and shared pathogeneses, namely, those associated with the SNS, RAS, inflammation, and oxidative injury pathways. In this review, we will summarize potential mechanisms and beneficial effects of in hypertension comorbidities, including atherosclerosis, heart failure (HF), arrhythmia, and diabetes mellitus.[2],[21],[22],[23],[24]


  Potential Mechanisms of Renal Denervation Top


The kidney is typically a target organ of SNS activity. In response to chemical or mechanical stimuli, efferent fibers from the brain to the kidneys stimulate local release of NE from renal sympathetic neurons onto juxtaglomerular cells leading to the release of renin, thus activating the RAS system and increasing sodium tubular reabsorption, water retention, and renal vascular resistance, contributing to the development and maintenance of HTN. Renal afferent fibers to the brain regulate kidney–brain feedback, creating a self-maintaining sympathetic activation loop, which contributes to the progression of RH and organ damages.[25]

After RDN, RAS hyperactivity tends to return to normal with restricted renin secretion, effectively controlling HTN. While directly cutting off nerves conduction, RDN also exhibits other effects such as anti-inflammation and antioxidation.[26],[27] Less NE is released from presynaptic membrane, which not only suppresses immune cell activation, limiting subsequent inflammation, but also drops nicotinamide adenine dinucleotide phosphate (NADPH) oxidase concentration, decreasing reactive oxygen species (ROS) and superoxide,[28],[29] and lower the pressure from oxidative injury. Sympathetic nerves in both the peripheral and central nervous systems and RAS can no longer be overstimulated by oxidative stress or inflammatory cytokines.[30] Breaking this cycle ameliorates symptoms throughout the whole circulating system.


  Renal Denervation Alleviates Atherosclerosis Top


Atherosclerosis, a chronic disease, is represented by endothelial damage,[22],[23] vascular dysfunction and plaque formation.[31] Based on the presence of an overactivated SNS, inflammation is an identical feature of atherosclerosis, together with oxidative stress.[32] Norepinephrine (NE) and angiotensin II (Ang II) induced from RAS overactivation lead to the imbalance between inflammatory and anti-inflammatory responses, as well as oxidation and antioxidation factors,[33] damaging endothelial cells and vascular structure and function. In reverse, the SNS and RAS are further activated. As shown in [Figure 1], four of these primary origins result in the initiation and progression of atherosclerosis.
Figure 1: RDN in atherosclerosis. SNS hyperactivity initiates RAS, immune cells, and oxidative stress, which interact with each other at downstream, causing endothelial cells apoptosis, VSMCs proliferation, immune cells accumulation, also HTN, cytotoxicity, lipid oxidation, and impaired endothelial dilation in atherosclerosis. Through RDN, overactivations are all cut down, suppressing the pathophysiological progression of atherosclerosis. Color red represents the effect of RDN treatment. Inflammatory cytokines and chemokines above represent MMP-2/-9, VCAM, ICAM, MCP-1, TNFα, etc. RDN: Renal denervation, SNS: Sympathetic nerve system, RAS: Renin–angiotensin system, VSMC: Vascular smooth muscle cells, HTN: Hypertension, MCP: Monocyte chemotactic protein, TNFα: Tumour necrosis factor-α, ICAM: Intercellular adhesion molecule, VCAM: Vascular cell adhesion molecule, MMP: Matrix metalloproteinases

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RDN directly cuts down afferent renal nerve (ARN) input to the central nervous system (CNS) and output to peripheral targets; attenuating SNS and RAS activation; decreasing NE, Ang II, and aldosterone concentration; and alleviating the activation of inflammatory and endothelial cells and oxidative injury. In rat models,[26] the RDN has been shown to decrease monocyte activation and inflammatory cytokines (monocyte chemotactic protein-1 [MCP-1], interleukin [IL]-6, tumor necrosis factor-α [TNF-α], and nuclear factor-kappa B [NF-κB]). Additional of experimental studies had elucidated, the RDN suppression of inflammation, oxidative stress, and RAS helps alleviate or even reverse atherosclerosis.[27],[34],[35]

The mechanism mentioned above supports the hypothesis that RDN protects endothelial cells and improves endothelium function. Elevated Ang II concentration increases apoptosis of endothelial cells through dephosphorylation of protein kinase B (Akt),[36] which is expected to be inhibited by RDN since it dramatically lowers Ang II concentration. It has also been suggested that RDN limits the production of harmful factors for endothelial cells in terms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and MCP-1, attributed to restrained NF-κB production which upregulates the transcription of these harmful factors.[37] Apart from refining changes on endothelial cells induced by inflammation, dysfunction caused by the oxidative injury can also be improved. After the procedure, reduction in distensibility of aortic is observed prevented as associated with a reduction in aortic fibrosis formation.[35] Depleted nitric oxide (NO) level ascends back after TNFα restriction by RDN, recovering endothelial dilation [38] and endothelial-dependent relaxation.[35] The deletion of ROS deduces the chance of monocyte/macrophage infiltration, lipid oxidation, foam cell formation, and preventing lesion improvement.[38],[39],[40],[41] Moreover, the amount of vascular smooth muscle cells is thought to be reduced, since Ang II is no longer abundant enough in concentration to promote excessive vascular smooth muscle cell proliferation.[42] Less endothelium impairment leads to less-activated RAS and less NE release, breaking the cycle between inflammation, oxidative injury, and atherosclerosis advancement.

Moreover, it has been demonstrated in studies [26],[43],[44] that conventional drug aldosterone blockade has the ability to reduce atherosclerosis, coinciding with a reduction in oxidative stress markers and MCP-1 expression; AT1 blocker can inhibit MMP activation. Perhaps such effects will also be found in RDN as it can directly suppress RAS hyperactivity and limit the release angiotensin-1 and aldosterone.


  Cardioprotective Effects of Renal Denervation in Heart Failure and Arrhythmia Top


HF after myocardial infarction (MI), together with arrhythmia, often occurs one after another. Both systolic and diastolic dysfunction can be attributed to fibrosis in cardiac pathophysiological conditions,[45] including myocardial hypertrophy and cardiac dilation with multiple mechanisms. When cardiac dysfunction happens, further alteration in the heart can be anticipated structurally, electrically, and neutrally. Oxidative stress is considered as a pivotal contributor to long-term cardiac remodeling after MI.[5] Hypertrophy and fibrosis can be augmented by pro-inflammatory cytokines (TNF-α, IL-6) and Ang II.[46] RAS activated by SNS hyperactivity also directly affects all the way through as it has direct pro-inflammatory, prohypertrophic, and profibrotic effects in cardiac cells.[46],[47],[48]

The cardioprotective effect of RDN has been observed in both animal models and human trials with mutual improvement in heart failure rates and arrhythmia,[30],[49] as RDN can help improve cardiac function [2] by preventing or even reversing cardiac remodeling.[50] To value left ventricular (LV) function, improvement has been seen in LV end-systolic dimension, LV end-diastolic diameter, and LV ejection fraction of LV dimensions.[25],[49] The overall illustration is demonstrated in [Figure 2].
Figure 2: RDN in HF and arrhythmia. SNS hyperactivity initiates RAS, immune cells, and oxidative stress, interacting with each other. Temporal functional alterations lead to cardiac hypertrophy and fibrosis with structural, electrical, and neural remodeling. HF and arrhythmia show up. Communication from SNS to RAS, immune cells, and oxidase are all reduced by RDN, suppressing the reoccurrence of HF and arrhythmia. Color red represents the effect of RDN treatment. Inflammatory cytokines and chemokines above represent MMP-2/-9, VCAM, ICAM, MCP-1, TNFα, etc. SNS: Sympathetic nerve system, RAS: Renin–angiotensin system, VSMC: Vascular smooth muscle cells, HTN: Hypertension, MCP: Monocyte chemotactic protein, TNFα: Tumour necrosis factor-α, ICAM: Intercellular adhesion molecule, VCAM: Vascular cell adhesion molecule, MMP: Matrix metalloproteinases, HF: Heart failure

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  Renal Denervation Reduces Cardiac Structural Remodeling Top


According to a study in the exploration of left ventricular structure,[51] a reduction in left ventricular mass was observed after RDN. In dog models,[21] RDN decreased myocardial oxidative level through blocking superoxide generation, by cutting down NADPH oxidase subunit p47phox, which promotes interstitial fibrosis. Apart from its oxidative stress mechanism, well-known inflammatory cytokines, TNFα, and CRP can trigger fibrosis and lead to systolic and diastolic dysfunction in heart, abrogated by RDN. Additionally, recovered NOS function reduces VEGF and hindering the process to hypertrophy and fibrosis.[52] Hence, inflammation controlled, oxidative-stressed ceased, cardiac structural remodeling can be stabilized or even reversed.[2]


  Renal Denervation Reduces Cardiac Electrical Remodeling Top


RDN is effective on pleiotropic changes in the heart conduction system. Alteration in ion channel activities brings on changes in action potential duration (APD).[53] APD-alternans (APD-ALT) and calcium-alternans (Ca-ALT) are closely coupled as longer APD; larger Ca transient. Because of overactivated SNS, defected Ca dynamic induces spatial prolongation of APD and causes conduction block as well as ventricular arrhythmia initiation.[54] These varied Ca concentration and Ca-ALT progression can be prevented by RDN in HF conditions. In a rat atrial fibrillation (AF) model, Ca reuptake and its cytoplasmic clearance speed are recorded downregulated, while the previous high inducibility is blunted after denervation procedure,[55] bringing to prolongation of atrioventricular conduction and the increase in ventricles ERP.[56]


  Renal Denervation Mediates Neural Remodeling Top


In rats with ischemic HF, RDN preserves sympathetic nerve innervation in the ventricles, indicating further restoration of cardiac function, while in goats and dogs with AF induced by atrial tachypacing, RDN achieves a significant reduction in atrial sympathetic nerve sprouting in case of reoccurrence.[57],[58],[59],[60]

Recently, it has been hypothesized that the cardioprotective effect of RDN is comprised of CNS modulation to peripheral targets.[61] Previous studies [48],[62],[63] identified the participation of both ganglionated plexus (GP) and left stellate ganglion (LSG) in the initiation and prognosis of AF and renal sympathetic system mediates neural activities in superior left FP (SLGP) and LSG with profibrillatory effect. When stimulation was imposed on the proximal renal artery of dogs, directly recorded neural activity, as well as the gene and protein expression on c-fos and NGF in SLGP and LSG areas have been shown with significant upregulation.[64] The denervation, with potential, cuts down the connection between renal and central. Stimulation of left stellate ganglion and rapid atrial pacing in animals after RDN has no longer influence on increasing the inducibility of AF.[65]


  Renal Denervation Improves Glucose Metabolism and Insulin Sensitivity Top


It is commonly acknowledged that nearly 50% of patients with RH are combined insulin resistant. Same as in RH, SNS hyperactivity contributes to progression from impaired fasting glycemia to impaired glucose tolerance and to overt diabetes mellitus.[66] Sympathetic catecholamines activate a1 and b2 adrenergic receptors, motivating endocrine pancreas activity, and insulin secretion.[67],[68] Together with, the salt-retaining effect of insulin leads to downregulation of insulin receptors in the kidney and reduced insulin clearance.[69] Insulin concentration accumulates, whereas sensitivity to it is blunted. As there is a bidirectional relationship between sympathetic overactivity inducing insulin resistance and hyperinsulinemia producing sympathetic activation, initiating a vicious cycle, inflammatory factors (TNFα, IL-6) and ROS are also reported to have association with insulin resistance, glucose tolerance, and diabetes.[70],[71],[72],[73]

The SNS suppression, anti-inflammation, and antioxidation effects of RDN help regain insulin sensitivity and glucose metabolism, namely, through improving glucose uptake, decreasing gluconeogenesis, promoting glucose tolerance and reducing glycemia, restoring insulin sensitivity, or, in some cases, may reverse underlying diabetes mellitus.[66],[74],[75] In preliminary and animal studies, RDN has been found with profound effect on restoring glucose tolerance and insulin sensitivity. This has been proven in two PCOS patients underwent RDN,[76] coincides with the effect of moxonidine, an α2-receptor agonist that improves glucose metabolism with less glycogenolysis and gluconeogenesis by decreasing glucagon secretion and increasing skeletal blood flow.[75],[77],[78] In line with another study [24] where glucose oxidation also decreases significantly. RDN has also been found with effect to completely normalize hepatic insulin sensitivity in normotensive obese dogs, assessed by the HEC, conformed by Huang et al.,[79] who reported that insulin level of insulin infused rats dropped after RDN.

With RDN procedure [Figure 3], most afferent and efferent nerves are all denervated, resulting in less CNS and SNS activation. The decreased level of plasma NE dilates formerly constricted peripheral veins, mediating redistribution of blood flow from insulin-insensitive fat tissue back to insulin-sensitive striated muscle.[77],[80],[81] Meanwhile, the distance of insulin taken from plasma to cells is shortened after the relief of vasoconstriction.[74] Hence, glucose uptake in tissues, such as skeletal muscle, liver, and adipose tissue recovers. Besides, extrahepatic gluconeogenesis is suppressed by RDN through α-1 adriamycin,[76] natriuretic peptides,[82] and liver X receptor alpha pathway.[83] Sodium-glucose co-transporter 2 (SGLT2) reabsorbs approximately 90% of filtered renal glucose by coupling glucose transport to the electrochemical sodium gradient.[84],[85] RDN attenuates SGLT2 overexpression in the kidney, leading to a decline in proximal tubular glucose reabsorption. Therefore, accumulated glucose and insulin in plasma are excreted in urea. The insulin secretion of pancreas β-cells is well protected with no more mitochondria dysfunction caused by ROS.[72],[86] The inhibited AKT/eNOS/NO signaling pathway is relieved since TNF-α production is suppressed and NO in Akt/eNOS/NO signaling pathway is recovered in concentration, alleviating insulin resistance.[87] Eventually RDN breaks the vicious bidirectional relationship between sympathetic overactivity and Insulin resistance. Tissues in skeletal muscle, adipose and liver uptake normal doses of glucose, with blood glucose and plasma insulin restored, insulin resistance eliminated, and glucose metabolism recovered.
Figure 3: RDN in glucose metabolism. RAS, immune cells, and oxidative stress are overactivated by SNS. With interaction, glycogenesis, and renal reabsorption are upregulated, whereas insulin sensitivity and glucose uptake by insulin-sensitive tissue are declined. HTN, hyperglycemia, and insulin resistance establish. After RDN, abnormity of neural, immunological, and oxidative activity is suppressed and pathophysiological metabolism of glucose is ceased. Color red represents the effect of RDN. Inflammatory cytokines and chemokines above represent MMP-2/-9, VCAM, ICAM, MCP-1, TNFα, etc. RDN: Renal denervation, SNS: Sympathetic nerve system, RAS: Renin–angiotensin system, VSMC: Vascular smooth muscle cells, HTN: Hypertension, MCP: Monocyte chemotactic protein, TNFα: Tumour necrosis factor-α, ICAM: Intercellular adhesion molecule, VCAM: Vascular cell adhesion molecule, MMP: Matrix metalloproteinases

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HTN is a systematic disease and it is implicated as an independent risk factor of atherosclerosis, rising and worsening the incidence of HF and arrhythmia, and dampening glucose metabolism. As a multifactor disease, SNS hyperactivity with inflammatory reaction and oxidative stress contributes significantly to the development and maintenance of HTN, and also to the development of its comorbidities.

Besides, clinically speaking, RDN is always considered as a secondary alternative for RH. Conventional drugs for HTN normally aim at one target at a time and many HTN patients with or without RH are requested for a combination of drug therapy. RDN with multiple action sites is regarded as a supplementary treatment extending from RH to HTN. Through further exploration, it is now conceivable that comorbidities of HTN can benefit from RDN. Yet, because of the confound from drug adherence, and study design, researchers have not able to provide irrefutable proof that RDN is capable of lowering BP.[1],[84] Recently, there has even been a report that RDN promotes increase of atherosclerosis in size.[88] Nevertheless, this study failed to provide a clear explanation on the cause of death during the procedure, which is highly likely to be ascribed to plaque rupture which led to the negative outcome.

To sum up, beyond BP reduction, effects of RDN on ameliorating atherosclerosis, reversing HF, suppressing arrhythmia, and promoting glucose metabolism are well supported. These diseases above are not only associated with SNS overactivation, but they can also benefit from the collateral effects from RDN on anti-inflammation and antioxidation. Nerve–humoral–immunological modulation is the fundamental of homeostasis, any turbulence which goes beyond compensation will result in systemic diseases. SNS, RAS, inflammatory reaction, and oxidative stress trigger one another and accelerate one another. The introduction of RDN into treatment plans represents a breakthrough in neural modulation. However, the downstream cascades have yet to be fully investigated, and our knowledge of this phenomena remains limited. Of note, RDN's beneficial effects on reducing HF rates follows no additional alteration in BP.[55] As patients with cardiac dysfunction are often accompanied by relatively low BP, it is even more predictable to expect RDN utilization in clinical scenario apart from lowering BP. Since we find it as a promising measure that targets shared pathways and cytokines at once, RDN may be most effective on those with not only hypertension, but additional comorbid diseases, and may result in multiplicative increases in prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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