Sympathetic nervous system overactivity is constantly associated with left ventricular hypertrophy, tachycardia, electrical instability, kidney dysfunction, vasoconstriction, arterial stiffening, hypertension, and hypercoagulability 1. Metabolic disorders, such as obesity, hyperinsulinemia, metabolic syndrome, hyperlipidemia, and type 2 diabetes mellitus, have also been associated with increased sympathetic activity and high blood pressure (BP) 2. Furthermore, enhanced sympathetic drive has been proposed to be an important mechanism that promotes the development of cardiovascular events in the general population 3.
Indirect markers, such as plasma norepinephrine levels and heart rate, only marginally indicate the degree of sympathetic activation, whereas more sophisticated techniques, such as muscle nerve sympathetic activity and noradrenaline spillover, can refine the research on the interplay between generalized sympathetic nervous system activation and cardiometabolic disease 1,4. To what extent these latter measures reflect the centrally originated sympathetic outflow is still unknown because peripheral factors (i.e. insulin, leptin, adrenergic receptors’ downregulation, angiotensin II, systemic inflammatory milieu) may also modulate, at least partly, the turnover of postganglionic neurotransmitters and overall efferent sympathetic drive 5. However, beyond the potential participation of peripheral factors in the modulation of the centrally mediated efferent sympathetic activation, the centrally mediated neural participation is considered the main determinant of cardiovascular and metabolic homeostasis.
Besides lifestyle changes (e.g. weight loss and aerobic exercise training), therapeutic strategies to reduce excessive central sympathetic activity in hypertension include centrally acting drugs (i.e. imidazoline agonists, α-2 agonists) and drugs modulating the peripheral sympathetic tone. In the latter category, we recognize the traditional β1 blockers and β1 blockers with additional beneficial properties on the vasculature such as the increase in nitric oxide production (i.e. nebivolol) and the reduction of oxidative stress (i.e. carvedilol). Furthermore, α-1 antagonists and β2-agonists represent additional therapeutic options of peripheral adrenergic blockade. In recent years, device-based strategies have been introduced for the management of hypertension and include both the neuromodulation of carotid baroreceptors and the denervation of renal arteries (Fig. 1) 6.
A minimally invasive interventional technique, namely renal sympathetic denervation (RSD), has been adopted recently to treat severe drug-resistant hypertension through the administration of radiofrequency energy at the level of the renal arterial wall 7. This approach for the treatment of high BP in severe resistant hypertension aims to negatively modulate the afferent sympathetic drive from the kidneys to the central nervous system and indirectly downregulate the central efferent sympathetic drive versus various cardiovascular domains and the kidneys (Fig. 1). Moreover, it has also been postulated that the reduced efferent sympathetic drive following RSD might have beneficial effects on metabolic disorders, sleep apnea, and endocrine abnormalities such as polycystic ovary syndrome 8.
In this review, we focus on a brief description of the RSD technique, on the pathophysiological background for the treatment of metabolic disease with RSD, and we also present the available clinical evidence in the field. We also propose future investigative questions to strengthen the evidence so far.
The RSD technique in hypertension: why and how?
There is an established evidence of increased kidney sympathetic activation in essential hypertension because of the increased spillover of noradrenaline at the kidney level and of the observation that administration of phentolamine – an α-adrenoreceptor antagonist – within the renal artery of hypertensive and normotensive individuals is associated with increased renal flow in hypertensive but not in normotensive individuals 9,10. In addition, in animal hypertension models, pharmacological and surgical renal denervation was found to be associated with a reduction in either BP or hypertension 11. These experimental and clinical observations led to the hypothesis that renal sympathetic innervation might be the limiting step in the relationship between hypertension and the sympathetic nervous system.
Renal denervation is a catheter-based ablation procedure in which lesions are created along the walls of the renal arteries to disrupt the sympathetic nerve network located within the arterial adventitia. Thus, through the catheter-delivered lesions, it is expected that the energy administered interrupts both afferent and efferent renal innervation. At present, it is a clinical priority to select patients properly that are eligible for the procedure 12. Briefly, before an RSD intervention, patients with severe drug-resistant hypertension (i.e. office BP>160/100 mmHg despite treatment with three antihypertensive agents at the maximum tolerated doses including a diuretic) should undergo a computed tomography scan with an iodine contrast agent. Computed tomography scanning qualifies as the most appropriate imaging technique to understand the relevant renal artery anatomy compared with MRI and duplex ultrasonography (Table 1). Patients with renal artery irregularities (e.g. renal artery stenosis >50%, renal aneurysmatic lesions), multiple renal arteries of clinically meaningful caliber (i.e. diameter >20 mm), main renal arteries of inadequate length (i.e. <20 mm) or diameter (i.e. <4 mm), as well as patients with a history of renal artery intervention (e.g. balloon angioplasty or stenting) are excluded (Fig. 2). Additional criteria for preliminary exclusion are as follows: estimated glomerular filtration rate less than 45 ml/min/1.73 m2, type 1 diabetes mellitus, pregnancy and a history of recent (<6 months) myocardial infarction, unstable angina, or cerebrovascular accident. More details of the procedure are presented in Table 2 12.
Renal efferent sympathetic innervation contributes toward an increase in BP through 3 different mechanisms: first, activation of β1 receptors in the iuxtaglomerular apparatus and a subsequent increase in renin production; second, reduction of sodium tubular reabsorption through α-1B receptors; and finally at the vascular level, reduction of renal flow through activation of α-1A receptors 13. Additionally, in hypertensive patients, renal afferent sympathetic innervation is highly activated due to mechanoreceptor and chemoreceptor stimuli (renin–angiotensin system activation, reduction of renal blood flow, enhancement of sodium retention and electrolyte imbalance, renal ischemia, oliguria, and high adenosine levels) all generated at the renal hilum. When RSD is performed successfully, adverse stimuli from the kidney are not neurally projected to the brain, and consequently, central sympathetic drive through the efferent pathway becomes relatively deactivated. The functionally reduced efferent sympathetic firing is associated with decreased vasoconstriction, ameliorated cardiac performance, and beneficial renal effects (i.e. reduced renin release, natriuresis, and increased renal blood flow) 14. There is also evidence that sympathetic activity markers, such as MSNA and noradrenaline spillover, are decreased after the RSD procedure 15.
From a clinical point of view, in the Simplicity HTN-2 study 16, RSD was accompanied by a reduction in systolic and diastolic BP of 32 and 12 mmHg, respectively, whereas in the control group, no significant BP changes were observed during a 6-month follow-up period. Uncontrolled studies (Simplicity HTN-1 study, EnligHTN-1 study) showed similar decreases in office systolic and diastolic BP, which remained stable 2 years after the procedure 17,18. The reductions in 24 h BP were also significant but limited to only 10/5 mmHg reduction compared with preintervention levels. In addition, RSD should be considered a safe method because no serious vascular events related to the procedure or to denervation per se were reported, and also because renal function was not aggravated 19. However, we should also underline that 20% of patients did not experience reduction in BP levels following the RSD procedure (i.e. nonresponders). The causes of this lack of response are as yet unknown.
Furthermore, no definitive signs and symptoms of successful ablation have been identified so far both during and after the procedure. The recurrent abdominal pain during each individual ablation during the entire RSD procedure might be a vague symptom of successful ablation; however, we recognize that individual responses to painful stimuli and different dosing of analgesics weaken the clinical merit of this phenomenon 20. The increase in renal blood flow as assessed by flow wire measurements before and after the procedure was also proposed as a method of successful renal denervation 21. However, changes in renal blood flow only indirectly suggest withdrawal of renal sympathetic innervation following RSD. Additional unresolved issues related to RSD are as follows: does ablation of adequately sized accessory renal arteries contribute toward further reduction in BP; does atherosclerosis reduce the ability to denervate the artery; does RSD worsen eventual pre-existing atherosclerotic process in the same artery; does RSD improve clinical outcomes in terms of cardiovascular morbidity and mortality; does RSD work for other hypertensive subgroups such as those with earlier stages of hypertension, drug-intolerant patients, patients with metabolic diseases and chronic kidney disease; and finally, which is the optimal antiplatelet therapy regimen before and after RSD?
In the setting of hypertension, several large randomized trials comparing RSD with conventional antihypertensive treatment are underway or in the planning phase and may provide answers to some of the above questions. Some examples are EnligHTN-II (NCT 01705080), ReSET2 (NCT 01762488), Simplicity HTN-3 (NCT 01418261), ACHIEVE (NCT 01789918).
The RSD technique in metabolic disease: background
The burden of metabolic abnormalities in hypertension is increased compared with normotensive states and sympathetic overactivity represents a common denominator between metabolic and cardiovascular disease. In addition, insulin resistance, obesity, and hypertension may have activated the same pathophysiological pathways, which lead to the perpetuation of each individual clinical entity alone and an increase in the prevalence of metabolic syndrome. By contrast, each of the components of metabolic syndrome contributes toward the development of increased efferent sympathetic drive 2,22.
Insulin, through its excitatory action on sympathetic firing, promotes sodium and water retention, proliferation of smooth muscles at the arteries, whereas in hypertensive or obese patients, it exerts vasoconstrictive effects 23. Insulin resistance in striated muscle is associated with a complex mosaic of phenomena consisting of structural vascular changes associated with increased vasomotor tone, β-adrenergic stimulation, and alteration in muscular fibers (i.e. conversion in fast-twitch fibers) 24. The release of noradrenaline in the periphery is associated with reduction of the forearm blood flow and its redistribution from insulin-sensitive striated muscle toward the relatively insulin-insensitive fat tissue. Other mechanisms favoring insulin resistance associated with increased sympathetic drive comprises the vasoconstriction at least partly mediated by hypertension, closure of functional capillaries in the proximity of muscular cells, and finally of vascular rarefaction with inappropriate delivery of insulin to the skeletal muscle parenchyma 25.
Sympathetic activation plays a pivotal role in obesity-related hypertension 26,27. Among patients with resistant hypertension, the majority tend to be overweight and obese 28. In obesity, there is impaired glucose metabolism consisting of insulin resistance and hyperinsulinemia, both conditions that are associated with increased sympathetic activity 29. Increased body adiposity and increased insulin levels have been related directly to enhanced MSNA activity 30,31. In addition, the prevalence of high BP (>165/95 mmHg) is associated with more impaired postprandial insulinemia and higher levels of urinary norepinephrine excretion 30.
Central sympatholysis with moxonidine is associated with improvement in glucose metabolism by reduction of glucagon secretion and promotion of increased blood flow at the periphery, which is also accompanied by less pronounced glycogenolysis and gluconeogenesis 32. Although traditional β-blockers are constantly associated with deterioration of glycemic homeostasis, in the GEMINI trial, the randomization to either metoprolol or carvedilol in addition to renin–angiotensin blockers in hypertensive patients with diabetes mellitus indicated that patients receiving carvedilol were characterized by stabilization of glycemic control and improvement in insulin resistance 33.
The above considerations represent the pathophysiological background for the promising introduction of RSD as a potential intervention for amelioration of glucose metabolism in impaired metabolism. It is hypothesized that RSD might interrupt the progression of early glucose metabolic disorders (i.e. increased fasting glucose, insulin resistance, hyperinsulinemia) to overt disease or even control glycemic levels in patients with diabetes mellitus 34. Indeed, RSD is associated with reduced release of norepinephrine at the periphery, decreased activity of α-adrenergic tone, and downregulation of the renin–angiotensin system that could together ameliorate vascular blood flow in striated muscles 35. In turn, increased peripheral blood flow promotes the enhancement of glucose uptake and facilitates insulin delivery to the muscular tissue by a higher number of open capillaries in nearest proximity to muscular cells 24,25.
Also, RSD can contribute toward weight loss by different mechanisms. The first one is closely related to BP reduction as hypertensive patients are prone to weight gain through sympathetic overactivity associated with reduced responsiveness of β-receptors 36. This combined phenomenon is translated into a reduction in energy expenditure and consequent weight gain 37. In addition, the disruption of sympathetic system-related mechanisms promoting insulin resistance and central obesity through RSD may regress progressively. However, we should also recognize that withdrawal of sympathetic activity from adipose tissue is associated with decreased lipolysis and fat accumulation 38,39. Along these lines, although weight loss is associated with a reduction in sympathetic activity, whether RSD is also associated with weight loss is not yet clear.
RSD in sleep apnea: background
Obstructive sleep apnea (OSA) is diagnosed in 40% of hypertensive patients 40, whereas its symptomatic qualification, namely OSA syndrome, occurs in 15–20% of patients in the same setting 41. Patients with OSA are characterized by nocturnal hypertension, difficult-to-treat hypertension, and drug-resistant hypertension and, more importantly, the prevalence of obesity and impaired glucose metabolism including diabetes mellitus is very high (i.e. 70–80% and 30–40%, respectively) in these patients 42. In addition, OSA should not be considered a secondary cause of hypertension, but a frequent by-product of essential hypertension, and this clarification represents an important clinical repercussion 43.
Continuous positive airway pressure (CPAP) application in patients with OSA normalizes sleep disordered breathing dynamics. However, in OSA patients with hypertension, BP response following CPAP is not as effective as may be expected 44. We should acknowledge that OSA patients with severe hypertension or resistant hypertension achieve greater BP reductions compared with their counterparts with milder forms of hypertension 41. Along these lines, RSD might be seen as a promising therapeutic option to treat hypertension and potentially a metabolic impairment associated with OSA. RSD as an interventional treatment should be applied only to OSA patients already receiving effective CPAP treatment and potentially whenever measures to reduce increased body adiposity burden have failed. Indeed, RSD should not be considered an etiologic therapy to treat OSA because its effects are only limited to dampening the heightened sympathetic activity associated with OSA.
RSD in metabolic disease and OSA: the current evidence
So far, clinical data on the impact of RSD on metabolic parameters are quite limited. A pilot study by Mahfoud et al. 34 studied 37 patients with treatment-resistant hypertension who underwent bilateral catheter-based RSD and 13 patients with resistant hypertension assigned to a control group. Three months later, the mean BP was significantly reduced in the treatment arm, but in addition, both fasting glucose and insulin levels were also decreased. At 3 months, the 2-h glucose levels during the oral glucose tolerance test and homeostasis model assessment–insulin resistance (measure of insulin sensitivity) were significantly reduced by 27 mg/dl and 62%, respectively, compared with the baseline levels. No significant changes in BP and metabolic measures were detected in the control group. Although the study underscores that RSD may be a beneficial intervention for the combination of resistant hypertension and impaired glucose metabolism, the study represents a selective subanalysis of the Simplicity I and II trials. Furthermore, drug therapy attenuation after the procedure in the treatment group may have affected the results because of withdrawal interference on insulin sensitivity. Finally, no changes in body adiposity were observed, suggesting that this change might be evident at timeframes longer than 3 months or RSD might not be as effective in reducing body weight.
The study by Witkowski et al. 45 was an open-label interventional nonrandomized study that included 10 middle-aged obese patients with severe office drug-resistant hypertension and central or OSA mostly without daytime symptoms. The aim of the study was to determine the changes in metabolic measures and sleep apnea severity parameters before and 6 months after RSD. Although after RSD no significant changes in fasting plasma glucose concentrations were observed at 3-month and 6-month periods, oral glucose tolerance test and glucosized hemoglobin levels were improved compared with preintervention measurements at the same time intervals. Interestingly, no changes in body size and severity of sleep apnea were observed in the entire cohort during the follow-up period. However, RSD improved the severity of OSA in seven of eight participants and in one of two patients with central and obstructive components of sleep apnea, respectively. For the latter observation, the most plausible hypothesis is the changes in sodium-volume status mediated by renal nerves. Indeed, during the sleeping period, a reduction in extracellular fluid volumes and a reduction in rostral fluid shifts occur with recumbent sleep that might resemble the action of aldosterone antagonists on sleep apnea severity. Although the study by Witkowski et al. 45 provides evidence that RSD is associated with improvement in the indices of insulin action and glucose metabolism in a heterogeneous cohort of patients with drug-resistant hypertension, the missing implementation of CPAP therapy and lifestyle measures question the clinical message of the study 46. Well-designed RSD studies possibly complemented by a control arm in OSA patients following effective CPAP and ongoing lifestyle changes should be carried out to confirm or dispute any possible beneficial impact of RSD on metabolic and sleep apnea severity parameters.
Future research pathways
Several randomized and nonrandomized prospective studies are currently being planned to investigate the effect of RSD on insulin sensitivity and insulin resistance indices in patients with hypertension. Some examples are as follows: Denervation of the Renal Artery in Metabolic Syndrome (DREAMS) study (NCT 01465724), Renal Sympathetic Modification in Patients with Metabolic Syndrome study (NCT01417247), Effects of Renal Denervation on Insulin Sensitivity study (NCT 01631370), Renal Sympathetic Denervation and Potential Effects on Glucose Metabolism and Cardiovascular Risk Factors (Re-Shape) study (NCT 01630928), Renal Sympathetic Denervation and Insulin Sensitivity (RENSYMPIS Study) (NCT01785732), and Renal Denervation in Diabetic Nephropathy (DERENEDIAB) (NCT01588795). Similarly, metabolic measures have also been ncluded in the design of studies recruiting patients with resistant hypertension and sleep apnea: Renal Denervation in Patients with Resistant Hypertension and Obstructive Sleep Apnea (NCT01366625), Effect of Catheter-based Radiofrequency Ablation Therapy in Patient with Therapy-resistant Hypertension and Sleep Apnea Syndrome (NCT01879566). It should be noted that, the above-mentioned studies will extend the current evidence in a longer follow-up period after RSD exposure and will also include hypertensive patients without the resistant phenotype.
Important questions to be answered in the context of patients with metabolic disease undergoing RSD are as follows: what is the impact of RSD on lipid metabolism; can RSD promote hypoglycemic phenomena in diabetic patients in addition to the conventional hypoglycemic treatment; can RSD reduce the progression of diabetic nephropathy; what is the impact of RSD on intramuscular triglyceride pool and its interplay with the remaining intramuscular lipid pattern; and finally what is the long-term impact of RSD on hard cardiovascular endpoints? In optimally treated sleep apnea patients, the main question is whether there is a synergistic or even an additive effect of RSD with CPAP in addition to conventional pharmacotherapy and implementation of lifestyle changes?
Where we stand now?
Lifestyle changes represent the cornerstone preventive measure to reduce the increasing burden of cardiovascular disease. Drug treatment for the management of cardiometabolic traditional risk factors has steadily and undoubtedly proven to be effective in reducing the magnitude of cardiovascular risk. RSD was proposed as a ‘last-resort’ treatment for the management of severe drug-resistant hypertension to decrease the risk of both BP and cardiovascular disease. The technique is effective for office and possibly for ambulatory BP reduction, and it is also characterized by enough evidence in terms of safety. However, knowledge of the long-term effects of RSD on hard cardiovascular endpoints is currently lacking.
Attenuation of the central sympathetic drive with RSD might also have beneficial effects on metabolic parameters beyond the reduction of BP. The limited evidence so far indicates that glucose metabolism measures are ameliorated in resistant hypertension patients; however, definitive conclusions on this latter phenomenon are at best premature because of the following: first, studies that have already been published are quite small and in many cases these studies have been carried out with an uncontrolled design; second, important technical issues have not yet been standardized; third, the impact of RSD on metabolic measures remains biologically plausible, but still clinically speculative; and fourth, although treatment innovations in medicine are always useful, whether these innovations will be translated into long-term clinical benefits remains to be confirmed. On the basis of the above, at present, RSD should be considered a therapeutic option for the reduction of high BP in patients with severe drug-resistant hypertension. Whether this option can ameliorate metabolic derangement in these individuals with or without sleep apnea remains to be determined in the near future.
Conflicts of interest
Costas Tsioufis received travel expenses from SJM and Medtronic and research grants from SJM. The remaining authors have no conflicts of interest.
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