The pathogenesis of primary hypertension is multifactorial. However, the sympathetic nervous system plays an important role in circulatory and metabolic control and has clearly been established as a major contributor to the development of hypertension, with blood pressure elevation being initiated and sustained by elevated sympathetic nervous activity. Increased sympathetic outflow to the heart resulting in increased cardiac output and neurally mediated vasoconstriction of peripheral blood vessel are obvious examples of neural pathophysiological pathways leading to elevated blood pressure. The consequences of increased sympathetic outflow to the kidneys, perhaps most important in this context, are sodium and water retention, increased renin release and alterations of renal blood flow, effects that contribute substantially to blood pressure elevations both acutely and in the long term. Accordingly, targeting the sympathetic nervous system directly appears to be a logical therapeutic approach for the treatment of hypertension.
A Specific Role of Renal Nerves in Hypertension
The renal nerves are of particular importance in control of kidney function, volume homeostasis and blood pressure control. Using gold standard radiotracer methodology to investigate regional overflow of norepinephrine from the kidneys to plasma clearly demonstrated that renal norepinephrine spillover rates are markedly elevated in patients with essential hypertension1,2 and are associated with hypertensive target organ damage such as left ventricular hypertrophy.3 Interestingly, activation of cardiorenal sympathetic nerve activity is even more pronounced in heart failure,4 a common clinical consequence of long-term and sustained elevated blood pressure. Indeed, renal sympathetic activation has been shown to predict allcause mortality and heart transplantation in patients with congestive heart failure.5 Similarly, elevated norepinephrine plasma levels have been identified as major contributors to adverse cardiovascular outcomes in end-stage renal disease,6 another condition commonly characterised by substantially elevated sympathetic nerve activity.7
The kidneys have a dense afferent sensory and efferent sympathetic innervation and are thereby strategically positioned to be the origin as well as the target of sympathetic activation.8 Renal sensory afferent nerve activity directly influences sympathetic outflow to the kidneys and other highly innervated organs involved in cardiovascular control, such as the heart and peripheral blood vessels, by modulating posterior hypothalamic activity.9,10 Interestingly, abrogation of renal sensory afferent nerves has been demonstrated to reduce both blood pressure and organ-specific damage caused by chronic sympathetic overactivity in various experimental models.11,12
Post-ganglionic sympathetic efferent nerve fibres innervate all essential renal structures including the renal vasculature, the tubules and the juxtaglomerular apparatus.13 The consequences of renal sympathetic activation include volume retention and sodium reabsorption,14 renal blood flow reduction15,16 and renin-angiotensin- aldosterone system activation.17
Therapeutic efforts applying pharmacological principles to counteract the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, such as clonidine and moxonidine, and beta-blockers due to their inhibiting properties on renin release. Targeting downstream consequences of elevated efferent sympathetic outflow to the kidneys, i.e. initiation of the renin-angiotensin-aldosterone cascade, has also been proved to be very successful, with use of angiotensin-converting enzyme inhibitors and receptor blockers providing substantial improvements in achieving blood pressure control and cardiovascular outcomes. However, given the importance of renal sympathetic nerves in blood pressure control, efforts to functionally denervate the human kidney by directly and specifically targeting both efferent sympathetic and afferent sensory nerves appear to be a valuable treatment strategy for hypertension.
Therapeutic Benefits of Renal Denervation
Renal denervation has been widely applied in experimental models of various conditions characterised by heightened sympathetic drive to unravel the contribution of renal sympathetic efferent and sensory afferent nerves. Pre-clinical experiments utilising renal denervation as a therapeutic strategy have included multiple animal species (rodents, swine, canine, ovine) and consistently demonstrated the importance of renal sympathetic efferent and sensory afferent nerves and their contribution to the pathophysiology of hypertension, heart failure and chronic kidney disease. In a large number of diverse animal models of experimental hypertension including genetic, salt-sensitive and obesity hypertension, bilateral renal denervation prevented the development or attenuated the magnitude of hypertension.18
In view of the current pandemic of obesity, it may be of particular importance that experimental models of obesity-related hypertension using high-fat-fed dogs revealed that the blood pressure increase associated with the 50% increase in body mass was abolished in denervated dogs and that sodium retention was halved in denervated dogs compared with control animals. This study demonstrated chronic durability of benefit and identified no abnormalities of renal function following surgical denervation.19
The potential of therapeutic renal denervation to attenuate hypertension and the progression of renal disease has also been explored in experimental 5/6 nephrectomy rat models of chronic renal failure and hypertension.8 This model suggests that afferent impulses from the kidney to central integrative structures in the brain may be responsible for the rise in blood pressure in chronic renal failure commonly associated with hypertension, which could be diminished by renal denervation.
Although more difficult to assess in humans, there is very convincing evidence of increased sympathetic activity in various forms of hypertension including essential hypertension,2 obesity-related hypertension,20 renal hypertension,6 hypertension associated with obstructive sleep apnoea21 and pre-eclampsia.22 Unfortunately, the involvement of the sympathetic nervous system in the development of hypertension, progression of renal failure and cardiovascular prognosis in patients with renal disease has been somewhat neglected in the past despite evidence for beneficial effects of sympathetic inhibition on progression of renal failure23 and microalbuminuria, even in the absence of blood pressure changes.24 Furthermore, nephrectomy in patients with end-stage renal disease is associated with consistent reductions in blood pressure and total systemic vascular resistance,25 perhaps indicating the potential therapeutic utility of denervation of the native kidney for blood pressure lowering and target organ protection in these patients.
Novel Catheter-based Approaches to Renal Denervation
Against this background, a recent safety and proof-of-concept study for the first time applied a novel catheter-based technique to selectively denervate the kidneys in patients with treatment-resistant hypertension.26 In this approach renal sympathetic nerve ablation is achieved percutaneously via the lumen of the renal artery using a catheter connected to a radiofrequency (RF) generator. After introducing the treatment catheter (Symplicity┬«; Ardian, Inc., Palo Alto, CA, US) into each renal artery, discrete RF ablations lasting up to two minutes each are applied in order to achieve up to six ablations separated both longitudinally and rotationally within each renal artery (see Figure 1). Catheter tip temperature and impedance are constantly monitored during ablation, and RF energy delivery is regulated according to a pre-determined algorithm.
A total of 45 patients with a mean age of 58±9 years and an average blood pressure of 177/101±20/15mmHg despite concurrent use of a mean of 4.7±1.5 antihypertensive agents were treated. The median duration of the procedure to achieve bilateral denervation was 38 minutes. Vascular safety analysis consisting of renal angiography at 14-30 days after the procedure and magnetic resonance angiographies at six months post-procedure revealed no instances of renal artery aneurysm or stenosis or other long-term adverse events. Although participating patients were repeatedly exposed to contrast media during serial angiographies, renal function remained unchanged, indicative of a favourable vascular and renal safety profile. The ablation procedure was accompanied by diffuse visceral non-radiating abdominal pain that did not persist beyond the RF energy application and could be managed by intravenous narcotics and sedatives.
Radiotracer dilution methodologies were applied to assess overflow of norepinephrine from the kidneys into the circulation before and after the procedure to assess the effectiveness at reducing renal sympathetic nerve activity. These analyses revealed a substantial reduction in mean norepinephrine spillover of 47% (95% confidence interval [CI] 28-65%) at one month post-bilateral denervation.
Most importantly, the ablation procedure was associated with a significant and progressive reduction in both systolic and diastolic blood pressure at up to 12-month follow-up with mean (±95% CI) decreases in office blood pressures of -14/-10±4/3, -21/-10±7/4, -22/-11±10/5, -24/-11±9/5 and -27/-17±16/11mmHg at one, three, six, nine and 12 months, respectively. Longer-term follow-up data beyond two years indicate that the blood pressure reduction is sustained over this period of time, suggesting the absence of nerve fibre recovery, nerve fibre re-growth or development of counter-regulatory blood-pressure-elevating mechanisms. Alternatively, if these mechanisms occurred, they did not appear to affect the blood pressure reductions achieved.
Additional observations from these studies may shed some light on the potential mechanisms involved in the blood pressure reduction achieved by this approach. As discussed above, experimental data clearly indicate a role for afferent sensory nerves. Although afferent signalling cannot be measured directly in humans, the recent demonstration of a substantial and progressive reduction in central sympathetic outflow from baseline through to 12-month follow-up is perhaps indicative of alterations in afferent fibre signalling that may play an important role in the blood pressure effects associated with this procedure.27 Furthermore, it is also noteworthy that renal denervation decreased renin secretion by around 50%27 and that cardiac baroreflex sensitivity was also improved after renal denervation (from 7.8 to 11.7msec/mmHg). In addition, cardiovascular imaging using magnetic resonance imaging revealed a substantial reduction of left ventricular mass from 184 to 169g (78.8 to 73.1g/m2) at 12-month follow-up compared with baseline.27
Devices Interfering with Baroreflex Sensitivity
As discussed above, renal denervation improves baroreflex sensitivity, which to some extent may account for the favourable effects on blood pressure. Indeed, baroreflex mechanisms are also crucial contributors to blood pressure control via stretch-sensitive baroreceptors in the carotid artery and the aortic wall that are activated by increases in blood pressure and induce counter-regulatory adjustments in sympathetic and parasympathetic activity to stabilise blood pressure. Hence, diminished baroreflex sensitivity in the scenario of hypertension is another obvious target for therapeutic intervention. Indeed, electric stimulation of baroreflex afferent nerves was the subject of various previous attempts to lower blood pressure in hypertensive patients via stimulation-induced central sympathoinhibition.28
Recently, a novel implantable device has been developed that appears to have overcome the technical problems of earlier approaches. The Rheos System (CVRx, Minneapolis, MN, US) is a chronically implanted carotid sinus baroreflex-activating system with a pulse generator and bilateral perivascular carotid sinus leads. Implantation is performed bilaterally with patients under narcotic anaesthesia (to preserve the reflex for assessment of optimal lead placement). Dose-response testing is assessed before discharge and at monthly intervals thereafter; the device is activated after a one-month recovery period. The device produces an electric field stimulation of the carotid sinus wall, which in dogs has been demonstrated to produce a sustained reduction in sympathetic nervous system activity and blood pressure.28
This system has recently been tested in pre-clinical and clinical studies including patients with severe hypertension refractory to drug therapy.29 In this small series of 10 patients with resistant hypertension on a median of six antihypertensive medications, implantation of the device was successful without significant morbidity. Pre-discharge dose-response testing revealed consistent reductions in systolic blood pressure of ~41mmHg.29 Two- and three-year data from these studies indicate substantial and sustained (>30mmHg) reductions in patients with resistant hypertension.30 Larger-scale randomised, controlled trials are ongoing to verify potential chronic benefits.
A recent report addressing potential long-term safety concerns of device implantation in sheep (three to six months post-implantation) and in patients (one to four months post-implantation using duplex ultrasound of the carotid artery) did not reveal evidence of carotid injury or stenosis.31
From a mechanistic point of view, a recent study in 12 patients with an implanted Rheos system indicates that the depressor response to electric field stimulation of carotid sinus baroreflex afferents seems to be mediated mainly through sympathetic inhibition, without negative effects on physiological baroreflex regulation.32 Ultimately, the benefits of blood pressure reduction and neurohormonal inhibition will have to be weighed against the cost and fairly invasive nature of the procedure.
Conclusion and Future Perspectives
Hypertension remains a challenging and growing clinical problem. A concerted effort is needed to address this issue, and currently established therapeutic strategies need to be utilised more stringently and aggressively with a particular focus on lifestyle interventions and appropriate pharmacological combination treatment. Nevertheless, there is clearly a need for additional therapeutic strategies, some of which have shown promise in the setting of resistant hypertension, as outlined above. These approaches may require further substantiation in larger and appropriately designed clinical trials, but very clearly establish a crucial role of sympathetic activation in various forms of hypertension. Currently available device-based approaches targeting the sympathetic nervous system may offer novel non-pharmacological approaches, which for now may have particular relevance in uncontrolled patients already on multiple antihypertensive drugs and those intolerant of pharmacological treatment. Given the favourable safety profile and obvious efficacy of the procedure, its application in patients with less severe forms of hypertension with the potential to perhaps cure their hypertension does not appear to be unreasonable.