The sympathetic nervous system in hypertension: back to the future?

Esler M.
Curr Hypertens Rep. 2015 Mar;17(3):519. doi: 10.1007/s11906-014-0519-8

Introduction

Nineteenth century physiologists already understood that the nervous system was involved in high blood pressure (BP). Surgical sympathectomy was performed to cut as many ‘pressor nerves’ as possible to remove their systemic vasoconstrictor effects. This procedure prolonged the life of patients with severe hypertension, but a the price of disabling side effects.
The period of surgical sympathectomy was ended with the introduction of ganglionic-blocking drugs; the first antiadrenergic antihypertensive pharmacotherapy. Ganglion blockers had disabling complications similar to sympathectomy, but soon other neuron-blocking drugs were developed.

Fall from grace of antiadrenergic antihypertensives (and the sympathetic nervous system)

Nowadays, drugs antagonising the renin-angiotensin system are the dominant antihypertensive treatment, and they have replaced antiadrenergic drugs as the first choice treatment because they are at least as effective and better tolerated. In addition, dihydropyridine calcium channel-blocking drugs, the anti-renin drugs, calcium channel blockers and diuretics are recommended by guidelines, while interest in the sympathetic nervous system as a treatment target in essential hypertension has diminished.

A parallel, but largely inconsequential, research stream demonstrating the neural pathophysiology of essential hypertension

Several lines of research have studied the human sympathetic nervous system in relation to hypertension. This has revealed an activated outflow to skeletal muscle vasculature, heart and kidneys in 40-65% of hypertension patients. Increased renal sympathetic outflow is particularly pronounced in drug-resistant hypertension. Also, single-fibre recordings have demonstrated increased sympathetic firing frequencies, and multiple firings within a cardiac cycle in hypertensive subjects. Although the regulatory effects of renal sympathetic nerves on renal tubular reabsorption of sodium, renin release and glomerular filtration rate are now considered to be involved in the development of hypertension, the results of this research stream have had little to no influence on antihypertensive drug-prescribing patterns.

A sympathetic nervous system renaissance, driven by antiadrenergic devices

Despite widespread use of ACE inhibitors and angiotensin receptor blockers, in combination with diuretics and calcium channel blockers, BP targets are not met in a substantial minority of patients. It is possible that contemporary ‘optimal’ treatment does not target the primary pathophysiology of essential hypertension. A new strategy came in the form of device-based therapies targeting the sympathetic nervous system, such as the surgically implanted barostimulator device and catheter-based renal denervation (RDN).

Arterial baroreceptor stimulation

In experimental models, activation of central baroreflex pathways by continuous electrical stimulation of the nerves of the carotid sinus baroreceptors was shown to reduce sympathetic outflow from the central nervous system and to lower BP long term. Implantable carotid sinus stimulation devices have also been tested in humans. BP lowering was seen, but in a randomised trial in which patients with drug-resistant hypertension either received immediate or 6-months delayed stimulation, the primary efficacy endpoint was not met, in part because BP also decreased in many control subjects. The future of this device therefore remains uncertain.

Historical origins of catheter-based renal denervation

A  high level of activation of renal sympathetic outflow (renal noradrenaline spillover) has been demonstrated in untreated essential hypertension patients. Renal tubules are highly innervated by sympathetic nerves, and promote renal tubular reabsorption of sodium, stimulate secretion of renin from the juxtaglomerular apparatus and to cause renal vasoconstriction, thereby reducing renal blood flow, which may all contribute to elevating BP. Surgical sympathectomy in experimental models abolishes hypertension or prevents its development.
In addition to these observations, insight into the anatomy of the postganglionic renal sympathetic nerves in their passage to the kidneys paved the way for the development of catheter-based RDN. Since in humans the nerves pass via the outer adventitia of the renal arteries, or just beyond in perirenal adipose tissue and connective tissue, they may be within reach of radiofrequency energy delivered by a catheter in the artery lumen.

The renal denervation clinical trials

Trials evaluating RDN devices have taught important therapeutic principles, namely that efferent sympathic RDN can be achieved with luminal delivery of radiofrequency and ultrasonic energy. Also, mean BP reduction across the trials shows consistency, with office systolic BP durably falling on average by 20-30 mmHg, while renal function is preserved. Furthermore, new renal artery stenosis in the field of radiofrequency energy delivery are very uncommon.
However, some patients fail to experience a drop in arterial pressure (reported to occur in 15-50% of patients in different studies). It has been suggested that in these patients, sympathetic nervous system activation may not be the primary pathophysiology. Alternatively, it may be that in these patients the denervation procedure was technically.

Need for a reality check in RDN trials: testing for achieved denervation

Good experimental design necessitates that the effectiveness of denervation is confirmed in studies of surgical RDN in experimental hypertension, typically by documenting 90-95% reduction in the kidney content of norepinephrine. RDN was confirmed in Symplicity HTN-1 by means of measuring norepinephrine spillover as a validated test for denervation. The degree of RDN achieved in this trial was less than expected (on average 47%), but was accompanied by an adequate antihypertensive response. It should be noted, however, that denervation is often incomplete and surprisingly non-uniform between patients. It may be less than 25%, which is no doubt inadequate for a full therapeutic effect.
Achieving denervation with the catheter technique is complex and difficult. Thus, conclusions on the efficacy of RDN after negative trials lose all force without the reality check of testing for RDN.

Retreat from a bold new sympathetic nervous system future: Simplicity HTN-3

The pivotal study for US FDA licensure of percutaneous RDN treatment of resistant hypertension was Symplicity HTN-3. Expectations of this larger trial with a blinded sham design were high, but the primary endpoint was not met.

Illusory ‘truths’ from Symplicity HTN-3

* Lauding of the sham procedure but neglect of trial neuroscience failings

In the design of Symplicity HTN-3, the proscribed process (the sham procedure) outranked and overrode the specific and essential knowledge base (neuroscientific knowledge of renal nerves and their denervation). But there were some issues with the study. In addition to the too high number of institutions (88) and proceduralists (110) involved, no hands-on experience with RDN prior to the trial was possible in the USA, unlike in the earlier Symplicity trials. While the proceduralists were experts in their field of interventional cardiology, they were new to the RDN procedure. Indeed, it is now known that in 74% of patients, not even one fully circumferential renal artery application of energy was achieved, although the mandatory protocol required this to be achieved bilaterally.

The path forward for renal denervation

The author considers that the Symplicity HTN-3 inflicted a ‘flesh wound’ on the RDN field, which is not fatal, because it is acknowledged that the trial has failed in its neuroscience execution.
The failure to denervate is the ever-present confounder in studies in which denervation was not tested. Thus, methods need to be improved to achieve optimal and uniform RDN; higher radiofrequency and ultrasonic energy doses are envisaged.
Patients may be preselected once the two determinants of responder status, namely effectiveness of denervation and hypertension pathophysiology can be discriminated. It may already be postulated that patients with renal hypertension may benefit most.
It can be questioned whether a blinded sham element should be incorporated in all subsequent RDN trials. It may be defended that in proof-of-principle trials or in studies of biological mechanisms it is not required, whereas a consensus view is emerging for its necessity in trials aiming for governmental regulatory approval.

Conclusion

Renal sympathetic nerves provide a universal common pathway of hypertension pathogenesis, thus renal nerve ablation interferes at the intersecting influence of the sympathetic nervous system, the kidneys and dietary salt in hypertension pathogenesis. Each of these three factors is too often thought of as a unitary progenitor of hypertension, while they act in concert.
In the presence of high dietary sodium intake, activation of the renal sympathetic outflow by factors such as obesity, sedentary life and chronic mental stress, yields inter-connected neural, renal and sodium mechanisms of hypertension development. Endovascular RDN can disrupt the link between salt and the nervous system.  

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