Targeting sympathetic activation in the treatment of hypertension

There is ample evidence that sympathetic activation contributes to several cardiovascular and metabolic derangements associated with hypertension 1, including endothelial dysfunction 2 and insulin resistance 3. It follows that targeting sympathetic activation would be beneficial in the treatment of hypertension. Indeed, studies in the 1950s showed that thoracolumbar splanchnicectomy significantly improved survival rates in patients with severe hypertension compared to those treated medically 4. This in part reflected the lack of effective antihypertensives at the time. The main limitations in translating these early successes to current medical management are the many side effects that plague sympatholytic agents, and the availability of other classes of effective antihypertensive drugs. Current guidelines relegate sympatholytic agents to second-line therapies or to specific clinical conditions such as resistant hypertension and pregnancy 5. Nonetheless, recent studies have documented that usual antihypertensive therapy fails to normalize sympathetic activation in patients with hypertension, despite optimal blood pressure (BP) control 6, and some studies have shown increases in sympathetic activity induced by antihypertensive treatment 7. It has been argued that this residual sympathetic activation could contribute to the persistence of increased cardiovascular risk in treated hypertensive patients 8. Thus, there is an unmet need for novel therapies that target sympathetic activation. It came as no surprise, therefore, that early reports of the use of renal denervation to treat hypertension were greeted with great enthusiasm. Multiple studies and meta-analysis have confirmed the efficacy of renal denervation both as single treatment or as add-on therapy 5,9. In sham-controlled randomized trials, renal denervation decreased SBP by about 5–10 mmHg, a relatively modest effect but of a magnitude comparable to that produced by an antihypertensive drug, and known to improve cardiovascular outcomes. Significant interindividual variability of response has been observed in these studies and there has been great interest in discovering predictors of response that may assist in improving patient selection. In the current issue of the Journal, Nolde et al.10 performed a retrospective posthoc analysis in a large number of patients (2712) treated with renal denervation, and found that those that were receiving central sympatholytics as part of their antihypertensive regimen had a marginally but significantly lower decrease in BP in response to renal denervation. They interpreted this finding as indicative that renal denervation shares a similar mechanism to reduce BP as central sympatholytics, namely a reduction in sympathetic activity, and that renal denervation would be more effective in patients not previously receiving central sympatholytics by providing a complementary sympathetic target for BP control. Differences between groups were statistically significant (reflecting the large sample size) but of questionable clinically significance (about 1 mmHg in SBP). Also, patients on central sympatholytics were receiving on average 5.3 medications to manage hypertension compared to 4.1 medications in the control group, and even patients receiving central sympatholytics at baseline benefited from renal denervation with a sustained reduction in daytime systolic blood pressure of 6–8 mmHg. Being on central sympatholytics, therefore, is an unlikely clinical characteristic that would help decide who should receive renal denervation. The results of Nolde et al. are consistent with the concept that renal denervation lowers BP by targeting sympathetic activation, but it does not shed light about its precise mechanism. It has been argued that denervation of the hypertensive kidney interrupts afferent nerves that activate brainstem pathways that result in central sympathetic activation. Thus, afferent renal nerve denervation would result of a reduction in efferent sympathetic nerve activity relevant to autonomic cardiovascular regulation and hypertension. The latter can be assessed directly by measuring muscle sympathetic nerve activity (MSNA). Even though most studies have shown a decrease in MSNA following renal denervation, a recent comprehensive meta-analysis concluded that renal denervation is associated with a relatively modest central sympathoinhibition, and that this mechanism does not completely explain the BP-lowering effect of the procedure 9. It is possible, therefore, that interruption of efferent nerves providing sympathetic innervation to the kidneys contribute to its efficacy. Alternative approaches to target sympathetic activation are being developed in parallel for the treatment of heart failure 11. Devices that directly stimulate the carotid sinus nerve (Barostim) provide a more direct target to sympathetic activation. Early versions of the device (Rheos) produced large reductions in MSNA but required extensive surgical implantation of bipolar electrodes on both carotid arteries 12. A second-generation device (Barostim Neo) relies on a single unipolar electrode placed usually on the right carotid sinus wall and has received premarket approval by the FDA for the treatment of heart failure. Because of its unipolar design, it often requires higher intensities of stimulation that are associated with local side effects. No randomized clinical trials are available to determine its safety and efficacy for the treatment of hypertension. A similar approach is the basis for the MobiusHD device, an endovascular implant placed in the carotid sinus that purportedly alters the carotid geometry to “amplify” natural baroreceptor signaling, increasing carotid sinus afferent input to the brainstem. Open-label uncontrolled studies have reported durable BP-lowering effects 13, but data from randomized sham-controlled trials are needed to further evaluate the risk-benefit profile of this procedure. Over the horizon are novel approaches targeting carotid body chemoreceptors, rather than carotid sinus afferents, to reduce sympathetic activity 14. This is based on the observation that unilateral carotid body resection lowers MSNA and BP in resistant hypertension 15. Not as much progress is being done in developing novel pharmacological agents that target sympathetic activation. It should be noted, however, that we already have a class of central sympatholytics, such as moxonidine, that are different from classical alpha 2 receptor agonists like clonidine in that they are also imidazoline receptor agonists and are devoid of central sedative side effects. The antihypertensive effectiveness of moxonidine is comparable to hydrochlorothiazide, angiotensin-converting enzyme inhibitors, or alpha-blockers and beta-blockers 16. In contrast to clonidine and beta blockers, moxonidine appears to have a positive metabolic profile, inducing modest weight loss 17 and, importantly, improving insulin sensitivity 18,19. Moxonidine was never submitted for approval to the FDA for the treatment of hypertension in part because a pivotal study in patients with heart failure resulted in higher mortality in patients receiving moxonidine than placebo 20, but that study used a specially formulated sustained-release, high-dose preparation. Moxonidine is available in Europe, Australia and Asia for the treatment of hypertension, but the drug has not been tested in large clinical trials for its ability to improve cardiovascular outcomes, and is, therefore, relegated as second line therapy. It is unlikely that such outcome trials will be forthcoming given that moxonidine is now available in generic form. In summary, progress is being made in developing novel therapies that target sympathetic activity in the treatment of hypertension (and heart failure), particularly in the area of devices and nonpharmacological interventions. Renal denervation has the strongest evidence base. It is fair to say that the magnitude of the antihypertensive effects of this procedure, documented in controlled clinical trials, is relatively modest compared to that reported in initial proof-of-concept studies. Also, it has been difficult to identify predictors of response that will help in patient selection. In this regard, the contribution by Nolde et al.10 in this issue of the Journal revealed that patients already receiving central sympatholytics had a blunted antihypertensive response to renal denervation. It should be noted, however, that such patients did benefit from renal denervation, and differences between groups was too small to help with patient selection. There remains an unmet need to develop well tolerated and effective approaches targeting sympathetic activation in the management of hypertension. ACKNOWLEDGEMENTS This work was supported by the National Institutes of Health (NIH) grant HL149386 and the Overton and Jeannette Smith and the Lori Ann Fishel Funds. Conflicts of interest There are no conflicts of interest.