Neuromodulation for Systolic Heart Failure: More than a Placebo Effect?

This article refers to ‘Carotid body resection for sympathetic modulation in systolic heart failure: results from first-in-man study,’ by P. Niewinski et al., published in this issue on pages 391–400. The current treatment options for patients suffering from heart failure (HF) with reduced ejection fraction (HFrEF) include a large arsenal of lifestyle changes, medication, surgery, and device options.1 With regard to the latter, implantable cardioverter defibrillators (ICDs), and CRT are accepted in guidelines with a class I indication in selected patients1 and they are increasingly used in Europe.2 However, prognosis remains poor in the majority of patients with HFrEF. Optimal medical therapy proven by large-scale randomized controlled trials include medication with impact on the neurohormonal axis and those modulating sympathetic activity. Experimental studies have suggested that modulating sympathetic activity by device therapy or surgical procedures might be attractive targets to treat patients with HFrEF. Electrical neuromodulation has been effective both for angina3 and for a variety of non-cardiac ailments.4 In the light of these achievements, several attempts have been made to use these techniques in HF patients. Most studies, however, were terminated prematurely due to futility or as a consequence of slow enrolment. The largest trial so far in the field, INOVATE-HF, failed to show a beneficial effect on morbidity and mortality in patients treated with vagal nerve stimulation.5 In this open label study, secondary endpoints such as quality of life did improve, as did NYHA functional class and 6-min walking distance. In contrast to experimental studies, spinal cord stimulation in patients has also failed in inducing reverse remodelling in patients with HFrEF in the DEFEAT-HF study.6 Another interesting opportunity to modulate the sympathetic nervous system is removal of the carotid bodies. Carotid bodies consist of chemoreceptors to sense oxygen concentration and regulate oxygen homeostasis. Another function of the chemoreflex is to increase sympathetic tone in response to hypoxaemia, to counteract the vasodilatory effects of low oxygen concentrations. It is this reflex which is exaggerated in HF and related to outcome. In this issue of the journal, Niewinski et al. describe a first-in-man trial of carotid body resection for sympathetic modulation in patients with HFrEF.7 In this small, proof-of-concept study, sympathetic activity could be decreased and exercise tolerance was improved. However, since the carotid body plays an important role in oxygen homeostasis, patients with bilateral carotid body resection were at increased risk of developing sleep apnoea, with one patient needing non-invasive ventilation to treat desaturations. So, the question is whether electrical modulation of the nervous system to treat HF, making use of an ablative, electrical chemical or surgical method, at a specific site along the nervous axis, is worth taking into consideration. One of the reasons that most studies on neuromodulation failed is endpoint selection. With respect to devices, a placebo effect of implanted device has been reported in trials investigating pacemakers for vasovagal syncope.8 Procedures that are simple to perform and do not require permanent implantation of devices are even more acceptable to patients and physicians. Effects can be seen on soft endpoints, but even objectively measurable parameters such as blood pressure are influenced by a ‘sham effect’, as seen in renal denervation.9 It is thus important to interpret results from device and procedure trials with regard to their design. Randomized controlled trials are warranted, with a sham operation or a blinded crossover design. Most HF studies investigate the effect of drugs or devices on HF hospitalization and mortality. Though these hard endpoints are most often used to judge efficacy of a therapy in all patients suffering from HF, we also need to take improvement in quality of life of our patients into consideration, maybe even before trying to increase life expectancy. Some therapies may have unexpected effects that are not adequately reflected in the chosen endpoints. One example is the occurrence of isolated atrial reverse remodelling without ventricular reverse remodelling in patients treated with CRT. This group has been associated with better outcome than expected.10 A second reason for study failure is the wrong patient selection for testing a new technique. Non-responders to therapy should be avoided; however, if the effect of treatment is large enough, study outcome can be driven by super responders such as seen in CRT studies. Pharmacological treatment success has been disappointing in patients with HF and preserved ejection fraction (HFpEF) compared with those with HFrEF. Patients with HFpEF are therefore an attractive target group to study the effect of device therapy.11 Furthermore, extracardiac conditions associated with HF are an attractive target for device therapy if they are not amenable to pharmacological therapy. In a first attempt, unilateral transvenous phrenic nerve stimulation improves sleep parameters and quality of life in patients with systolic HF and central sleep apnoea.12 Current device and procedure studies are designed to provide a benefit on top of optimal medical treatment. The question arises of whether that is the correct strategy. Compliance with medication remains a large problem, especially outside of studies, even more so in patients that had been hospitalized for HF.13 A lot of patients cannot tolerate adequate doses of HF medication or do not tolerate certain medication groups at all due to side effects. Studies investigating invasive procedures or devices as an alternative to pharmacological treatment might be useful in these subgroups or even in all-comers to increase patient acceptance and compliance. A third reason for failure of neuromodulation lies in the technique that is used. For device therapy, the exact anatomical position and intensity of stimulation might change the outcome. For surgical procedures, the position of the procedure is also of influence as well as whether the procedure is performed on one side or bilaterally. Most probaby, optimal therapy needs to be individualized for each patient. Most clinical studies are preceded by experimental animal studies, but ultimately the exact anatomical location and intensity of the procedures are no more than an ‘educated guess’. For unknown reasons, device therapy and surgical procedures are viewed as being more efficient and more widely accepted than drug therapy14 (Figure 1). Patients are often more willing to undergo a single procedure than continuously to use drugs on a daily basis. Possible complications are accepted more readily than side effects of drug therapy. Possible long-term complications are often neglected by patients, but also often underestimated by physicians that counsel for informed consent before medical procedures. The advantage of using devices or procedures is that the problem of therapy compliance is negligible. Long-term efficacy, however, has to be demonstrated, as well as long-term freedom from complications before new techniques should be widely adopted in everyday practice. For carotid body resection, we may need a larger trial with hard endpoints such as all-cause mortality and HF hospitalization, and at the same time we would need to monitor the occurrence of serious side effects such as nocturnal desaturations. Neuromodulation so far failed for different reasons. These may include wrong patient selection and endpoint selection as well as the wrong anatomical target. However, electrical neuromodulation with device therapy remains an attractive treatment option and perhaps an alternative in HFrEF patients that are intolerant to beta-blockers and/or ivabradine, or in patients in which medication has been shown to be ineffective, such as those suffering from HFpEF. Operative procedures for neuromodulation are an alternative for device implantation that require only one procedure and might not carry long-term risks associated with device implantation such as infection or material failure. On the other hand, side effects of surgical procedures are often permanent as damage is irreversible. Carotid body resection may be a surgical alternative to device therapy, and the trial of Niewinski and colleagues shows in a first attempt the feasibility of this strategy.7 Sleep apnoea, as occurs especially in patients with bilateral procedures, is a serious side effect that needs to be taken into account. More studies are certainly warranted and, despite the disappointing results of the INOVATE-HF5 and DEFEAT-HF6 trials, this field should not be abandoned and trials with careful patient and endpoint selections should be encouraged. Conflict of interest: A.H.M. received lecture fees from Medtronic and LivaNova. M.J.L.dJ. received lecture fees from Medtronic and St Jude Medical, P.vdM. has no conflicts to declare.