CrossTalk opposing view: Which technique for controlling resistant hypertension? Carotid sinus stimulation

Blood pressure is not sufficiently controlled in a substantial proportion of patients (ALLHAT, 2002; Wolf-Maier et al. 2004) providing a rationale for developing new device-based treatments. Baroreflexes are a logical treatment given their involvement in long-term blood pressure control (Krieger, 1964; Thrasher, 2002). Furthermore, sympathetic activity, which is restrained by baroreflexes, is associated with cardiovascular risk (Cohn et al. 1984). Baroreflexes also promote cardiac parasympathetic outflow, thereby improving heart rate variability and baroreflex heart rate control. Finally, baroreflexes control vasopressin release in human beings (Jordan et al. 2000). Increased circulating C-terminal provasopressin (copeptin) levels and hypernatraemia secondary to excess vasopressin release are prognostically unfavourable in cardiovascular patients (Dargie et al. 1987; Khan et al. 2007). The idea that baroreceptors or baroreflex afferent nerves could be electrically activated is not new. The brain senses the electrical stimulus elicited by the device as blood pressure increase. Then, sympathetic and parasympathetic activity is adjusted to counteract the perceived blood pressure increase. Electrical stimulators directly activating afferent baroreflex nerves were developed several decades ago but vanished mainly for technical reasons (Rothfeld et al. 1969). Recently, novel implantable devices stimulating the carotid sinus have been developed and clinically tested (Tordoir et al. 2007; Mohaupt et al. 2007; Scheffers et al. 2010). Carotid sinus stimulators produce an electrical field stimulation of the carotid sinus wall, presumably activating carotid baroreceptors. The first-generation device applies bilateral stimulation through bipolar electrodes placed around the carotid sinuses. Once a good electrode position has been identified during intraoperative testing, electrodes are fixed and the pacemaker wires are subcutaneously tunnelled and connected to the pacemaker device (Tordoir et al. 2007). Commonly, the carotid sinus stimulator is switched on following a postsurgical recovery period of approximately 1 month. There is no blood pressure feedback or entrainment with an electrocardiogram. The stimulator settings can be adjusted independently for each electrode. Recently, smaller second-generation devices have been developed (Hoppe et al. 2012). These devices rely on unilateral carotid sinus stimulation through a smaller unipolar disc-shaped electrode. However, much of the published data on electrical carotid sinus stimulation have been obtained using the first-generation device. Given the size of the carotid sinus stimulator, dogs are particularly suited for preclinical experiments. In normotensive dogs, electrical carotid sinus stimulation elicited a sustained decrease in mean arterial pressure exceeding 20 mmHg (Lohmeier et al. 2004). Plasma noradrenaline (norepinephrine) also decreased suggesting that the depressor response was secondary to sympathetic inhibition. Despite the marked depressor response, plasma renin activity remained unchanged, which is consistent with suppression of efferent renal sympathetic nerve activity (Iliescu et al. 2012). Following initiation of carotid sinus stimulation, sodium balance was restored through mild reduction in glomerular filtration rate probably through tubuloglomerular feedback. Remarkably, carotid sinus stimulation also lowered blood pressure in dogs following surgical renal denervation (Lohmeier et al. 2007b). In angiotensin II-mediated arterial hypertension, carotid sinus stimulation decreased mean arterial pressure by only 5 mmHg (Lohmeier et al. 2005). The treatment was more effective in sympathetically mediated arterial hypertension induced by obesity (Lohmeier et al. 2007a). Moreover, electrical carotid sinus stimulation and surgical renal denervation improved blood pressure in dogs with established obesity-associated arterial hypertension (Iliescu et al. 2013). With electrical carotid sinus stimulation, heart rate decreased while heart rate variability and baroreflex heart rate regulation improved. No such change occurred with renal denervation. Surgical renal denervation and electrical carotid sinus stimulation also elicited a differential effect on renal function in dogs with obesity-induced arterial hypertension (Lohmeier et al. 2012). Both treatment modalities reduced plasma renin activity. While electrical carotid sinus stimulation attenuated renal hyperfiltration, renal denervation further augmented glomerular filtration rate. The European Device Based Therapy in Hypertension Trial (DEBuT-HT) was a multicentre, non-randomized feasibility study testing safety and efficacy of electrical carotid sinus stimulation in patients with severe treatment-resistant hypertension. Average blood pressure at baseline was 179/105 mmHg with a median of five antihypertensive drugs including a diuretic. After 3 months of treatment, blood pressure decreased by 21/12 mmHg. In 17 patients completing 2 years of follow-up, blood pressure decreased by 33/22 mmHg. Seven patients experienced a procedure-related serious adverse event. One patient experienced a device-related serious adverse event, and one patient died, probably due to medication-induced angioneurotic oedema. In a patient subset, we observed that the depressor response to electrical carotid sinus stimulation was associated with acute reductions in centrally generated sympathetic activity (Heusser et al. 2010). However, there was large variability in the response of blood pressure and sympathetic activity to acute carotid sinus stimulation with a significant proportion of non-responders. Improvements in heart rate variability were shown in another sub-study (Wustmann et al. 2009). After 1 year of treatment, patients pooled from feasibility studies showed improvements in left atrial dimension and left ventricular mass (Bisognano et al. 2011b). To confirm these encouraging results from uncontrolled clinical trials, 265 patients with treatment-resistant arterial hypertension were included in a double-blind randomized trial (Bisognano et al. 2011a). In this trial, patients were randomized in a 2:1 fashion to early or delayed treatment such that the device was activated 1 month or 6 months following implantation. While carotid sinus stimulation significantly lowered blood pressure in the controlled phase of the trial, the predefined endpoint of early efficacy (defined as proportion of patients achieving ≥10 mmHg systolic blood pressure reduction at month 6) was not significantly different between groups. However, there was a positive sustained blood pressure response in the uncontrolled phase of the trial at month 12. The response was maintained during 22–53 months follow-up (Bakris et al. 2012). Meanwhile, the second-generation carotid sinus stimulator with unilateral electrode implantation has shown promising safety and efficacy in an uncontrolled clinical trial (Hoppe et al. 2012). By engaging carotid afferent baroreflex input, electrical carotid sinus stimulation targets multiple neuro-humoral abnormalities predisposing to arterial hypertension while promoting cardiovascular damage. Clinical trials suggest that the treatment may ameliorate resistant arterial hypertension in high-risk patients. Electrical carotid sinus stimulation, catheter-based renal nerve ablation, deep brain stimulation, and peripheral chemoreflex denervation are in different stages of clinical development for treatment-resistant arterial hypertension. Thus far, none of these treatments showed efficacy and safety in sufficiently large double-blind controlled clinical trials. Indeed, catheter-based renal nerve ablation did not significantly lower blood pressure in the first properly controlled clinical trial (Bhatt et al. 2014). Carotid sinus stimulation has certain advantages compared with other device-based treatments. While catheter-based renal nerve ablation and peripheral chemoreceptor denervation disrupt regulatory mechanisms, baroreflex regulation is maintained or even improved during electrical carotid sinus stimulation (Heusser et al. 2010). The stimulation can be individually adjusted or switched off in case of haemodynamic instability. Because the device can be switched off, true non-responders can be identified. Whether a patient's blood pressure changes because of renal nerve ablation or for another reason cannot be discerned. Finally, renal sensory and sympathetic nerves re-innervate the kidney in rats within 9–12 weeks (Mulder et al. 2013). Implantation of electrical carotid sinus stimulators requires an experienced team comprising hypertension specialists, surgeons and anaesthetists, who may limit indiscriminate spreading of the therapy. However, there are several challenges ahead which should be addressed. Implantation of an electrical carotid sinus stimulator carries risks, such as nerve damage or device infection, which have to be weighed against the potential clinical benefit. Given the high costs and invasiveness, a large proportion of non-responders is not acceptable. Carefully conducted physiological investigations may identify patients more or less likely to respond. Battery life has to be improved. Perhaps, device design and implantation procedure could be further modified to decrease the invasiveness. However, efficacy should not be sacrificed for convenience. In addition to providing a new treatment, carotid sinus stimulators can serve as an exciting tool to elucidate human baroreflex physiology. For example, we conducted a study in patients equipped with such a device to assess baroreflex influences on peripheral glucose supply and insulin sensitivity (May et al. 2014). Some of the older antihypertensive drugs, such as guanethidine or ganglionic blockers, also target the sympathetic nervous system. These drugs are no longer available. It is tempting to speculate that these drugs could also play a role in the management of patients with treatment-resistant arterial hypertension and reduce the number of patients considered for device-based treatments. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment to journals@physoc.org. Jens Jordan is director of the Institute of Clinical Pharmacology at Hannover Medical School in Germany. Before he moved to Hannover, he was head of the Franz-Volhard Clinical Research Center at the Medical Faculty of the Charité and clinical group leader at the Max-Delbrück Centrum in Berlin, Germany. He received his training in clinical pharmacology and in internal medicine at the Franz-Volhard Clinic in Berlin and at Vanderbilt University in Nashville. His group pursues cardiovascular and metabolic control mechanisms in man. A particular research focus is the pathogenesis and treatment of disorders affecting cardiovascular autonomic regulation including resistant arterial hypertension. Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. None declared.