Hypertension is the most common chronic disease in the US, affecting 29% of the adult population.1 Once considered a benign, compensatory mechanism for ageing, high blood pressure (BP) is now recognised as an important risk factor for cardiovascular disease. It is estimated that inadequate BP control is responsible for 62% of cases of cerebrovascular disease, 49% of cases of ischemic heart disease and 7.2 million deaths per year.2 Despite increasing awareness and available medical regimens, BP control in the US is far from optimal.3 Only 25–30% of patients with hypertension are thought to achieve the target BP of <140/90mmHg.4
Poor BP control is frequently attributed to patient non-adherence, financial barriers and inadequate dosing of pharmacotherapy. However, a subset of patients who fail to achieve goal BP despite an appropriate drug regimen, suffer from ‘resistant hypertension’. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure5 defines resistant hypertension as the failure to achieve a goal BP (<140/90mmHg for the overall population and <130/80mmHg for those with diabetes or chronic kidney disease), despite proper adherence to the maximum tolerated doses of an appropriate regimen of three antihypertensive drugs, one of which is a diuretic. Although this definition of resistant hypertension is somewhat arbitrary in terms of the number of medications required, it aims to identify patients who have true ‘treatment resistance’ – and, thus, who may have a distinct pathophysiology – who may benefit from special diagnostic or therapeutic considerations.6
While it is impossible to measure the exact prevalence of resistant hypertension, several clinical trials suggest that it is not rare. In a study7 in the late 1980s, the prevalence appeared to be anywhere from 8 to 15% among patients with hypertension. A more recent and ethnically diverse clinical trial, known as the Antihypertensive and lipid-lowering treatment to prevent heart attack (ALLHAT) trial,6 suggests that the prevalence may be significantly higher: approximately 20–30%. Age and obesity are strong risk factors and the incidence and prevalence may be rising as the population ages and becomes heavier.6 There are number of possible causes for resistant hypertension, including chronic kidney disease, diabetes, atherosclerosis and sleep apnoea. Most cases are thought to be multifactorial.6
A genetic component may also play a part. The prognostic implications of resistant hypertension relative to hypertension that is responsive to pharmacotherapy have not been analysed. It is not difficult to imagine that the prognosis may be significantly impaired in patients with long-standing high BP, as numerous studies point to the poor outcome associated with elevated BP. Hence, the benefits of successful treatment in these patients are likely to be substantial. Here, we give an overview of three novel, non-pharmacological therapies available for patients with resistant hypertension. These unique approaches in treating hypertension have demonstrated safe and reliable results so far and are likely to benefit patients who fail antihypertensive pharmacotherapy. Further investigation is necessary to establish the role of these devices in relation to conventional antihypertensive medication. Nonetheless, some of these approaches may prove to be less expensive and safer alternatives to conventional antihypertensive medication in lowering BP, or at least a beneficial adjunctive therapy among patients with resistant hypertension.
Implantable Baroreflex Stimulators
The baroreceptors of the carotid sinus and aortic arch are mechanoreceptors that respond to vascular distention.8 In response to a sensed distention, usually due to increased BP or blood volume, baroreceptors send signals to the nucleus tractus solitarius in the medulla via the glossopharyngeal (IX) and vagus (X) cranial nerves, leading to activation of parasympathetic nuclei and inhibition of sympathetic nuclei.9–11 The result is a fall in peripheral vascular resistance, heart rate, stroke volume and, in turn, BP.
The short-term homeostatic effect of the baroreflex in maintaining physiological BP is well known. However, its role in long-term BP control, is less clear. Studies have observed that baroreceptor response gradually diminishes (over minutes to days) in the setting of a sustained increase in BP, setting a new, higher threshold for activation.12–14 Such apparent ‘blunting’ of the baroreflex in the face of chronically elevated BP led to the belief that it played only a minimal role in chronic BP modulation.15 Additionally, vessels subjected to chronically elevated BP in combination with atherosclerosis are thought to lose the distensability crucial to baroreceptor activation, further leading to the blunted baroreflex response.8,16,17
However, recent studies suggest that baroreceptors may have a substantial role in chronic BP control by modulating renal salt excretion and, consequently, systemic fluid balance.17 In animal models with experimentally induced hypertension, abolishing the baroreceptor pathway results in decreased sympathetic stimulation of the kidneys, preventing an expected increase in sodium excretion.18 Moreover, a more recent study19 demonstrated that experimentally induced hypertension is associated with increased baroreceptor pathway activity and suppressed sympathetic response over the course of five days. This suggests a sustained role for the baroreflex response.
Current Device – Rheos®
Electrical stimulation of baroreceptors has been explored, although many early devices failed for technical reasons.20–23 The latest, implantable carotid stimulator, manufactured by CVRx®, Inc. (Minnesota, US), is a device called Rheos®. The device is surgically implanted under general anaesthesia similarly to a conventional pacemaker: below the clavicle, subcutaneously. Electrodes tunnel subcutaneously from the main device, reaching the perivascular space of the carotid sinus bilaterally, allowing stimulation of the baroreceptors with minimal effect on surrounding chemoreceptors and nerves.24 The device can be programmed after implantation to allow for the adjustment of stimulation parameters.
An early trial in the US (the Rheos feasibility trial),25 in which 10 patients with resistant hypertension (average age 50±13) underwent Rheos implantation, showed promising results. The mean procedure time was 198 minutes and no significant adverse events were reported.26 Patients continued to take their medical antihypertensive regimen after the procedure. At a three-month follow-up, patients demonstrated a sustained drop in mean systolic BP of 22mmHg (p=0.01) and in mean diastolic BP of 18mmHg (p<0.01).25 No orthostasis, bradycardia or adverse renal effects were reported after three months of active device therapy and continued stable medical therapy. The Rheos has been successfully implanted in 16 patients with refractory BP elevation in Europe with similar results: a sustained reduction in BP of 34/20mmHg (p<0.001) after three months, 38/27mmHg (p<0.001) after 12 months and 35/24mmHg (p<0.001) after two years of active therapy.27
Although small in terms of sample size, these results are promising and suggest that the Rheos carotid stimulator is safe and effective. Larger randomised controlled trials are under way to definitively test the safety and efficacy of Rheos as a treatment for resistant hypertension. The Rheos pivotal trial began enrolling patients late in 2006 and anticipates enrolling 300 patients at 42 centers in the US and in Europe. This randomised, double-blind, parallel trial will examine patients with a BP of >160/80mmHg, despite therapy for a minimum of one months using at least three antihypertensive medications, including a diuretic. The primary outcomes measured will include office BP at six months and one year after device activation, along with therapy-related adverse events over six months’ post-implantation.
Breathing exercises are associated with physical and psychological benefits in various cultures across the world. In biomedical literature, slow and deep breathing (‘paced breathing’) has demonstrated short-term antihypertensive properties.28–30 Such hypotensive effects were initially attributed to the ‘relaxation response’ induced by slow breathing techniques.28 However, techniques thought to cause this relaxation response have shown variable outcomes, reflecting the likely diverse mechanisms these techniques may be triggering.31
Although the exact mechanism remains to be elucidated, it is now thought that paced breathing initiates distinct physiological responses, leading to attenuated BP. Proposed mechanisms include increasing baroreceptor and/or cardiopulmonary receptor response, enhancing central inhibitory rhythms or decreasing chemoreflex sensitivity.32–35 Regardless of the actual mechanism, it appears that slow breathing initiates a decrease in sympathetic nervous system activity, which in turn regulates both the respiratory and cardiovascular systems. Since the respiratory and cardiovascular systems are regulated by similar mechanisms (such as the sympathetic nervous system), introducing a change in one system may modify the function of the other.34,36
Current Device – RESPeRATE®
It is not easy for most patients to perform paced breathing sessions on their own effectively. RESPeRATE, a device manufactured by InterCure™ Ltd (New York, US, and Lod, Israel), is designed to guide patients through paced breathing using feedback. The device consists of a control box with a microprocessor, a belt-type respiration sensor and headphones.
The device senses and analyses the user’s breathing rate and pattern and creates a personalised percussion tone – one tone for inhalation and another for exhalation. The user synchronises his or her breathing with the tones. During each session, the device gradually prolongs the tones to slow the user’s breathing to a rate of <10 breaths/minute. It is recommended that patients participate in 45 minutes of slow breathing per week. The device is able to record patient participation time, creating a log of regimen adherence.
Seven studies,37–43 including four randomised double-blind studies, have examined the efficacy and safety of RESPeRATE. All studies compared RESPeRATE use with other interventions, such as listening to relaxing music, home BP monitoring or both. As summarised by Elliott and Izzo,44 a total of 286 patients have participated in these studies to date. The average age of subjects was 57±11 years and 55% were male. The subjects’ initial office BP was 150±13/90±9mmHg (9% prehypertensive; 25% stage 2 hypertension). Seventy-eight per cent of the subjects were taking antihypertensive medications. Among the patients who adhered to the regimen, the mean change from baseline across all the studies was 14mmHg after eight weeks of device use (p=0.008), compared with 9mmHg (p=0.002) for the control treatment. This change from baseline was fairly homogeneous across (p=0.61 by analysis of variance), independent of gender and medication use. Further, the drop in BP was directly related to the duration of paced breathing device use during the eight weeks of treatment. Generally, three to five weeks of device use was necessary before subjects achieved a sustained reduction in BP.
A larger decrease in office BP was seen in older individuals and those with higher baseline BPs, whether taking antihypertensive medications or not. No adverse events have been reported so far and there are no known contraindications. RESPeRATE is currently indicated by the US Food and Drug Administration for the reduction of stress and as an adjunctive therapy in hypertension. It can be combined with other pharmacological and non-pharmacological interventions.
Isometric Handgrip Training
Aerobic exercises, such as walking, running and cycling, are recommended by professionals for lowering baseline BP. A recent meta-analysis45 supports the beneficial effects of aerobic exercises on BP in normotensive, pre-hypertensive and hypertensive adults. Dynamic resistance training, where muscle contraction occurs against an external resistance leading to significant joint movement, may also have antihypertensive properties.46 However, these interventions require time, motivation, baseline fitness and, at times, cost, all of which can dissuade patients from participating. A growing number of studies now support the view that isometric exercise – in which muscle contraction is accompanied by little or no joint movement, requiring less time and effort – may have significant antihypertensive properties. Handgrip training is an example of isometric exercise. In medical literature, unilateral or bilateral isometric handgrip (IHG) training has repeatedly been shown to attenuate resting arterial BP in both hypertensive and normotensive individuals.47–50 The mechanism for this remains unclear. Acutely, IHG actually elevates BP. In those who regularly practice IHG, paradoxically, a drop in baseline BP can be observed, usually in four to eight weeks.47,49,51,52 A decrease in baseline BP has also been observed following other isometric exercises, such as isometric leg exercises.51
Proposed mechanisms include a change in muscle sympathetic nerve activity, modulation of the autonomic nervous system, and/or formation of reactive oxygen species.48–50 It was once thought that isometric exercise might increase arterial endothelium-dependent flow-mediated vasodilation. It was later demonstrated that, although IHG improved endothelium-dependent vasodilation, this effect was only observed locally, suggesting that enhanced systemic endothelial-dependent vasodilation was not the mechanism for the BP reduction.53 Further research is necessary to uncover the physiological basis of the observed efficacy of isometric exercises in reducing BP.
Current Device – Zona Plus™
Zona Plus™, manufactured by Zona HEALTH (Idaho, US), is a small, handheld device designed to guide users through effective IHG exercise. Patients are initially directed to squeeze the device as hard as possible, allowing the device to record an individual’s maximum voluntary contraction (MVC). MVC values are recorded for both the right and left hand.
After MVC values are recorded, patients are instructed to squeeze the device just enough to make ‘Hold’ appear on the liquid crystal display (this occurs at 30% of the MVC pressure); they then hold this pressure for two minutes as directed by the built-in timer, during which time, the device advises patients to squeeze more or less to maintain the target pressure. After the two minutes, the timer measures a further one-minute period, designated for rest. These steps are then repeated with the other hand. At the end of the exercise, the device displays a score, which reflects how well the user was able to maintain the desired pressure. It is recommended to perform a 12-minute session of exercise as directed by the Zona Plus at least three times a week.
Several clinical studies have evaluated the efficacy and safety of Zona Plus or other handheld devices with a similar protocol, including three randomised controlled trials.47,49,52 As summarised by Kelley and Kelley,54 81 men and women (42 exercise and 39 control) participated in randomised controlled trials involving at least four weeks of IHG training. The pooled results were statistically significant: there was a 13.8mmHg reduction in systolic BP (95% confidence interval [CI], -15.3 to -11.0mmHg) and a 6.1mmHg reduction in diastolic BP (95% CI, -16.5 to -3.2mmHg). These results are promising; however, as the authors point out, the generalisability of these findings is limited because of the small number of participants. After analysing the data from 43 medicated patients with hypertension who participated in eight weeks of IHG training in three clinical trials,49,55,56 Millar and colleagues also concluded that IHG training lowered BP among these patients.57 Statistical analysis demonstrated that BP reduced in a linear fashion over the eight weeks of training, further supporting the efficacy of IHG. Furthermore, the authors noted that reductions were more pronounced among subjects with higher baseline BP. Changes in BP were not associated with gender, age or whether the subject was trained in unilateral or bilateral IHG.
To date, no side effects of the device have been reported in participating in IHG exercises. In theory, the device is perhaps not recommended for those with arthritis in the hands, carpal tunnel syndrome or other pain syndromes where the device may trigger unnecessary pain, or in those with an aneurysm or mitral valve problems, where the initial rise in BP triggered with the use of the device could be dangerous.
A recent study52 examined the efficacy of using a simple, spring-loaded handgrip device, instead of a programmable digital handgrip such as the Zona Plus. In this randomised controlled study involving 49 normotensive participants (25 exercise and 24 control), the exercise group demonstrated a significant reduction in systolic BP and diastolic BP relative to the control group. The estimated drop in systolic BP was 5.4mmHg (p<0.001) over eight weeks of training. Further comparative study involving patients with hypertension is necessary to determine the relative efficacy of programmable devices such as Zona Plus relative to simple handgrip devices.
Rheos, the implantable carotid stimulator; RESPeRATE, a paced breathing assistive device; and Zona Plus, which guides users through effective IHG exercises, are promising non-pharmacological therapies available for patients with resistant hypertension. These devices may prove to be less expensive and safer alternatives to lowering BP, or at least a beneficial adjunctive therapy among patients with resistant hypertension. These unique approaches in treating resistant hypertension have also allowed researchers to further elucidate possible mechanisms of resistant hypertension. Specifically, Rheos and RESPeRATE suggest the potential crucial role that baroreflex and the sympathetic nervous system may have in long-term BP modulation in humans. Recent data58 suggests that transcatheter ablation of renal sympathetic nerves may also have an important role in treating hypertension and the results of randomised trials are encouraging. The optimal role of these non-pharmacological therapies, relative to conventional medical regimens, remains unknown. These are likely effective and safe adjunctive modes of therapy. Further research is necessary before these devices are utilised as an complete alternative to antihypertensive pharmacotherapy, which have already consistently demonstrated unequivocal benefits in 37 randomised clinical trials in the prevention of stroke (by 29±2%), myocardial infarction (by 21±2%), heart failure (by 29±3%) and cardiovascular death (by 14±2%) compared with placebo or no treatment.