Nondrug Interventions for Treatment of Hypertension

Abstract

J Clin Hypertens (Greenwich). 2011;13:829–835. ©2011 Wiley Periodicals, Inc.

The treatment of hypertension is no longer limited to the simple prescription of pharmaceuticals. For many patients, maximal medical therapy is insufficient to adequately treat refractory hypertension. In addition, some patients may prefer to explore therapies that do not involve drugs as an initial step. Utilizing our broadening understanding of the physiology of hypertension, new technology and interventions have been developed that allow for treatments that do not rely on medications. In addition, dietary supplements and modification, as well as herbal supplements, may be useful under the right circumstances. Lifestyle modification remains a necessary part of treatment for all patients with hypertension. This article will review the evidence behind some available nondrug interventions for the treatment of hypertension.

The treatment of hypertension is no longer limited to the simple prescription of pharmaceuticals. For many patients, maximal medical therapy is insufficient to adequately treat refractory hypertension. In addition, some patients may prefer to explore therapies that do not involve drugs as an initial step. Utilizing our broadening understanding of the physiology of hypertension, new technology and interventions have been developed that allow for treatments that do not rely on medications. In addition, dietary supplements and modification, as well as herbal supplements, may be useful under the right circumstances. Of course, lifestyle modification remains a necessary part of treatment for all patients with hypertension. This article will review the evidence behind some available nondrug interventions for the treatment of hypertension.

Lifestyle Modification

Despite the abundance of pharmaceutical options for the treatment of hypertension, lifestyle modification remains an important approach in management. This is reflected by the inclusion of lifestyle and dietary modification in the approach recommended by the American Heart Association (AHA). ¹ The benefit of exercise, salt restriction, the Dietary Approaches to Stop Hypertension (DASH) diet, and weight reduction has been well established. The DASH diet emphasizes fruits and vegetables and is high in fiber and low in fats. The DASH diet was found to lower systolic blood pressure (SBP) by 5.5 mm Hg in all patients. The effect was more pronounced in patients with hypertension, lowering the SBP by an average of 11.4 mm Hg. ² Reducing salt intake in combination with the DASH diet appears to lower blood pressure (BP) further. ³ The addition of a regimented exercise routine and weight loss counseling reduced SBP by 3.7 mm Hg—the effect was more pronounced if added to the DASH diet. ⁴ Thus, the current AHA guidelines recommend the low‐salt DASH diet in combination with an exercise and weight loss regimen universally for patients with hypertension. ¹

Limiting alcohol intake has also demonstrated improvement in BP control. Those who drink ≥3 glasses of alcohol per day have a higher incidence of hypertension. ⁵ The effect increases as the alcohol intake increases. ⁶ Reducing alcohol intake lowers BP. ⁷ Again, the effect appears to be related to the degree of reduction. It should be noted that a moderate alcohol intake appears to have a cardioprotective role, decreasing the incidence of myocardial infarction ⁸ and mortality. ⁹

The relationship of smoking and hypertension is somewhat less clear. Cigarette smoking has an acute vasoconstrictive effect. ¹⁰ Those who smoke >15 cigarettes per day have a higher incidence of hypertension, ¹¹ although there are conflicting data on whether smoking, in general, chronically raises BP. ¹² , ¹³ , ¹⁴ Irrespective of the relationship of smoking with hypertension, all patients with hypertension should be counseled to quit smoking due to the excess cardiovascular risk associated with smoking.

Dietary Supplements

Potassium

Diets low in potassium cause a rise in systemic BP. Conversely, it appears that potassium supplementation causes a decrease in SBP on an order of magnitude of 3 mm Hg to 12 mm Hg. ¹⁵ , ¹⁶ , ¹⁷ While the mechanism of this effect is not clear, it may be the result of a correction of a disturbance in norepinephrine‐mediated vasoconstriction occurring in the setting of relative hypokalemia. ¹⁸ In addition, there is a demonstrated protective effect of potassium on the cardiovascular damage induced by salt‐sensitive hypertension, ¹⁹ postulated to be due to antioxidant effects of potassium. ²⁰ There is evidence that an increase in dietary potassium may carry similar benefit to supplementation. ¹⁶

Calcium

Calcium supplementation causes a mild decrease in BP from vascular relaxation due to a paradoxical decrease in intracellular calcium. In one study, a 1500‐mg daily dose of oral calcium caused a nonsignificant reduction of 1.7 mm Hg ²¹ in SBP. Benefits seen with calcium supplementation may be more pronounced in patients with a low baseline dietary intake of calcium. ²²

Vitamin D

Patients with hypertension are more likely than controls to have diminished levels of vitamin D. ²³ Vitamin D supplementation causes a decrease in SBP of approximately 2.4 mm Hg, with no apparent effect on diastolic BP (DBP). ²⁴ Low levels of vitamin D may stimulate smooth muscle proliferation and renin production, resulting in abnormal BP homeostasis.

Folate

Low dietary intake of folate has been associated with elevations in BP. ²⁵ Women with an increased dietary or supplement‐based intake of folate have been shown to have a lower incidence of hypertension. ²⁶ Although prospective data are limited, a small study showed a 4‐mm Hg drop in nocturnal SBP with high‐dose folate supplementation. ²⁷

Coenzyme Q10

Coenzyme Q10, a mitochondrial enzyme involved in energy production and an antioxidant, may have a role in hypertension. Patients with hypertension tend to have lower levels of Coenzyme Q10. ²⁸ Treatment with Coenzyme Q10 supplements was shown to reduce SBP by 16 mm Hg in a meta‐analysis of randomized controlled trials. ²⁹ The mechanism of action is not well established but may be related to its antioxidant effects.

Fish Oil

Numerous studies have shown a small but significant decrease in BP in patients taking high‐dose fish oil supplements, with a 2‐ to 3‐mm Hg decrease in SBP. ³⁰ , ³¹ , ³² Various mechanisms have been postulated, including a resultant large‐vessel dilatation after integration of fatty acids into membrane phospholipids.

Garlic

Garlic extract may decrease BP. Several studies have shown a 10‐ to 16‐mm Hg decline in SBP in patients taking garlic extract. ³³ , ³⁴ However, study design and blinding may have been suboptimal, ³⁵ so the efficacy of garlic remains at question.

Fruits and Vegetables

As mentioned previously, the DASH diet, which combines a relative increase in fruits and vegetables with a reduction in saturated and total fats, lowers BP. As part of the initial DASH trial, the group assigned to a fruit‐ and vegetable‐rich diet alone showed a modest reduction in SBP of 2.8 mm Hg. ² As mentioned previously, the greatest benefit was derived with a low‐sodium, fruit‐ and vegetable‐rich, and low‐fat diet. ³

Soy Protein

Some of the beneficial effects of a diet high in fruits and vegetables may be due to a relative decrease in the intake of animal protein. However, the addition of vegetable protein appears to have a beneficial effect on BP. The addition of soy protein has been studied, and a supplement of 40 g daily has been seen to cause a statistically significant decrease in SBP of 7.8 mm Hg. ³⁶ While the mechanism is not well established, this may be due to high concentrations of the amino acid arginine, which is a nitric oxide precursor. Soy protein may also decrease plasma glucose concentration and decrease insulin resistance, which may be a risk factor for development of hypertension.

Flavonoids

Flavonoids are compounds found in high concentrations in tea, cocoa, wine, and grapes. These substances appear to have beneficial effects via nitric oxide–mediated vascular dilation. ³⁷ Diets high in cocoa appear to lower SBP by 3 mm Hg to 5 mm Hg. ³⁸ , ³⁹ However, tea did not seem to show a benefit in pooled analysis. ³⁸

Vegetarian Diet

A vegetarian diet may result in lower BP although the mechanism is unclear. Patients randomized to a vegetarian diet demonstrated a reduction in SBP of 5 mm Hg. ⁴⁰ Whether this effect is due to an increase in intake of substances present in the diet, an increase in dietary fiber, or a reduction in animal protein is not clear.

High‐Fiber Diet

Numerous studies have evaluated diets high in fiber and fiber supplementation and their effects on BP. Several meta‐analyses have shown a very mild 1‐mm Hg to 2‐mm Hg decrease in SBP in patients ingesting a high‐fiber diet. ⁴¹ , ⁴² The benefit seems to be most pronounced in older patients and patients who are hypertensive at baseline.

Herbal/Alternative Approaches

Hawthorn

Hawthorn (Crataegus laevigata) is a tree, the extract from which has been used for reducing BP. Two studies showed a trend towards lower BP, which was not statistically significant. ⁴³ , ⁴⁴

Coleus forskohlii

Coleus forskohlii, or forskolin, is an Indian plant that appears to have a vasodilatory and positive inotropic effect in animal models. While this extract has not been well evaluated in terms of effects on BP, it was effective in lowering cardiac filling pressures in patients with congestive heart failure. ⁴⁵

Mistletoe

Mistletoe, or viscum album, extracts have been used in traditional Chinese medicine to treat hypertension. ⁴⁶ While no placebo‐controlled trials have been performed, animal models have shown a reduction in BP with mistletoe extract. ⁴⁷ Of note, mistletoe may be toxic at high concentrations.

Rauwolfia

Rauwolfia is a genus of evergreen trees and shrubs found mainly in tropical regions. This extract was previously widely used in the 1950s and does have a hypotensive effect. ⁴⁸ Rauwolfia can have pronounced side effects, including restlessness, insomnia, dyspnea, and weight gain.

Acupuncture

Acupuncture has been proposed for treatment of hypertension. Studies have been mixed and quite heterogeneous in terms of population and methods. While there is no conclusive evidence that acupuncture lowers BP, several studies have shown a lower BP with acupuncture vs placebo in patients also prescribed antihypertensive medications. ⁴⁹ , ⁵⁰

Meditation

As with acupuncture, studies regarding meditation’s effects on BP have been fairly heterogeneous. In a meta‐analysis, transcendental meditation appeared to lower SBP by 4.7 mm Hg. ⁵¹ Other techniques that may show benefit include Zen Buddhist meditation and Qi Gong. ⁵²

Supplements That May Increase BP

In the evaluation of a patient with hypertension, it is important to identify factors that may exacerbate hypertension. Several herbal remedies may cause an increase in BP, including St John’s wort, ephedra/ma huang, yohimbine, and licorice. ⁵³ , ⁵⁴ St John’s wort may also interfere with the metabolism of other medications, including calcium channel blockers.

Devices

Numerous devices have been developed to provide an alternative or supplemental approach to treating hypertension. Several devices involve an invasive approach, while others use technology that requires the patient to participate in various exercises.

Implantable Baroreflex Stimulator: Rheos

The Rheos device (CVRx Inc, Minneapolis, MN) is an implantable system that consists of leads implanted around the carotid sinus which connect to a generator. The device uses the baroreflex pathways in the carotid sinus. Typically, a rise in SBP or blood volume causes vascular stretch. ⁵⁵ This is detected by baroreflex receptors in the carotid sinus and elsewhere that signal the nucleus tractus solitarius in the medulla, via the glossopharyngeal and vagus nerves. This, in turn, causes inhibition of central sympathetic nuclei and activation of parasympathetic nuclei. The physiologic result is a decrease in vascular tone, heart rate, and cardiac contractility. There are also renal effects, with a resulting diuresis and decreased renin excretion. ⁵⁶ These effects lead to a fall in BP.

The Rheos system delivers electrical impulses to the carotid sinus baroreceptors, stimulating them and mimicking a high pressure/volume state. The baroreflex cascade is initiated, resulting in a decrease in vascular tone and a drop in BP. The device is implanted under general anesthesia, with the leads tunneled subcutaneously into the space surrounding the carotid sinus. After implantation, the device‐stimulation parameters can be adjusted. The device has been evaluated in patients with resistant hypertension. In an early efficacy study of 10 patients, there was a reduction in SBP of 22 mm Hg and DBP of 18 mm Hg. ⁵⁷ The implantation of the system was well tolerated with no adverse events related to the device. The mean surgical time of implantation was 198 minutes. ⁵⁸ These results were reproduced in a European sampling of 45 patients, with some having a sustained reduction in BP after 2 years. ⁵⁹ Recently, the Rheos Pivotal Trial ⁶⁰ demonstrated that 54% of patients with the device had a ≥10‐mm Hg reduction in SBP at 6 months and 88% had a sustained response at 12 months. In addition, there were significantly decreased short‐ and long‐term adverse events in patients with the system. A total of 81% of patients were found to be “responders” to the Rheos system, with an average SBP decrease in these patients of 44 mm Hg at 12 months. Patients with the device also demonstrated a decline in left ventricular hypertrophy at 1 year. The system was generally well tolerated, although some short‐term surgical complications were noted. These included a 4.4% rate of permanent nerve injury, a 4.8% rate of transient nerve injury, and a 4.4% rate of general surgical complications, of which 86% completely resolved. A second‐generation system with a miniaturized carotid sinus lead may decrease the rate of adverse surgical outcomes.

Renal Sympathetic Denervation: Symplicity Catheter

There is a suggestion that hypertension in chronic kidney disease may be driven by sympathetic overactivity originating from renal afferent pathways. ⁶¹ , ⁶² , ⁶³ The central mechanism appears to stem from a reflex mechanism to preserve renal perfusion in a chronic ischemic state. ⁶⁴

The Symplicity catheter (Ardien, Inc, Mountain View, CA) system is designed to ablate these sympathetic renal pathways. It is inserted percutaneously through the femoral artery and into the renal arteries and radiofrequency pulses are delivered at several points throughout the renal arteries. The overactive sympathetic pathways are disrupted, resulting in a decrease in the inappropriately elevated sympathetic tone and a decrease in BP. Initial trials have been favorable. In a proof of concept study enrolling 50 patients with refractory hypertension, SBP was reduced by 14 mm Hg after 1 month and 27 mm Hg at 1 year. ⁶⁵ Further follow‐up and pooled data demonstrated a 2‐year SBP reduction of 32 mm Hg. ⁶⁶ In the randomized Symplicity HTN‐2 trial, 100 patients with resistant hypertension underwent renal sympathetic denervation or were assigned to the control group. ⁶⁷ Patients who received the ablation had a reduction in SBP by 32 mm Hg after 6 months, compared with a control group where there was no change in BP. In these studies, there were few procedural‐based complications, with one patient in the pilot study having the procedure aborted due to a renal artery dissection that resolved without complication or intervention and one patient having progression of a previously existing atherosclerotic plaque. Longer‐term studies are currently ongoing to confirm the safety and efficacy of this technique.

Paced Breathing: RESPeRATE

As discussed earlier, techniques such as meditation have been shown to decrease BP. Slowed respiratory rates appear to have a beneficial effect on BP. ⁶⁸ , ⁶⁹ , ⁷⁰ As respiratory rates slow, lung inflation increases. This then increases activation of stretch receptors in the lungs, which feed back to the central nervous system, and leads to vasodilation.

The RESPeRATE device (InterCure, Inc, New York, NY) uses biofeedback to progressively slow breathing. The system utilizes a controller unit, a respiration sensor, and headphones. Musical tones are played based on the patient’s respirations, and the patient is instructed to follow the tones to adjust their breathing pattern. The device is used for 15 minutes daily. By progressively prolonging the expiratory phase, the patient’s breathing cycle is slowed. The device decreased the SBP by 15 mm Hg at 2 months, compared with 11.3 in the placebo (music relaxation) group. ⁷¹ The response appeared to persist beyond the period where the device was in use. ⁷¹ , ⁷² Subsequent studies showed a more modest, but significant, 5‐mm Hg decrease in SBP. ⁷³

Isometric Handgrip Exercises: Zona Plus

Isometric exercise is defined as exercise performed without muscle shortening or joint angle change. This type of exercise has been shown to decrease BP when performed in the arms, legs, or hands. ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ Previously, exercise was thought to increase BP due to a pressor response. Isometric exercise, however, does not increase heart rate (suggesting that there is no sympathetic effect) ⁷⁵ and, in fact, increases vagal tone and improves autonomic function. ⁷⁷ , ⁷⁸ Isometric exercise also decreases oxygen radicals ⁷⁹ and enhances endothelial‐mediated vasodilation, ⁸⁰ perhaps accounting for some of the BP benefits.

The Zona Plus (Zona Health, Boise, ID) is a dynamometer that is held in either hand. It initially prompts the user to squeeze as hard as possible. It uses this to calculate the maximal voluntary contraction and provides feedback to the user to a goal of 30% of this number. The device prompts the user to perform 42‐minute sets of squeezing, with 1‐minute rest in between. In pooled data, this device showed a decrease in SBP of 5.7 mm Hg in patients exercising 3 days per week for 8 weeks. ⁸¹

Areas of Uncertainty

Much of the evidence for these therapies comes from small studies with end points that typically include only BP. Clinical outcomes such as stroke or myocardial infarction have not been evaluated, although lower BP correlates with improved clinical outcomes. ⁸² , ⁸³ While many of the device therapies have been evaluated in addition to currently recommended pharmacologic therapy, the efficacy of adding dietary, herbal, or alternative therapies is not well established. While combinations of antihypertensive drugs from different classes is a recommended approach that results in an additive benefit, it is not clear whether combinations of herbal or dietary supplements will also be additive. Safety profiles of the herbal supplements have not been rigorously established. Formulations can be variable and they are not regulated by the United States Food and Drug Administration. Many of the studies evaluating the supplements referenced here are small and data are often derived from pooled analysis. In particular, studies to date evaluating garlic as well as many of the alternative approaches have significant limitations in study design. The Table summarizes the available evidence. Ideally, randomized, placebo‐controlled trials are needed to confirm the efficacy of many of the herbal or dietary supplements on the treatment of hypertension. The invasive device‐based therapies are currently being evaluated for use in refractory hypertension. Should they prove efficacious and safe their use as a first‐line therapy may come into play. Longer‐term clinical trials of the invasive therapies are ongoing and will further delineate their safety profiles.

Table TABLE.

 Summary of Nondrug Interventions for Treatment of Hypertension

Intervention	Treatment Effect	Type of Evidence Available
Lifestyle modification
DASH diet	↓ SBP 5.5 mm Hg (↓ SBP 11.4 mm Hg in hypertensive patients)	R, O
Low‐salt DASH diet	↓ SBP 7.1 mm Hg (↓ SBP 11.5 mm Hg in hypertensive patients)	R, O
Dietary supplements
Potassium	↓ SBP 3–12 mm Hg	R, B, P, M
Calcium	↓ SBP 1.4–1.7 mm Hg	R, B, P, M
Vitamin D	↓ SBP 1.9–3.6 mm Hga	R, B, P, M
Folate	↓ SBP 4 mm Hg	R, B, P, C
Coenzyme Q10	↓ SBP 16 mm Hg	R, B, P, M
Fish oil	↓ SBP 2–3 mm Hg	R, B, P, M
Garlic	↓ SBP 10–16 mm Hgb	R, P, M
Fruits and vegetables	↓ SBP 2.8 mm Hg	R, O
Soy protein	↓ SBP 7.8 mm Hg	R, B, P
Flavonoids	↓ SBP 3–5 mm Hg	R, P, M
Vegetarian diet	↓ SBP 5 mm Hg	R, O
High‐fiber diet	↓ SBP 1–2 mm Hg	R, B, P, M
Herbal/alternative approaches
Hawthorn	↓ SBP 3.6 mm Hga	R, B, P
Coleus forskohlii	↓ Cardiac filling pressures	Comp
Mistletoe	↓ BP in rats	Comp, A
Rauwolfia	↓ SBP and DBP	Comp
Acupuncture	↓ SBP 5 mm Hga	R, B, P, M
Meditation	↓ SBP 4.7 mm Hg	R, B, P, M
Devices/interventions
Rheos implantable baroreflex stimulator	↓ SBP 22 mm Hg, >10 mm Hg reduction in SBP in 54% of patientsc	R, B, P
Symplicity renal sympathetic denervation	↓ SBP 32 mm Hgc	R, O
RESPeRATE Paced Breathing	↓ SBP 5–15 mm Hg	R, O
Zona Plus isometric handgrip exercises	↓ SBP 5.7 mm Hg	R, O, M

Abbreviations: ↓ decreased; A, animal model; B, blinded; C, cross‐sectional; Comp, comparative; DASH, Dietary Approaches to Stop Hypertension; O, open‐label; P, placebo‐controlled; M, meta‐analysis; R, randomized; SBP, systolic blood pressure. ^aNonsignificant. ^bStudy design/blinding issues are present. ^cRefractory hypertension.

Conclusions

The first‐line approach to hypertension refractory to lifestyle modification remains pharmacologic therapy in combination with the low‐salt DASH diet. ⁸⁴ However, a wide variety of alternative therapies are available for treatment of hypertension, whether using them to improve BP control to complement medications, as a first‐line approach in combination with lifestyle modification to treat mild hypertension, or in combination with maximal drug therapy for refractory hypertension. These therapies may be of particular use in patients who are reluctant to take medications or are in search of methods to reduce their BP further in combination with pharmacologic therapy. Device‐ or intervention‐based approaches are proving to be safe and effective and may offer the advantage of a one‐time treatment that has lasting benefit.