The Role of Botanicals in Hypertension and Cardiovascular Disease

The Role of Botanicals in Hypertension and Cardiovascular Disease

Tieraona Low Dog, MD

The role of botanicals, or herbal medicines, in the management of cardiovascular disease has been a long and distinguished one. Numerous plants with cardioactive glycosides were used to treat “dropsy,” a folk term for congestive heart failure. One of the more famous was foxglove (Digitalis purpurea), written about as early as 1250 AD, which would eventually serve as the source for standardized digitalis, a drug still in use today.1 The first truly effective antihypertensive drug, reserpine, was extracted from Rauwolfia serpentina, a plant with a long history of use in Ayurveda, the traditional medicine of India.

Botanical products are popular in the United States with sales topping $8 billion in 2017, growing at a rate of 8.5% since the previous year.2 People use natural remedies for a variety of reasons including access, cost, and a perception that they are “safer” than pharmaceuticals.

Although many clinicians express interest in dietary supplements, including botanicals, they also voice legitimate concerns regarding efficacy, quality, safety, and potential drug interactions. Although it is beyond the scope of this chapter to discuss quality, clinicians should be cognizant of the tremendous variability that exists for botanical products in the US marketplace. Products that have been studied in controlled clinical trials are generally of higher quality and should be recommended when possible. Using clinically tested products also allows clinicians recommend an effective dose based on study results.

Clinicians concerns about the concomitant use of botanicals with prescription or over-the-counter medications, particularly in children, elders, and those with diminished renal or hepatic function, is justified. It is difficult to predict pharmacokinetic interactions. There are numerous herb-drug interaction checkers online: one that this author uses is Natural Medicines Comprehensive Database ( Clinicians input medications, vitamins, botanicals, and other supplements, and potential interactions will be displayed, the strength of the risk rated, and links to the primary research provided. Potential risks should be explained to patients and documented in the chart. If monitoring drug levels or serum tests (eg, liver function tests) would help mitigate risk, this should also be offered to the patient.

Although most plants have multimodal effects within the body, this chapter will solely focus on the role of specific botanicals in the management of hypertension.

Beet Root (Beta vulgaris L.)

Lifestyle modifications, particularly dietary, are the primary recommendation for those with prehypertension or stage 1 hypertension. These modifications include a reduction in salt and increase in fruit and vegetable intake. It is the latter, increasing vegetable consumption, that has grabbed the attention of researchers as they try to ascertain which constituents may be responsible for their hypotensive effects. One highly promising constituent is inorganic nitrate, which is found in leafy greens, spinach, beetroot, celery, and others.3 For plasma nitrate to be successfully converted to nitric oxide (NO), the “enterosalivary circuit” plays a crucial role. Approximately 25% of the nitrate that enters the circulation from the gut becomes concentrated in the salivary glands through active uptake by the sialin transporter.58 On interaction with oral bacteria, nitrate is reduced to nitrite, swallowed, and then absorbed, increasing plasma nitrite levels. Endogenous nitrite reductases in the circulation reduce plasma nitrite further to bioactive NO, which can then act as a vasodilator.4 Of interest, daily use of an antiseptic mouthwash caused a decrease in salivary and plasma nitrite levels of healthy volunteers by 90% and 25%, respectively, an effect associated with an average increase in blood pressure of 3.5 mm Hg.5 Alteration of the oral microflora may have broader significance to cardiovascular health than originally thought.

Gastric acid may also be an important part of the equation when it comes to dietary nitrates and blood pressure (BP). Proton pump inhibitors (PPIs), by suppressing gastric acidity, may prevent the formation of nitrous acid from inorganic nitrite after conversion by oral bacteria, blunting the release of NO.6 PPIs also elevate levels of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) via inhibition of dimethylarginine dimethylaminohydrolase, the enzyme responsible for the degradation of ADMA.7 Elevation of ADMA is often seen in patients with cardiovascular disease. A randomized, double-blind, placebo-controlled crossover study of 15 healthy nonsmoking, normotensive subjects (19-39 years) who were pretreated with placebo or esomeprazole (3 × 40 mg) before ingesting sodium nitrite (0.3 mg/kg) found that systolic blood pressure (SBP) was reduced by a maximum of 6 ± 1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect.8 These effects could partially account for the growing body of evidence suggesting a link between these drugs and cardiovascular disease.9

Beetroot is naturally rich in inorganic nitrates and is gaining popularity for its purported benefits for the cardiovascular system and on athletic performance. Studies confirm that beetroot has a beneficial effect on endothelial function. A review of nine crossover trials and three parallel trails found that both inorganic nitrate and beetroot consumption were associated with an improvement in vascular function.10 A meta-analysis found that inorganic nitrate and beetroot juice supplementation were associated with a significant reduction of blood pressure in adults.11

Additional studies have been published since these reviews, included two contradictory results in elder patients. A placebo-controlled, crossover trial in 12 healthy elders (mean age 64 years) randomized participants to receive 140 mL of nitrate-rich beetroot juice (12.9 mmol nitrate) or nitrate-depleted beetroot juice (≤0.04 mmol nitrate) after obtaining baseline data. Systolic, diastolic, and mean arterial blood pressure (MAP) decreased 3 hours relative to baseline only after ingestion of the high-nitrate beetroot juice (P < .05), with plasma nitrate and nitrite levels being elevated 3 and 6 hours post intake (P < .05). The number of blood monocyte-platelet aggregates decreased 3 hours after ingestion of only the high-nitrate beetroot juice (P < .05), indicating a reduction in platelet activation.12 These results suggest that, in addition to a beneficial effect on blood pressure, beetroot may also exert antithrombotic activity in the aging population.

However, another randomized, double-blind, crossover, placebo-controlled study of 20 nonsmoking healthy participants aged 60 to 75 years (10 male and 10 female) with a body mass index (BMI) 20.0 to 29.9 kg/m2 failed to note any beneficial effects on resting systolic or diastolic blood pressure after 7 days of nitrate-rich beetroot juice.13 The study also failed to note any improvement in indexes of central and peripheral cardiac function during cardiopulmonary exercise training compared with nitrate-depleted beetroot as placebo.

Does beetroot supplementation have an “additive effect” in individuals already treated for hypertension? Researchers conducted a randomized, placebo-controlled, double-blind crossover study in 27 treated hypertensive men and women. Like other trials, this study assessed the effect of 1-week intake of nitrate-rich beetroot juice compared with 1-week intake of nitrate-depleted beetroot juice (placebo). Relative to placebo, 1-week intake of nitrate-rich beetroot juice resulted in a threefold increase in plasma nitrite and nitrate, a sevenfold increase in salivary nitrite, an eightfold higher salivary nitrate, and a fourfold increase in both urinary nitrite and nitrate (P < .001). However, no differences in home blood pressure and 24-hour ambulatory blood pressure were observed with 1-week intake of nitrate-rich beetroot juice in comparison with the placebo.14 In those adequately treated for hypertension, the addition of beetroot did not impact blood pressure in this study.

Although there is well-documented biological rationale for the potential of beetroot to have a hypotensive effect, clinical trials have yielded varying results. This variance may be due to a variety of factors: dose of dietary nitrate and duration of supplementation, study design, measurement protocols of blood pressure, populations with low baseline blood pressures at start of trial, or its use in an aging population in which there is a decline in the reducing capacity to convert nitrates to nitrites.13

Dose: Most research trials used beetroot juice providing ˜6.5 to 7.0 mmol NO3 per 70 mL serving, with 2 to 3 servings taken per day. Studies included products from James White Drinks Ltd.: Beet It Sport (6.5-7.0 mmol NO3 per 70 mL serving); Beet It Stamina Shot (6.0 mmol NO3 per 70 mL serving), and Beet It (3.1 g nitrate/L and 0.1 g nitrite/L or 8.0-10.0 mmol NO3 per 140 mL). Other juices studied include Love Beets Beetroot Juice (Gs Fresh Ltd) containing 210 mg nitrate per 250 mL and a standardized juice (Biotta AG) containing 350 mg nitrate per 80 mL.15 A lozenge supplement Neo 40 (Neogenis Labs, Austin, TX, USA) containing beet root extract, hawthorn berry, vitamin C, L-citrulline, and sodium nitrite was also shown to lower SBP by an average of 6 mm Hg and diastolic blood pressure (DBP) by 6 mm Hg at 20 and 60 minutes post ingestion.16

Safety: There are no known safety issues with consumption of powdered beets or beet juice. Beeturia, a reddish hue in the urine, occurs in roughly 10% to 14% of the population and is harmless.17

Summary: The hypotensive effects of beetroot are modest but including beets in the diet, as nitrate-rich juice or standardized beet powder, can be healthy lifestyle recommendations. Patients wising to use beets for hypertension should be instructed to avoid the use of antibacterial mouthwash.

Dandelion Leaf (Taraxacum officinale G.H. Weber ex Wiggers)

Dandelion flower, leaf, and root have been consumed as food, beverage, and medicine since ancient times. Dandelion has been widely recognized as a diuretic for centuries. In fact, the French name pissenlit, from the verb pisser and the noun lit, translates to piss in bed, a nod to
its diuretic activity, particularly when consumed later in the day. The German Commission E recognizes both the root and leaf of dandelion for the stimulation of diuresis,18 although studies suggest the leaf is superior.59 The European Medicines Agency recognizes dandelion as a “traditional herbal medicinal product to increase the amount of urine to achieve flushing of the urinary tract as an adjuvant in minor urinary complaints.”19

In addition to preclinical animal data, a small pilot study examined the effects of fresh dandelion leaf hydroethanolic extract (1 g/mL, 43.5% EtOH final extract) in 28 healthy women aged 18 to 65 years. Subjects self-administered an 8-mL dose of dandelion leaf extract at 8:00 AM, 1:00 PM, and 6:00 PM on the study day. They were asked to measure fluid intake the day before and both fluid intake and urine output for 3 days starting on the study day. There was a significant (P < .05) increase in the frequency of urination for the study group on the day of the trial but not on the total daily urination volume.20 Limitations of the study include significant drop-out (11 participants were unable to complete the study, citing difficulty collecting and measuring of fluid output and/or input) and lack of blinding and placebo group.

Clinicians should note that numerous botanicals have diuretic activity, such as parsley (Petroselinum crispum) and celery seed (Apium graveolens), and may be found in a variety of products designed for managing blood pressure and possibly for mild cases of congestive heart failure. Celery seed was shown in a rat model to reduce BP, likely through inhibition of intracellular calcium influx.21

Dose: 3 to 4 g/d of leaf three times daily.18

Safety: Dandelion has an excellent safety profile. Studies on rabbits, mice, and rats, with rabbits treated orally with dried dandelion plant (3-6 g/kg body) and mice treated with dandelion ethanolic extracts, showed no significant or visible signs of toxicity.22 Contact dermatitis can occur in sensitive individuals when handling fresh dandelion.23 When using large doses of dandelion leaf as a diuretic for a prolonged period, it would seem reasonable to periodically monitor potassium, sodium, magnesium levels.

Summary: Dandelion leaf has a long history of use as a diuretic with some data confirming its traditional use. There are no human clinical trials for dandelion in the management of hypertension.

Garlic (Allium sativum L.)

Garlic is widely consumed in many ethnic cuisines and has a long history as an herbal medicine. A member of the Allium family, which includes onions and leeks, garlic is popular as a dietary supplement. It is promoted for both immune and cardiovascular health, particularly for managing lipids and blood pressure. The mechanism by which it lowers blood pressure is biologically plausible owing to its interaction with hydrogen sulfide- and nitric oxide-signaling pathways.24

Garlic in various forms (eg, aged garlic, garlic powder) has been studied for its impact on blood pressure. A meta-analysis including 17 trials showed that garlic intake resulted in a 3.75-mm Hg reduction (P < .001) in SBP and a 3.39-mm Hg reduction (P < .001) in DBP compared with controls. When subgroups were examined, a significant reduction in SBP was seen in hypertensive (−4.4 mm Hg; P = .004) patients but not in normotensive participants. The authors concluded that “garlic supplements are superior to controls (placebo in most trails) in reducing BP, especially in hypertensive patients.”25

An updated meta-analysis that included 20 trials reported a significant effect of garlic on blood pressure, with an average decrease in SBP of 8.6 mm Hg and in DBP of 6.1 mm Hg in participants with hypertension (n = 14 trial arms, n = 468 participants).26

Arterial stiffness is one of many other risk factors contributing to hypertension and is an important predictor of cardiovascular risk. To test whether garlic has an impact on arterial stiffness, as well as peripheral and central blood pressure, a 12-week randomized, double-blind, placebo-controlled trial of 88 participants with uncontrolled hypertension were given aged garlic extract (AGE; 1.2 g containing 1.2 mg S-allyl cysteine) or placebo. The mean BP was significantly reduced by 5.0 ± 2.1 mm Hg (P = .016) systolic, and in responders by 11.5 ± 1.9 mm Hg systolic and 6.3 ± 1.1 mm Hg diastolic compared with placebo (P < .001). Central hemodynamic measures tended to improve in the AGE group more than in the placebo group, including central blood pressure, central pulse pressure, mean arterial pressure, augmentation pressure, pulse-wave velocity, and arterial stiffness. Trends in beneficial effects of garlic on the inflammatory markers tumor necrosis factor -α, total cholesterol, low-density lipid cholesterol, and apolipoproteins were observed. The treatment was well tolerated, and there was no increase in bleeding risk in those taking blood-thinning medications.27

In 2018, a 12-week double-blind randomized placebo-controlled trial of 49 participants with uncontrolled hypertension found that AGE (1.2 g/d containing 1.2 mg S-allyl cysteine) significantly reduced SBP by 10 ± 3.6 mm Hg and DBP by 5.4 ± 2.3 mm Hg, compared with placebo. Garlic also significantly lowered central blood pressure, pulse pressure, and arterial stiffness (P < .05) Interestingly, this study also noted that the garlic extract increased microbial diversity in the gut, with a marked increase in Lactobacillus and Clostridia species.28

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Feb 27, 2020 | Posted by in CARDIOLOGY | Comments Off on The Role of Botanicals in Hypertension and Cardiovascular Disease
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