The cardiovascular system

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Chapter 15 The cardiovascular system

Cardiovascular (CV) disorders are responsible for many deaths in the Western world, and are a consequence of lifestyle and diet, as well as being hereditary to some extent. Serious conditions such as heart failure should be treated only under the guidance of a qualified physician, but some minor forms of CV disease respond well to changes in diet and taking more exercise, as well as phytotherapy. Cardiology has benefited greatly from the introduction of some newer semi-synthetic drugs based on natural products, including aspirin, an antiplatelet agent derived from salicin, and warfarin, an anticoagulant derived from dicoumarol. Others have been developed using a natural product as a template, for example, verapamil, a calcium channel antagonist used to treat hypertension and angina, is based on the opium alkaloid papaverine, and nifedipine, a calcium channel antagonist and amiodarone, an anti-arrhythmic, were both developed from khellin, the active constituent of Ammi visnaga. Cocaine has cardioactive as well as central nervous system effects, and was the starting material for the development of the anti-arrhythmics procaine and lignocaine, which are more effective and without the unwanted stimulant activity (Hollmann 1992).

Cardiovascular conditions discussed here include heart failure, venous insufficiency, thrombosis and atherosclerosis. Other conditions such as hypertension and cardiac arrhythmias are rarely treated with phytomedicines, although there are some natural products used in their treatment which will be mentioned briefly. Synthetic diuretics are widely used as antihypertensives, but phytomedicines are not suitable for this purpose as they are not sufficiently potent to reduce blood pressure. Instead, they are often incorporated into remedies for urinary tract complaints (see Chapter 20) or to reduce bloating (mild water retention, for example pre-menstrual).

Heart failure and arrhythmias

These conditions can be treated with cardiac glycosides (cardenolides and bufadienolides) such as digoxin, isolated from the foxglove. Lily of the valley (Convallaria majalis) contains convallotoxin (a mixture of cardenolides), and squill (Drimys maritima) contains the bufadienolides scillaren A and proscillaridin, but these are rarely used now. Ouabain, isolated from Strophanthus spp., has been used in emergency cases. The cardiac glycosides have a positive inotropic effect, meaning that they increase the force of contraction of the heart. They are emetic and toxic in large doses and have a cumulative effect and are, therefore, unsuitable for use in the form of herbal extracts. Single isolated compounds for which the pharmacokinetics can be monitored are used instead.

There are, however, other herbal drugs that have beneficial effects upon the heart, the most important of which are hawthorn (Crataegus) and motherwort (Leonurus cardiaca). Hawthorn has anti-arrhythmic activity, and will be discussed briefly below. There is not enough evidence available at present to justify the inclusion of motherwort. In general, however, arrhythmias are treated with isolated compounds, most of which are synthetic, although quinidine (an alkaloid from Cinchona spp.; Fig. 15.1) is still used occasionally. Ajmaline, from Rauvolfia spp., is used as an anti-arrhythmic in some parts of the world; sparteine, from broom (Cytisus scoparius), was formerly employed. Both of these compounds are alkaloids.

Fig. 15.1

Foxglove (digitalis) leaf, Digitalis purpurea L. (Digitalis purpureae folium)

The purple foxglove (Digitalis purpurea) and its close relative the woolly foxglove (D. lanata L., Scrophulariaceae), yield cardiac glycosides. These plants are very common; they are indigenous to Europe and cultivated elsewhere. They do not have a long history of herbal use because of their toxicity, although the famous surgeon William Withering described their use for ‘dropsy’ (an old term for congestive heart failure) in 1870, and this was the first time an effective treatment for this condition had been found. The leaves are the source of the drug and are usually gathered in the second year of growth.

Constituents

Both species contain cardenolides, which are glycosides of the steroidal aglycones digitoxigenin, gitoxigenin and gitaloxigenin. There are very many cardiac glycosides, but the most important is digoxin (Fig. 15.2) and to a much lesser extent digitoxin, and the purpurea glycosides A and B. Digitalis lanata contains higher concentrations of glycosides, including digoxin and lanatosides, and is the main source of digoxin for the pharmaceutical industry.

Fig. 15.2

Therapeutic uses and available evidence

Digoxin increases the force of myocardial contractility and reduces conductivity within the atrioventricular node. It is used primarily in the treatment of supraventricular tachycardia and heart failure and is given as a once-daily dosage in the range 62.5–250 μg. Digitalis glycosides increase the force of contraction of the heart without increasing the oxygen consumption, and slow the heart rate when atrial fibrillation is present. Due to their cumulative effect, the glycosides can easily give rise to toxic symptoms, such as nausea, vomiting and anorexia, especially in the elderly, thus blood levels should be monitored.

Hawthorn, Crataegus spp. (Crataegi folium cum flore, Crataegi fructus)

Hawthorn is a common plant found in hedgerows and gardens throughout Europe and elsewhere; it is sometimes known as mayflower or whitethorn. The flowers, leaves and berries of at least two species are used: Crataegus oxycanthoides Thuill. and C. monogyna Jacq. (Rosaceae). These are hairless, thorny, deciduous shrubs with 3–5 lobed leaves, bearing white, dense clusters of flowers, followed by deep red fruits containing one seed (in C. monogyna) or two seeds (in C. oxycanthoides). The flowers appear in early summer and the berries or ‘haws’ in early autumn. Jams and wines are often made from the fruit.

Constituents

The main constituents of the leaf are flavonoids, including vitexin, vitexin-4-rhamnoside, quercetin and quercetin-3-galactoside, hyperoside, rutin, vicentin, orientin; the fruit contains flavonoids, procyanidins, catechins and epicatechin dimers, as well as phenolic acids such as chlorogenic and caffeic acids. Amines such as phenethylamine and its methoxy derivative, as well as dopamine, acetylcholine and tyramine, have also been isolated. It is thought that a mixture of active constituents may be necessary for the therapeutic effect. The drug prepared from hawthorn is often standardized to contain 4–30 mg of flavonoids, calculated as hyperoside, or 30–160 mg of procyanidins, calculated as epicatechin. In the Eur. Ph., the leaf and flower, and also the berries, are identified using thin layer chromatography (TLC) with the hyperoside, rutin and chlorogenic acid as reference standards. The assays are different, however; whereas the leaf and flower use the flavonoid content, the berries are assayed for anthocyanin content.

Therapeutic uses and available evidence

Hawthorn is used as a cardiac tonic, hypotensive, coronary and peripheral vasodilator, anti-atherosclerotic and anti-arrhythmic. Animal studies have shown beneficial effects on coronary blood flow, blood pressure and heart rate, as well as improved circulation to the extremities (Alternative Medicine Review (Crataegus) 2010). Hawthorn extract inhibits myocardial Na⁺, K⁺-ATPase and exerts a positive inotropic effect and relaxes the coronary artery. It blocks the repolarizing potassium current in the ventricular muscle and so prolongs the refractory period, thus exerting an anti-arrhythmic effect. It seems to protect heart muscle by regulating Akt and HIF-1 signalling pathways (Jayachandran et al 2010), and reducing oxidative stress (Bernatoniene et al 2009, Swaminathan et al 2010). There are as yet few clinical trials of the drug, although a recent double-blind pilot study indicated a promising role for hawthorn extract in mild essential hypertension (Walker et al 2002). However, other studies have found that tolerance to exercise was not improved in patients with class II congestive heart failure (Zick et al 2009). It seems likely that hawthorn can be used as an adjunct or sole treatment only in milder cases of heart disease. The usual recommended dose of standardized extract (see Constituents, above) is 160–900 mg daily. Few side effects have been observed, and both patients and physicians rated the tolerance of the drug as good, although nausea and headache have been reported infrequently.

Venous insufficiency and circulatory disorders

Improvements in circulatory disorders arise from a number of different pharmacological effects, particularly those involving anti-inflammatory and antioxidant activity. Plant drugs with these actions are important in the treatment of haemorrhoids, varicose veins, impaired visual acuity and even in memory enhancement, when blood flow to the brain may be affected. They usually contain saponins with anti-inflammatory activity, or anthocyanidins and other antioxidants. The most important are bilberry, butcher’s broom, horse chestnut, ginkgo and garlic.

Bilberry, Vaccinium myrtillus L. (Myrtilli fructus)

The bilberry, also known as the huckleberry or blueberry (Vaccinium myrtillus L., Vacciniaceae), grows on acid soil in hilly and mountainous regions of Europe, Asia and North America. It is cultivated extensively for its delicious fruit, which ripen from July to September. The soft blue-black berries, about 0.5–1 cm in diameter, have a persistent calyx ring at the apex and contain numerous small oval seeds. Both the ripe fruit and the leaves are used medicinally.

Constituents

The fruit contains anthocyanosides (Fig. 15.3), mainly galactosides and glucosides of cyanidin, delphidin and malvidin, together with vitamin C and volatile flavour components such as trans-2-hexenal and ethyl-2- and -3-methylbutyrates. Unlike other Vaccinium spp., bilberry does not contain arbutin or other hydroquinone derivatives. The anthocyanins can be estimated using their absorption at 528 nm, as described in the Eur. Ph.

Fig. 15.3

Therapeutic uses and available evidence

The berries were traditionally used as an antidiabetic, and an astringent and antiseptic for diarrhoea. However, bilberry is now more important as an agent to improve blood circulation in venous insufficiency, especially for vision disorders such as retinopathy caused by diabetes or hypertension. The anthocyanosides are mainly responsible for these properties, due to their antioxidant and free radical scavenging properties. Other cardiovascular benefits include antiplatelet and anti-atherosclerotic effects. Bilberry extracts have a spasmolytic action on the gut and inhibit certain proteolytic enzymes. Anti-inflammatory, antiulcer effects have also been noted, and many of these have been supported by clinical studies (e.g. Christie et al 2001), although the quality of the trials for improving vision have been criticised for their methodology (Canter and Ernst 2004). The usual daily dose of a standardized anthocyanoside extract of bilberry is 480 mg, taken in divided doses. Few side effects have been observed, as would be expected of a widely consumed food substance.

Butcher’s broom, Ruscus aculeatus (Rusci rhizoma)

Butcher’s broom (Ruscus aculeatus L., Liliaceae) is an evergreen shrub native to Europe, and is found in dry woods and among rocks. It is often cultivated for its tough, spiky twigs and ‘leaves’, which can be preserved and used for decoration. The true leaves are reduced to small scales and the stems flattened at the ends into oval ‘cladodes’ which resemble leaves, each bearing a small white flower in the centre, followed by a round scarlet berry, and ending in a sharp spine. The rhizome or whole plant can be used.

Constituents

Actives are saponin glycosides, including ruscine and ruscoside, aculeosides A and B, which are based on ruscogenin (1β-hydroxydiosgenin) and neoruscogenin.

Therapeutic uses and available evidence

Butcher’s broom has anti-inflammatory effects and is used mainly for diseases of venous insufficiency, such as varicose veins and haemorrhoids. The ruscogenin constituents have been shown to reduce vascular permeability and improve symptoms of retinopathy and lipid profiles of diabetic patients. The extract is either taken internally as a decoction or, more often, applied topically in the form of an ointment (or a suppository in the case of haemorrhoids). The saponins inhibit elastase activity in vitro and for this reason extracts are widely used in cosmetic preparations (Redman 2000). When applied topically, few side effects have been observed, apart from occasional irritation.

Ginkgo, Ginkgo biloba (Ginkgo folium)

See Chapter 17 for more detail about the plant. Ginkgo biloba can also be used in cases of peripheral arterial occlusive disease and other circulatory disorders. Although probably less potent than some synthetic drugs, it has the advantage of being well tolerated. Ginkgo improves blood circulation and can alleviate some of the symptoms of tinnitus, intermittent claudication and altitude sickness. Ginkgo extracts have complex effects on isolated blood vessels. The ginkgolides are specific platelet-activating factor (PAF) antagonists and inhibit effects produced by PAF, including platelet aggregation and cerebral ischaemia. The usual dose is 120–160 mg of extract daily.

Horse chestnut, Aesculus hippocastaneum L. (Hippocastani semen)

Aesculus hippocastaum (syn. Hippocastanum vulgare, Gaertn., Hippocastanaceae) is native to western Asia, but is now cultivated and naturalized in most temperate regions. It is a large tree, bearing large sticky leaf buds, which open in early spring. The leaves are composed of 5–7 large oval leaflets; the flowers have a candle-like appearance and are white or pink in colour. The bark is thick, rough, grey or brown on the external surface and pinkish-brown and finely striated on the inside. The fruits are spiny capsules, each with two to four compartments containing the well-known large shiny brown seeds or ‘conkers’. The seeds, and occasionally the bark, are used.

Constituents

Both contain a complex mixture of saponins based on protoescigenin and barringtogenol-C, which is sometimes known as ‘aescin’ (or ‘escin’), although this term refers more properly to the isomeric compound aescin (see Fig. 15.4). More than 30 saponins have been identified, including α- and β-escin, together with escins Ia, Ib, IIa, IIb, IIIa, etc. Sterols and other triterpenes such friedelin, taraxerol and spinasterol are present, as well as coumarins (e.g. esculin=aesculin) and fraxin, flavonoids and anthocyanidins.

Fig. 15.4

Therapeutic uses and available evidence

Extracts of horse chestnut, or, more usually, extracts standardized to the escin content, are used particularly for conditions involving chronic venous insufficiency (CVI), bruising and sports injuries. They can be taken internally or applied topically. A number of clinical studies have shown benefits in CVI (Pittler and Ernst 2006), deep vein thrombosis (DVT), including after surgery, varicose veins (including those of pregnancy) and for the prevention of oedema during a long (15 h) aeroplane flight. It was found to be beneficial in the treatment of cerebral oedema following road accidents. Venotonic effects, and an improvement in capillary resistance, have also been noted in healthy volunteers (Suter et al 2006). Escin has been shown to reduce oedema, decrease capillary permeability and increase venous tone, and horse chestnut extract to contract both veins and arteries in vitro, with veins being the more sensitive. The extract also significantly reduced ADP-induced human platelet aggregation, and these effects appear to be at least partly mediated through 5-HT(2A) receptors (Felixsson et al 2010). Horse chestnut extract also antagonizes some of the effects of bradykinin and produces an increase in plasma levels of adrenocorticotrophin, corticosterone and glucose in animals. Escin is widely used in cosmetics. The usual dose is 600 mg of extract daily, which corresponds to about 100 mg of escin. Extracts are well tolerated at therapeutic doses, but higher amounts can cause gastrointestinal upset with internal use, and occasional irritation with external application.

Red root sage, Salvia miltiorrhiza L. (Salviae miltiorrhizae radix)

The root and rhizome of Salvia miltiorrhiza Bunge, also known as Danshen, are widely used in traditional Chinese medicine to treat many types of cardiovascular diseases, including ischaemic and circulatory disorders such as angina, after stroke and atherosclerosis. The root has a characteristic bright red colour, which is due to the active constituents, the tanshinones.

Constituents

The main active constituents are diterpene quinones, known as tanshinones (one of the transliterations of danshen is tan-shen, hence the quinones were called tanshinones). Tanshinone I, tanshinone II, cryptotanshinone are the major constituents, although nearly 40 variants of the basic tanshinone structures have been found in the roots. The total tanshinone content of the roots is about 1%, with tanshinone I and II and cryptotanshinone being the major components.

Therapeutic uses and available evidence

Animal studies have shown many relevant effects, such as protecting heart muscle from ischaemia and improving microcirculation. The isolated tanshinones have been shown to reduce fever and inflammation, inhibit platelet aggregation, dilate the blood vessels and aid urinary excretion of toxins. Salvia miltiorrhiza has a mild vasodilatory effect but does not increase cardiac output. Clinical studies carried out in China have shown benefit to patients with heart and circulatory diseases, including ischaemic stroke and acute myocardial infarction, but many of these do not fulfil the criteria required for acceptance in the West, and the efficacy has, therefore, not been accepted there (Wu et al 2007, Wu et al 2008, Yu et al 2009). In general, Salvia miltiorrhiza seems to be safe and well-tolerated at the usual dose of 2–6 g day for the dried root, or equivalent in the form of an extract, but there is a potential for drug interactions, especially with other cardiovascular drugs (Williamson et al 2009).

Red vine leaf, Vitis vinifera L. (Vitis viniferae folium)

Certain varieties of grape vine (Vitis vinifera L., a plant which needs no description) produce red leaves which are used in the treatment of CVI and, in particular, varicose veins. Unusually, however, the definition of the botanical drug not only covers the species and a certain plant part, but also the use of a specific prominently coloured variety.

Constituents

Grape leaves contain a wide range of polyphenols including quercetin-3-O-beta-D-glucuronide and isoquercetrin (the main flavonoids), anthocyanins, oligomeric proanthocyanidins, catechin, epicatechin monomers and dimers, gallic acid and astilbine. The phytoalexin trans-resveratrol, another polyphenolic substance belonging to the stilbene group, can also be found in grape vine, organic acids, mainly malic and oxalic acid. The dried leaves of red vine should contain at least 4% of total polyphenols and 0.2% of anthocyanins.

Therapeutic uses and available evidence

Clinical studies have shown that the extract can improve objective symptoms of CVI and that it may prevent further CVI deterioration (Kalus et al 2004). Red vine leaf extracts are also used to improve the microcirculation and aid wound healing (Wollina et al 2006). In vitro studies indicate that they have antioxidant and anti-inflammatory properties, and that they inhibit platelet aggregation and hyaluronidase, and reduce oedema, possibly by reducing capillary permeability. Preclinical in vivo experiments demonstrated anti-inflammatory and capillary wall thickening effects.

Red vine leaf extract can be applied topically and taken internally, and is well-tolerated, although minor gastrointestinal effects have been reported. Commercial products are usually standardized to 90% polyphenols and 5% astilbine, with a daily dose of 360 mg red vine leaf extract being the recommended internal dose.