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From The August 2000 Issue of Nutrition Science News
Hawthorn: Old Reliable for the Heart
by The American Herbal Pharmacopoeia
A military physician practicing during the time of Roman emperor Nero, about the first century A.D., was the first to document the medicinal properties of hawthorn (Crataegus spp.). Ancient medical writers such as Dioscorides Pedanius (ca. A.D. 4080) and Claudius Galen (ca. A.D. 131208) noted the botanical in their respective works, but they provided little data as to its medicinal use. According to French naturalist and author Georges-Louis Leclerc, it was in the 1600s that hawthorn became known as a heart medicine. In fact, a syrup prepared from the fruit was used as a heart medicine in the late 1500s by Josephus Quercetanus, the private physician of King Henry IV of France.1 Over time, hawthorn's popularity as a heart medicine appears to have caught on, making it one of the most popular of all the botanical cardiovascular medicines from 1894 onward.2
Even today, hawthorn remains one of the the more popularly used botanical medicines for heart conditions throughout Europe, particularly in Germany and Switzerland where numerous preparations are available. Preparations are made as jams and wines of the fruit; the fruit itself; leaf and flower preparations including teas, tinctures and liquid extracts; and various powdered preparations including nonstandardized and standardized extracts. Injectable preparations are also available in Europe. In addition, most of these same preparations are available on the American market as dietary supplements.
Pharmacodynamics
Various hawthorn preparations have been studied for their pharmacological properties, with the research primarily focusing on the herb's cardiovascular activity. The majority of recent clinical studies have been conducted using proprietary preparations prepared from the leaves and flowers. Other preparations used include fresh leaf/flower/fruit combinations as well as aqueous extracts, methanolic extracts and ethanolic extracts. In addition, one study used only dried blossoms. It should be noted that different preparations may be marketed with the same name in different countries, and some preparations may have undergone modification over the time span of the studies cited.
Each hawthorn preparation has a number of active compounds, and no single constituent has proven to be the primary agent for the effects seen. Among the active constituents identified, the most important are the phenols, specifically the flavonoids and the oligomer procyanidin (OPC) fractions derived from the catechin and epicatechin chemical units. Numerous studies have also been conducted using isolated compounds. Each gives a similar pharmacodynamic profile. Cardioactivity has been observed in vitro and in animal and human clinical trials. Preparations administered orally are reported to have a more prolonged effect than those administered parenterally.1
The results of such research suggest the primary activity of hawthorn is to increase coronary blood flow.3 This may be due to a relaxation of coronary arteries, which directly increases blood flow, or through an increase in contraction and relaxation velocities, which increases the diastolic interval and thus allows more time for blood passage through the heart's arteries.4 Postively influencing the force of heart muscle contractility, called inotropic action, may also be due to inhibition of myocardial Na+/K+ATPase, which is an integral membrane enzyme that maintains the heart's resting potential.5 Hawthorn also slightly increases the strength of the contraction and decreases blood pressure.6,7 This latter effect results in an increase in exercise tolerance during the early stages of congestive heart failure.8
One mechanism most commonly proposed to explain hawthorn's cardioactive effects is its ability to inhibit the enzyme phosphodiesterase, which ultimately results in an increase in intracellular cyclic nucleotides and a subsequent positive inotropic effect.9 Using computer-assisted model analysis, catechin, the flavonoid vitexin and the flavonol kaempferol from hawthorn were observed to be structurally similar to papaverine and theophylline, two chemical agents known to inhibit phosphodiesterase. In the same analysis, another constituent of hawthorn, ursolic acid, was also reported to interact with the digitaloid binding site for Na+/K+ATPase.10 Hawthorn may also have a cardioprotective effect due to its ability to decrease the oxygen demands of cardiac tissue.11,12
Varying results have been observed regarding the effects of hawthorn and its constituents on heart rate. In the majority of in vitro studies, an increase in heart rate has been observed while, conversely, most in vivo studies report a decrease in heart rate.13
Cardioactivity in Clinical Studies
Hawthorn has been studied primarily for its clinical use in the treatment of early-stage heart failure. Early stages consist of class I and class II cardiac insufficiency, as classified by the New York Heart Association (NYHA). The stage designations are as follows: class I (no limitations on physical activity even when engaging in heavy physical activities), class II (fatigue or shortness of breath when engaging in heavy physical activities), class III (limitation of physical activity even on light exertion), and class IV (symptoms of congestive heart failure even at rest). Many clinical studies have investigated the use of hawthorn extracts on class I and class II cardiac insufficiency.9 It is important to note that it is a matter of debate whether or not patients with NYHA class I cardiac insufficiency require pharmacological intervention.
In one study, the effect of 200 mg three times/day of a proprietary methanolic extract adjusted to 18 mg flavonoids was tested on 78 patients with class II heart failure. The eight-week study included 30 male and 48 female patients with an average age of 61.3 years. This was an eight-week, multicenter, double-blind, placebo-controlled study of exercise ability (work capacity) as tested by ergometer bicycle. Maximum work capacity was determined by measuring work output in watts over a three-minute period using an increasing load. Secondary parameters measured included blood pressure, heart rate and the patients' subjective feelings of health.
At the beginning of the study there was no statistical difference in exercise capacity between control and hawthorn groups. The median value of work capacity in the hawthorn group increased from 79 watts to 99 watts after four weeks. Placebo controls showed no increase in work capacity. The difference between the two groups was statistically significant at four and eight weeks. Secondary parameters were unchanged in the placebo group but were significantly improved in the hawthorn group, evidenced by a decrease in systolic blood pressure and heart rate, and a decrease in severity of symptoms by subjective analysis.14
In a second, double-blind crossover study, 36 patients with multiple comorbidities, or diseases coexisting with the primary disease, tested the effects of the proprietary ethanolic extract containing 18.75 percent proanthocyanidins.15 These patients averaged 74 years in age and exhibited class I or class II cardiac insufficiency. Patients given one capsule of this hawthorn extract three times/day showed a decrease in heart rate and improvements in cardiac output under resting and exercise conditions that were not seen in the control group. Treated patients also had significant improvements in psychological assessment according to the Brief Psychiatric Rating Scale, including a reduction in anxiety and improvements in sleep behavior.
Such studies demonstrate that hawthorn extracts can produce significant improvements in early-class heart insufficiency.
Other Effects
In a number of studies, hawthorn has been shown to exhibit antioxidant activity, which is considered to be primarily associated with its flavonoid and procyanidin content. Pharmacognosy lab researchers at the University of Lille in France report that various preparations exhibited low antiviral IC50 values in vitro in three different models of reactive oxygen species (ROS) generation (superoxide anion, hydrogen peroxide, and hypochlorus acid). These researchers report that the most significant antioxidant activity was observed using an extract of fresh, young leaves, followed by fresh floral buds and dried flowers.16
In another in vitro study, a dried leaf and flower extract standardized to 15 mg OPCs, given at dosages of 5, 10 and 20 ug/mL to sarcoma 180 cancer cells, significantly countered the free radical-damaging effects of the chemotherapeutic drug doxorubicin without compromising its antitumor activity.17 This free radical-scavenging function is likely to contribute to hawthorn's cardiac-protective properties after inadequate blood flow to the heart, called ischemia. This antioxidant activity is reported to be primarily correlated with the oligomer procyanidins.18
Hawthorn or its constituents also have been shown to have a mild to marked sedative effect in human and animal studies.19 OPCs have been reported to be partially responsible for this effect.20
Side Effects
Side effects of hawthorn use are minimal. It is classified as an herb that can be safely consumed when used appropriately. It does, however, show an ability to potentiate digitalis medications.21 Human subjects taking 180900 mg daily of preparations consisting of extracts of leaf with flower, leaf with flower and fruit, and fruit only (standardized to 5 percent OPCs, 19 percent OPCs, and 2.2 percent flavonoids, respectively) reported no side effects.9
In a surveillance study of 3,664 patients with class I or II heart insufficiency, 940 practicing physicians documented the tolerability and efficacy of a 300 mg, three times/day dose of a hawthorn extract adjusted to 18 mg flavonoids. A total of 72 adverse drug reactions were reported in 48 patients. A connection between symptoms and hawthorn therapy was seen in 26 patients, and a causal relationship was confirmed in 22 patients. Adverse effects were considered probable in another four patients. Seven patients reported gastrointestinal disorders, three complained of palpitations, and two of headaches and dizziness. Circulatory disturbances, sleeplessness and agitation were each reported once. Data on the adverse effects reported by five additional patients were not reported.22
No changes in blood status, liver enzymes, electrolytes, glucose or blood sedimentation rate were observed in a human clinical study of 136 patients treated with 160 mg of the WS 1442 hawthorn extract.23
Finally, patients with cardiovascular disease, or those who are using cardiovascular medications, should inform their primary health care provider if they are using hawthorn preparations.
Sidebars:
AHP Sets Standard Of Excellence
Hawthorne Structure/Function Claim
Excerpt reprinted with permission from American Herbal Pharmacopoeia and Therapeutic Compendium, a bimonthly series of peer-reviewed monographs. Complete monographs are available individually or by subscription and are published by the American Herbal Pharmacopoeia, Santa Cruz, Calif., 1999.
References
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3. Taskov M. On the coronary and cardiotonic action of Crataemon. Acta Physiol Pharm 1977;3:53-7.
4. Schussler M, et al. Myocardial effects of flavonoids from Crataegus species. Arzneim Forsch Drug Res 1995;45:842-5.
5. Holzl J, et al. [Studies of pharmacological mechanism of action of Craetaegus fraction and their analytical characteristics.] Arch Pharm 1988;321:631.
6. Abdul-Ghani AS, et al. Hypotensive effect of Crataegus exyacantha. Int J Crude Drug Res 1987;25:216-20.
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8. Leuchtgens H. Crataegus special extract WS 1442 in NYHA II heart failure. A placebo-controlled randomized double-blind study. Fortschr Med 1993 Jul 20;111(20-21):352-4.
9. ReutXer HD. [Crataegus as cardiac plant.] Z Phytother 1994;15:73-81.
10. Holtje H-D. [Mechanism of Crataegus components.] Munch med Wschr 136(Suppl 1):S61-3.
11. Nasa Y, et al. Protective effect of Crataegus extract on the cardiac mechanical dysfunction in isolated perfused working rat heart. Arzneim Forsch Drug Res 1993;43:945-9.
12. Kanno T, et al. Reduction of the hypoxia-induced depression in the intracellular electrical activity of the ventricular muscle fibers of the rabbit fed on food containing Crataegutt. Jpn Heart J 1976 Jul;17(4):512-20.
13.Ammon H, Kaul R. [Heart circulation mechanism of action of Crataegus extract, flavonoid and procyanidin: How it affects the heart.] Dtsch Apoth Ztg 1994;134(27):2521-35.
14. Schmidt U, et al. Efficacy of the hawthorn (Crataegus) preparation LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II. Phytomedicine 1994;1:17-24.
15. O'Connolly M, et al. [Handling of older, multimorbidity patients with stenocardio with those symptoms.] Therapiewoche 1987;37:3587-600.
16. Bahorun T, et al. Oxygen species scavenging activity of phenolic extracts from hawthorn fresh plant organs and pharmaceutical preparations. Arzneim Forsch Drug Res 1996;11:1086-9.
17. Brehm M, et al. Comparable antitumor activity of doxorubicin plus two radical scavenging plant extract preparations (Ginkgo biloba, Crataegus oxyacantha) and of doxorubicin alone. Conbrib Oncol 1995;48:48-52.
18. Chatterjee S, et al. Antioxidative and human neutrophil elastase inhibitory activity of Crataegus extract (WS-1442) standardized on oligomeric procyanidins (OPC). Proceedings of the 2nd International Congress on Phytomedicine; 1996 Sep 11-14; Munich. Munich: ESCOP. p SL-43.
19. Della Loggia R, et al. Depressive effect of Crataegus oxyacantha L on central nervous system in mice. 30 Pharm 1983;51:319-24.
20. Rewerski V, et al. [Some pharmacological properties of Craegus oxycantha compound, an isolated oligometric procyanidin.] Arzneim Forsch Drug Res 1971;21:886-8.
21. McGuffin M, et al. Botanical Safety handbook. Boca Raton (FL): CRC;1997.p.231.
22. Loew D, et al. Efficacy and tolerability of a hawthorn preparation in patients with heart failure stage I and II according to NYHA—a surveillance study. Proceedings of the 2nd International Congress on Phytomedicine 1996 Sep 11-14; Munich. Munich: ESCOP p SL-70.
23. Weikl A, et al. [Crataegus special extract WS 1442: Understanding efficacy on patients with heart insufficiency (NYHA II)]. Fortschr Med 1996;114:291-6.
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