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Review Article Effect of Crataegus Usage in Cardiovascular Disease Prevention: An Evidence-Based Approach

Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID , 16 pages Review Article Effect of Crataegus Usage in Cardiovascular Disease Prevention:
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Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID , 16 pages Review Article Effect of Crataegus Usage in Cardiovascular Disease Prevention: An Evidence-Based Approach Jie Wang, Xingjiang Xiong, and Bo Feng Department of Cardiology, Guang anmen Hospital, China Academy of Chinese Medical Sciences, Beijing , China Correspondence should be addressed to Bo Feng; Received 6 October 2013; Accepted 24 November 2013 Academic Editor: Tabinda Ashfaq Copyright 2013 Jie Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hawthorn (Crataegus oxyacantha) is a widely used Chinese herb for treatment of gastrointestinal ailments and heart problems and consumed as food. In North America, the role of treatment for heart problems dates back to Currently, evidence is accumulating from various in vivo and in vitro studies that hawthorn extracts exert a wide range of cardiovascular pharmacological properties, including antioxidant activity, positive inotropic effect, anti-inflammatory effect, anticardiac remodeling effect, antiplatelet aggregation effect, vasodilating effect, endothelial protective effect, reduction of smooth muscle cell migration and proliferation, protective effect against ischemia/reperfusion injury, antiarrhythmic effect, lipid-lowering effect and decrease of arterial blood pressure effect. On the other hand, reviews of placebo-controlled trials have reported both subjective and objective improvement in patients with mild forms of heart failure (NYHA I III), hypertension, and hyperlipidemia. This paper discussed the underlying pharmacology mechanisms in potential cardioprotective effects and elucidated the clinical applications of Crataegus and its various extracts. 1. Introduction Hawthorn (Crataegus oxyacantha), also known as haw, maybush, or whitehorn, is part of a genus of spiny shrubs and trees native to temperate regions in the Northern Hemisphere in Europe, Asia, and North America [1]. It belongs to the Rosaceae family and consists of bright green leaves, white flowers, and bright red berries (as shown in Figure 1).Hawthornhasbeenusedinfolkmedicineforthe treatment of diarrhea, gall bladder disease, insomnia, and as an antispasmodic agent in the treatment of asthma [2]. In Chinese, hawthorn was also used for a variety of conditions including digestive problems, hyperlipidemia, poor circulation, and dyspnea [3, 4]. For example, the dried fruits are traditionally used as a digestive aid and are often made into jam, jelly, candies, or wine [5]. Also, preparations of hawthorn are available in various forms ranging from infusions and tinctures to standardized extracts and may be available variously as authorized prescription drugs, over-the-counter (OTC) medications, authorized herbal medicinal products, dietary supplements, or unregulated herbal remedies. The use of hawthorn for the treatment of cardiovascular heart disease dates back to the late 1800s [6, 7]. Current claims suggested that hawthorn could be used as an alternative therapy for various cardiovascular diseases, such as angina, hypertension, hyperlipidemia, arrhythmia, and New York Heart Association (NYHA) functional class II congestive heart failure [8, 9]. Nowadays, it is gaining attention for its potential cardiovascular enhancing and protective properties [10] and numerous laboratory tests and clinical trials have demonstrated hawthorn s efficacy in the treatment or preventionofcardiovasculardiseasesandthemostsubstantial evidence for clinical benefits of hawthorn is its use in chronic congestive heart failure (CHF) [11]. A meta-analysis of randomized, placebo-controlled trials of hawthorn extract in combination with standard CHF therapy suggested several beneficial cardiovascular effects of hawthorn as compared to placebo [12]. Similarly, a 2008 Cochrane review, wherein all primary literature pertaining to the health effects of hawthorn on humans was assessed, found a significant benefit in symptom control and physiologic outcomes from hawthorn extract as an adjunctive treatment for chronic heart failure [13]. Besides, the antioxidant, positive inotropic, anti-inflammatory, and anticardiac remodeling effects and 2 Evidence-Based Complementary and Alternative Medicine O R 2 OR 1 (a) O R 1 = H or sugar R 2 = H, or O-sugar R 2 (a) O R 3 (b) R 1 O R 1 = H or sugar R 2 = H or sugar R 3 = H or (b) Figure 2: Example of flavonols (a) and flavones (b) in Crataegus leaves and flowers. (c) Figure1: Different parts ofcrataegus monogyna used as traditional food and folk medicine in China. (a) Flowers. (b) Ripened fruits. (c) Dried fruit for pharmaceutical use. other cardiovascular protective effect of the hawthorn active ingredients were demonstrated in various in vivo and in vitro experiments. Crataegus has a number of pharmacological properties, but the specific mechanism is not clear. 2. Chemical Constituents Crataegus oxyacantha is popularly known for its cardioprotective action. Crataegus monogyna and Crataegus laevigata are the major hawthorn species in middle Europe, Crataegus pentagyna, Crataegus nigra, andcrataegus azarolus in southern and southeastern Europe, and Crataegus pinnatifida and Crataegus scabrifolia in China [14, 15]. Available products include tinctures, tablets, teas, and aqueous extracts [16, 17]. Extracts may be prepared using hydroalcoholic (methanol or ethanol) or water-based extraction and are derived from various plant parts including, most commonly, berries or leaves and flowers [18]. The source material contains a range of pharmacologically active substances, of which the most widespread compounds reported are flavonoids, triterpenic acids, and phenol carboxylic acids [19]. Flavonoids (as shown in Figure 2) such as vitexin, hyperoside, rutin, or vitexin-2 -O-α-L-rhamnoside, and catechin/epicatechin derived oligomeric procyanidins (OPC) (as shown in Figure 3) are the most important constituent. Triterpenic acids (ursolic, oleanolic, and crataegolic acids) and phenol carboxylic acids (chlorogenic and caffeic acids and various amines) are thoroughly also investigated in in vitro experiments, in animal studies, and in human clinical trials [20 23]. Currently, the most studied hawthorn extracts are WS 1442 (45% ethanol extract) and LI 132 (70% methanol extract) [24]. WS 1442 is a standardized dry extract adjusted to a content of 18.75% OPC with a starting plant material/extract ratio of 4 to 7 : 1, while LI 132 is adapted to a content of 2.2% flavonoids [25, 26]. Evidence-Based Complementary and Alternative Medicine 3 O O force of contraction in left ventricular papillary muscle strips through a camp-independent mechanism. As suggested by the concentration-dependent displacement of specifically bound 3 H-ouabain from its receptor, the sarcolemmal Na + /K + -ATPase, WS 1442 seems to increase the force of contraction by inhibition of the sodium pump. Also, they can enhance the peak intracellular Ca 2+ concentration as well in human myocardium from patients with congestive heart failure [31]. Similarly, hawthorn most probably acts on the Na + /K + -ATPase and increases the efficiency of calcium transport in cardiomyocytes [32]. Figure 3: Example of an oligomeric procyanidin (OPC) consisting of three epicatechin monomers. 3. Cardiovascular Effect 3.1. Antioxidant Activity. Oxidative stress is a major concern in the pathogenesis of myocardial ischaemia. Therapeutic intervention showing antioxidant or free radical scavenging activity should exert beneficial effects against oxidative stress associated with various cardiovascular diseases (CVDs) [27]. Possible mechanisms of tincture of Crataegus (TCR) include preventingtheincreaseinlipidperoxidationandactivity of marker enzymes, preventing the isoproterenol-induced decrease in antioxidant enzymes in the heart, and increasing therateofadp-stimulatedoxygenuptakeandrespiratory coupling ratio in isoproterenol-induced rats [28]. As we know, CVDs are associated with the structural and functional disturbances in heart mitochondria. As mitochondria produce 95% of energy necessary for heart function, therapeutic agents that could influence mitochondrial dysfunction are of special importance. Alcoholic extract of Crataegus oxyacantha (AEC) pretreatment maintained mitochondrial antioxidant status and prevented mitochondrial lipid peroxidative damage and decrease in Krebs cycle enzymes induced by isoproterenol in rat heart [29]. Another research showed that Crataegus fruit extracts decreased the mitochondrial membrane potential by mv measured with a tetraphenylphosphonium-selective electrode and H 2 O 2 productionmeasuredfluorometrically.alsoitslightlyreduced the maximal ADP-stimulated and uncoupled respiration, which might be due to inhibition of the mitochondrial respiratory chain between flavoprotein and cytochrome [30] Positive Inotropic Effect. One research elucidated the potential inotropic mode of action of Crataegus special extract WS It is demonstrated that WS 1442 as well as its lipophilic ethyl acetate-soluble fraction A increased O 3.3. Anti-Inflammatory Effect. Chronic and uncontrolled inflammation plays an important role in CVDs. Inflammation has been increasingly recognized as an important pathogenic component of chronic heart failure [33, 34]. Many transcriptional factors, inflammatory cytokines, enzymes, and other mediators have been shown to be related to these effects [35]. The observed anti-inflammatory effects of the waterfractionofhawthornfruitmightbeattributedtothe downregulation of COX-2, TNF-α, IL-1β, and IL-6 expression in LPS-stimulated RAW cells [36]. AEC most likely achieves its myocardial protection by reducing nitritive stress and oxidative stress and decreasing apoptosis. This conclusion is supported by reduced inos expression, nitrite levels, downregulated COX-2, decreased lipid peroxidation, decreased release of cytochrome c, and protection of DNA fragmentation [37]. Besides, hawthorn extract inhibited N- formyl-met-leu-phe (FMLP-) induced superoxide anion generation, elastase release, and chemotactic migration and reduced leukotriene B4 production and lipopolysaccharideinduced generation of TNF-α and IL-8.Also the extract inhibited intracellular calcium signal and the extracellular calcium entry into calcium-depleted neutrophils [38]. Moreover, the anti-inflammatory mechanism also illustrated that the activity of triterpene fraction isolated from Crataegus was closely related to inhibition of peritoneal leukocyte infiltration and weak inhibition of phospholipase A2 (PLA2) in vitro [39] Anticardiac Remodeling Effect. Cardiac remodeling comprises changes in heart structure such as alterations in cardiac wall thickness, chamber size, cell dimension, cell number, and extracellular matrix volume. These structural changes can influence heart function [40]. Hawthorn markedly reduced LV chamber volumes (VOL) after aortic constriction (AC) and augmented relative wall thickness and attenuated the ACinduceddecreaseinvelocityofcircumferentialshortening (Vcfc) showing antileft ventricular remodeling and antimyocardial dysfunction in early pressure overload-induced cardiac hypertrophy [41] Antiplatelet Aggregation Effect. Activated platelets play a crucial role in the pathological development of several arterial disorders, including strokes and acute coronary syndromes, which are initiated by plaque disruption and subsequent platelet-thrombus formation [42 44]. Crataegus extract had effective antiplatelet activity at low doses of 100, 200, and 4 Evidence-Based Complementary and Alternative Medicine 500 mg/kg as indicated by the increase in bleeding time, decrease in platelet aggregation as assessed by PFA-100, and reduction in serum levels of thromboxane B2 [45] Vasodilating Effect. Vascular protection might be associated with the direct action on endothelial cells. The endothelium regulates the contractility of the underlying vascular smooth muscle cells by releasing a number of factors, the most important of which are the nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF). These two factors play a major role in the controlling of vascular homeostasis [46 49]. Endothelial NO-release is related to an activation of the endothelial nitric oxide synthase (enos) and can be stimulated by various agonists. It is concludedinvitroandvivoresearchthatws1442induced an endothelium-dependent, NO-mediated vasorelaxation via enos phosphorylation at serine 1177 [50]. Besides, WS 1442 induced endothelium-dependent No-mediated relaxations of coronary artery rings through the redox-sensitive Src/PI3- kinase/akt-dependent phosphorylation of enos [51]. Moreover, it preserves endothelium-dependent relaxation and vascular contraction in STZ-induced diabetes, possibly by reducing inos expression in the aorta, by decreasing plasma levels of TNF-α and IL-6, and by preventing lipid peroxidation [52]. There is evidence that NO may increase activation of both the ATP-dependent K + -channel and the Ca 2+ -dependent K + - channel in vascular smooth muscle cells [53]. Similar experiment showed that procyanidins in Crataegus extract may be responsible for the endothelium-dependent NO-mediated relaxation, possibly via activation of tetraethylammonium sensitive K + channels in isolated rat aorta [54]. Quite recently it has been demonstrated that red blood cells (RBCs) express a functional NO-synthase (rbcnos) and rbcnos activation has been associated with increased RBC deformability. WS 1442 activates rbcnos and causes NO-formation in RBCs [55]. There is another opinion that hawthorn does have a vasodilating action both in the coronary circulation and the peripheral vasculature that may be mediated by inhibition of angiotensin-converting enzyme (ACE) [56] Endothelial Protective Effect. Endothelial hyperpermeability, that is, a compromised endothelial barrier function, and the subsequent formation of edema are hallmarks of many severe disorders, such as atherosclerosis, asthma, sepsis, or heart failure [57 60]. One research showed that the herbal drug WS 1442 effectively protects against endothelial barrier dysfunction by its action on key determinants of endothelial permeability (adherens junctions, actin cytoskeleton, and contractile apparatus) by inhibiting the barrier-destabilizing calcium/pkc/rho A signaling and activating the barrier-stabilizing camp/epac1/rap1 pathway [61]. Another research showed that WS 1442 prevented the deleterious hyperpermeability-associated rise of [Ca 2+ ] i by interferring with sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase (SERCA) and the inositol 1,4,5- trisphosphate (IP3) pathway without inducing store-operated calcium entry (SOCE) [62]. Past and ongoing studies also suggest that chronic intake of Crataegus prevented agingrelated endothelial dysfunction by reducing the prostanoidmediated contractile responses, most likely by improving the increased oxidative stress and the over expression of COX-1 and COX-2 [63] Reduction of Smooth Muscle Cell Migration and Proliferation. There have been few studies on the migration and proliferation effects of herbal medications such as hawthorn. Hawthorn appears to exhibit some cardioprotective effects due to reduction of smooth muscle cell migration and proliferation properties. Currently, up to 50% of patients undergo conventional balloon angioplasty recurrent stenosis [64]. After vessel injury, biologically active components are released that trigger a dedifferentiation of vascular smooth muscle cell (VSMCs). They start to migrate and proliferate resulting in neointimal hyperplasia. Mediators involved in these processes are platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and to a lesser extent epidermal growth factor (EGF). WS 1442 decreased VSMC migration by 38% and proliferation by 44%. It inhibited VSMC DNA synthesis induced by PDGF, blocked recombinant human PDGF receptor (PDGFR)-β kinase activity and decreased PDGFR-β activation and extracellular signalregulated kinase (ERK) activation in VSMCs [65] Protective Effect against Ischemia/Reperfusion Injury. Ischemia and reperfusion (I/R) exerts multiple injuries in microcirculation, frequently accompanied by endothelial cell injury, enhanced adhesion of leukocytes, macromolecular efflux, production of oxygen free radicals, and mast cell degranulation [66]. Thus, much effort has been made to attenuate the microcirculatory disturbance by ablating one of the insults in the pathogenetic process. Preliminary research demonstrated the cardioprotective effects of hawthorn in vivo models of ischemia/reperfusion. There are at least three experiments showing the effect. Hawthorn extract WS 1442 significantly reduced the deterioration of contractile function and infarct size in rat myocardium exposed to prolonged ischemia and reperfusion [67]. Besides, it showed evident effect against reperfusion arrhythmias by reducing the average prevalence of malignant arrhythmias (VF + Flutter) and the average prevalence of ventricular tachycardia (VT) [68]. Moreover, it prevented the isoproterenol-induced decrease in antioxidant enzyme activity [69] Antiarrhythmic Effect. Hawthorn extract may produce some antiarrhythmic effects in the rat heart, but the mechanism underlying the effect remains elusive. One result shows that Crataegus extract prolongs action potential duration and delays recovery of V max [70]. On the other hand, concerns have been raised regarding blocking repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrthemic effects described for Crataegus extract [71]. Another mechanism showed that extract from Crataegus resulted in a significant decrease in the total number of ventricular ectopic beats, mainly by reduction of Evidence-Based Complementary and Alternative Medicine 5 beats occurring as ventricular tachycardia. Also it reduced the total number of ventricular ectopic beats but this reduction was due to the decrease of single extrasystoles [72] Lipid-Lowering Effect. As we know, oxidation of the low-density lipoprotein (LDL) cholesterol plays an important role in atherosclerosis [73]. This accumulation causes a cascade of inflammatory processes, resulting in an unstable atherosclerotic plaque that ultimately bursts, causing myocardial infarction [74]. Many herbs can reduce low-density lipoprotein oxidation. One research investigated the effects of seven Chinese herbs and concluded that Shan Zha (Hawthorn Fruit) is effective in lowering blood lipid levels [75]. Similar study showed that Hawthorn fruit compound lowered blood lipids in atherogenic diet fed, ApoE gene deficient atherosclerotic mice. The results showed that Hawthorn fruit compound significantly reduced the ratio between low-density lipoprotein cholesterol (LDL-C) and serum cholesterol (TC): (LDL-C)/TC, especially the triglyceride (TG) levels [76]. Besides, TCR can significantly increase the binding of 125 I- LDL to the liver plasma membranes in vitro. This may be related to enhancement of the LDL-receptor activity. TCR was also shown to increase bile acid excretion and to depress hepatic cholesterol synthesis in atherogenic diet fed rats by upregulating hepatic LDL-receptors resulting in greater influx of plasma cholesterol into the liver [77]. Treatment usinghawthornfruitcandecreaseserumcholesterolthat involves the inhibition of cholesterol absorption mediated by downregulation of intestinal acyl CoA: cholesterol acyltransferase (ACAT) activity in Caco-2 cells. In animals research, hawthorn significantly lowered plasma non-hdl (VLDL + LDL) cholesterol concentrations and decreased hepatic cholesterol ester content [78]. The flavonoids fraction showed inhibitory effects on TG a
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