BETEL QUID CHEWING AND CARDIOVASCULAR DISEASES: A TRADITIONAL ORAL HABIT WITH POTENTIAL NEW HEALTH ISSUES

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1 BETEL QUID CHEWING AND CARDIOVASCULAR DISEASES: A TRADITIONAL ORAL HABIT WITH POTENTIAL NEW HEALTH ISSUES Jiiang-Huei Jeng a and Mei-Chi Chang b, a Laboratory of Pharmacology and Toxicology, School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, b Biomedical Science Team, Chang Gung Institute of Technology, Taoyuan, Taiwan, mcchang@mail.cgit.edu.tw Betel quid (BQ) chewing has been a popular oral habit in Taiwan, India, Sri Lanka, and many Southeast Asian countries for a long time [1,2]. BQ chewing habit has become the top five oral habits (including smoking, alcohol, tea, coffee, and betel chewing) in the world. There are about million BQ chewers in the world [1,2]. BQ chewing has been linked to the risk of oral cancer and oral precancerous lesions [1,2]. Recently, this oral habit is thought to associate with hepatocarcinoma, diabetes mellitus (DM), cardiovascular diseases, and other systemic diseases. For these reasons, the International Agency for Research on Cancer (WHO), Lyon, France (2003) organized a meeting to further remind populations about the critical health issues including its impact on oral cavity, gastrointestinal, cardiovascular, and endocrine systems, etc. [1]. BQ consumption is shown to be a risk factor in the initiation of hypertension [3], cardiovascular diseases [4], metabolic syndrome with hyperglycemia and hyper-triacylglycerolemia, asthma, and other life threatening diseases [1,5]. The precise reasons why prolonged exposure to BQ components affects the cardiovascular system are still not fully clear. The increase of appetite in BQ chewers is a possible factor of obesity, which further contributes to later hypertension [6]. In 47 healthy chronic, occasional, and new BQ chewers, chewing BQ increases the heart rate lasting for an average of 16.8 minutes. Only new chewers show an elevation in systolic blood pressure [7]. An elevation of plasma noradrenaline and adrenaline in BQ chewers was also noted [8]. In addition, BQ chewing may elicit acute toxic symptoms including tachycardia/palpitation, tachypnea/dyspnea, hypotension/sweating, vomiting, dizziness, chest discomfort, acute myocardiac infarction, ventricular fibrillation, and related manifestations as reported in 17 cases by the Taiwan Poison Control Center [9]. Chiang et al. [10] also reported two cases with cardiac dysrhythmias after chewing BQ. One case showed chest tightness, dyspnea, diaphoresis, palpitation, and finally death, even after cardiopulmonary resuscitation. The second case suffered from palpitation and paroxysmal supraventricular tachycardia, which was controlled after administration of verapamil. These events are possibly due to parasympthomimetic effects by areca alkaloids on vessels with abnormal endothelium in some people [9,11]. These reports raise

2 an important health issue of the acute detrimental effects of BQ chewing on the cardiovascular system. These cardiovascular effects by BQ chewing can be partially due to its contents of alkaloids such as arecoline, arecaidine, guvacine, etc.; however, more clinical studies are needed to further elucidate the mechanistic insight and other contributing factors. Why BQ chewing may increase the risk of DM and cardiovascular diseases is still not clear. BQ is usually comprised of areca nut (AN) (Figure 1 and Figure 2), inflorescence Piper betle (IPB), and lime with or without betel leaf (Piper betle L., PBL) (Figure 3). DM and metabolic syndrome, which are independent risk factors leading to atherosclerosis and other cardiovascular diseases, show strong association with BQ chewing habit [5,12]. Patients with metabolic syndrome have greater risk of coronary heart disease and stroke, as well as 4-6 times greater risk of dying from atherosclerotic coronary heart disease than those of healthy subjects [13]. Additionally, triglyceride, a critical factor of atherosclerosis and other cardiovascular diseases [14], is also elevated in serum of BQ chewers relative to those who do not consume BQ (54% versus 29%) [15]. Dr Phatak also found that the saliva collected from BQ chewers with oral submucous fibrosis (OSF) has a thrombin-like enzyme activity, which promotes clot formation on citrated plasma, and a defective fibrinolytic activity [16,17]. In addition to local coagulopathy, presence of a chronic disseminated intravascular coagulation was also suspected in OSF patients [18]. Abnormal arachidonic acid (AA) metabolism and platelet aggregation has been linked to vascular thrombus formation and hypertension [19]. Interestingly, water extract of PBL inhibites platelet aggregation and induces vasorelaxation [2,20]. On the contrary, AN extract evidently stimulates platelet aggregation and thromboxane B 2 production [21]. Arecoline, the major areca alkaloid, is shown to induce vasorelaxation as well as suppress endothelial cell growth [22]. Moreover, generation of higher amounts of inflammatory mediators (such as IL-1β, IL-6, IL-8, and TNF-α) by peripheral blood mononuclear cells isolated from BQ chewers relative to healthy persons was observed in vitro [23]. This is possibly due to stimulation the production of various inflammatory mediators such as prostaglandins, interleukin-6, and TNF-alpha by AN ingredients [24], because these inflammatory mediators are crucial for the pathogenesis of metabolic syndrome, DM, atherosclerosis, and other cardiovascular diseases [25,26]. In conclusion, BQ chewing as a major etiologic factor of oral cancer increases the risk of systemic diseases such as asthma, DM, metabolic syndrome, myocardiac infarction, hypertension, and other cardiovascular diseases. This highlights our attention to BQ chewing habit as a new and crucial health issue, because there are about million chewers in the world. More in vitro, in vivo, and epidemiological studies are needed to further evaluate whether BQ chewing habit really has a health impact on the cardiovascular system and its mechanisms. References 1. IARC. Betel-quid and areca nut chewing and some areca-nut-derived nitrosamines. In: IARC monographs Vol Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol 2001;37: Chiu YH, Wu SC, Tseng CD, Yen MF, Chen THH. Progression of prehypertension, stage 1 and 2 hypertension (JNC 7): a population-based study in Keelung, Taiwan (Keelung Community based integrated screening No. 9). J Hypertension 2006;24: Tsai CC. The association between areca/betel quid chewing, cigarette smoking, alcohol drinking and asthma, heart disease and peptic ulcer in Taiwan. Master thesis. Kaoshiung Medical

3 University Yen AM, Chiu YH, Chen LS, et al. A population-based study of the association between betelquid chewing and the metabolic syndrome in men. Am J Clin Nutr 2006;83: Chang WC, Hsiao CF, Chang HY, et al. Betel nut chewing and other risk factors associated with obesity among Taiwanese male adults. Int J Obes 2006;30: Chu NS. Cardiovascular responses to betel chewing. J Formos Med Assoc 1993;92: Chu NS. Neurological aspects of areca and betel chewing. Addict Biol 2002;7: Deng JF, Ger J, Tsai WJ, Kao WF, Yang CC. Acute toxicities of betel nut: rare but probably overlooked events. J Toxicol Clin Toxicol 2001;39: Chiang WT, Yang CC, Deng JF, Bullard M. Cardiac arrhythmia and betel nut chewing is there a causal effect? Vet Hum Toxicol 1998;40: Hung DZ, Deng JF. Acute myocardial infarction temporally related to betel nut chewing. Vet Hum Toxicol 1998;40: Mannan N, Boucher BJ, Evans SJ. Increased waist size and weight in relation to consumption of Areca catechu (betel-nut): a risk factor for increased glycemia in Asians in east London. Br J Nutr 2000;83: Tamasma JT, Jazet IM, Beishuizen ED, Fogteloo AJ, Meinders SE, Huisman MV. The metabolic syndrome: a vascular perspective. Eur J Intern Med 2005;16: Geluk CA, Halkes CJ, De Jaegere PP, Plokker TW, Cabezas MC. Daytime triglyceridemia in normocholesterolemic patients with premature atherosclerosis and in their first-degree relatives. Metabolism 2004;53: Liao CD. The study of oral health status and health related risk factors of adults aged 40 and over in Taoyuan.county. Master thesis. Kaoshiung Medical University Phatak AG. Fibrin producing factor in oral submucous fibrosis. Indian Journal of Orolaryngology 1979;31: Phatak AG. Hypercoalgulation and fibrinolysis in oral submucous fibrosis. Am J Clin Pathol 1984;81: Phatak AG. Oral submucous fibrosis--a chronic disseminated intravascular coagulation syndrome with local coagulopathy. Gut 1993;33: Robbins IM, Kawut SM, Yung D, et al. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J 2006;27: Runnie I, Salleh MN, Mohamed S, Head RJ, Abeywardena MY. Vasorelaxation induced by commom edible tropical plant extracts in isolated rat aorta and mesenteric vascular bed. J Ethnopharmacol 2004;92: Jeng JH, Chen SY, Liao CH, et al. Modulation of platelet aggregation by areca nut and betel leaf ingredients: roles of reactive oxygen species and cyclooxygenase. Free Radical Biol Med 2002;32: Kuo FC, Wu DC, Yuan SS, et al. Effects of arecoline in relaxing human umbilical vessels and inhibiting endothelial cell growth. J Perinat Med 2005;33: Haque MF, Meghji S, Khitab U, Harris M. Oral submucous fibrosis patients have altered levels of cytokine production. J Oral Pathol Med 2000;29: Jeng JH, Wang YJ, Chiang BL, et al. Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis 2003;24: Antoniades C, Tousoulis D, Tountas C, et al. Vascular endothelium and inflammatory process, in patients with combined type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C. Diabet Med 2004;21: Larsson PT, Hallerstam S, Rosfors S, Wallen NH. Circulating markers of inflammation are related to carotid artery atherosclerosis. Int Angiol 2005;24:43-51.

4 Figure 1. Areca Catechu Palm trees were planted around the full area of some mountains in Taiwan.

5 Figure 2. Areca nut were collected from the areca catechu palm and transported by a truck to a local factory for further preparation.

6 Figure 3. Compositions of the betel quid (BQ) in Taiwan. Left: A BQ enrolled by a piece of betel leaf. Right: Lao-Hua BQ contains areca nut with red lime (brownish paste placed in areca nut) and a piece of piper betle inflorescence.