The present study mainly found that chewing areca nut increased the risk of obstructive CAD in Taiwanese men, particularly among subjects who smoked cigarettes. Several previous studies have reported the association between areca nut chewing and the risk of cardiovascular diseases in Taiwan [8
]. Although two of the four epidemiological studies were prospective cohort designs [8
], their exposure and outcome of interest were from a questionnaire and ICD-9 codes, respectively, neither of which were validated by the authors. In addition, a variety of cardiovascular diseases, such as hypertensive heart disease, cardiomyopathy, ischemic heart disease and arrhythmia, were included and analyzed as the same disease in these studies.
Lan et al. first reported that in an elderly population, people who ever chewed areca nut were at a higher risk of all-cause (hazard ratio (HR) = 1.19, 95% CI: 1.05, 1.35) and cerebrovascular disease mortality (HR = 1.66, 95% CI: 1.19, 2.30), compared with those who never chewed areca nut [8
]. In the same year, Guh et al. found that the OR for prevalent heart disease and a betel-quid consumption rate of 10 times/day was 1.37 (95% CI = 1.1-1.6) among women [18
]. Subsequently, a study conducted by Lin et al. also found that former and current betel nut chewers had an increased risk for cardiovascular and all-cause mortality [9
]. The former betel nut chewers had adjusted relative risk (RR) 1.56 (95% CI = 1.02-2.38) and 1.40 (95% CI = 1.17-1.68) for CVD and all-cause mortality respectively, when compared with never chewer. The current chewers had RR 2.02 (95% CI = 1.31-3.13) and 1.40 (95% CI = 1.16-1.70) for CVD and all-cause mortality respectively, when compared with never chewer. Yen et al. also found an independent dose-response effect between chewing betel nut and an increasing risk of incident CVD among men [10
]. The betel-quid ever chewers were at higher risk of CVD (HR = 1.24, 95% CI = 1.11-1.39) when compared with never chewer.
To minimize outcome misclassification, the present study used CAG to confirm the diagnosis of obstructive CAD. In addition, the exposure of interest (areca nut chewing) in this study was validated in our previous research [14
]. The prevalence of areca nut chewing was 7.9% in the control group in our study, which was compatible with the corresponding figures (~10%) in the previous survey [19
We also found a dose-dependent relationship between areca nut chewing and CAD risk, as a higher amount of areca nut chewing was associated with a higher risk of obstructive CAD. The additive interactions in the risk of obstructive CAD between "areca nut chewing and cigarette smoking," "areca nut chewing and HTN" and "areca nut chewing and dyslipidemia" were also observed. CAD, which is similar to other atherosclerotic diseases, has been previously associated with risk factors such as DM, HTN, dyslipidemia, age and obesity [20
]. Areca nut chewing has been previously reported to be associated with many risk factors of CAD. In one study, general and central obesity were related to areca nut chewing in Chinese males [5
]. Areca nut chewing has also been associated with HTN in Taiwanese patients with type-2 DM [7
]. The association between metabolic syndrome and areca nut chewing has also been reported [6
]. Indians living in the United Kingdom were found to have high incidences of cardiovascular disease, HTN and late onset diabetes [22
]. Those findings, along with ours, suggest that areca nut might act as an independent risk factor for CAD or as a mediator that modifies the risk of HTN or dyslipidemia.
The present study found that the Lao-hwa regimen was more potent than the betel leaf regimen by comparing the ORs for their associations with obstructive CAD. Betel leaf may have some beneficial effects for cardiovascular disease through its vasorelaxation, antioxidant effects and inhibition of platelet aggregation [23
], which is consistent with our clinical findings.
There are several possible mechanisms to explain the link between areca nut chewing, CAD and atherosclerosis. Atherosclerosis, especially CAD, was related to chronic inflammation in previous studies [20
]. Arecoline, the most well-known content of the areca nut, was reported to induce COX-2 up-regulation and higher TIMP expression in in-vitro
]. Hydroxychavicol, another major phenolic compound in the inflorescence, could induce reactive oxygen species production via redox cycling [31
], increase superoxide dismutase activity in mice liver [32
] and reduce glutathione in cell line studies [33
]. One study, done by Lee et al., reported that betel-quid could increase PKC and NF-κB expressions in mice [35
]. Subsequently, Ni et al. found that human buccal mucosa cells exposed to areca nut could activate NF-κB expression [36
]. The expressions of tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6 and IL-8 were also increased in human peripheral blood mononuclear cells after being treated with areca nut extract [37
]. The extracts of areca nut, piper inflorescence and betel quid were found to enhance the cytotoxic effects of oxidized low-density lipoprotein (LDL) toward bovine aortic endothelial cells [23
]. Because cigarette smoking might enhance the oxidation of LDL cholesterol and lead to atherosclerosis, the enhancement of cytotoxic effects of oxidized LDL by arecoline might explain the additive effect of areca nut chewing and smoking on the risk of CAD.
There were several limitations in the study. The healthy controls were drawn from healthy volunteers attending general health check-ups; thus, this group may not be representative of the general population. The detailed lifestyle information about vegetable consumption and exercise status was not routinely collected in our questionnaire, which might influence the risk of CAD studied here.