In conclusion, persistent levels of circulating IL-16 and apoptosis markers were specifically Baohuoside-I associated with active WD, whatever the clinical manifestations of the disease. Many of the known or suspected cardiovascular effects of coffee have been attributed to caffeine, but coffee is a mixture of hundreds of chemical substances, many of which have been shown to be pharmacologically active. In addition, the association was stronger during the first years of follow-up, which indicates that coffee intake is more relevant with respect to the acute rather than chronic processes related to coronary disease. Caffeine is metabolized by the polymorphic cytochrome P450 1A2 enzyme. Recently Cornelis and co-workers determined whether CYP1A2 genotype modifies the association between intake of caffeinated coffee and the risk of nonfatal myocardial infarction. They found that intake of coffee was associated with an increased risk of myocardial infarction only among individuals with slow caffeine metabolism and suggested that caffeine plays a role in this association. These findings led us to consider novel explanations behind the dose�Cresponse relationship between coffee consumption and CHD incidence. Coffee and caffeine have been shown to stimulate adrenomedullary secretion, resulting in raised levels of circulating catecholamines, adrenaline in particular. In a subgroup of the present study population with urinary catecholamine excretion measured at baseline, we also observed a marked increase in adrenaline excretion and some increase in the excretion of Presapogenin-CP4 noradrenaline with increasing coffee intake. Nevertheless, we were able to control for the most important potential confounding factors and still the difference in CHD incidence between the COMT activity categories among heavy coffee drinkers persisted. Residual confounding alone is unlikely to explain the remaining excess incidence. Another major limitation of our study is restriction of the study population to men only. Female hormones may influence catecholamine pharmacodynamics and thus our findings are not necessarily applicable to women.