We have recently reported a U-shaped dose�Cresponse relationship between intake of caffeine-containing coffee and incidence of acute coronary events; similar findings have been reported from at least two other studies. In order to gain further insight into the pathogenetic mechanisms, we hypothesized that the increased risk in heavy drinkers of caffeine-containing coffee is, at least partly, mediated by increased circulating catecholamine activity. Caffeine is a potent stimulator of plasma renin activity and adrenomedullary secretion; acute ingestion results in substantial increases in plasma concentrations of adrenaline and noradrenaline. Tolerance to these acute humoral effects may develop in the course of one to four days of habitual consumption, but is not complete and may be lost after abstinence for as little as 12 hours. To test this hypothesis, we examined whether the functional polymorphism of the catechol-O-methyltransferase gene, resulting in several-fold differences in the metabolism of circulating catecholamines, modifies the effect of heavy consumption of caffeine-containing coffee on the risk of acute coronary events. In this population-based, we found a relationship between consumption of caffeine containing coffee and the incidence of fatal or nonfatal CHD events that is highly dependent on COMT genotype. In men who were either homozygous for the high COMT activity Amikacin hydrate allele or heterozygotes, heavy coffee intake did not increase the incidence of acute coronary events. In men who were homozygous for the low-activity COMT allele, however, heavy coffee intake was associated with a considerably higher incidence of acute coronary events. The relative excess in CHD incidence in the low-activity Neohesperidin genotype was over two-fold among drinkers of more than 6.5 cups of coffee per day, after adjustment for age, smoking, family history of CHD, plasma vitamin C concentration, systolic blood pressure, serum LDL and HDL cholesterol concentration, and diabetes.Despite decades of research, controversy persists regarding the effects of coffee consumption on cardiovascular health. Coffee drinking is a prevalent habit worldwide and one constituent of coffee, caffeine, is probably the most frequently ingested pharmacologically active substance in the world.