Increases in circulating catecholamine levels and cortisol are characteristic of the response to stress, both psychological and physiological, and caffeine has been shown to potentiate stress-related increases in plasma adrenaline and cortisol concentrations, both in habitual and light consumers. Stress in turn is a recognized risk factor for CHD. Furthermore, stress appears to be more strongly related to the rapid and more transient processes that lead to acute coronary syndromes rather than to the long-term atherosclerotic process. On the other hand, treatment with beta-adrenoceptor blocking agents has been shown to effectively reduce the risk of acute coronary syndromes during acute periods of stress, such as surgical stress, which is characterized by elevated adrenaline and cAMP levels. Hence, we hypothesized that heavy intake of caffeine-containing coffee induces a ����chemical stress���� and that the effect of this stress response on CHD incidence is more evident in those whose catecholamine Tenacissoside-X metabolism is slower than usual and the mechanisms of tolerance may be overwhelmed. The main enzyme responsible for the metabolism of circulating catecholamines is COMT. COMT activity shows functional polymorphism determined by the COMT gene: those who are homozygous for the low activity allele have only one-half to one-fourth of the enzyme activity of the other genetic variants. These differences in COMT activity by genotype are likely to be more pronounced in heavy consumers of coffee, because caffeic acid directly inhibits COMT activity and caffeine inhibits adenosine deaminase, resulting in a shift in homocysteine metabolism to the direction of Sadenosyl-homocysteine and consequent further inhibition of COMT activity. Our finding of a 2.2 fold increase in the incidence of acute coronary events among heavy coffee drinkers in the low-activity COMT category, compared with the other two COMT categories, is highly compatible with this hypothesis.Our study is limited by the small study cohort and the fact that only 78 CHD events were observed during an average follow-up of 13 years, resulting in imprecise effect estimates reflected as wide confidence Lucidenic-acid-A intervals.