CLINICAL STUDY The risk of myocardial infarction is enhanced by a synergistic interaction between serum insulin and smoking Anna M Bennet 1 , Kerstin Brismar 4 , Johan Hallqvist 3 , Christina Reuterwall 2 and Ulf de Faire 1,5 1 Division of Cardiovascular Epidemiology, Karolinska Institute, 2 Division of Epidemiology, National Institute of Environmental Medicine, 3 Division of Social Medicine, Department of Public Sciences, 4 Endocrine and Diabetes Unit, Department of Molecular Medicine, Karolinska Hospital and 5 Department of Cardiology, Karolinska Hospital, Stockholm, Sweden (Correspondence should be addressed to A M Bennet, Institute of Environmental Medicine, Box 210, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Email: Anna.Bennet@imm.ki.se) Abstract Objectives: To evaluate the relationship between levels of serum insulin, the homeostasis model assess- ment (HOMA) and IGF-binding protein-1 (IGFBP-1) as factors related to myocardial infarction (MI) risk, and their interaction with lifestyle-related risk factors. Design: The Stockholm epidemiology programme (SHEEP), a case-control study, consisting of 749 first-time MI cases (510 men, 239 women) and 1101 healthy controls (705 men, 396 women) was used. Methods: The risk of developing MI was assessed by calculating odds ratios (OR) and synergistic inter- actions (SI) between serum insulin, IGFBP-1, HOMA and other variables related to MI risk (including smoking) in men and women. Results: Subjects with elevated levels of insulin and HOMA (. 75th percentile) had increased MI risks when compared with individuals with low levels. ORs for elevated insulin and HOMA (adjusted for age and residential area) for men: insulin 1.6 (95% confidence interval (CI) 1.3 – 2.1) and HOMA 1.5 (95% CI 1.1–1.9) and for women: insulin 2.1 (95% CI 1.5–2.9) and HOMA 1.9 (95% CI 1.3 –2.8). Women with low levels of IGFBP-1 (, 10th percentile) showed a tendency towards elevated MI risk even if this was not statistically significant (OR 1.5 (95% CI 0.9–2.6)). Smokers with high levels of serum insulin had greatly increased MI risk (OR for men: 4.7 (95% CI 3.0–7.2) and OR for women: 8.1 (95% CI 4.5 –14.8)). SI scores based upon these interactions were statistically significant. Conclusions: These results might have preventive cardiovascular implications as they clearly suggest that subjects with insulin resistance are particularly susceptible to the hazards of smoking. European Journal of Endocrinology 147 641–647 Introduction Insulin resistance, desensitisation of the peripheral tissues to the effects of insulin, is associated with a cardiovascular risk pattern referred to as the insulin resistance syndrome (IRS) including elevated blood pressure, serum triglycerides and body weight (particu- larly of the abdominal type), as well as decreased levels of high density lipoprotein (HDL). Since its discovery during the late 70s and early 80s, IRS has been con- cluded to be an important risk factor for the develop- ment of coronary heart disease (CHD) in several large prospective studies such as the Paris prospective study (1), the Busselton study (2), the Whitehall study (3) and the Helsinki policemen study (4). Central obesity, insulin resistance, or both, have been proposed as underlying risk factors for IRS and several possible causal links between the cluster of metabolic disturbances have been suggested. It is possible that changes in the levels of one component may initiate the change of levels of another component, such as insulin resistance leading to changes in blood pressure and blood lipid metabolism (5). Furthermore, insulin- like growth factor-1 (IGFBP-1), one of the proteins that bind to circulating insulin-like growth factor (IGF)-I, is negatively correlated to low density lipo- protein (LDL) cholesterol, triglycerides, blood pressure, body mass index (BMI) and insulin resistance and posi- tively correlated to HDL cholesterol (6, 7). All of the above mentioned data provide evidence suggesting a possible role for IGFBP-1 in the network of risk factors that may eventually lead to myocardial infarc- tion (MI). There are no previous studies of this size investigating the relationship between IGFBP-1 and CHD or the relationship between IGFBP-1 and insulin resistance. European Journal of Endocrinology (2002) 147 641–647 ISSN 0804-4643 q 2002 Society of the European Journal of Endocrinology Online version via http://www.eje.org