Risk factors in ischemic stroke

Abstract

Ischemic stroke is a complex disease in which environmental and genetic factors make about equal contributions to the etiology. However, knowledge regarding the molecular basis of the genetic influence and the impact of specific lifestyle factors is limited. Hypertension, diabetes, and smoking have been identified as major risk factors, but data for the different ischemic stroke subtypes are incomplete. Potential novel vascular risk factors, such as hemostasis, have mainly been investigated in relation to coronary heart disease, and associations to stroke remain to be established. The aim of the present thesis was therefore to study risk factors for ischemic stroke with focus on genetics, fibrinolysis, and lifestyle.The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) was designed for genetic association studies. Six hundred patients with ischemic stroke before the age of 70 years, and 600 matched population controls were recruited. Great emphasize was put on classification of ischemic stroke subtypes, as we hypothesized that their risk factor profiles may differ. Accordingly, we found that the associations for established risk factors differed by subtype. Furthermore, family history of stroke was independently associated with overall ischemic stroke, large vessel disease (LVD), small vessel disease (SVD), and cryptogenic stroke, but not with cardioembolic (CE) stroke. Lifestyle factors were investigated prospectively in a cohort of 7,402 men. After 28 years of follow-up, we found an independent association between increased body mass index and ischemic stroke. Self-perceived psychological stress showed independent association with total stroke (i.e. ischemic and hemorrhagic stroke combined), but no significant association was found when the two stroke types were analyzed separately. Self-perceived psychological stress was further investigated in SAHLSIS. An independent association with overall ischemic stroke, LVD, SVD, cryptogenic stroke, but not with CE stroke was found. The importance of endogenous fibrinolysis was investigated using genetic markers for the expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1), i.e. the t-PA -7,351C>T and the PAI-1 -675 4G>5G polymorphism. When analyzed as independent covariates, neither of the two genetic variants showed significant association with ischemic stroke. However, a protective effect for the t-PA CC/PAI-1 4G4G genotype combination (i.e. corresponding to high t-PA and high PAI-1 expression) was observed. We also investigated the pattern of acute t-PA release in a smaller experimental study. Compared to controls, patients with ischemic stroke showed a preserved, but delayed, acute t-PA release.In conclusion, we found distinct differences in risk factor patterns for the ischemic stroke subtypes. This was true for both established and novel risk factors, which highlights the importance of subtype characterization in stroke research. Regarding the fibrinolytic system, we found a protective effect of the t-PA CC/PAI-1 4G4G genotype combination, suggesting a gen-gen interaction and a complex role for t-PA and PAI-1 during brain ischemia.