Longitudinal Serum Lipid Trends and APOE in Primary Intracerebral Hemorrhage

Abstract

Primary intracerebral hemorrhage (ICH) comprises 10-15% of all strokes, but is associated with the greatest mortality and morbidity amongst all stroke subtypes. While hypercholesterolemia increases risk of cardiac disease and ischemic stroke, a preponderance of evidence suggest an inverse relationship with risk of ICH. However, it remains indeterminate whether the relationship is causal or associative. Prior studies examining association between serum lipid levels and ICH risk have relied on single-point measurements pre- or post-ICH, with the majority utilizing measurements obtained at time of ICH. These measurements are unlikely representative of long-term serum lipid levels due to large measurement inconsistencies from variable sampling time, and confounding by medical, environmental, and dietary exposures. To address the limitations of inter- and intra-individual serum lipid variability, we proposed to study the relationship between cholesterol and risk of ICH using serial serum lipid measurements and focusing on patterns of change in serum lipid levels over time in a case-control cohort. The central hypothesis of the study is that ICH patients will show distinct patterns of serum lipid changes, with decline in serum levels preceding the occurrence of ICH if lipids were in the causal pathway for ICH risk. We tested this hypothesis by (1)comparing temporal serum lipid changes in ICH cases versus controls comprising of acutely ill patients hospitalized for non-cerebral illnesses using mixed-effects modeling to allow evaluation of the impact of random ‘critical events’ on time intervals, enabling dissection of changes in serum lipid trends over distinct, biologically relevant time periods. In addition, given known APOE pleiotropy in lipoprotein metabolism and ICH risk, we attempted to determine whether APOE allelic status might influence temporal serum lipid trends in ICH. Notably, the presence of a subset of ICH patients with known APOE genotype status represented a unique opportunity to disentangle lipid-dependent and lipid-independent mechanisms of APOE towards development of ICH. We hypothesized that APOE genotype may influence temporal serum lipid changes in ICH and tested this hypothesis by (2)investigating APOE allele-specific effects on changes in serum lipid levels over time in a cohort of ICH patients with known APOE genotype and serial serum lipid measurements.