Subacute decline in serum lipids precedes the occurrence of primary intracerebral hemorrhage

Abstract

Objective: We aimed to describe the temporal variation in circulating lipid levels among patients with intracerebral hemorrhage (ICH) and investigate their association with ICH risk.

Methods: This was a single-center, retrospective, longitudinal, case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a hospital-based clinical data registry. Piecewise linear mixed-effect random coefficient models were used to determine the significance of changes in serum lipid trends on ICH risk.

Results: Two hundred twelve ICH cases and 301 control individuals were analyzed. Overall trends in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels differed between ICH cases and non-ICH controls (p = 0.00001 and p = 0.0092, respectively). Patients with ICH experience accelerated decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 and 24 months pre-ICH (TC: -29.25 mg/dL, p = 0.001; LDL: -21.48 mg/dL, p = 0.0038), which was not observed in non-ICH controls. Subgroup analysis confirmed that this phenomenon cannot be attributed to statin or alcohol exposure. Serum triglycerides and high-density lipoprotein trends did not differ between groups.

Conclusions: Longitudinal lipid levels differ between ICH cases and non-ICH controls, most notably for a decline in serum TC and LDL levels within 6 months preceding primary ICH, independent of statin or alcohol use. These changes in serum TC and LDL trends suggest a biological pathway that precipitates ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.

Figure 1. Flowchart describing study cohorts and analysis plan

ICH = intracerebral hemorrhage; MGH ICH Database = Massachusetts General Hospital–based patients in the Genetics of Cerebral Hemorrhage on Anticoagulation Study; RPDR = MGH Research Patient Data Registry.

Figure 2. Serum lipid trends in patients with ICH and non-ICH controls

(A–D) Loess smoothed curves of serum lipid levels (mg/dL) against time (in months) for ICH cases and patients who were hospitalized for acute noncerebral illnesses (controls). Light gray areas indicate SE for controls. Dark gray areas indicate SE for ICH cases. (E) Comparison of difference in rates of change of serum lipid levels (slope) between time interval 6–24 months before acute illness and 0–6 months before acute illness in ICH and non-ICH controls. Test statistic, Wald test; degree of freedom in parentheses. Statistical significance at p < 0.0125 (Bonferroni-corrected). HDL = high-density lipoprotein; ICH = intracerebral hemorrhage; LDL = low-density lipoprotein; P = time interval 0–6 months before acute illness; SE = standard error; TC = total cholesterol; TG = triglyceride.

Figure 3. Serum lipid trends by statin use in patients with ICH

(A–D) Loess smoothed curves of serum lipid levels (mg/dL) against time (in months) for comparison between ICH cases that were either on statin medication or statin-naive. (A) Total cholesterol; (B) low-density lipoprotein; (C) triglycerides; (D) high-density lipoprotein. Dark gray areas indicate SE for statin-naive ICH cases. Light gray areas indicate SE for ICH cases on statin. ICH = intracerebral hemorrhage; SE = standard error.