PubMed · 14908434
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B P CLARK. 1952. Pediatric case reports.. https://pubmed.ncbi.nlm.nih.gov/14908434/
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Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.
The germinal matrix neuroepithelium and the choroidal fissure of the fetal choroid plexus commonly possess microvessels that are often poorly developed. There may be a reduction of type IV collagen that surrounds these fragile microvessels. During the first and second trimester of neural development, these microvessels are friable and can undergo intraventricular hemorrhage under a number of circumstances. Early subtle changes in the integrity of germinal matrix epithelium are not easily visualized by ultrasound. The current investigation employing scanning electron microscopy clearly defines subtle hemorrhagic events and tearing of the germinal matrix neuroepithelium in the brains of human fetuses. A 23-week-old fetus survived for 11 days but died from other causes. The choroid plexus of this fetus was compared with the choroid plexus and germinal matrix epithelium of a 22-week-old fetus that was the product of an elective termination due to severe anhydramnios of unknown origin and a 19-week-old male fetus from an elective termination. All tissues were autopsy material not requiring institutional review board approval.
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