Sophie Henry

A recent study involving Yale researchers found a link between higher levels of low density cholesterol and protective effects on the brain that potentially decrease the risk of hemorrhage. 

The paper detailing the study’s findings was published this month in the Annals of Neurology and shows that elevated lipid levels could be correlated to decreasing the risk of subarachnoid hemorrhage, or SAH, which is an infrequent subtype of stroke caused by brain aneurysm that is associated with high morbidity and mortality. This research was led by two research fellows working in the Falcone Lab, Julian N. Acosta and Cameron Both, who were supported by the National Institutes of Health and the American Heart Association. 

“Observational studies, clinical trials, and genetic evidence suggest an inverse relationship with cerebral intraparenchymal hemorrhage [a bleed that occurs within the functional tissue of the brain], with very low cholesterol levels being associated with higher risk of this type of brain bleeds,” Acosta wrote in an email to the News. “Last year, a pivotal study published in Nature Genetics also showed that cerebral intraparenchymal hemorrhages share up to 50% of its genetic architecture with intracranial aneurysms and subarachnoid hemorrhage (SAH). These findings became the basis of our study.”

Acosta explained that the team chose to investigate low density cholesterol because, though higher levels of total cholesterol have been historically found to be strongly linked to higher risk of ischemic cardiovascular disease, other studies have found evidence that indicates positive effects of higher cholesterol levels. 

The study sourced its genetic association data from publicly available large consortia and utilized Mendelian randomization, an analytical tool which allows researchers to draw causal resolutions from observational data by sorting the random assortment of genetic information during meiosis.

Natalia Szejko, a member of the research team, explained that the main challenges associated with conducting this study was the prevalence of inconsistent results at the beginning of the study. 

“Conducting this kind of study is always challenging for several reasons. We had previously explored this hypothesis with more limited data, which showed promising results but inconsistent results when changing the analytical approach,” Szejko wrote in an email. “Fortunately, completion of large genetic studies of SAH gave us the tools to strengthen our analysis.”

The study found that a one millimole increase of genetically-instrumented low density cholesterol was associated with a 17 percent lower risk of intracranial aneurysm presence and aneurysm rupture, signifying a decreased risk of hemorrhage. These results confirmed the researchers’ hypothesis that LDL-C levels are inversely associated with the risk of intracranial aneurysms and SAH.

Although the exact function of low density cholesterol in preventing SAH is still undetermined, these results were consistent when considering individuals from “any race, ethnicity or European ancestry only.”

Cameron Both explained that the research team plans to conduct further research to validate these results to model how LDL-lowering medications may influence the risk of intracranial aneurysms and SAH. 

“Additionally, while we provide evidence for an inverse association between LDL-C and SAH, the specific mechanisms underlying this relationship remain unknown, providing a clear goal in terms of next research steps,” Both wrote in an email to the News. 

These findings highlight lipid metabolism as an important biological factor in the development and rupture of intracranial aneurysm. In the future, clarifying the causal pathways underlying this association may lead to medical applications in potential preventive or therapeutic strategies. 

Subarachnoid hemorrhage affects 30,000 people in the United States annually, according to the US National Library of Medicine.