The brain has about 100 billion cells called neurons. It is made up of distinct parts that developed through human evolution. [copyright American Heart Association]
Insomnia may be a potential risk factor for a brain bleed from a ruptured aneurysm, according to new research headed by scientists at the Karolinska Institutet. The team analyzed data from several large-scale genome-wide association studies (GWAS) to gauge genetic associations to lifestyle and cardiometabolic risk factors, as part of their study to determine any association between various modifiable lifestyle factors and cardiometabolic factors, with intracranial aneurysm (IA) and aneurysm rupture. The results, published in the Journal of the American Heart Association, supported existing evidence that smoking and high blood pressure represent the strongest risk factors for IA and aneurysmal subarachnoid hemorrhage (aSAH), but also demonstrated evidence that insomnia may be a novel risk factor for IA and aSAH.

“Ruptured aneurysms are highly fatal,” said Susanna C. Larsson, PhD, associate professor in the unit of cardiovascular and nutritional epidemiology at the Karolinska Institutet in Stockholm, Sweden, and the unit of medical epidemiology at Uppsala University in Uppsala, Sweden, “It is, therefore, extremely important to identify modifiable risk factors that can help prevent aneurysms from rupturing … The association between insomnia and intracranial aneurysm has not been reported previously, and these findings warrant confirmation in future studies.”

Larsson and colleagues reported on their findings in a paper titled, “Modifiable Risk Factors for Intracranial Aneurysm and Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.”

Susanna Larsson, PhD, senior researcher and associate professor of cardiovascular and nutritional epidemiology, Karolinska Instituet Stockholm, Sweden. [copyright Institute of Environmental Medicine, Karolinska Institutet]
More than 3% of adults worldwide have unruptured blood vessel malformations in the brain. The majority of these intracranial aneurysms will never rupture. But about 2.5% of intracranial aneurysms will rupture, resulting in a subarachnoid hemorrhage, also known as a brain bleed. SAH is a type of stroke that occurs when a blood vessel on the surface of the brain ruptures and bleeds into the space between the brain and the skull. “In light of poor outcomes of aSAH, identification of modifiable risk factors for IA formation and rupture is of great importance,” the authors wrote.

Suggested risk factors for aSAH include smoking, heavy alcohol consumption, hypertension, and sleep apnea. Conversely, coffee consumption, regular physical activity, high body mass index, diabetes, and hypercholesterolemia have been proposed as risk-reducing factors, the team continued. However, they pointed out, available data on risk factors for aSAH are mainly based on observational studies, which may be vulnerable to confounding and not conclusive. “Hence, the causal associations of most modifiable risk factors other than smoking and high blood pressure with aSAH risk remain unestablished.”

Mendelian randomization (MR) is an epidemiologic method that uses randomly allocated genetic variants related to the risk factor as instrumental variables to infer causality of the exposure–outcome relationship. For their study, the team applied Mendelian randomization to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

Data from several genome-wide association studies were used to assess such genetic associations to lifestyle and cardiometabolic risk factors. “Genetic associations for the lifestyle and cardiometabolic factors were obtained from summary statistics of large-scale GWAS comprising individuals of European ancestry,” the scientists commented.

Genetic information from a meta-analysis conducted by the International Stroke Genetics Consortium was then used to identify nearly 6,300 cases of intracranial aneurysm and nearly 4,200 cases of aneurysmal subarachnoid hemorrhage. Cases of intracranial aneurysm and subarachnoid hemorrhage were compared with over 59,500 controls to determine genetic predisposition for aneurysms.

According to the resulting analysis, the risk for intracranial aneurysm was about three times higher for smokers vs. non-smokers, while the risk for intracranial aneurysm was almost three times higher for each 10 mm Hg increase in diastolic blood pressure. The findings also indicated that a genetic predisposition for insomnia was associated with a 24% increased risk for intracranial aneurysm and aneurysmal subarachnoid hemorrhage. Conversely, high triglyceride levels and high BMI (body mass index) did not demonstrate an increased risk for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

“The present MR study found further evidence for smoking and high blood pressure as the strongest risk factors for IA and aSAH,” the team stated. “This study additionally found evidence that insomnia may be a novel risk factor for IA and aSAH.” Larsson further noted, “Our research supports the thinking that risk factors that people can change or manage may impact brain aneurysms and hemorrhage risk. Once confirmed, future studies should examine ways to incorporate this knowledge into prevention programs and therapies.”

The authors acknowledged a number of study limitations, including inadequate information for them to properly analyze some of the risk factors, and the analysis included only people of European ancestry, which means that the findings may not be generalizable to people from different racial and ethnic groups. Nevertheless, they concluded, “ … this MR study found that genetic predisposition to smoking, insomnia, and high blood pressure was robustly associated with increased risk of IA and aSAH … These results add to the body of evidence on causal risk factors for IA and aSAH, and warrant further investigation towards identifying preventative and therapeutic opportunities.”

Interestingly, according to a 2016 American Heart Association scientific statement, Sleep Duration and Quality: Impact on Lifestyle Behaviors and Cardiometabolic Health, insufficient and poor-quality sleep and sleep disorders are linked to a higher risk of high blood pressure. The statement summary notes that treating people with sleep disorders may provide clinical benefits, particularly for blood pressure.

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