gms | German Medical Science

Objective: Cerebral cavernous malformations (CCMs) are frequently diagnosed vascular malformations of the brain. Although most CCMs are asymptomatic, some can be responsible for intracerebral hemorrhage or seizures. Treatment with the β-blocker propranolol has been presumed to stabilize and eventually lead to CCM size regression in a limited number of published case series; however, the underlying mechanism and evidence for this effect remain unclear.

Methods: Single-center database containing data on patients harboring CCMs was retrospectively interrogated for a time period of 20 years. The database included information about hemorrhage and antihypertensive medication. Statistical analyses were performed, focusing on the risk of hemorrhage and the size of the lesion at presentation and during follow-up in patients on β-blocker medication versus those who were not. Furthermore, cavernoma tissue was cultured in a cell culture incubator after surgical resection for 72 hours. Experiments were performed in the presence of propranolol or solvent DMSO. The expression level of SDF-1, CXCR4, and dependent factors was measured by qRT-PCR. CXCR4 antagonist, AMD3100, was also used to detect its effects on cerebral vasculogenesis and SDF-1 expression.

Results: 488 CCMs among 338 patients, 69 (20,4%) were under treatment with β-blocker. 26% CCMs presented with hemorrhage at diagnosis. Patients under β-blocker treatment had a lower risk of hemorrhage at the time of diagnosis in a univariate descriptive analysis (p<0,05;OR2). Univariate descriptive and univariate Cox proportional-hazards regression analysis showed a decreased risk for follow-up hemorrhage under treatment with β-blocker medication (p<0,05,HR3,5). Multivariate regression analysis including brainstem location, hemorrhage at diagnosis, age, and β-blocker treatment showed reduced risk for follow-up hemorrhage under β-blocker treatment (p<0,05,HR1,36).

The expression of CXCR4 was suppressed by propranolol most likely through the Akt and MAPK pathways. The gene expression of vasculogenesis factors such as VEGF was decreased in with propranolol incubated CCM.

Conclusion: In this study, β-blocker medication seems to be associated with a decreased risk of CM-related hemorrhage and CM-growth at presentation or during follow-up.

Propranolol inhibits SDF1α-induced vasculogenesis by suppressing the expression of CXCR4 most likely through the Akt and MAPK pathways. The SDF-1/CXCR4 axis plays an important role in the vasculogenesis in cerebral CM lesions.