The disease understanding of intracranial aneurysms is changing. In formation and growth, as well as in destabilization mechanisms, inflammatory processes are currently the focus of clinical research. Recent findings could change the treatment of unstable aneurysms in the future: From neurosurgical and endovascular interventions to drug therapy – with aspirin?
It is known that aneurysms are caused by excessive flow velocities in the arteries. Aneurysms are not congenital, as was once believed, but develop during life, usually after age 40. It is changes in hemodynamics in the brain that cause aneurysm development, this has been shown in animal studies [1]. In this process, the arterial wall is remodeled, by macrophages and the enzyme cyclooxygenase, COX-2 [2]. Signs of instability and therefore risk of rupture are the size of the aneurysm and contrast uptake along the aneurysm wall indicating inflammation. Irregular shape also increases risk, regardless of size: about 40% of aneurysms that rupture are small (<10 mm) [3].
Not every aneurysm becomes unstable
Prof. Juhana Frösen, MD PhD from Kuopio University Hospital in Finland, explained in his presentation that it is important to understand that not every aneurysm actually ruptures. The pathobiological mechanisms leading to formation and rupture are different. A lifetime follow-up study of aneurysms at high risk of rupture that were not treated showed that rupture occurred in only one-third [4]. The fact that an aneurysm forms does not necessarily mean that it will also become unstable, with the known consequences of a possible rupture. On the contrary, says Prof. Frösen, an aneurysm can remain stable for the rest of a person’s life. The reason for the stability is adaptive remodeling, i.e., the vessel wall is remodeled. It thickens and new collagen is formed [5]. In this way, the vessel wall reacts to the mechanical stress caused by high flow velocity and tries to adapt to the new conditions.
High flow rate associated with inflammation
Aneurysm growth is a consequence of adaptive remodeling of the vessel wall [6]. The vessel wall enlarges, the geometry changes and thus the flow conditions in the vessel. The driving force in this biomechanical process is the energy of blood flow acting on the vessel walls. If the factor causing the high flow velocity is removed, regression of the aneurysm can be observed, even if the aneurysm itself is not treated.
Further, Prof. Frösen reports a link between flow conditions and inflammation driving remodeling. Depending on the flow velocity, friction forces that are too high or too low lead to inflammation of the aneurysm vessel wall. Inflammation, in turn, is associated with remodeling of the vessel wall and rupture. The result of degenerative remodeling or remodeling is a loss of smooth muscle cells, which prevents adaptive remodeling. Inflammation of the aneurysm wall causes the remaining matrix to be destroyed [5,7].
Do drugs prevent aneurysm growth?
An ongoing study at Kuopio University Hospital is examining patients to determine whether drugs can prevent aneurysm growth and thus prevent destructive remodeling and rupture. The initial results on pharmaceutical inhibition of flow-related destructive remodeling are promising: a lower risk of aneurysm formation can be observed, fewer neoplasms occur after initial diagnosis, and the risk of aneurysm growth and rupture is also lower. If the results are further confirmed, this study may significantly change the understanding of the disease. Until now, aneurysms have been treated mostly by endovascular or neurosurgical means; the new perspective is drugs. According to Prof. Frösen, there is a need for drug therapy that prevents remodeling from taking place and the aneurysm from growing, thereby reducing the risk of rupture.
Phase 3 study with aspirin
Prof. David M. Hasan, MD of the University of Iowa Hospitals and Clinics is currently investigating drug therapy options for aneurysms in a Phase 3 trial using aspirin. This is based on the hypothesis that aspirin attenuates the inflammatory process in the aneurysm wall and decreases the number of aneurysm ruptures [8]. The hypothesis is that aspirin has the potential to reduce the risk of subarachnoid hemorrhage (SAH). With a better understanding of the aneurysm, says Prof. Hasan, therapy will also change: Until now, aneurysms have been treated based on the criterion of size. The new approach is that therapy should be tailored to the individual patient because, depending on a patient’s biological background, each aneurysm behaves differently.
Fragmentation of the inner elastic membrane
In defining an aneurysm, Prof. Hasan focuses on the structural change of the internal elastic membrane, i.e., fragmentation. Until now, it was assumed that this membrane was dense tissue that formed a barrier to external influences. However, a study [9] has shown that age alone causes a significant change in the membrane, called fenestration.
If the percentage of fenestrations is high, the membrane is weakened, the smooth muscle cells are degraded, and a bulge is formed. If the elastic membrane is intact, this does not happen. It is not yet known exactly how this process will work. The process of fenestration increases in zones with high flow velocities, i.e. in sections where strong frictional forces act on the vessel wall. This is what Prof. Hasan calls “high shear wall stress,” which marks the beginning of the disease with inflammation of the endothelial cells and increasing fenestration.
Balance of macrophages ensures stability
Using large databases, Prof. Hasan and his team examined tissue from ruptured and unruptured aneurysms. They found that more cytokines such as COX-2, mPGES-1, and COX-1 were present in ruptured aneurysms, as were more inflammatory cells and macrophages. An invasion of inflammatory cells takes place until eventually mast cells are involved [10].
Another finding relates to the different types of macrophages (M1 and M2). M1 cause inflammation and produce cytokines, while M2 have anti-inflammatory effects and activate the self-healing process. In unstable aneurysms, more M1 macrophages are present than M2 macrophages and more mast cells are observed in the aneurysm wall than in healthy vessel sections. These two types of cells interact and destroy the cells of the aneurysm wall. It is inflammatory cells or the messengers (cytokines/chemokines) that lead to phenotypic changes in endothelium and smooth muscle cells. This leads to a vicious circle with closed loop feedback. The aneurysm then activates self-repair mechanisms and attempts to regulate itself and establish a stable equilibrium.
This stabilized state can last for several years until a second event occurs that causes this equilibrium to tip. Prof. Hasan and his team now want to find out what triggers this second event. This would be another important answer to disease understanding in relation to aneurysm instability.
Literature:
- Aoki T, Frösen J, et al: Prostaglandin E2-EP2-NF-KB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Sci. Signal. Feb. 2017: Vol. 10, Issue 465, DOI: 10.1126/scisignal.aah 6037.
- Ishibashi R, Aoki T, et al: Contribution of mast cells to cerebral aneurysm formation. Curr Neurovasc Res. 2010(7): 113-124.
- Lindgren AE, et al: Irregular shape of intracranial aneurysm indicates rupture risk irrespective of size in a population-based cohort. Stroke 2016; 47(5): 1219-1226.
- Etminan N, et al: The unruptured intracranial aneurysm treatment score. Neurology 2015. vol. 85 no. 10; 881-889.
- Frösen J, et al: Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm walls: Implications for biological therapy preventing rupture. Neurosurgery. 2006; 58(3): 534-541.
- Wagenseil J, Mecham RP: Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res. 2012; 5(3): 4-73.
- Frösen J, et al: Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004; 35(10): 2287-2293
- Hasan DM, et al: Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011(42): 3156-3162.
- Chalouhi N, et al: Review of cerebral aneurysm formation, growth, and rupture. Stroke 2013(44): 3613-3622.
- Hasan D, et al: Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflammation. 2012(9): 222.
InFo NEUROLOGY & PSYCHIATRY 2017; 15(4): 32-33.
