by Christian Boehme, ESO Social Media and PR Committee

Twitter: @chris7ianb

Arthur Liesz from Munich, Germany and Ethem Murat Arsava from Ankara, Türkiye chaired this last session of the day on inflammation in stroke.

Yaw Asare (Munich, Germany) presented Atherosclerotic Plaque Inflammation: Mechanistic insights from experimental studies. He pointed out that common variants in HDAC9 are associated with atherosclerotic phenotypes. An experimental study deleted the cis regulatory element (CRE) at HDAC9 which exacerbated atherosclerosis. Also, HDAC9 promotes inflammasome activation and is associated with increased atherosclerosis plaque instability in humans. HDAC9-targeted immunotherapy stabilizes atherosclerotic plaques thereby offering a poterntisl target for stroke prevention. NLRP3 inflammasome is a central inflammatory pathway driving atherosclerosis. HDAC9 is a major cardiovascular risk gene and an upstream modulator of NLRP3, therefore nanobiologics targeting HDAC9 at the site of myeloid-driven vascular inflammation confer vascular protection. These studies serve as basis for development of powerful anti-inflammatory drugs to reduce the risk of atherosclerotic stroke.

Alba Simats (Barcelona, Spain) followed with Systemic inflammation after ischemic stroke. She points out the role of the chronic immune response after stroke which lasts up to one year. Systemic inflammation is a risk factor for lots of diseases, among others, dementia, cerebrovascular disease and depression and i.e. bone and joint diseases or lung diseases. Systemic inflammation influences the brain-heart immune axis after stroke inducing development of AF, ECG abnormalities and LV-diastolic dysfunction. Stroke induces long-lasting transcriptomic changes in monocytes and drive chronic cardiac fibrosis, and in a study, blocking monocyte infiltration into the heart reduced LV-diastolic dysfunction. The exact mechanisms in the numerous comorbidities and their relevance in clinical outcomes are yet to be determined.

Next, Maria Moro (Madrid, Spain) did a presentation on The role of neutrophils as a therapeutic target in stroke. She emphasizes the role of neurophils in cerebral damage in case of ischemia. Previous studies showed that neutrophil depletion or inhibition of their infiltration improve stroke outcome after MCA occlusion in mice but this is not the case in all studies. There is evidence that neutrophil heterogeneity is an important feature in immune pathophysiology and that neutrophil ageing is regulated by the microbiome, which might be a source of neutrophil heterogeneity. Also, neutrophil heterogeneity is determined by circadian rhythms and Maria’s research on this topic will be published soon. These circadian effects might be an explanation for the translational failure in neuroprotection.

Furthermore, she implies that TLR4 might be a future therapeutic target in acute stroke and RCTs are needed to confirm this. She concludes that, regardless of the mechanism underlying phenotypic heterogeneity, strategies that interfere with the pathogenic function of deleterious neutrophil phenotypes are promising targets for stroke treatment.

Anna Bersano (Milan, Italy) followed with the Role of inflammation in cerebral amyloid angiopathy. She emphasized on the role of amyloid deposition into blood vessel walls which make them predispose for rupture, causing ICH. One proposed pathogenic mechanism of CAA is that inefficient Aß clearance leads to abnormal Aß accumulation in the brain and vessels, causing CAA in the aged brain. In rare cases, patients suffer from the inflammatory form of CAA – CAA-ri which has different histopathological features compared to CAA. CAA-ri patients do not frequently present with ICH, but more often with acute or subacute cognitive impairment, headaches, seizures and focal deficits. Recent research found laboratory differences including increased leukocytes, protein and tau levels. Regarding treatment, no standard treatment is recommended but clinical and neuroradiological improvement is achieved by using corticosteroids and immunosuppressants, albeit mortality is around 30%. In conclusion, CAA-ri expands the clinical spectrum of CAA, it is increasingly recognized and treatable, the clinical presentation is usually acute or subacute, bit may be similar to CAA. MRI shows characteristics of CAA features in addition to white matter lesions with extension to subcortical areas but also edema and/or contrast enhancement. The disease can be monophasic but also relapsing and usually responds fast to immune-modulating treatment. Limitations to the available evidence are the small size of the reported series and large multicenter studies are needed to improve diagnosis, treatment and outcomes in CAA-ri affected patients.

Aristeidis Katsanos (Hamilton, Canada) completed the session with a talk on Inflammation as a target in secondary prevention after ischemic vs. hemorrhagic stroke. He highlights the high risk of recurrence of stroke in ischemic and hemorrhagic stroke, especially in the first months after the event. The common unmet need of these entities is the need for novel treatments which lower the long-term risk of future cardiovascular events and that can be initiated early after stroke when patients are at most risk. A stufdy of 8,420 patients found that hsCRP and IL-6 were associated with recurrent vascular events after stroke. So the goal is clear, we have to try to reduce inflammation. CHANCE 3 assessed short-term use of colchicine and the results were neutral, CONVINCE assessed long-term use of colchicine and found lower risk for atherosclerotic events but was terminated prematurely. Ongoing trials include RIISC-THETIS from France assessing colchicine in combination with DAPT in ischemic stroke and ipsilateral atherosclerotic stenosis, CASPER from Australia assessing colchicine in ischemic stroke/TIA with increased CRP levels and CoVasc-ICH from Canada assessing colchicine in ICH patients. Patients after ischemic or hemorrhagic stroke are at risk for stroke recurrence and other atherosclerotic cardiovascular events. Targeting atherosclerosis-related inflammation in addition to standard care may attenuate this risk. Long-term colchicine treatment should be evaluated further in RCTs for stroke prevention and the prevention of atheroslcerotic cardiovascular events in stroke survivors.

Aristeidis finished the session with a quote from John Lennon: “You may say I’m a dreamer. But I’m not the only one. I hope someday you’ll join us”.