By: Corinne Benakis, Arthur Liesz
ESO European Stroke Science Workshop 2023
Session 6: New Horizons
Keynote lecture: Uric acid in stroke: the next frontier
Angel Chamorro (Spain)
Prof. Chamorro started his lecture on uric acid in stroke by first introducing he metabolism of uric acid, which is the end product of purine metabolism in humans. Uric acid is found as an end product in urine, usually known to form crystals and accumulate in joints when in high concentration. In lower concentration, uric acid is an antioxidant, and neutralizes free radicals with potential beneficial effect in ageing and cancer. Prof. Chamorro made the analogy of uric acid as a “vacuum cleaner”. In 2002, he and his team published results that showed that an increase of uric acid in patients with acute ischemic stroke is an independent predictor of good clinical outcome, highlighting the importance of oxidative damage induced early in the ischemic cascade. He re-emphasized the huge disappointment of “neuroprotection failure” in translating positive pre-clinical research to clinical trials. He addressed that perhaps this failure was due to mostly targeting the early excitotoxic events mediated by excessive glutamate toxicity but that might not be relevant since the time course of glutamate peaks very acutely after stroke but quickly recovers thereafter. In contrast, the formation of radical species continues to rise after stroke, especially in the penumbra participating in the no-reflow phenomenon. Hence, he emphasized neuroprotective strategies should be a “redox-centered neuroprotection” strategy, especially targeting the salvageable penumbra tissue in combination with mechanical thrombectomy.
URICO-ICTUS 2b/3 was a randomised, double-blind, placebo-controlled trial, that recruited patients with acute ischaemic stroke (The Lancet Neurology 2014), with a primary outcome of patients with excellent outcome at 90 days. The study showed an absolute treatment effect of 8% but no significance. The speaker mentioned the relatively small number of patients recruited that would make finding any significant results difficult.
He then took the audience on to describe the efforts taken by the Stroke Preclinical Assessment Network (SPAN) to test uric acid in preclinical stroke models. SPAN consisted of six research laboratories that conduced preclinical stroke modelling, with a coordinating center which was solely involved in drug preparation, randomization, collection and management of data, assessing blinded outcomes and performing statistical analysis. Outcome was addressed at 30 days based on behavioural improvement post-stroke as primary end-point. Of all drugs tested, among the four stages (including rodent models with comorbidities: hypertensive, obesity) only uric acid showed efficacy on the primary outcome which was validated iuntil the final stage 4 (validation in a rat model). These very impressive and promising results were published this year in Science Translational Medicine. The next frontier is to perform an interventional clinical trial in patients receiving endovascular thrombectomy (AURORA) in combination with uric acid. The stroke field is following the outcome of such intervention closely, as it could bring important benefits for stroke patients, their relatives and clinical stroke practice.
Prof. Chamorro received a nice round of applause and the first question asked him to explain the rationale behind limiting this kind of clinical trial to patients with thrombectomy. Prof. Chamorro mentioned that ideally uric acid would be administrated to any stroke patients, however it is important now that beneficial effect of uric acid is proven in highly responsive patients. This was followed by a question regarding the best timing of drug administration, and whether blood biomarkers can be used to test efficacy or perhaps to stratify receiver patients. Because previous work showed that the level of uric acid peaks immediately after reperfusion, uric acid will be administered immediately when the thrombectomy is decided. Biomarkers are now not the focus of the study, but rather primary outcome. A participant raised that giving uric acid may be counter intuitive since it can induce gout, however this was a highly epi-phenomenon among the patients enrolled and not specific to the treatment and might underlined pre-existing condition. There was then some debate from participants regarding the interpretation of sub-group analysis, that could be either futile or meaningful. What matters at the end is overall benefit for the patient and perseverance will tell us more.
Stephanie Debette
Multiomics into vascular brain health
Stephanie Debette’s scientific presentation delved into the pressing issue of vascular brain disease, which still lacks adequate treatment. She emphasized that genomics could potentially offer a targeted approach to address this condition, revealing over 150 genetic risk loci associated with vascular brain disease, mostly small vessel disease (SVD) with increased risk of stroke and dementia. However, the mechanisms underlying these genetic risk variants remain poorly understood.
Debette highlighted Montaner et al.’s work in Nat Rev Neurol 2020 (co-authored by Alba Simats, next speaker in this session), showcasing the transition from stroke treatment to multiomics strategies, stressing the importance of circulating biomarkers in understanding the underlying biology and hastening omics-driven discoveries in vascular diseases.
The integration of omics biomarkers such as metabolites, methylation, microRNAs, and proteins, along with genetic information, was emphasized to establish causal relationships, though research in multiomics for stroke has been hindered by limited sample sizes, predominantly focusing on blood-based biomarkers as shown in Chen Nat Comm 2020 and Mishra Nature 2022, utilizing Mendelian Randomization to obtain clues for causality.
Another referenced study by Sliz et al (Circulation 2022) described using mendelian randomization that circulating metabolites are associated with white matter hyperintensities (WMH). Metabolites are either endogenous or from exogenous sources like diet and chemical exposures, associating specific metabolites with risk factors for vascular brain disease, although the precise correlations are not fully investigated.
Debette discussed epigenomics, citing Yang, Brain 2023, and the importance of proteomics due to its proximity to function. Her focus leaned towards plasma proteins, as exemplified in Kuipers JCBFM 2022, which highlighted a cluster of proteins, including coagulation factors, associated with white matter hyperintensities (WMH). Employing a pQTL approach (protein quantitative trait loci), Debette outlined her study associating 21 proteins with a higher risk of SVD, specifically mentioning cathepsin b and immune response enrichment. This research would significantly enhance the prediction of SVD. She posed critical questions in her conclusion, pondering whether the proteins linked to SVD could predict stroke and dementia while exploring the feasibility of developing drugs targeting these proteins. She emphasizes that taking a more global approach towards vascular brain health by integrating multiomics to not only address risk prediction, but also early prevention and to accelerate the development of new drugs. And the development of interdisciplinary experts would significantly accelerate discovery.
Alba Simats
Innate immune memory after stroke drives inflammatory cardiac dysfunction
Alba Simats’ presentation exemplified the profound impact of post-stroke inflammatory responses, and it’s influence on other diseases like atherosclerosis, diabetes, and heart dysfunction. The chronic inflammatory state persisting in stroke patients over time raises questions about its consequences on peripheral organs, such as the heart.
Within a month of stroke, increase of myeloid cells were identified in various peripheral organs, particularly highlighting the dominance of monocytes/macrophages exhibiting a pro-inflammatory signature. Remarkably, the heart emerged as the most affected organ in this cellular population, exhibiting altered left ventricle diastolic dysfunction, a finding mirrored in the SICFAIL previously describing cardiac dysfunction in stroke patients.
Investigations into cardiac fibrosis, collagenase and MMP9 accumulation in the heart showed as association with with an increase in heart and circulating inflammatory CCR2+ monocytes expressing MMP9. A cohort of cardiac autopsy samples from stroke and control patients further substantiated these findings, demonstrating fibrosis, MMP9, CCR2+ expression, and inflammatory genes in the hearts of stroke patients.
Insights into bone marrow as a potential source of these monocytes wasrevealed, showcasing increased monocytes/neutrophils and their precursors after one month post-stroke. Notably, both pluripotent stem cells and monocytes from the bone marrow exhibited distinct gene profiles similar to those in the periphery, speculating that the inflammatory cardiac monocytes originate and are polarized in the bone marrow.
A groundbreaking experiment, showing causality, involved bone marrow transplantation from stroke-affected mice to mice lacking bone marrow, demonstrated that progenitor cells and monocytes carrying the Ly6C high marker exhibited identical signatures, leading to similar cardiac dysfunction characterized by increased fibrosis and MMP9 expression in the heart. The potential therapeutic avenue of inhibiting monocyte infiltration from the bone marrow to the heart using a dual chemokine inhibitor showed promising results. Blocking monocyte access to the heart not only restored left ventricle volume but also decreased cardiac fibrosis, hinting at a potential intervention strategy for post-stroke cardiac complications. These are the first evidence that stroke impacts cardiac function chronically mediated by recruitment of inflammatory monocytes to the heart.
Floris HBM Schreuder
Inflammation after Intracerebral Hemorrhage
Floris HBM Schreuder’s presentation on “Inflammation in Intracerebral Hemorrhage (ICH): The Ugly, The Bad, and The Good” highlighted the nuanced nature of inflammatory responses in this condition. He outlined the phases of inflammation, emphasizing both detrimental and beneficial aspects. Hence, the classical view of good and bad inflammation in ICH is more complicated.
The road map of his talk navigated through three main areas: the role of inflammation in ICH, mechanisms of secondary brain injury, and therapeutic approaches.
In discussing the role of inflammation in ICH, Schreuder focused on the transition to a hemorrhagic phenotype, attributing it to reduced clearance in Amyloid beta deposition, leading to vessel fragmentation (loss of smooth muscle cells) and subsequent perivascular inflammation.
ICH develops into hematoma growth but also to an accumulation of parenchymal blood components inducing secondary brain injury with BBB breakdown, inflammation and perhematomal edema. This was portrayed as a time-dependent process, where the inflammatory response played a complex role.
Preclinical studies faced limitations due to induced ICH via collagenase or blood injection, which do not necessarily recapitulate the complex inflammatory cascade in human ICH. Importantly there is still only limited data derived from investigating human brains and systemic inflammation. He highlighted the recent meta-analysis showing association with circulating inflammatory biomarkers and clinical outcome following ICH (Kirby et al. Wellcome Open Res 2023).
Therapeutic strategies to mitigate post-ICH inflammation include surgical blood removal and reducing perihematomal edema: The Dutch ICH surgery trial, and a new sub-study DIST-INFLAME to investigate immunoprofile between surgically versus conservatively treated patients are investigating these approaches. Schreuder stressed the need for early intervention due to the vulnerability of ICH patients to infections, posing the question of whether modulating inflammation, possibly with steroids like Dexamethasone, could be effective or if this type of intervention is alreafdy a “closed case” considerating previous (futile) studies using this intervention..
Ongoing trials targeting inflammation and potential therapeutic avenues like neutralization of IL-1b as a target were discussed; including potential complications and the their limitations. Schreuder concluded by emphasizing the importance in targeting multiple phases and mechanisms of ICH, such as stopping ICH growth, treat hypertension, reduce secondary brain inflammation (IL1b), promote repair (stem cell strategy?) and rehabilitation, combining experts from different fields from the emergency to the rehab teams. He finished his talk mentioning there is certainly possibility of leveraging inflammation for therapeutic intervention in ICH while acknowledging the complexity and challenges involved.
