Role of aspirin and statin therapy in patients with cerebral cavernous malformations

Gomez-Paz, Santiago; Salem, Mohamed M.; Maragkos, Georgios A; Ascanio, Luis C; Enríquez-Marulanda, Alejandro; Lee, Michelle; Kicielinski, Kimberly; Moore, Justin M.; Thomas, Ajith J.; Ogilvy, Christopher S.

doi:10.1016/j.jocn.2020.04.012

Cited by 16 publications

(22 citation statements)

References 31 publications

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“…This prognostic model is consistent with the existing knowledge on CA disease, including hyperpermeability's longitudinal association with CA bleed/growth 14 . Low perfusion in the prognostic model is also consistent with a recent study showing that aspirin and statin therapies aimed at attenuating disrupted blood flow were associated with lower odds of CA hemorrhage 29 . Finally, the DCEQP lesional imaging descriptors and proteins of the plasma biomarker 18,30 may reflect complementary biological mechanisms.…”

Section: Discussionsupporting

confidence: 88%

“…14 Low perfusion in the prognostic model is also consistent with a recent study showing that aspirin and statin therapies aimed at attenuating disrupted blood flow were associated with lower odds of CA hemorrhage. 29 Finally, the DCEQP lesional imaging descriptors and proteins of the plasma biomarker 18,30 may reflect complementary biological mechanisms. Permeability and perfusion descriptors of the prognostic model may reflect the dysregulated angiogenesis and angioarchitecture of CA disease modulated by vascular endothelial growth factor 31,32 and its functionally related proteins.…”

Section: Discussionmentioning

confidence: 99%

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Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

Sone

Hobson

Srinath

et al. 2021

Magnetic Resonance Imaging

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Background Cerebral cavernous angioma (CA) is a capillary vasculopathy affecting more than a million Americans with a small fraction of cases demonstrating lesional bleed or growth with major clinical sequelae. Perfusion and permeability are fundamental features of CA pathophysiology, but their role as prognostic biomarkers is unclear. Purpose To investigate whether perfusion or permeability lesional descriptors derived from dynamic contrast‐enhanced quantitative perfusion (DCEQP) magnetic resonance imaging (MRI) can predict subsequent lesional bleed/growth in the year following imaging. Study Type Single‐site case‐controlled study. Subjects Two hundred and five consecutively enrolled patients (63.4% female). Field Strength/Sequence Three‐Tesla/T1‐mapping with contrast‐enhanced dynamic two‐dimensional (2D) spoiled gradient recalled acquisition (SPGR) sequences. Assessment Prognostic associations with bleed/growth (present or absent) in the following year were assessed in 745 CA lesions evaluated by DCEQP in the 205 patients in relation to lesional descriptors calculated from permeability and perfusion maps. A subgroup of 30 cases also underwent peripheral blood collection at the time of DCEQP scans and assays of plasma levels of soluble CD14, IL‐1β, VEGF, and soluble ROBO4 proteins, whose weighted combination had been previously reported in association with future CA bleeding. Statistical Tests Mann–Whitney U‐test for univariate analyses. Logistic regression models minimizing the Bayesian information criterion (BIC), testing sensitivity and specificity (receiver operating characteristic curves) of weighted combinations of parameters. Results The best prognostic biomarker for lesional bleed or growth included brainstem lesion location, mean lesional permeability, and low‐value perfusion cluster mean (BIC = 201.5, sensitivity = 77%, specificity = 72%, P < 0.05). Adding a previously published prognostic plasma protein biomarker improved the performance of the imaging model (sensitivity = 100%, specificity = 88%, P < 0.05). Data Conclusion A combination of MRI‐based descriptors reflecting higher lesional permeability and lower perfusion cluster may potentially predict future bleed/growth in CAs. The sensitivity and specificity of the prognostic imaging biomarker can be enhanced when combined with brainstem lesion location and a plasma protein biomarker of CA hemorrhage. Level of Evidence 2 Technical Efficacy Stage 5

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

Sone

Hobson

Srinath

et al. 2021

Magnetic Resonance Imaging

View full text Add to dashboard Cite

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“…Animal studies and one retrospective cross-sectional study have reported promising outcomes. [5][6][7][8] Beta-adrenoceptor blocking drugs (beta-blockers), specifically propranolol, are also of interest as a drug treatment for CCM. 9 Beta-blockers might reduce the risk of CCM hemorrhage via antiangiogenic pathophysiological mechanisms, based on in vitro and in vivo findings.…”

mentioning

confidence: 99%

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations

Zuurbier¹,

Hickman²,

Rinkel³

et al. 2022

Stroke

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BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01–0.66]; P =0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01–1.07]; P =0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM.

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“…Therefore, future research should focus on further identifying the molecular mechanisms that contribute to the increase of NLRP3 during CCM disease and investigate the therapeutic effect of drugs targeting NLRP3 inflammasome signaling 77 in CCM disease. Indeed statins, aspirin and inhibitors of ROS activity, negatively regulate NLRP3 inflammasome activity 77, 78 and have been identified as a potential therapy for CCM disease in pre-clinical and clinical studies 79–81 . It is possible that different mutations in CCM genes (CCM1, CCM2 or CCM3) may result in different biological mechanisms that lead to lesion aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation plays a critical role in cerebral cavernous malformation disease

Lai

Nelsen

Frias-Anaya

et al. 2022

Preprint

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BackgroundCerebral Cavernous Malformations (CCMs) are neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). CCMs affect ∼1/200 children and adults, and no pharmacologic therapy is available. CCM lesion count, size, and aggressiveness vary widely among patients of similar ages with the same mutation or even within members of the same family. However, what determines the transition from quiescent lesions into mature and active (aggressive) CCM lesions is unknown.MethodsWe use genetic, RNA-seq, histology, flow cytometry and imaging techniques to report the interaction between CCM-endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils (CALMN interaction) during the pathogenesis of CCMs in the brain tissue.ResultsExpression profile of astrocytes in adult mouse brains using translated mRNAs obtained from the purification of EGFP-tagged ribosomes (Aldh1l1-EGFP/Rpl10a) in the presence or absence of CCM lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) identifies a novel gene signature for neuroinflammatory astrogliosis. CCM reactive astrocytes have a neuroinflammatory capacity by expressing genes involved in angiogenesis, chemotaxis, hypoxia signaling, and inflammation. RNA-seq analysis on RNA isolated from brain endothelial cells (BECs) in chronic Pdcd10BECKO mice (CCM-endothelium), identified crucial genes involved in recruiting inflammatory cells and thrombus formation through chemotaxis and coagulation pathways. In addition, CCM- endothelium was associated with increased expression of Nlrp3 and Il1b. Pharmacological inhibition of NLRP3 significantly decreased inflammasome activity as assessed by quantification of a fluorescent indicator of caspase-1 activity (FAM-FLICA caspase-1) in BECs from Pdcd10BECKO in chronic stage. Importantly, our results support the hypothesis of the crosstalk between astrocytes and CCM endothelium that can trigger recruitment of inflammatory cells arising from brain parenchyma (microglia) and the peripheral immune system (leukocytes) into mature active CCM lesions that propagate lesion growth, immunothrombosis, and bleedings. Unexpectedly, partial or total loss of brain endothelial NF-kB activity (using Ikkbfl/fl mice) in chronic Pdcd10BECKO mice does not prevent lesion genesis or neuroinflammation. Instead, this resulted in elevated number of lesions and immunothrombosis, suggesting that therapeutic approaches designed to target inflammation through endothelial NF-kB inhibition may contribute to detrimental side effects.ConclusionsOur study reveals previously unknown links between neuroinflammatory astrocytes and inflamed CCM endothelium as contributors that trigger leukocyte recruitment and precipitate immunothrombosis in CCM lesions. However, therapeutic approaches targeting brain endothelial NF-kB activity may contribute to detrimental side effects.

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Role of aspirin and statin therapy in patients with cerebral cavernous malformations

Cited by 16 publications

References 31 publications

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations

Neuroinflammation plays a critical role in cerebral cavernous malformation disease

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