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Association Between Systemic Amyloidosis and Intracranial Hemorrhage

2022; Lippincott Williams & Wilkins; Volume: 53; Issue: 3 Linguagem: Inglês

10.1161/strokeaha.121.038451

1524-4628

Dora Chen, Cenai Zhang, Neal S. Parikh, Alexander E. Merkler, Babak B. Navi, Matthew E. Fink, Kevin N. Sheth, Guido J. Falcone, Mony J. de Leon, Ajay Gupta, Hooman Kamel, Santosh B. Murthy,

Sarcoidosis and Beryllium Toxicity Research

HomeStrokeVol. 53, No. 3Association Between Systemic Amyloidosis and Intracranial Hemorrhage Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessLetterPDF/EPUBAssociation Between Systemic Amyloidosis and Intracranial Hemorrhage Dora Chen, AB, Cenai Zhang, MS, Neal Parikh, MD, MS, Alexander E. Merkler, MD, MS, Babak B. Navi, MD, MS, Matthew E. Fink, MD, Kevin N. Sheth, MD, Guido J. Falcone, MD, ScD, MPH, Mony J. de Leon, PhD, Ajay Gupta, MD, MS, Hooman Kamel, MD, MS and Santosh B. Murthy, MD, MPH Dora ChenDora Chen https://orcid.org/0000-0001-8991-0673 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Cenai ZhangCenai Zhang https://orcid.org/0000-0001-8137-1644 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Neal ParikhNeal Parikh https://orcid.org/0000-0002-8802-2380 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Alexander E. MerklerAlexander E. Merkler https://orcid.org/0000-0002-2211-299X Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Babak B. NaviBabak B. Navi https://orcid.org/0000-0001-8424-6128 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Matthew E. FinkMatthew E. Fink https://orcid.org/0000-0001-6649-3184 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. , Kevin N. ShethKevin N. Sheth https://orcid.org/0000-0003-2003-5473 Division of Neurocritical Care and Emergency Nerology, Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S., G.J.F.). , Guido J. FalconeGuido J. Falcone https://orcid.org/0000-0002-6407-0302 Division of Neurocritical Care and Emergency Nerology, Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S., G.J.F.). , Mony J. de LeonMony J. de Leon https://orcid.org/0000-0003-4741-406X Department of Radiology (M.J.d.L., A.G.), Weill Cornell Medicine, NY. , Ajay GuptaAjay Gupta Department of Radiology (M.J.d.L., A.G.), Weill Cornell Medicine, NY. , Hooman KamelHooman Kamel https://orcid.org/0000-0002-5745-0307 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. and Santosh B. MurthySantosh B. Murthy Correspondence to: Santosh B. Murthy, MD, MPH, 525 East 68th St, Room F610, New York, NY 10065. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4950-0992 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology (D.C., C.Z., N.P., A.E.M., B.B.N., M.E.F., H.K., S.B.M.), Weill Cornell Medicine, NY. Originally published3 Feb 2022https://doi.org/10.1161/STROKEAHA.121.038451Stroke. 2022;53:e92–e93Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 3, 2022: Ahead of Print Isolated amyloid deposition in the brain in the form of amyloid Aβ, as seen in cerebral amyloid angiopathy, is associated with intracranial hemorrhage.1 Systemic amyloidosis is caused by the deposition of insoluble amyloid fibrils, mainly amyloid light-chain, or hepatic-derived transthyretin, in the extracellular space of tissues, which leads to progressive organ failure and death.2 Animal studies suggest that peripheral administration of misfolded amyloid aggregates contribute to the transmission of cerebral amyloid pathology.3 It is, however, unknown if systemic amyloidosis increases the risk for intracranial hemorrhage.Data supporting this study will be available upon approval by the Center for Medicare Services. This study was approved by the Weill Cornell Medicine institutional review board which provided an exemption for informed consent of this deidentified data set.We used a 5% sample of Medicare claims data from 2008 to 2015. Our exposure variable was a diagnosis of systemic amyloidosis. Our primary outcome was nontraumatic intracranial hemorrhage, a composite of intracerebral hemorrhage, subarachnoid hemorrhage, and subdural hemorrhage. The exposure and outcomes were identified using International Classification of Diseases, Ninth Revision diagnosis codes (Supplemental Material). Secondary outcomes were the intracranial hemorrhage subtypes, assessed separately. We used hip fracture, a common incident condition among the elderly, as a negative control. Cox proportional hazards models were adjusted for demographics, vascular risk factors, and Charlson comorbidities.Among 1.8 million Medicare beneficiaries, 924 were diagnosed with systemic amyloidosis (Table S1). During a median follow-up of 5.3 years (interquartile range, 2.8–6.7), the cumulative incidence of intracranial hemorrhage with systemic amyloidosis was 19 per 1000 patient-years versus 2 per 1000 without systemic amyloidosis. In the adjusted Cox model, systemic amyloidosis was associated with an increased risk of intracranial hemorrhage (hazard ratio [HR], 3.0 [95% CI, 2.0–4.5]; Figure). In adjusted secondary analyses, systemic amyloidosis was associated with an increased risk of ICH (HR, 3.5 [95% CI, 2.2–5.4]), subarachnoid hemorrhage (HR, 6.7 [95% CI, 4.0–11.4]), and subdural hemorrhage (HR, 2.7 [95% CI, 1.5–4.8]). There was no association between systemic amyloidosis and hip fracture (HR, 0.9 [95% CI, 0.6–1.4]). Additional analyses are shown in the Supplemental Material.Download figureDownload PowerPointFigure. Systemic amyloidosis and intracranial hemorrhage. Risk of intracranial hemorrhage (A), intracerebral hemorrhage (ICH; B), subarachnoid hemorrhage (SAH; C), and subdural hemorrhage (SDH; D) among beneficiaries with and without systemic amyloidosis.In a large, heterogeneous cohort of Medicare beneficiaries, we observed an estimated 3-fold increased risk of intracranial hemorrhage after a diagnosis of systemic amyloidosis. Importantly, this elevated risk was present in all intracranial hemorrhage subtypes. Possible mechanisms include increased peripheral deposition of amyloid leading to decreased central nervous system clearance and subsequent accumulation within the brain4; and direct hematogenous spread of systemic amyloid to the brain4; suggesting a close link between systemic amyloidosis and central amyloid deposition. While further research is warranted, clinicians should be aware of this heightened intracranial bleeding risk, especially in the context of prescribing antithrombotic drugs.Article InformationSources of FundingNational Institutes of Health (NIH) to Dr Murthy (K23NS105948).DisclosuresDr Parikh reports National Institutes of Health (NIH)/National Institutes of Aging (NIA), NY State Empire Clinical Research Investigator Program, Florence Gould Foundation, Leon Levy Foundation, medicolegal consulting in Stroke. Dr Merkler reports medicolegal consulting in Stroke; Dr Fink reports compensation from Relias; Dr Sheth: Compensation from Sense, Cerevasc, Certus, Rhaeos, Zoll Medical Corporation, CSL Behring, Alva Health patent, service as President for Advanced Innovation in Medicine; grants from NIH, American Heart Association (AHA), Biogen, Hyperfine, Novartis, Bard, for consultant services. Dr Falcone reports NIH and AHA. Dr Kamel reports NIH, Bristol Myers Squibb-Pfizer Alliance for Eliquis and Roche Diagnostics, Deputy Editor for JAMA Neurology, compensation from Janssen Biotech, Boehringer Ingelheim, Medtronic, and Novo Nordisk. Dr deLeon reports NIH. The other authors report no conflicts.Supplemental MaterialSupplemental MethodsTable S1FootnotesThis article was sent to Irene L. Katzan, Guest Editor, for review by expert referees, editorial decision, and final disposition.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.038451.For Sources of Funding and Disclosures, see page e93.Presented in part at the International Stroke Conference, New Orleans, LA, and virtual, February 9–11, 2022.Correspondence to: Santosh B. Murthy, MD, MPH, 525 East 68th St, Room F610, New York, NY 10065. Email [email protected]cornellReferences1. Viguier A, Raposo N, Patsoura S, Calviere L, Albucher JF, Ruidavets JB, Chollet F, Cognard C, Olivot JM, Bonneville F. Subarachnoid and subdural hemorrhages in lobar intracerebral hemorrhage associated with cerebral amyloid angiopathy.Stroke. 2019; 50:1567–1569. doi: 10.1161/STROKEAHA.119.024837LinkGoogle Scholar2. Gertz MA, Dispenzieri A. Systemic amyloidosis recognition, prognosis, and therapy: a systematic review.JAMA. 2020; 324:79–89. doi: 10.1001/jama.2020.5493CrossrefMedlineGoogle Scholar3. Morales R, Bravo-Alegria J, Moreno-Gonzalez I, Duran-Aniotz C, Gamez N, Edwards Iii G, Soto C. Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates.Mol Psychiatry. 2021; 26:5690–5701. doi: 10.1038/s41380-021-01150-wCrossrefGoogle Scholar4. Marques MA, Kulstad JJ, Savard CE, Green PS, Lee SP, Craft S, Watson GS, Cook DG. Peripheral amyloid-beta levels regulate amyloid-beta clearance from the central nervous system.J Alzheimers Dis. 2009; 16:325–329. doi: 10.3233/JAD-2009-0964CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mehta A, Isaacson J, Calabria S, Burton S, Craft V, Somani S, Harris B, Kim Y, Mai J and Hsia A (2023) Amyloid Beta-Related Angiitis Presenting as Multiple Cerebral Infarcts, Neuroimmunology Reports, 10.1016/j.nerep.2022.100158, 3, (100158), . Bukhari S, Oliveros E, Parekh H and Farmakis D (2022) Epidemiology, mechanisms, and management of atrial fibrillation in cardiac amyloidosis, Current Problems in Cardiology, 10.1016/j.cpcardiol.2022.101571, (101571), Online publication date: 1-Dec-2022. Singh P, Chen Z, Horn K and Norris E (2022) Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms, Research and Practice in Thrombosis and Haemostasis, 10.1002/rth2.12815, 6:7, (e12815), Online publication date: 1-Oct-2022. March 2022Vol 53, Issue 3 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.121.038451PMID: 35109677 Originally publishedFebruary 3, 2022 Keywordssubarachnoid hemorrhageamyloidincidencebraincerebral hemorrhagePDF download Advertisement SubjectsIntracranial Hemorrhage