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Atrial Fibrillation, Thromboembolic Risk, and Anticoagulation in Cardiac Amyloidosis: A Review

Published:September 16, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.08.008

      Highlights

      • Cardiac amyloidosis (CA) is associated with higher prevalence of atrial fibrillation compared with age-matched population without CA, and the prevalence is higher in wild-type transthyretin cardiac amyloidosis compared with hereditary transthyretin cardiac amyloidosis and AL variants.
      • CA causes elevated risk of thromboembolism, regardless of atrial fibrillation status and CHA2DS2Vasc score, and can potentiate bleeding simultaneously.
      • Both direct oral anticoagulants and vitamin K antagonists can be used to provide thromboembolic protection in CA, and have comparable efficacy and bleeding rates.

      Abstract

      Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of amyloid fibrils that are primary derived either from misfolding of transthyretin (ATTR) or light-chain (AL) proteins. CA is associated with atrial fibrillation, potentiated by electromechanical changes as a result of amyloid infiltration in the myocardium. CA also predisposes to thromboembolism and could potentially simultaneously elevate bleeding risk. In this review, we aim to explore and compare the prevalence and pathophysiological mechanisms of atrial fibrillation and thromboembolism in ATTR and AL, examine bleeding risk and factors that promote bleeding, and compare anticoagulation strategies in CA. Finally, we highlight knowledge gaps in the field of thromboembolism in CA to guide future research.

      Key Words

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      References

        • Maleszewski JJ.
        Cardiac amyloidosis: pathology, nomenclature, and typing.
        Cardiovasc Pathol. 2015; 24: 343-350https://doi.org/10.1016/j.carpath.2015.07.008
        • Donnelly JP
        • Hanna M.
        Cardiac amyloidosis: an update on diagnosis and treatment.
        Cleve Clin J Med. 2017; 84: 12-26https://doi.org/10.3949/ccjm.84.s3.02
        • Kyle RA
        • Linos A
        • Beard CM
        • Linke RP
        • Gertz MA
        • O'Fallon WM
        • et al.
        Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989.
        Blood. 1992; 79: 1817-1822
        • Fontana M
        • Banypersad SM
        • Treibel TA
        • Abdel-Gadir A
        • Maestrini V
        • Lane T
        • et al.
        Differential myocyte responses in patients with cardiac transthyretin amyloidosis and light-chain amyloidosis: a cardiac MR imaging study.
        Radiology. 2015; 277: 388-397https://doi.org/10.1148/radiol.2015141744
        • Shi J
        • Guan J
        • Jiang B
        • Brenner DA
        • Del Monte F
        • Ward JE
        • et al.
        Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway.
        Proc Natl Acad Sci U S A. 2010; 107: 4188-4193https://doi.org/10.1073/pnas.0912263107
        • González-López E
        • Gallego-Delgado M
        • Guzzo-Merello G
        • de Haro-Del Moral FJ
        • Cobo-Marcos M
        • Robles C
        • et al.
        Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.
        Eur Heart J. 2015; 36: 2585-2594https://doi.org/10.1093/eurheartj/ehv338
        • Pilebro B
        • Suhr OB
        • Näslund U
        • Westermark P
        • Lindqvist P
        • Sundström T.
        (99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis.
        Ups J Med Sci. 2016; 121: 17-24https://doi.org/10.3109/03009734.2015.1122687
        • Buxbaum J
        • Jacobson DR
        • Tagoe C
        • Alexander A
        • Kitzman DW
        • Greenberg B
        • et al.
        Transthyretin V122I in African Americans with congestive heart failure.
        J Am Coll Cardiol. 2006; 47: 1724-1725https://doi.org/10.1016/j.jacc.2006.01.042
        • Masri A
        • Bukhari S
        • Eisele YS
        • Soman P.
        Molecular imaging of cardiac amyloidosis.
        J Nucl Med. 2020; 61: 965-970https://doi.org/10.2967/jnumed.120.245381
        • Masri A
        • Bukhari S
        • Ahmad S
        • Nieves R
        • Eisele YS
        • Follansbee W
        • et al.
        Efficient 1-hour technetium-99 m pyrophosphate imaging protocol for the diagnosis of transthyretin cardiac amyloidosis.
        Circ Cardiovasc Imaging. 2020; 13e010249https://doi.org/10.1161/CIRCIMAGING.119.010249
        • Kwong RY
        • Heydari B
        • Abbasi S
        • Steel K
        • Al-Mallah M
        • Wu H
        • et al.
        Characterization of cardiac amyloidosis by atrial late gadolinium enhancement using contrast-enhanced cardiac magnetic resonance imaging and correlation with left atrial conduit and contractile function.
        Am J Cardiol. 2015; 116: 622-629https://doi.org/10.1016/j.amjcard.2015.05.021
        • Feng D
        • Edwards WD
        • Oh JK
        • Chandrasekaran K
        • Grogan M
        • Martinez MW
        • et al.
        Intracardiac thrombosis and embolism in patients with cardiac amyloidosis.
        Circulation. 2007; 116: 2420-2426https://doi.org/10.1161/CIRCULATIONAHA.107.697763
        • Dubrey S
        • Pollak A
        • Skinner M
        • Falk RH.
        Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation.
        Br Heart J. 1995; 74: 541-544https://doi.org/10.1136/hrt.74.5.541
        • Longhi S
        • Quarta CC
        • Milandri A
        • Lorenzini M
        • Gagliardi C
        • Manuzzi L
        • et al.
        Atrial fibrillation in amyloidotic cardiomyopathy: prevalence, incidence, risk factors and prognostic role.
        Amyloid. 2015; 22: 147-155https://doi.org/10.3109/13506129.2015.1028616
        • Sanchis K
        • Cariou E
        • Colombat M
        • Ribes D
        • Huart A
        • Cintas P
        • et al.
        Toulouse Amyloidosis Research Network Collaborators. Atrial fibrillation and subtype of atrial fibrillation in cardiac amyloidosis: clinical and echocardiographic features, impact on mortality.
        Amyloid. 2019; 26: 128-138https://doi.org/10.1080/13506129.2019.1620724
        • Mints YY
        • Doros G
        • Berk JL
        • Connors LH
        • Ruberg FL.
        Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience.
        ESC Heart Fail. 2018; 5: 772-779https://doi.org/10.1002/ehf2.12308
        • Bukhari S
        • Barakat AF
        • Eisele YS
        • Nieves R
        • Jain S
        • Saba S
        • et al.
        Prevalence of atrial fibrillation and thromboembolic risk in wild-type transthyretin amyloid cardiomyopathy.
        Circulation. 2021; 143: 1335-1337https://doi.org/10.1161/CIRCULATIONAHA.120.052136
        • Lowres N
        • Neubeck L
        • Redfern J
        • Freedman SB.
        Screening to identify unknown atrial fibrillation. A systematic review.
        Thromb Haemost. 2013; 110: 213-222https://doi.org/10.1160/TH13-02-0165
        • Rapezzi C
        • Merlini G
        • Quarta CC
        • Riva L
        • Longhi S
        • Leone O
        • et al.
        Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.
        Circulation. 2009; 120: 1203-1212https://doi.org/10.1161/CIRCULATIONAHA.108.843334
        • Kristen AV
        • Brokbals E
        • Aus dem Siepen F
        • Bauer R
        • Hein S
        • Aurich M
        • et al.
        Cardiac amyloid load: a prognostic and predictive biomarker in patients with light-chain amyloidosis.
        J Am Coll Cardiol. 2016; 68: 13-24https://doi.org/10.1016/j.jacc.2016.04.035
        • Papathanasiou M
        • Jakstaite AM
        • Oubari S
        • Siebermair J
        • Wakili R
        • Hoffmann J
        • et al.
        Clinical features and predictors of atrial fibrillation in patients with light-chain or transthyretin cardiac amyloidosis.
        ESC Heart Fail. 2022; 9: 1740-1748https://doi.org/10.1002/ehf2.13851
        • Aikawa T
        • Maki H
        • Ibe T
        • Manabe O
        • Oyama-Manabe N.
        Interatrial septal 99mTc-pyrophosphate uptake and reduced strain in wild-type transthyretin amyloid cardiomyopathy.
        J Nucl Cardiol. 2022; 29: 363-366https://doi.org/10.1007/s12350-021-02707-6
        • Middlekauff HR
        • Stevenson WG
        • Stevenson LW.
        Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients.
        Circulation. 1991; 84: 40-48https://doi.org/10.1161/01.cir.84.1.40
        • Torp-Pedersen C
        • Møller M
        • Bloch-Thomsen PE
        • Køber L
        • Sandøe E
        • Egstrup K
        • et al.
        Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.
        N Engl J Med. 1999; 341: 857-865https://doi.org/10.1056/NEJM199909163411201
        • Carson PE
        • Johnson GR
        • Dunkman WB
        • Fletcher RD
        • Farrell L
        • Cohn JN.
        The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group.
        Circulation. 1993; 87: VI102-VI110
        • Leone O
        • Boriani G
        • Chiappini B
        • Pacini D
        • Cenacchi G
        • Martin Suarez S
        • et al.
        Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation.
        Eur Heart J. 2004; 25: 1237-1241https://doi.org/10.1016/j.ehj.2004.04.007
        • Röcken C
        • Peters B
        • Juenemann G
        • Saeger W
        • Klein HU
        • Huth C
        • et al.
        Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.
        Circulation. 2002; 106: 2091-2097https://doi.org/10.1161/01.cir.0000034511.06350.df
        • Mesquita ET
        • Jorge AJL
        • Junior Souza CV
        • Andrade TR
        Cardiac amyloidosis and its new clinical phenotype: heart failure with preserved ejection fraction.
        Arq Bras Cardiol. 2017; 109: 71-80https://doi.org/10.5935/abc.20170079
        • Tyberg TI
        • Goodyer AV
        • Hurst 3rd, VW
        • Alexander J
        • Langou RA
        Left ventricular filling in differentiating restrictive amyloid cardiomyopathy and constrictive pericarditis.
        Am J Cardiol. 1981; 47: 791-796https://doi.org/10.1016/0002-9149(81)90175-2
        • Plehn JF
        • Southworth J
        • Cornwell 3rd, GG
        Brief report: atrial systolic failure in primary amyloidosis.
        N Engl J Med. 1992; 327: 1570-1573https://doi.org/10.1056/NEJM199211263272205
        • Cornwell 3rd, GG
        • Murdoch WL
        • Kyle RA
        • Westermark P
        • Pitkänen P.
        Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation.
        Am J Med. 1983; 75: 618-623https://doi.org/10.1016/0002-9343(83)90443-6
        • Brand A
        • Frumkin D
        • Hübscher A
        • Dreger H
        • Stangl K
        • Baldenhofer G
        • et al.
        Phasic left atrial strain analysis to discriminate cardiac amyloidosis in patients with unclear thick heart pathology.
        Eur Heart J Cardiovasc Imaging. 2021; 22: 680-687https://doi.org/10.1093/ehjci/jeaa043
        • Lohrmann G
        • Patel MA
        • Brauneis D
        • Sanchorawala V
        • Sarosiek S
        • Vellanki N
        • et al.
        Left atrial mechanics associates with paroxysmal atrial fibrillation in light-chain amyloidosis following stem cell transplantation.
        JACC CardioOncol. 2020; 2: 721-731https://doi.org/10.1016/j.jaccao.2020.10.010
        • Henry WL
        • Morganroth J
        • Pearlman AS
        • Clark CE
        • Redwood DR
        • Itscoitz SB
        • et al.
        Relation between echocardiographically determined left atrial size and atrial fibrillation.
        Circulation. 1976; 53: 273-279https://doi.org/10.1161/01.cir.53.2.273
        • De Jong AM
        • Maass AH
        • Oberdorf-Maass SU
        • Van Veldhuisen DJ
        • Van Gilst WH
        • Van Gelder IC
        Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation.
        Cardiovasc Res. 2011; 89: 754-765https://doi.org/10.1093/cvr/cvq357
        • De Jong AM
        • Van Gelder IC
        • Vreeswijk-Baudoin I
        • Cannon MV
        • Van Gilst WH
        • Maass AH.
        Atrial remodeling is directly related to end-diastolic left ventricular pressure in a mouse model of ventricular pressure overload.
        PLoS One. 2013; 8: e72651https://doi.org/10.1371/journal.pone.0072651
        • Barbhaiya CR
        • Kumar S
        • Baldinger SH
        • Michaud GF
        • Stevenson WG
        • Falk R
        • et al.
        Electrophysiologic assessment of conduction abnormalities and atrial arrhythmias associated with amyloid cardiomyopathy.
        Heart Rhythm. 2016; 13: 383-390https://doi.org/10.1016/j.hrthm.2015.09.016
        • Vilches S
        • Fontana M
        • Gonzalez-Lopez E
        • Mitrani L
        • Saturi G
        • Renju M
        • et al.
        Systemic embolism in amyloid transthyretin cardiomyopathy.
        Eur J Heart Fail. 2022; 24: 1387-1396https://doi.org/10.1002/ejhf.2566
        • Donnellan E
        • Wazni OM
        • Hanna M
        • Elshazly MB
        • Puri R
        • Saliba W
        • et al.
        Atrial fibrillation in transthyretin cardiac amyloidosis: predictors, prevalence, and efficacy of rhythm control strategies.
        JACC Clin Electrophysiol. 2020; 6: 1118-1127https://doi.org/10.1016/j.jacep.2020.04.019
        • Selvaraj S
        • Claggett B
        • Minamisawa M
        • Windham BG
        • Chen LY
        • Inciardi RM
        • et al.
        Atrial fibrillation and ischemic stroke with the amyloidogenic V122I transthyretin variant among Black Americans.
        J Am Coll Cardiol. 2021; 78: 89-91https://doi.org/10.1016/j.jacc.2021.04.042
        • Cappelli F
        • Tini G
        • Russo D
        • Emdin M
        • Del Franco A
        • Vergaro G
        • Di Bella G
        • et al.
        Arterial thrombo-embolic events in cardiac amyloidosis: a look beyond atrial fibrillation.
        Amyloid. 2021; 28: 12-18https://doi.org/10.1080/13506129.2020.1798922
        • Feng D
        • Syed IS
        • Martinez M
        • Oh JK
        • Jaffe AS
        • Grogan M
        • et al.
        Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis.
        Circulation. 2009; 119: 2490-2497https://doi.org/10.1161/CIRCULATIONAHA.108.785014
        • Martinez-Naharro A
        • Gonzalez-Lopez E
        • Corovic A
        • Mirelis JG
        • Baksi AJ
        • Moon JC
        • et al.
        High prevalence of intracardiac thrombi in cardiac amyloidosis.
        J Am Coll Cardiol. 2019; 73: 1733-1734https://doi.org/10.1016/j.jacc.2019.01.035
        • Mitrani LR
        • De Los Santos J
        • Driggin E
        • Kogan R
        • Helmke S
        • Goldsmith J
        • et al.
        Anticoagulation with warfarin compared to novel oral anticoagulants for atrial fibrillation in adults with transthyretin cardiac amyloidosis: comparison of thromboembolic events and major bleeding.
        Amyloid. 2021; 28: 30-34https://doi.org/10.1080/13506129.2020.1810010
        • El-Am EA
        • Dispenzieri A
        • Melduni RM
        • Ammash NM
        • White RD
        • Hodge DO
        • et al.
        Direct current cardioversion of atrial arrhythmias in adults with cardiac amyloidosis.
        J Am Coll Cardiol. 2019; 73: 589-597https://doi.org/10.1016/j.jacc.2018.10.079
        • Hausfater P
        • Costedoat-Chalumeau N
        • Amoura Z
        • Cacoub P
        • Papo T
        • Grateau G
        • et al.
        AL cardiac amyloidosis and arterial thromboembolic events.
        Scand J Rheumatol. 2005; 34: 315-319https://doi.org/10.1080/03009740510015203
        • Russo D
        • Limite LR
        • Arcari L
        • Autore C
        • Musumeci MB.
        Predicting the unpredictable: how to score the risk of stroke in cardiac amyloidosis?.
        J Am Coll Cardiol. 2019; 73: 2910-2911https://doi.org/10.1016/j.jacc.2019.02.078
        • Zubkov AY
        • Rabinstein AA
        • Dispenzieri A
        • Wijdicks EF.
        Primary systemic amyloidosis with ischemic stroke as a presenting complication.
        Neurology. 2007; 69: 1136-1141https://doi.org/10.1212/01.wnl.0000276951.39112.2b
        • Berghoff M
        • Kathpal M
        • Khan F
        • Skinner M
        • Falk R
        • Freeman R.
        Endothelial dysfunction precedes C-fiber abnormalities in primary (AL) amyloidosis.
        Ann Neurol. 2003; 53: 725-730https://doi.org/10.1002/ana.10552
        • Marmont AM
        • Merlini G.
        Monoclonal autoimmunity in hematology.
        Haematologica. 1991; 76: 449-459
        • Gamba G
        • Montani N
        • Anesi E
        • Palladini G
        • Lorenzutti F
        • Perfetti V
        • et al.
        Abnormalities in thrombin-antithrombin pathway in AL amyloidosis.
        Amyloid. 1999; 6: 273-277https://doi.org/10.3109/13506129909007339
        • Yood RA
        • Skinner M
        • Rubinow A
        • Talarico L
        • Cohen AS.
        Bleeding manifestations in 100 patients with amyloidosis.
        JAMA. 1983; 249: 1322-1324
        • Mumford AD
        • O'Donnell J
        • Gillmore JD
        • Manning RA
        • Hawkins PN
        • Laffan M
        Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.
        Br J Haematol. 2000; 110: 454-460https://doi.org/10.1046/j.1365-2141.2000.02183