Canadian Journal of Cardiology

Hydroxychloroquine-Induced Cardiomyopathy: Case Report, Pathophysiology, Diagnosis, and Treatment

Published:August 23, 2014DOI:


      Drug-induced heart and vascular disease remains an important health burden. Hydroxychloroquine and its predecessor chloroquine are medications commonly used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders. Hydroxychloroquine interferes with malarial metabolites, confers immunomodulatory effects, and also affects lysosomal function. Clinical monitoring and early recognition of toxicity is an important management strategy in patients who undergo long-term treatment with hydroxychloroquine. Retinal toxicity, neuromyopathy, and cardiac disease are recognized adverse effects of hydroxychloroquine. Immediate withdrawal of hydroxychloroquine is essential if toxicity is suspected because of the early reversibility of cardiomyopathy. In addition to recommended ophthalmological screening, regular screening with 12-lead electrocardiogram and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients. Cardiac magnetic resonance imaging and endomyocardial biopsy are valuable tools to provide prognostic insights and confirm the diagnosis of hydroxychloroquine-induced cardiomyopathy. In conclusion, chronic use of hydroxychloroquine can result in an acquired lysosomal storage disorder, leading to a drug-induced cardiomyopathy characterized by concentric hypertrophy and conduction abnormalities associated with increased adverse clinical outcomes and mortality.


      Les maladies cardiaques et vasculaires induites par les médicaments constituent un lourd fardeau pour le système de santé. L’hydroxychloroquine et le médicament qui l’a précédée, la chloroquine, sont fréquemment utilisés dans le traitement du lupus érythémateux systémique, l’arthrite rhumatoïde et d’autres troubles du tissu conjonctif. L’hydroxychloroquine interfère avec les métabolites malariens, a des effets immunomodulatoires et perturbe également le fonctionnement des lysosomes. La surveillance clinique et la détection précoce de la toxicité font partie intégrante d’une importante stratégie de prise en charge chez les patients qui subissent un traitement à long terme par hydroxychloroquine. La toxicité rétinienne, la neuromyopathie et la cardiopathie sont des effets indésirables reconnus de l’hydroxychloroquine. Le retrait immédiat de l’hydroxychloroquine est essentiel si une toxicité est suspectée puisqu’à un stade précoce la cardiomyopathie est réversible. Outre le dépistage ophtalmologique recommandé, le dépistage régulier au moyen de l’électrocardiogramme à 12 dérivations et de l’échocardiographie transthoracique afin de détecter les anomalies du système de conduction et/ou les modifications morphologiques ou fonctionnelles des deux ventricules devrait être envisagé chez les patients traités par hydroxychloroquine. L’imagerie cardiaque par résonance magnétique et la biopsie endomyocardique sont des outils valables pour donner un aperçu du pronostic et confirmer le diagnostic de cardiomyopathie induite par l’hydroxychloroquine. En conclusion, l’utilisation à long terme de l’hydroxychloroquine peut entraîner une maladie de surcharge lysosomale acquise conduisant alors à une cardiomyopathie d’origine médicamenteuse caractérisée par l’hypertrophie concentrique et les anomalies de la conduction associées à l’augmentation des résultats cliniques indésirables et de la mortalité.
      To read this article in full you will need to make a payment


        • Truong J.
        • Yan A.T.
        • Cramarossa G.
        • Chan K.K.
        Chemotherapy-induced cardiotoxicity: detection, prevention, and management.
        Can J Cardiol. 2014; 30: 869-878
        • Yeh E.T.
        • Bickford C.L.
        Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.
        J Am Coll Cardiol. 2009; 53: 2231-2247
        • Dec G.W.
        • Fuster V.
        Idiopathic dilated cardiomyopathy.
        N Engl J Med. 1994; 331: 1564-1575
        • Mackenzie A.H.
        Pharmacologic actions of 4-aminoquinoline compounds.
        Am J Med. 1983; 75: 5-10
        • Slater A.F.
        • Cerami A.
        Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites.
        Nature. 1992; 355: 167-169
        • Saag K.G.
        • Teng G.G.
        • Patkar N.M.
        • et al.
        American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.
        Arthritis Rheum. 2008; 59: 762-784
        • Ruiz-Irastorza G.
        • Ramos-Casals M.
        • Brito-Zeron P.
        • Khamashta M.A.
        Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.
        Ann Rheum Dis. 2010; 69: 20-28
        • Tang C.
        • Godfrey T.
        • Stawell R.
        • Nikpour M.
        Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects.
        Intern Med J. 2012; 42: 968-978
        • Sullivan Jr., D.J.
        • Gluzman I.Y.
        • Russell D.G.
        • Goldberg D.E.
        On the molecular mechanism of chloroquine's antimalarial action.
        Proc Natl Acad Sci U S A. 1996; 93: 11865-11870
        • Katz S.J.
        • Russell A.S.
        Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action.
        Curr Opin Rheumatol. 2011; 23: 278-281
        • Fox R.I.
        Mechanism of action of hydroxychloroquine as an antirheumatic drug.
        Semin Arthritis Rheum. 1993; 23: 82-91
        • Teixeira R.A.
        • Borba E.F.
        • Pedrosa A.
        • et al.
        Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus.
        Europace. 2014; 16: 887-892
        • Hassan S.Z.
        • Gheita T.A.
        • Kenawy S.A.
        • et al.
        Oxidative stress in systemic lupus erythematosus and rheumatoid arthritis patients: relationship to disease manifestations and activity.
        Int J Rheum Dis. 2011; 14: 325-331
        • Roman M.J.
        • Shanker B.A.
        • Davis A.
        • et al.
        Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus.
        N Engl J Med. 2003; 349: 2399-2406
      1. Putko BN, Wen K, Thompson RB, et al. Anderson-Fabry cardiomyopathy: prevalence, pathophysiology, diagnosis and treatment [e-pub ahead of print]. Heart Fail Rev, accessed August 8, 2014.

        • Marmor M.F.
        • Carr R.E.
        • Easterbrook M.
        • et al.
        Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology.
        Ophthalmology. 2002; 109: 1377-1382
        • Michaelides M.
        • Stover N.B.
        • Francis P.J.
        • Weleber R.G.
        Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy.
        Arch Ophthalmol. 2011; 129: 30-39
        • Wolfe F.
        • Marmor M.F.
        Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus.
        Arthritis Care Res. 2010; 62: 775-784
        • Whisnant J.P.
        • Espinosa R.E.
        • Kierland R.R.
        • Lambert E.H.
        Chloroquine Neuromyopathy.
        Proc Staff Meet Mayo Clin. 1963; 38: 501-513
        • Siddiqui A.K.
        • Huberfeld S.I.
        • Weidenheim K.M.
        • Einberg K.R.
        • Efferen L.S.
        Hydroxychloroquine-induced toxic myopathy causing respiratory failure.
        Chest. 2007; 131: 588-590
        • Mastaglia F.L.
        Adverse effects of drugs on muscle.
        Drugs. 1982; 24: 304-321
        • Stein M.
        • Bell M.J.
        • Ang L.C.
        Hydroxychloroquine neuromyotoxicity.
        J Rheumatol. 2000; 27: 2927-2931
        • Estes M.L.
        • Ewing-Wilson D.
        • Chou S.M.
        • et al.
        Chloroquine neuromyotoxicity. Clinical and pathologic perspective.
        Am J Med. 1987; 82: 447-455
        • Ratliff N.B.
        • Estes M.L.
        • Myles J.L.
        • Shirey E.K.
        • McMahon J.T.
        Diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy.
        N Engl J Med. 1987; 316: 191-193
        • Roos J.M.
        • Aubry M.C.
        • Edwards W.D.
        Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease.
        Cardiovasc Pathol. 2002; 11: 277-283
        • Naqvi T.Z.
        • Luthringer D.
        • Marchevsky A.
        • et al.
        Chloroquine-induced cardiomyopathy-echocardiographic features.
        J Am Soc Echocardiogr. 2005; 18: 383-387
        • Reffelmann T.
        • Naami A.
        • Spuentrup E.
        • Kuhl H.P.
        Images in cardiovascular medicine. Contrast-enhanced magnetic resonance imaging of a patient with chloroquine-induced cardiomyopathy confirmed by endomyocardial biopsy.
        Circulation. 2006; 114: e357-e358
        • Pieroni M.
        • Smaldone C.
        • Camporeale A.
        • et al.
        Images in cardiology. Chloroquine-induced transition from dilated to restrictive cardiomyopathy.
        J Am Coll Cardiol. 2011; 57: 515
        • Tonnesmann E.
        • Stroehmann I.
        • Kandolf R.
        • et al.
        Cardiomyopathy caused by long-term treatment with chloroquine: a rare disease, or a rare diagnosis?.
        J Rheumatol. 2012; 39: 1099-1103
        • Frustaci A.
        • Morgante E.
        • Antuzzi D.
        • Russo M.A.
        • Chimenti C.
        Inhibition of cardiomyocyte lysosomal activity in hydroxychloroquine cardiomyopathy.
        Int J Cardiol. 2012; 157: 117-119
        • Arbustini E.
        • Narula N.
        • Dec G.W.
        • et al.
        The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: endorsed by the World Heart Federation.
        J Am Coll Cardiol. 2013; 62: 2046-2072
        • Tonnesmann E.
        • Kandolf R.
        • Lewalter T.
        Chloroquine cardiomyopathy - a review of the literature.
        Immunopharmacol Immunotoxicol. 2013; 35: 434-442
        • Fitch C.D.
        Plasmodium falciparum in owl monkeys: drug resistance and chloroquine binding capacity.
        Science. 1970; 169: 289-290
        • Silva J.C.
        • Mariz H.A.
        • Rocha Jr., L.F.
        • et al.
        Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients.
        Clinics. 2013; 68: 766-771
        • Kahlenberg J.M.
        • Kaplan M.J.
        The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus.
        Arthritis Res Ther. 2011; 13: 203
        • Ducharme J.
        • Farinotti R.
        Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements.
        Clin Pharmacokinet. 1996; 31: 257-274
        • Tett S.E.
        Clinical pharmacokinetics of slow-acting antirheumatic drugs.
        Clin Pharmacokinet. 1993; 25: 392-407
        • Sumpter M.D.
        • Tatro L.S.
        • Stoecker W.V.
        • Rader R.K.
        Evidence for risk of cardiomyopathy with hydroxychloroquine.
        Lupus. 2012; 21: 1594-1596
        • Costedoat-Chalumeau N.
        • Hulot J.S.
        • Amoura Z.
        • et al.
        Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases.
        Rheumatology. 2007; 46: 808-810
        • Edwards A.C.
        • Meredith T.J.
        • Sowton E.
        Complete heart-block due to chronic chloroquine toxicity managed with permanent pacemaker.
        Br Med J. 1978; 1: 1109-1110
        • Vereckei A.
        • Fazakas A.
        • Balo T.
        • et al.
        Chloroquine cardiotoxicity mimicking connective tissue disease heart involvement.
        Immunopharmacol Immunotoxicol. 2013; 35: 304-306
        • Yap Y.G.
        • Camm A.J.
        Drug-induced QT prolongation and torsades de pointes.
        Heart. 2003; 89: 1363-1372
        • Stas P.
        • Faes D.
        • Noyens P.
        Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine.
        Int J Cardiol. 2008; 127: e80-e82
        • Seferovic P.M.
        • Ristic A.D.
        • Maksimovic R.
        • et al.
        Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases.
        Rheumatology. 2006; 45: iv39-42
        • Comin-Colet J.
        • Sanchez-Corral M.A.
        • Alegre-Sancho J.J.
        • et al.
        Complete heart block in an adult with systemic lupus erythematosus and recent onset of hydroxychloroquine therapy.
        Lupus. 2001; 10: 59-62
        • Martinezcosta X.
        • Ordi J.
        • Barbera J.
        • et al.
        High-grade atrioventricular heart-block in 2 adults with systemic lupus-erythematosus.
        J Rheumatol. 1991; 18: 1926-1928
        • Fonseca E.
        • Crespo M.
        • Sobrino J.A.
        Complete heart block in an adult with systemic lupus erythematosus.
        Lupus. 1994; 3: 129-131
        • Olken D.
        • Volastro P.
        • Finck D.
        • Tulgan H.
        • Mazur P.
        Heart block in systemic lupus erythematosus complicated by pacemaker “exit block”.
        Arthritis Rheum. 1991; 34: 121-123
        • Wozniacka A.
        • Cygankiewicz I.
        • Chudzik M.
        • Sysa-Jedrzejowska A.
        • Wranicz J.K.
        The cardiac safety of chloroquine phosphate treatment in patients with systemic lupus erythematosus: the influence on arrhythmia, heart rate variability and repolarization parameters.
        Lupus. 2006; 15: 521-525
        • Acharya D.
        • Robertson P.
        • Kay G.N.
        • et al.
        Arrhythmias in Fabry cardiomyopathy.
        Clin Cardiol. 2012; 35: 738-740
        • Ferrans V.J.
        • Hall R.J.
        • McAllister Jr., H.A.
        Images in cardiovascular medicine. Chloroquine-induced cardiomyopathy.
        Circulation. 1993; 88: 785-786
        • Nishino I.
        • Fu J.
        • Tanji K.
        • et al.
        Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).
        Nature. 2000; 406: 906-910
        • Ben-Zvi I.
        • Kivity S.
        • Langevitz P.
        • Shoenfeld Y.
        Hydroxychloroquine: from malaria to autoimmunity.
        Clin Rev Allergy Immunol. 2012; 42: 145-153
        • Lee J.H.
        • Chung W.B.
        • Kang J.H.
        • et al.
        A case of chloroquine-induced cardiomyopathy that presented as sick sinus syndrome.
        Korean Circ J. 2010; 40: 604-608
        • Perry C.N.
        • Kyoi S.
        • Hariharan N.
        • et al.
        Novel methods for measuring cardiac autophagy in vivo.
        Methods Enzymol. 2009; 453: 325-342
        • Daniels B.H.
        • McComb R.D.
        • Mobley B.C.
        • et al.
        LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases.
        Am J Surg Pathol. 2013; 37: 1014-1021
        • Gerard J.M.
        • Stoupel N.
        • Collier A.
        • Flament-Durand J.
        Morphologic study of a neuromyopathy caused by prolonged chloroquine treatment.
        Eur Neurol. 1973; 9: 363-379
        • Soong T.R.
        • Barouch L.A.
        • Champion H.C.
        • Wigley F.M.
        • Halushka M.K.
        New clinical and ultrastructural findings in hydroxychloroquine-induced cardiomyopathy–a report of 2 cases.
        Hum Pathol. 2007; 38: 1858-1863
        • Nandagudi A.
        • Jury E.C.
        • Alonzi D.
        • et al.
        Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry's disease.
        Lupus. 2013; 22: 1070-1076
        • Pieroni M.
        • Bellocci F.
        • Crea F.
        Letter by Pieroni et al regarding article, “Contrast-enhanced magnetic resonance imaging of a patient with chloroquine-induced cardiomyopathy confirmed by endomyocardial biopsy”.
        Circulation. 2007; 115 ([author reply: e68]): e67
        • Goenka A.H.
        • Flamm S.D.
        Cardiac magnetic resonance imaging for the investigation of cardiovascular disorders. Part 1: current applications.
        Tex Heart Inst J. 2014; 41: 7-20
        • Thompson R.B.
        • Chow K.
        • Khan A.
        • et al.
        T(1) mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex.
        Circ Cardiovasc Imaging. 2013; 6: 637-645
        • Yoshida A.
        • Ishibashi-Ueda H.
        • Yamada N.
        • et al.
        Direct comparison of the diagnostic capability of cardiac magnetic resonance and endomyocardial biopsy in patients with heart failure.
        Eur J Heart Fail. 2013; 15: 166-175
        • Elliott P.
        • Arbustini E.
        The role of endomyocardial biopsy in the management of cardiovascular disease: a commentary on joint AHA/ACC/ESC guidelines.
        Heart. 2009; 95: 759-760
        • Yilmaz A.
        • Kindermann I.
        • Kindermann M.
        • et al.
        Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
        Circulation. 2010; 122: 900-909
        • Leone O.
        • Veinot J.P.
        • Angelini A.
        • et al.
        2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology.
        Cardiovasc Pathol. 2012; 21: 245-274
        • Cooper L.T.
        • Baughman K.L.
        • Feldman A.M.
        • et al.
        The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology.
        Circulation. 2007; 116: 2216-2233
        • Casado E.
        • Gratacos J.
        • Tolosa C.
        • et al.
        Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients.
        Ann Rheum Dis. 2006; 65: 385-390
        • Singh J.A.
        • Furst D.E.
        • Bharat A.
        • et al.
        2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2012; 64: 625-639
        • Guidelines for referral and management of systemic lupus erythematosus in adults
        American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines.
        Arthritis Rheum. 1999; 42: 1785-1796
        • Scott D.L.
        • Wolfe F.
        • Huizinga T.W.
        Rheumatoid arthritis.
        Lancet. 2010; 376: 1094-1108
        • White N.J.
        Cardiotoxicity of antimalarial drugs.
        Lancet Infect Dis. 2007; 7: 549-558
        • Saussine A.
        • Loriot M.A.
        • Picard C.
        • et al.
        Chloroquine cardiotoxicity in long-term lupus therapy in two patients [in French].
        Ann Dermatol Venereol. 2009; 136: 530-535
        • Figueredo V.M.
        Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart.
        Am J Med. 2011; 124: 480-488