Copyright © 2006, The European Society of Cardiology
Hydroxychloroquine-induced restrictive cardiomyopathy: Correlation between clinical, Echocardiographic and pathologic findings
aDepartment of Cardiology, The Northern Hospital, Melbourne, Australia
bDepartment of Cardiology, Robinson Memorial Hospital, Ravenna, OH 44266, USA
cDepartment of Anatomic Pathology, Cleveland Clinic, Cleveland, USA
dDepartment of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F15, Cleveland, OH 44195, USA
Received 22 December 2005; accepted after revision 1 February 2006.
* Corresponding author. Tel.: +1 216 444 3932; fax: +1 216 445 2309. kleina{at}ccf.org
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Abstract |
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Chloroquine (Hydroxychloroquine)-induced cardiomyopathy is a rare but potentially life-threatening condition. Cessation of the culprit drug, along with aggressive afterload reduction therapy, has been associated with halting of disease progress and even improvement in patients' clinical and histologic status. Echocardiography is a fundamental tool in the identification and assessment of patients with cardiomyopathy, with particular utility in the detailed assessment of biventricular systolic and diastolic function. It also provides an objective and non-invasive means of assessing treatment response. We present a case of a 51-year-old woman with hydroxychloroquine-induced restrictive cardiomyopathy and correlate clinical, echocardiographic and anatomic pathologic findings both at initial presentation and following treatment.
Keywords: Chloroquine; Hydroxychloroquine; Cardiomyopathy; Restrictive cardiomyopathy
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Case report |
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A 51-year-old female with no history of cardiac disease or hypertension was admitted for treatment of congestive heart failure at a local hospital in 2001. Two months earlier, the patient noted worsening exertional dyspnea, easy fatigability and increasing weight and abdominal girth. Upon presentation she was treated with intravenous furosemide and her condition stabilized. The patient was transferred to the Cleveland Clinic for further management.
The patient's medical history is notable for severe deforming polyarthropathy due to a long-standing, juvenile-onset admixture of rheumatoid arthritis and systemic lupus erythematosus. These have been controlled with the use of prednisone (<10mg/d) and hydroxychloroquine (100–200mg bid) since 1970. She has also undergone multiple orthopedic surgeries – primarily to the hips, hands and feet.
On admission, physical examination revealed a heart rate of 94BPM, blood pressure of 103/53mmHg, and temperature of 37°C. Pertinent findings include jugular venous distention, bilateral pleural effusions and severe peripheral edema. Auscultation revealed a grade 1/6 ejection systolic murmur in the aortic area.
Laboratory studies recorded hemoglobin of 109g/L and normal white blood cell count with normal differential. Blood urea nitrogen was 5.4mmol/L and serum creatinine was 80µmol/L. Electrocardiography revealed sinus rhythm with normal QRS amplitude and incomplete right bundle branch block.
Transthoracic echocardiography (Fig. 1) revealed increased left ventricular septal and posterior wall thickness measuring 1.8cm and 1.5cm respectively, mild left ventricular systolic dysfunction with an ejection fraction of 40%, and increased RV free wall thickness with mild right ventricular systolic dysfunction. There was mild biatrial enlargement and mild (1+) mitral regurgitation. Mild valvular thickening is evident.
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Assessment of diastolic function (Fig. 1) revealed restrictive left ventricular physiology as demonstrated by very short mitral inflow deceleration time, high mitral E/A ratio, blunted systolic flow in the pulmonary veins, prominent atrial reversal of pulmonary vein flow and reduced peak mitral annular Ea (DTI). Evidence of restrictive right ventricular physiology was also noted.
Magnetic resonance imaging (MRI) demonstrated restrictive physiology with increased wall thickness and diminished systolic function of both ventricles. Pericardial thickness was normal. Right heart catheterization produced the classic "dip and plateau" pressure recording.
The patient underwent endo-myocardial biopsy to confirm the diagnosis. Examination by light microscopy revealed vacuolated myocytes (H&E-stained sections). Electron microscopy demonstrated abundant intra-myocyte lysosomes with numerous, large, dense myelin figures occupying large portions of the myocyte sarcoplasm. Lysosomal inclusions with curvilinear substructures were also seen. There was no evidence of amyloid deposition, myocarditis or an acute vasculitic process (Fig. 2).
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Diagnosis of hydroxychloroquine-induced restrictive cardiomyopathy was made based on the clinical, hemodynamic and pathologic findings. Hydroxychloroquine-induced retinopathy was also diagnosed.
Hydroxychloroquine therapy was discontinued and aggressive afterload reduction therapy was commenced. The patient noticed marked, progressive improvement in her symptoms. Normalization of atrial size and ventricular systolic function was noted by echocardiography at 3 months. Regression of diastolic dysfunction from restrictive physiology to pseudonormal diastolic dysfunction (Fig. 3) was documented by serial transthoracic echocardiography over the next 2 years. With preload reduction by Valsalva maneuver, stage 1 diastolic dysfunction (impaired relaxation) was demonstrable at 4 years (Fig. 4). Furthermore, almost complete resolution of histopathologic findings of hydroxychloroquine toxicity was observed on follow-up endo-myocardial biopsy (Fig. 4). Rheumatologic disease has been adequately controlled with low-dose prednisolone and analgesia but further orthopedic surgery has been required.
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Discussion |
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Hydroxychloroquine was used initially for malaria prophylaxis and treatment. It later became indicated for the treatment of rheumatoid arthritis and other connective tissue disorders. Non-malarial indications, however, require prolonged use of larger doses of hydroxychloroquine.1–3 Such regimens give rise to the most commonly encountered chronic complications. These complications include retinopathy, hyperpigmentation, blood dyscrasias, corneal deposits, encephalopathy, neuropathy, myopathy and impaired auditory function. The cardiovascular complications include myocardial thickening, restrictive cardiomyopathy, cardiac insufficiency and conduction disorders – the last of which is most common. The time interval between the beginning of treatment and development of these complications varies, ranging between 7 months and 25 years. Total cumulative doses reportedly resulting in toxicity ranged from 292g to 4380g.1,4 To date 23 cases have been reported in the literature.1,3–6
The pathologic findings in this case are consistent with previous well-documented descriptions from similar cases. Histopathologic examination also enabled exclusion of lipofuscinosis, secondary amyloidosis, myocarditis and active vasculitis – differential diagnoses that may mimic this condition.3,4,7,8
We have outlined a case of protracted hydroxychloroquine use resulting in a severe increase in ventricular wall thickness and restrictive cardiomyopathy – in this case without significant cardiac conduction abnormalities. Clinical heart failure and restrictive cardiomyopathy are rare but life-threatening complications of long-term treatment with chloroquine or hydroxychloroquine. The echocardiogram in this setting has rarely been recorded and restrictive physiology was previously detected by invasive methods.3,6 This case report reinforces the importance of 2-D echocardiographic and Doppler assessment of diastolic function in patients who present with symptoms and signs of heart failure. A finding of restrictive physiology should prompt the clinician to consider various etiologies and investigate accordingly. This case report also highlights the need for periodic cardiac evaluation in patients receiving long-term chloroquine/hydroxychloroquine therapy.
Discontinuation of hydroxychloroquine and institution of aggressive afterload reduction therapy may lead to dramatic improvement in disease state as assessed clinically, echocardiographically and histopathologically. Tasneem et al. recently illustrated a case of congestive heart failure and restrictive cardiomyopathy in the setting of chloroquine use, albeit with conduction disturbance, valvular thickening and dysfunction also present.8 Clinical resolution and significant regression of diastolic dysfunction were demonstrated with discontinuation of chloroquine. Our study reproduces these findings by demonstrating gradual recovery of left ventricular diastolic function. Specifically we document improvement in this case from stage 3 restrictive to stage 2 (pseudonormal) diastolic dysfunction over a two-year period. There is also evidence to suggest further improvement to stage 1 diastolic dysfunction (in the context of preload reduction) over the subsequent two-year period. To our knowledge this is the first case that documents the presence and subsequent improvement of right ventricular restrictive physiology and correlates clinical and echocardiographic improvement with near complete resolution of the hallmark pathologic features of this disease.
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References |
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- Cervera A., Espinosa G., Font J., Ingelmo M. Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis (2001) 60:301.
[Free Full Text] - Iglesias Cubero G., Rodriguez Reguero J.J., Rojo Ortega J.M. Restrictive cardiomyopathy caused by chloroquine. Br Heart J (1993) 69:451–452.
[Abstract/Free Full Text] - 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.[Web of Science][Medline]
- August C., Holzhausen H.J., Schmoldt A., Pompecki R., Schroder S. Histological and ultrastructural findings in chloroquine-induced cardiomyopathy. J Mol Med (1995) 73:73–77.[CrossRef][Web of Science][Medline]
- Estes M.L., Ewing-Wilson D., Chou S.M., Mitsumoto H., Hanson M., Shirey E., et al. Chloroquine neuromyotoxicity. Clinical and pathologic perspective. Am J Med (1987) 82:447–455.[CrossRef][Medline]
- Naqvi T.Z., Luthringer D., Marchevsky A., Saouf R., Gul K., Buchbinder N.A. Chloroquine-induced cardiomyopathy-echocardiographic features. J Am Soc Echocardiogr (2005) 18:383–387.[CrossRef][Medline]
- Baguet J.P., Tremel F., Fabre M. Chloroquine cardiomyopathy with conduction disorders. Heart (1999) 81:221–223.
[Abstract/Free Full Text] - Sanmarti R., Gomez-Casanovas E., Sole M., Canete J., Gratacos J., Carmona L., et al. Prevalence of silent amyloidosis in RA and its clinical significance. J Rheumatol (2004) 31:1013–1014.[Medline]
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