Eur J Echocardiography (2007) 8, 247e251

CLINICAL/ORIGINAL PAPERS

Hydroxychloroquine-induced restrictive
cardiomyopathy
John Cotroneo a, Khaled M. Sleik b, E. Rene Rodriguez c,
Allan L. Klein d,*

a
Department of Cardiology, The Northern Hospital, Melbourne, Australia
b
Department of Cardiology, Robinson Memorial Hospital, Ravenna, OH 44266, USA
c
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, USA
d
Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F15,
Cleveland, OH 44195, USA

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Received 22 December 2005; accepted 1 February 2006
Available online 5 April 2006

KEYWORDS Abstract Chloroquine (Hydroxychloroquine)-induced cardiomyopathy is a rare but

Chloroquine; potentially life-threatening condition. Cessation of the culprit drug, along with ag-
Hydroxychloroquine; gressive afterload reduction therapy, has been associated with halting of disease
Cardiomyopathy; progress and even improvement in patients’ clinical and histologic status. Echocar-
Restrictive diography is a fundamental tool in the identification and assessment of patients
cardiomyopathy with cardiomyopathy, with particular utility in the detailed assessment of biventri-
cular 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 clini-
cal, echocardiographic and anatomic pathologic findings both at initial presentation
and following treatment.
ª 2006 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.

Case report treatment of congestive heart failure at a local

A 51-year-old female with no history of cardiac
disease or hypertension was admitted for
* Corresponding author. Tel.: þ1 216 444 3932; fax: þ1 216
445 2309.
E-mail address: kleina@ccf.org (A.L. Klein).
hospital in 2001. Two months earlier, the patient
noted worsening exertional dyspnea, easy fatiga-
bility and increasing weight and abdominal girth.
Upon presentation she was treated with intrave-
nous furosemide and her condition stabilized. The
patient was transferred to the Cleveland Clinic for
further management.

1525-2167/$32 ª 2006 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.euje.2006.02.002
248 J. Cotroneo et al.

The patient’s medical history is notable Laboratory studies recorded hemoglobin of

for severe deforming polyarthropathy due to a
long-standing, juvenile-onset admixture of rheu-
matoid arthritis and systemic lupus erythemato-
sus. These have been controlled with the use of
prednisone (<10 mg/d) and hydroxychloroquine
(100e200 mg bid) since 1970. She has also under-
gone multiple orthopedic surgeries e primarily to
the hips, hands and feet.
On admission, physical examination revealed
a heart rate of 94 BPM, blood pressure of 103/
53 mmHg, and temperature of 37  C. Pertinent
findings include jugular venous distention, bilat-
eral pleural effusions and severe peripheral
edema. Auscultation revealed a grade 1/6 ejection
systolic murmur in the aortic area.
109 g/L and normal white blood cell count with
normal differential. Blood urea nitrogen was
5.4 mmol/L and serum creatinine was 80 mmol/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 1.8 cm and 1.5 cm respec-
tively, mild left ventricular systolic dysfunction
with an ejection fraction of 40%, and increased RV
free wall thickness with mild right ventricular sys-
tolic dysfunction. There was mild biatrial enlarge-
ment and mild (1þ) mitral regurgitation. Mild
valvular thickening is evident.

Figure 1 Echocardiographic findings on presentation. (A) Parasternal long axis view showing increased left ventric- Downloaded from by guest on September 9, 2015

ular wall thickness. The anteroseptal and posterior walls measure 1.8 cm and 1.5 cm respectively. (B) Doppler tissue
imaging of lateral mitral annulus documents Ea 7.2 cm/s and Aa velocity 2.7 cm/s. This is consistent with a relaxation
abnormality. (C) Pulsed Doppler of mitral inflow demonstrates left ventricular restrictive physiology. E velocity
(E) ¼ 81 cm/s with A velocity (A) ¼ 18 cm/s. E/A ratio is 4.5. Deceleration time (DT) ¼ 90 ms. A duration ¼ 60 ms.
E:Ea ¼ 11.2. (D) Pulsed Doppler of pulmonary vein flow shows blunting of systolic flow and prominent atrial flow re-
versals. Systolic forward flow velocity (S) ¼ 47 cm/s. Diastolic forward flow velocity ¼ 77 cm/s. S/D ratio ¼ 0.6. Atrial
reversal velocity (AR) ¼ 37 cm/s. AR duration ¼ 150 ms. Difference between A duration (mitral) and A duration (PV
flow) ¼ 90 ms. (E) Pulsed Doppler of tricuspid inflow shows restrictive right ventricular physiology. E velocity
(E) ¼ 35 cm/s and A velocity (A) ¼ 11.5 cm/s. E/A ratio ¼ 3. Deceleration time (DT) ¼ 127 ms. A duration ¼ 70 ms.
(F) Pulsed Doppler of hepatic vein flow shows blunting of systolic flow with prominent atrial flow reversals in both in-
spiration and expiration. Systolic forward flow velocity (S) ¼ 30 cm/s. Diastolic forward flow velocity ¼ 54 cm/s. S/D
ratio ¼ 0.55. Atrial reversal velocity (AR) ¼ 50 cm/s. AR duration ¼ 240 ms. Difference between A duration (tricuspid)
and A duration (hepatic vein flow) ¼ 170 ms.
Correlation between clinical, echocardiographic and pathologic findings 249

Assessment of diastolic function (Fig. 1) revealed Hydroxychloroquine therapy was discontinued

restrictive left ventricular physiology as demon-
strated 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 ven-
tricular physiology was also noted.
Magnetic resonance imaging (MRI) demon-
strated 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 demon-
strated abundant intra-myocyte lysosomes with
numerous, large, dense myelin figures occupying
large portions of the myocyte sarcoplasm. Lyso-
somal inclusions with curvilinear substructures
were also seen. There was no evidence of amyloid
deposition, myocarditis or an acute vasculitic
and aggressive afterload reduction therapy was
commenced. The patient noticed marked, pro-
gressive improvement in her symptoms. Normali-
zation 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 histo-
pathologic 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.
Discussion

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process (Fig. 2).
Diagnosis of hydroxychloroquine-induced restric-
tive cardiomyopathy was made based on the clini-
cal, hemodynamic and pathologic findings.
Hydroxychloroquine-induced retinopathy was also
diagnosed.
Hydroxychloroquine was used initially for malaria
prophylaxis and treatment. It later became in-
dicated for the treatment of rheumatoid arthritis
and other connective tissue disorders. Non-
malarial indications, however, require prolonged
use of larger doses of hydroxychloroquine.1e3 Such

Figure 2 Pathologic appearances on presentation and at 2 years. At presentation (left) electron micrograph (mag-
nification 11000) shows central replacement and displacement of sarcomeres by marked accumulation of secondary
lysosomes including myeloid bodies (MB) and curvilinear bodies (CL). This appearance is typical and characteristic of
chloroquine and hydroxychloroquine toxicity. At 2 years (right) myocardial biopsy shows near complete resolution of
electron microscopic findings of hydroxychloroquine toxicity. Electron micrograph (magnification 6700) shows nor-
mal myocyte ultrastructure with secondary lysosomes that would appear by light microscopy as lipofuscin pigment.
The number of secondary lysosomes is consistent with the patient’s age.
250 J. Cotroneo et al.

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Figure 3 Echocardiographic findings at 2 years. (A) Parasternal long axis view showing a decrease in left ventricular
wall thickness. The anteroseptal and posterior walls measure 1.5 cm and 1.2 cm respectively. (B) Doppler tissue im-
aging of lateral mitral annulus documents Ea 2.7 cm/s and Aa velocity 5 cm/s. Ea:Aa reversal is noted here. (C) Pulsed
Doppler of mitral inflow demonstrates ‘‘pseudonormal’’ physiology. E velocity (E) ¼ 50 cm/s with A velocity
(A) ¼ 24 cm/s. E/A ratio is 2.1. Deceleration time (DT) ¼ 190 ms. A duration ¼ 100 ms. E:Ea ¼ 10. (D) Pulsed Doppler
of pulmonary vein flow shows normal forward flow characteristics (systolic velocity > diastolic velocity) but with per-
sisting prominent atrial flow reversals in both inspiration and expiration. Systolic forward flow velocity (S) ¼ 73 cm/s.
Diastolic forward flow velocity ¼ 40 cm/s. S/D ratio ¼ 1.8. Atrial reversal velocity (AR) ¼ 46 cm/s. AR du-
ration ¼ 170 ms. Difference between A duration (mitral) and A duration (PV flow) ¼ 70 ms. Overall these findings sug-
gest pseudonormal physiology. (E) Pulsed Doppler of tricuspid inflow demonstrates E velocity (E) ¼ 38 cm/s and A
velocity (A) ¼ 32 cm/s. E/A ratio ¼ 1.2. Deceleration time (DT) ¼ 160 ms. A duration ¼ 110 ms. (F) Pulsed Doppler of
hepatic vein flow shows normal forward flow characteristics (systolic velocity > diastolic velocity) but with persisting
prominent atrial flow reversals in both inspiration and expiration. Systolic forward flow velocity (S) ¼ 56 cm/s. Dia-
stolic forward flow velocity ¼ 17 cm/s. S/D ratio ¼ 3.3. Atrial reversal velocity (AR) ¼ 50 cm/s. AR duration ¼ 180 ms.
Difference between A duration (tricuspid) and A duration (hepatic vein flow) ¼ 70 ms.

regimens give rise to the most commonly encoun-
tered chronic complications. These complications
include retinopathy, hyperpigmentation, blood
dyscrasias, corneal deposits, encephalopathy,
neuropathy, myopathy and impaired auditory func-
tion. The cardiovascular complications include
myocardial thickening, restrictive cardiomyopathy,
cardiac insufficiency and conduction disorders e
the last of which is most common. The time interval
between the beginning of treatment and develop-
ment of these complications varies, ranging be-
tween 7 months and 25 years. Total cumulative
doses reportedly resulting in toxicity ranged from
292 g to 4380 g.1,4 To date 23 cases have been
reported in the literature.1,3e6
The pathologic findings in this case are consis-
tent with previous well-documented descriptions
from similar cases. Histopathologic examination
also enabled exclusion of lipofuscinosis, secondary
amyloidosis, myocarditis and active vasculitis e
differential diagnoses that may mimic this
condition.3,4,7,8
We have outlined a case of protracted hydroxy-
chloroquine use resulting in a severe increase
in ventricular wall thickness and restrictive
cardiomyopathy e in this case without significant
cardiac conduction abnormalities. Clinical heart
failure and restrictive cardiomyopathy are rare but
life-threatening complications of long-term treat-
ment with chloroquine or hydroxychloroquine. The
Correlation between clinical, echocardiographic and pathologic findings
Figure 4 Mitral inflow at 4 years follow-up. Mitral inflow pattern before and after preload reduction by Valsalva
maneuver. Stage 2 (pseudonormal) diastolic dysfunction is seen at baseline (left half of figure). With Valsalva maneu-
ver, stage 1 diastolic dysfunction (impaired relaxation) is seen (right side of figure) suggesting further lowering of
filling pressures. E:A ¼ 0.78.
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 echocardio-
graphic and Doppler assessment of diastolic func-
tion in patients who present with symptoms and
signs of heart failure. A finding of restrictive phys-
iology should prompt the clinician to consider var-
ious 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 in-
stitution of aggressive afterload reduction therapy
may lead to dramatic improvement in disease state
as assessed clinically, echocardiographically and
histopathologically. Tasneem et al. recently illus-
trated a case of congestive heart failure and
restrictive cardiomyopathy in the setting of
chloroquine use, albeit with conduction distur-
bance, valvular thickening and dysfunction also
present.8 Clinical resolution and significant regres-
sion of diastolic dysfunction were demonstrated
with discontinuation of chloroquine. Our study re-
produces these findings by demonstrating gradual
recovery of left ventricular diastolic function. Spe-
cifically 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
251
preload reduction) over the subsequent two-year
period. To our knowledge this is the first case that
documents the presence and subsequent improve-
ment of right ventricular restrictive physiology
and correlates clinical and echocardiographic
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improvement with near complete resolution of
the hallmark pathologic features of this disease.
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