Clin Res Cardiol
DOI 10.1007/s00392-016-1064-z
LETTER TO THE EDITORS
Hydroxychloroquine-induced cardiomyopathy in a patient
with limited cutaneous systemic sclerosis
Amr Abdin1 • Janine Pöss1 • Reinhard Kandolf2 • Holger Thiele1
Received: 24 July 2016 / Accepted: 15 December 2016
Ó Springer-Verlag Berlin Heidelberg 2016
Sirs:
Hydroxychloroquine (HCQ) is a widely used medication
in the management of many connective tissue diseases.
Cardiac toxicity is a rare but serious complication related to
the chronic use of HCQ. Possible manifestations are the
development of cardiomyopathy or of conduction abnor-
malities. Herein, we present the case of a 58-year-old female
with limited cutaneous systemic sclerosis who was admitted
to our institution with HCQ-induced cardiotoxicity.
A 58-year-old woman with a 2-year history of limited
cutaneous systemic sclerosis was referred to our institution
for further work-up of progressive dyspnea (NYHA class
2–3) over a period of 2 months. Her cardiac history before
admission includes a dual chamber pacemaker implanta-
tion (in 1993 due to complete AV-block). Her other med-
ical history included peripheral artery disease, arterial
hypertension and hyperlipidemia. She was receiving HCQ
(200 mg daily for 2 years) and sildenafil. Physical exami-
nation revealed bilateral lower leg swelling. The electro-
cardiogram was normal. Initial investigations at the time of
admission revealed an elevated NT-pro-BNP (17,825 ng/l).
Transthoracic echocardiography revealed concentric LV
hypertrophy (LV septal and posterior wall thickness mea-
suring 1.9 and 1.4 cm, respectively) with a severely
reduced systolic ejection fraction (EF) of 30% and a
& Amr Abdin
amr.abdin@uksh.de
1
Medical Clinic II (Cardiology/Angiology/Intensive Care
Medicine), University Heart Centre Luebeck, Ratzeburger
Allee 160, 23538 Lübeck, Germany
2 Subsequently, the patients’ clinical situation rapidly dete-
Institute for Pathology, Department of Molecular Pathology,
University Hospital of Tuebingen, Liebermeisterstrasse 8,
D-72076 Tuebingen, Germany
restrictive filling pattern with elevated filling pressure (E/E0
17) (Fig. 1a, b). Right ventricular function was normal. In a
right and left heart catheterization, significant coronary
artery disease was excluded. Left ventricular end diastolic
pressure (LVEDP) was elevated (L 16 mmHg). After
exclusion of pulmonary hypertension (mean pulmonary
artery pressure: 16 mmHg), sildenafil was stopped.
Cardiac magnetic resonance imaging could not be per-
formed because the patient had undergone pacemaker
implantation. For further diagnostic work-up, endomy-
ocardial biopsy was performed. The examination revealed
myocytes with numerous cytoplasmic vacuoles and low-
grade diffuse interstitial fibrosis (Fig. 2a, b). Importantly,
other differential diagnoses, such as amyloidosis,
myocarditis or an acute vasculitic process, were excluded.
Based on the clinical presentation and the histologic find-
ings, the diagnosis of HCQ-induced cardiomyopathy was
made. The drug was immediately discontinued and heart
failure medication was initiated. After 3 months, the
patient received the following medications: ramipril 5 mg
twice daily, carvedilol 25 mg twice daily, torsemide 10 mg
once daily and spironolactone 25 mg once daily. The
patient did not tolerate the maximum recommended doses
because of hypotension and worsening renal func-
tion. Unfortunately, the patient’s clinical situation did not
improve after 3 months of follow-up, and an internal car-
diac defibrillator upgrade was planned. Implantation of a
left ventricular assist device (LVAD) was impossible due
to the left ventricular geometry with severe concentric
hypertrophy. Cardiac transplantation was considered, but
there were serious concerns about the patients’ compliance
(history of multiple drug abuse, prior suicide attempt).
riorated with development of severe cardiogenic shock,
which led to the death of the patient.
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 Clin Res Cardiol

Fig. 1 a Concentric left ventricular (LV) hypertrophy. b Restrictive stage diastolic dysfunction showed by increased E-wave peak velocity to A-
wave peak velocity ratio (E/A) of [1.5

Fig. 2 a Myocyte hypertrophy with marked vacuolization and low-grade diffuse interstitial fibrosis. b Desmin immunohistochemical
documentation of the loss of desmin intermediate filaments in the cytoplasm

HCQ is being widely used for the treatment of con-
nective tissue disease. The chronic use of HCQ can result
in many complications such as retinal toxicity, blood
dyscrasias, neuromyopathy and cardiac toxicity. Cardiac
toxicity can be manifested as restrictive, hypertrophic or
dilated cardiomyopathy with or without conduction
abnormalities [1, 2]. The overall description of HCQ-in-
duced cardiomyopathy is one of concentric hypertrophy
with restrictive features [6, 7]. According to the US Food
and Drug Administration’s Adverse Event Reporting Sys-
tem, HCQ is one of the most common drugs causing car-
diomyopathy with a proportional reporting ratio of 28.2
[8].
Decompensated left or biventricular failure is the most
frequent symptom related to HCQ-induced cardiomyopa-
thy [3, 4]. The characteristic findings in transthoracic
echocardiography are diffusely thickened ventricular walls
with or without dilatation and systolic or diastolic dys-
function [5]. Currently, the degree, extent, and distribution
of hypertrophy and the extent of myocardial fibrosis can be
well detected using the cardiac Magnetic Resonance
Imaging (MRI). Generally, other possible aetiologies of
cardiomyopathy can be excluded by cardiac MRI before
performing the Endomyocardial Biopsy (EMB).
EMB with subsequent histologic examination plays a
major role in confirming the diagnosis of HCQ-induced
cardiomyopathy and excluding other causes such as lyso-
somal storage diseases, scleroderma and myocarditis. The
most specific finding in light microscopy is cytoplasmatic
inclusion bodies. This finding is induced by a lysosomal
dysfunction with accumulation of metabolic products
caused by HCQ and is considered as pathognomonic for
HCQ-induced cardiomyopathy. Other key findings are
myelinoid and curvilinear bodies within cardiac myocytes

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Clin Res Cardiol
on transmission electron microscopy [5, 6]. These
myocardial changes are quite similar to the changes seen in
the skeletal muscles in HCQ-induced myopathy. Therefore,
skeletal muscle biopsy might be an alternative way to
prove the diagnosis when EMB cannot be performed [8, 9].
In our patient, we were not able to perform electron
microscopy due to limited material of our biopsy. The
diagnosis was made based on the pathognomonic findings
in light microscopy in conjunction with the clinical pre-
sentation and the echocardiographic findings. Due to the
subsequent rapid clinical deterioration of the patient, we
decided not to perform muscle biopsy since this would be
without consequence. After withdrawing the HCQ, the
patient prognosis remains unclear among the overall cases
reported. The outcome of the patients may be varying from
complete recovery to cardiac transplantation, or, as in our
patient, to death [6]. As described in their case report, also
Muthukrishnan et al. lost a patient with HCQ-induced
cardiomyopathy in a similar clinical scenario [9]. In our
case, the hemodynamic and pathologic findings ruled out
systemic sclerosis-related cardiac involvement, as well as
other storage cardiomyopathy. Moreover, ischemic car-
diomyopathy was excluded.
HCQ-induced cardiomyopathy is a rare but significant
complication of HCQ-therapy, and should, therefore be
strongly suspected in patients developing conduction
abnormalities or heart failure. To the best of our knowl-
edge, this is one of the rare cases of HCQ-induced car-
diomyopathy confirmed by EMB.
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