Patient Case Report

Journal of Pharmacy Practice

1-5
Restrictive Cardiomyopathy Associated The Author(s) 2016
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With Long-Term Use of Hydroxychloroquine DOI: 10.1177/0897190016655726
jpp.sagepub.com
for Systemic Lupus Erythematosus

Leah A. Sabato, PharmD1, Lisa A. Mendes, MD2,

and Zachary L. Cox, PharmD3

Abstract
Hydroxychloroquine (HQ) is commonly prescribed for autoimmune diseases such as systemic lupus erythematosus. We report a
case of a 75-year-old female presenting with de novo decompensated heart failure and restrictive cardiomyopathy (left ventricular
ejection fraction: 40%-45%) after treatment with HQ for more than 11 years. Hydroxychloroquine was discontinued, and
follow-up echocardiogram 57 days after discontinuation showed normalization of her left ventricular ejection fraction. A score of
7 on the Naranjo Adverse Drug Reaction Probability Scale indicates that HQ is a probable cause of this patients cardiomyopathy.
An adverse drug effect due to HQ should be considered in treated patients who present with restrictive cardiomyopathy.
Discontinuation may allow for partial or complete reversal of the cardiomyopathy.

Keywords
hydroxychloroquine, cardiomyopathy, restrictive cardiomyopathy, systemic lupus erythematosus

Objective patient with SLE and present a brief review of literature

To report a case of hydroxychloroquine-associated restrictive
cardiomyopathy in a patient treated for systemic lupus erythe-
matosus and present a brief review of the related literature.
Background
Systemic lupus erythematosus (SLE) is a chronic systemic
autoimmune disease with a prevalence that ranges from 20 to
70 per 100 000.1 Patients with SLE are at increased risk of
various cardiovascular diseases as a result of their autoimmune
disease, including premature atherosclerotic coronary artery
disease, myocardial infarction, arterial stiffening, and left ven-
tricular hypertrophy2; however, cardiomyopathy has also been
reported in patients with SLE treated with chloroquine (CQ)3
and hydroxychloroquine (HQ).4-19
CQ and HQ are antimalarial 4-aminoquinolone compounds
recommended in patients with SLE to decrease SLE activity,
prevent lupus flares, increase long-term survival, and protect
against irreversible organ damage.20,21 HQ, which differs
from CQ only by the presence of a hydroxyl group,22 has
become a preferred agent due to improved side effect
profile.20 Reports have emerged regarding cardiomyopathy
associated with CQ 3 and HQ, 4-19 but documentation of
restrictive cardiomyopathy solely associated with HQ has
been rarely reported.8,10,11,13,14,18 Herein, we present a case
of restrictive cardiomyopathy presenting as decompensated
heart failure related to long-term HQ administration in a
related to restrictive cardiomyopathy attributed solely to HQ.
Case Description
A 75-year-old white female presented to the emergency depart-
ment from her home for worsening complaints of fatigue, dys-
pnea on exertion, and heaviness in her legs that began 2 months
ago. She had a past medical history of antinuclear antibody
(ANA)-positive SLE, anxiety, hypertension, hyperlipidemia,
and gastroesophageal reflux disease. Her SLE had been treated
with HQ 200 mg twice daily for at least 11 years, prednisone
5 mg daily as needed for joint pain (patient reported frequency
as rare), and naproxen (unknown dose) as needed for joint pain.
Other medications on presentation included atenolol 100 mg by
mouth daily, amlodipine 10 mg/benazepril 20 mg by mouth
daily, simvastatin 10 mg by mouth daily, and dexlansoprazole
1
Department of Pharmacy, Vanderbilt University Medical Center, Nashville,
TN, USA
2
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt
University Medical Center, Nashville, TN, USA
3
Department of Pharmacy Practice, Lipscomb University College of Pharmacy,
Nashville, TN, USA
Corresponding Author:
Leah A. Sabato, Department of Pharmacy, Vanderbilt University Medical
Center, 1211 Medical Center Drive VUH B-131, Nashville, TN 37232, USA.
Email: LeahSabato@gmail.com

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2 Journal of Pharmacy Practice
Table 1. Initial and Follow-Up Echocardiogram.
Initial echocardiogram Follow-up echocardiogram
LVEF 40%-45% 50%-60%
LVIDd 3.77 cm 4.01 cm
IVSD 1.23 cm 1.12 cm
Filling pattern Restrictive diastolic filling Restrictive diastolic filling
RVIDd 3.6 cm 3.6 cm
RV assessment Moderate dysfunction Mild dysfunction
Abbreviations: IVSD, intraventricular septal diameter; LVEF, left ventricular
ejection fraction; LVIDd, left ventricular internal diameter (diastolic); RV, right
ventricular; RVIDd, right ventricular internal diameter (diastolic).
30 to 60 mg by mouth daily. Family history was positive for
coronary artery disease (father and mother: myocardial infarc-
tion). On admission, vitals were as follows: blood pressure 120/
57 mm Hg, heart rate 50 beats per minute (BPM), temperature
36.4 C, respiratory rate 22 BPM, oxygen saturation 98% on
room air, weight 69.0 kg, and height 157.5 cm. Physical exam-
ination revealed 2 bilateral pitting edema, jugular venous
distention of 14 cm water, and bibasilar soft crackles in the
lungs. Notable laboratory findings upon admission included a
brain natriuretic peptide (BNP) elevated to 3625 pg/mL, tropo-
nin of 1.45 ng/mL, which remained consistently elevated with
medical therapy, and serum creatinine of 2.22 mg/dL, which
remained consistently elevated throughout the admission.
Other laboratory measurements including basic metabolic
panel and complete blood count were unremarkable. Admis-
sion electrocardiogram displayed sinus bradycardia with a rate
of 45 BPM but was otherwise unremarkable. Her admission
chest radiograph showed right lower lung atelectasis and
pleural effusion. Coronary angiography was not performed due
to acute kidney injury during the admission. Transthoracic
echocardiography (Table 1) showed normal left ventricular
size with mildly depressed left ventricular ejection fraction
(40%-45%), concentric left ventricular hypertrophy with
restrictive filling, moderate right ventricular dilation and dys-
function, severe biatrial enlargement, mild mitral regurgitation,
and moderate tricuspid regurgitation (Figure 1). Right heart
catheterization demonstrated elevated left- and right-sided fill-
ing pressures with near equalization of atrial filling pressures
supporting the diagnosis of restrictive cardiomyopathy (mean
right atrial pressure: 19 mm Hg, pulmonary capillary wedge
pressure: 16 mm Hg, pulmonary artery pressure: 41/25 mm Hg
[mean 32 mm Hg]), right ventricular pressure: 38/12). Endo-
myocardial biopsy results with Congo Red stain were negative
for amyloidosis. Light microscopy showed cytoplasmic vacuo-
lization, myocardial hypertrophy, and interstitial fibrosis. Elec-
tron microscopy showed nonspecific changes including large
areas of sarcoplasm filled with lipid and glycogen particles.
Mitochondrial assessment was not possible due to specimen
preservation techniques. Based on the clinical, echocardio-
graphic, and endomyocardial biopsy findings, a diagnosis of
HQ-induced restrictive cardiomyopathy was made. HQ was
discontinued in collaboration with her rheumatologist on day
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10 of admission. Her heart failure was managed with intrave-
nous bumetanide and metoprolol tartrate 12.5 mg by mouth
twice daily. Her inpatient stay was complicated by develop-
ment of new onset atrial fibrillation with rapid ventricular
response and tachy-brady syndrome, managed with warfarin
(dose-adjusted to international normalized ratio [INR] goal 2-
3), pacemaker implantation, and amiodarone (maintenance
dose of 200 mg by mouth daily). She reported improvement
in heart failure symptoms over her hospital stay, and she was
discharged to inpatient rehabilitation on day 17 of admission on
the following cardiovascular medications: amiodarone 200 mg
by mouth daily, atorvastatin 40 mg by mouth at bedtime, bume-
tanide 4 mg by mouth twice daily, metoprolol tartrate 12.5 mg
by mouth every 12 hours, and INR-adjusted warfarin (INR goal
2-3). Follow-up echocardiogram was performed 57 days after
discontinuation of HQ during a readmission for heart failure
exacerbation and demonstrated normalization of left ventricu-
lar ejection fraction with modest improvement in right ventri-
cular systolic function. However, restrictive LV filling pattern
remained (Table 1).
Discussion
We report a case of restrictive cardiomyopathy associated with
HQ treatment for SLE. The appearance of vacuolization on
cardiac biopsy is consistent with previous reports of HQ-
associated cardiomyopathy. Alternative etiologies of this
restrictive cardiomyopathy including sarcoidosis and amyloi-
dosis were excluded based on endomyocardial biopsy results.
Hypertension was excluded as the primary cause for her cardi-
omyopathy because her hypertension had been considered well
controlled, and the features of her cardiomyopathy were not
consistent with that caused by hypertension alone. Testing for
Fabry disease was not performed based on low suspicion given
symptoms and atypical patient characteristics for disease pre-
sentation.23 A score of 7 on the Naranjo Adverse Drug Reac-
tion Probability Scale indicates that HQ is a probable cause of
this patients cardiomyopathy.24 The patient received points on
the Naranjo scale for the following: previous conclusive reports
exist in the literature (1 point), the adverse drug effect appeared
after the suspected drug was administered (2 points), the
adverse drug effect improved when the drug was discontinued
(1 point), there were no alternative causes for the adverse effect
identified (2 points), and the adverse effect was confirmed by
objective evidence (1 point).
The mechanism by which antimalarials cause cardiotoxicity
has not been clearly elucidated. Antimalarials distribute in high
concentrations in cardiac tissue25 and are theorized to interfere
with cardiac lysosomal function causing an acquired lysosomal
storage disorder.19 HQ is a basic compound that enters lyso-
somes via diffusion at physiologic pH. In the acidic lysosomal
environment, the compound is positively charged and incap-
able of exiting via diffusion, effectively concentrating the drug
within the lysosome.26 The presence of the drug in the lyso-
some interferes with lysosomal enzyme function through alka-
lization and direct inhibition, leading to accumulation of
Sabato et al 3

Figure 1. Admission echocardiogram illustrating restrictive left ventricular filling. A (left), The apical 4-chamber view demonstrates features of
restrictive cardiomyopathy, including a nondilated ventricle, increased wall thickness, and severe biatral enlargement. B (right), A transthoracic
echocardiogram with Doppler examination of mitral inflow. The E wave represents early passive filling of the left ventricle with the deceleration
time of the E wave, a measure of how rapidly left atrial and left ventricular pressures equilibrate. The A wave represents active left ventricular
filling from atrial contraction. The increased peak E wave to A wave velocity ratio of 3.6 and short E wave deceleration time is typical in patients
with restrictive cardiomyopathy. This pattern is secondary to elevated left atrial pressures that result in rapid left ventricular inflow in early
diastole, followed by rapid equilibration of left ventricular and left atrial pressures in mid-diastole. Given the involvement of the left atrium with
the restrictive process, there is a minimal contribution to left ventricular filling with left atrial contraction.

Table 2. Previous Reports of Hydroxychloroquine-Associated Restrictive Cardiomyopathy.

Age in years/sex Daily Duration,

Author (Indication) dose, mg years Cardiac featuresa Follow-up (Time)
8
Cotroneo et al 51F (SLE, RA) 200-400 31 EF: 40%, restrictive filling, valve disease Improved (3 months)
Joyce et al18 52F (RA) 400 15 EF: 30%-35%, conduction abnormality, restrictive filling Expired (<2 months)
Lee et al11 52F (RA) NR >12 EF: 44%, restrictive filling, valve disease, conduction Improved (4 months)
abnormality
Manohar et al10 64F (SLE) NR >10 EF: 46%, restrictive filling Improved (9 months)
Muthukrishnan et al13 66F (SLE) 400 10 EF: 35%, restrictive filling, conduction abnormality Expired (2 months)
Newton-Cheh et al14 47M (SLE) 400-600 14 EF: 54%, restrictive filling, valve disease Stable (12 months)

Abbreviations: EF, left ventricular ejection fraction; F, female; M, male; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.
a
Cardiac features include ejection fraction, conduction abnormality (any arrhythmia or conduction block), valvular disease, and restrictive ventricular filling
(grade III diastolic dysfunction).

enzyme substrates (glycogen and membrane phospholipids)
and vacuolization seen on myocardial biopsy.6,17,19,27,28
The type of cardiomyopathy described in association with
HQ has been variable, and the presence of restrictive filling has
been extremely rare (Table 2). There have been 18 prior pub-
lished reports of cardiomyopathy (both restrictive and nonres-
trictive) associated solely with HQ use. Left ventricular
ejection fraction was reported to be depressed to <40% in 10
of 18 published cases,6-9,12,13,15,17,18 left ventricular wall thick-
ness was reported to be increased in 10 cases,7,8,10-14,17-19 but
restrictive filling has only been noted in 6 prior reported
cases.8,10,11,13,14,18 Conduction6,7,9,11-13,16-19 and valvular
abnormalities8,9,11,14 have also been reported. Our patient dis-
played all of these potential manifestations.
Patient-related risk factors for HQ-associated restrictive car-
diomyopathy have not been established, given the relative pau-
city of reports on the subject. However, the patient characteristics
of restrictive8,10,11,13,14,18 and nonrestrictive4-7,9,12,15-17,19 HQ-
associated cardiomyopathy are similar in the reported cases.
More than 80% of the patients were female and more than
60% were being treated for SLE, reflecting the predominant
use for HQ in this female-predominated disease state.1 There is
a wide variation in age at time of diagnosis (range 47-66 years),
however the majority (83%) occurred in patients older than 50
years of age. Our patient was typical of reported cases of
restrictive cardiomyopathy thus far (female, >50-years-old,
treated for SLE). It is also possible that genetic
predisposition or metabolic differences (renal or hepatic dys-
function) lead to increased exposure and contribute to the
development of HQ-associated cardiomyopathy.
Long-term use of the drug is the most consistent drug
regimen-related characteristic among the published reports.
Diagnosis of nonrestrictive cardiomyopathy has been reported
after as little as 2 years of drug therapy4; however, in all reports

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4 Journal of Pharmacy Practice
of restrictive cardiomyopathy secondary to HQ, the patient had
taken the drug for >10 years, consistent with the present case.
Daily doses of HQ reported in association with restrictive car-
diomyopathy have ranged from 200 to 600 mg daily with an
average cumulative dose of 1988 g. Cumulative dose in our
patient was more than 1606 g.
In this patients case, normalization of left ventricular ejec-
tion fraction and improvement in right ventricular function
occurred approximately 2 months after discontinuation of the
drug; however, the restrictive filling pattern remained. Three of
the 6 previous reports of restrictive cardiomyopathy have also
shown some marker of improvement upon discontinuation of
the drug,8,10,11 but only one report has shown improvement in
restrictive filling pattern.10 The time to echocardiographic
improvement was between 3 and 9 months in these reports.
Conclusion
HQ-associated restrictive cardiomyopathy is a rare side effect
that has been reported in the literature. An adverse drug effect
due to HQ should be considered in treated patients who present
with restrictive cardiomyopathy. Discontinuation of HQ may
allow for partial or complete reversal of the cardiomyopathy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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