JACC: CASE REPORTS

VOL. 2, NO. 11, 2020

ª 2020 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OFCARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE
CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

CASE REPORTEDITOR’S HIGHLIGHTS

Iron Deﬁciency Anemia-Induced
Cardiomyopathy With
Congestive Heart Failure
Reversible Cardiac Dysfunction Assessed byMulti-Imaging Modalities
Shiro Miura, MD, MSC,a Masanao Naya, MD, PHD,b Takehiro Yamashita, MD, PHDaABSTRACT
Iron deﬁciency anemia (IDA) can cause left ventricular (LV) dysfunction, causing heart failure. A 48-year-old woman withsevere IDA developed congestive heart failure that was properly diagnosed, managed, and followed with multiple imaging modalities to explore potential mechanisms, highlighting the reversibility of LV function in unique cardiomyopathy.
(Level of Difﬁculty: Intermediate.) (J Am Coll Cardiol Case Rep 2020;2:1806–11) © 2020 Published by Elsevier onbehalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

S

evere iron deﬁciency anemia (IDA) has been re-result of iron deﬁciency treatment even without ane-ported to play a pivotal role in the develop-mia (1). A remarkable feature of IDA-induced HF may

ment

left

be the reversibility of LV dysfunction with appro-

ventricular (LV) dysfunction and myocardial damage,ofheart

failure(HF)

through

priate treatment. However, the pathogenesis of car-and substantial clinical beneﬁts have been found as adiomyopathy associated with IDA is unknown due
to the limited number of affected patients. Here, we

LEARNING OBJECTIVES IDA-induced cardiomyopathy can be characterized by severe chronic anemia, signiﬁcantmicrovascular dysfunction, and high-output
HF, which is reversible if treated properly.
 Multi-imaging modalities such as transthoracic echocardiography, CMR, coronary
angiography with hemodynamics measurements, and cardiac positron emission tomography can improve accurate diagnosis
and appropriate management.

report an impressive case with severe IDA causing
LV dysfunction and congestive HF, which was appropriately diagnosed and managed. The patient was followed up with multiple imaging modalities exploring
the potential mechanisms of IDA-induced HF in termsof myocardial tissue characteristics and myocardial
blood ﬂow.

HISTORY OF PRESENTATION
A 48-year-old woman presented with chronic leg
edema and worsening exertional dyspnea. She also

From the aDepartment of Cardiology, Hokkaido Ohno Memorial Hospital, Sapporo, Japan; and the bDepartment of CardiovascularMedicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. The authors have reported that they have norelationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC: Case Reports author instructions page.
Manuscript received June 18, 2020; revised manuscript received July 15, 2020, accepted July 22, 2020.

ISSN 2666-0849

https://doi.org/10.1016/j.jaccas.2020.07.051

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complained of menorrhagia with irregular periods

PAST MEDICAL HISTORYABBREVIATIONS
AND ACRONYMS

more than 6 months ago. Vital sign measurements
showed blood pressure of 107/48 mm Hg, heart rate of

The patient’s medical history was unremark-81 beats/min, SpO 2 of 94% (room), and temperature ofable except for that she regularly smoked36.9  C. Physical examination revealed marked pallor

tobacco and consumed alcohol.

18

F-FDG = 18F-

ﬂuorodeoxyglucose

CMR = cardiac magneticof the skin and conjunctiva, jugular vein distention,
crackles in both lungs, rapid regular heart rhythm

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Iron Deﬁciency Anemia-Induced Cardiomyopathy and Multi-Imaging Modalities

resonance

DIFFERENTIAL DIAGNOSESHF = heart failure

without any murmur, palpable spleen, and pitting

IDA = iron deﬁciency anemia

edema of both lower extremities. Electrocardiogram

The patient showed high-output HF with ashowed normal sinus rhythm with horizontal ST

high cardiac index and low systemic vasculardepression in the limb leads (Figure 1A). Chest radi-resistance.

ography revealed marked cardiomegaly and mild

explained by severe anemia after excluding

pulmonary congestion (Figure 1B). The initial hemo-

other common causes, such as obesity, thy-

tomography/computed

globin level was 1.7 g/l, hematocrit level was 7.2%,

roid disease, arteriovenous shunts, and lungtomography

and mean corpuscular volume was 55 ﬂ. Iron param-

and liver diseases. By characterizing myocardial tis-eters suggested severe IDA with an iron level ofsue, cardiac magnetic resonance (CMR) helped to8 m g/dl, total iron-binding capacity of 468 m g/dl, anddistinguish secondary etiologies, such as myocarditis,

ferritin level of 2 ng/ml. The rest of the blood test

amyloidosis, sarcoidosis, noncompaction cardiomy-results and coagulation times, along with other lab-opathy, and dilated phase hypertrophic cardiomyop18Chronic

high-output

HF

was(18F-FDG)

LV = left ventricular
NT-proBNP = N-terminal pro–B-type natriuretic peptide

PET/CT = positron emission

oratory tests, including clinical chemistry, renal,athy.

liver, and thyroid function, were normal except for anemission tomography/computed tomography (PET/elevated level of N-terminal pro–B-type natriureticCT)

peptide (NT-proBNP) (1,547 pg/ml). Stool guaiac tests

sarcoidosis. Last, her benign clinical course, whichwere negative. The patient received three units of

was shortly controlled with iron replacement andpacked red blood cells in 4 days and was admitted fortransfusion of packed red blood cells, was more sug-evaluation and treatment of severe IDA and HF.

gestive of HF due to severe IDA.

F-ﬂuorodeoxyglucose

wasusefulinexcludingpositron

myocarditis

F I G U R E 1 Electrocardiogram and Chest X-Ray on Admission and at 4-Month Follow-Up

Electrocardiogram on admission (A) and at the 4-month follow-up (C). Initial (B) and 4-month follow-up (D) chest x-rays.

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Iron Deﬁciency Anemia-Induced Cardiomyopathy and Multi-Imaging Modalities

F I G U R E 2 Initial and Follow-Up TTE and Coronary Angiography

Initial transthoracic echocardiogram (TTE) (A) exhibiting biventricular dilatation with preserved left ventricular (LV) wall thickness on a short-axis view compared withthe 4-month follow-up TTE (B), which displayed a signiﬁcant reduction in LV size and an improvement in LV contractility. LV end-diastolic diameter, LV ejection
fraction, and stroke volume measured using Doppler ultrasound changed from 72 mm, 50%, and 103 ml, respectively, to 53 mm, 68%, and 67 ml, respectively, over
4 months. Coronary angiography (C) revealed no obstructive coronary disease.

INVESTIGATIONS

late gadolinium enhancement (Figures 3A to 3C). On
day 12, PET/CT with 13N-ammonia (Figures 4A to 4C)

Initial transthoracic echocardiography showed ademonstrated that ATP-induced stress myocardial

massively dilated LV chamber and left atrium withblood ﬂow was globally low with a considerable drop

eccentric LV hypertrophy and trivial pericardialin the global coronary ﬂow reserve to 1.70. Moreover,effusion (Figures 2A and 2B). On the seventh hospital

18F-FDG-PET/CT detected abnormally high 18 F-FDG

day, coronary angiography (Figure 2C) revealed non-uptake in the uterus with no metastases (Figure 5).

obstructive coronary arteries, and pressure studies

Finally, the patient was referred to our obstetrics andwere performed to assess LV end-diastolic pressure

gynecology department where the solid mass in her(9 mm Hg) and mean pulmonary capillary wedge

uterus was diagnosed as endometrioid cancer onpressures (9 mm Hg) with increased cardiac output athistology.

9.0 l/min and systemic vascular resistance at 691
dynes/s/cm 5. Endomyocardial biopsy was avoided toMANAGEMENT

prevent bleeding complications. CMR demonstrated
biventricular dilatation and diffusely reduced LV wall

Frusemide and enalapril were commenced, and themotion with preserved wall thickness and absence ofpatient was gradually weaned from supplemental

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Iron Deﬁciency Anemia-Induced Cardiomyopathy and Multi-Imaging Modalities

F I G U R E 3 Cine-CMR Images in Long- and Short-Axis Views

Cine-cardiac magnetic resonance (CMR) images in long-axis ([A] diastolic and [B] systolic phases) and short-axis views with late gadolinium enhancement imaging (C).
CMR studies at the 4-month visit were repeated with the corresponding images (D to F). Concentric left ventricular (LV) hypertrophy and biventricular enlargement
were visible with a reduced LV ejection fraction of 32%, which improved to 47% over 4 months with a signiﬁcant drop in the LV end-diastolic volume from 184 to 96 ml.
Late gadolinium enhancement was not present over the entire myocardium at both the acute (C) and follow-up phases (F).

oxygen. After the blood transfusion, she was treatedalong with global LV wall motion, and late gadolin-with 7-day intravenous saccharated ferric oxide, fol-ium enhancement was absent throughout the entire

lowed by oral sulfate. At 3 weeks after discharge, she

myocardium (Figures 3D to 3F). Perfusion PET/CT

underwent

revealed a total recovery of global coronary ﬂow

atotalhysterectomy

withbilateralsalpingo-oophorectomy at a university hospital;

reserve from 1.70 to 2.88 (Figures 4D to 4F).

endometrial carcinoma was conﬁrmed on pathological examination. At the 4-month follow-up visit, she

DISCUSSION

was free of symptoms, where ST changes on electrocardiogram were normal with a normal cardiac

We report a case of a middle-aged woman withsilhouette on the chest radiograph (Figures 1C and 1D).

chronic severe anemia and iron deﬁciency. We uti-Her LV ejection fraction improved to 69%, and LV

lized novel imaging modalities to elucidate the po-diastolic dimension was still enlarged (54 mm) with atential mechanisms causing unique HF. Not only can

mildly elevated LV mass index of 111 g/m 2 (Figure 2B).

progressiveSerum hemoglobin, iron, ferritin, and NT-proBNP

converse can also occur. Iron deﬁciency can promote

levels were within the normal range. Repeated CMR

the remodeling of cardiomyocytes (2). Iron has rolesdemonstrated that biventricular dilatation improved

beyond oxygen transport, including in the normal

HF

cause

irondeﬁciency,

butthe1809

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F I G U R E 4 Perfusion Imaging and Myocardial Blood Flow Quantiﬁcations Using 13 N-Ammonia PET in Acute Phase and at 4-Month Follow-Up

ATP-induced stress/rest 13N-ammonia positron emission tomography (PET) quantiﬁed the rest/stress myocardial blood ﬂow (MBF) and coronary ﬂow reserve (CFR) (A)with coronary territories (B) and myocardial perfusion imaging (MPI). (C) Both stress MBF and CFR were globally reduced at baseline and improved dramatically overthe next 4 months to within normal ranges with the global CFR increasing from 1.70 to 2.88 (D and E). The MPI study demonstrated the involvement of the anterolateral and inferior walls with reversible myocardial ischemia, which signiﬁcantly declined in size at follow-up (F). HLA ¼ horizontal long-axis; LAD ¼ left anteriordescending; LCX ¼ left circumﬂex; RCA ¼ right coronary artery; SA ¼ short-axis; VLA ¼ vertical long-axis.

F I G U R E 5 Whole Body FDG-PET/CT Images

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) (A) dedicated cardiac and whole-body imaging with a high-fat, low-carbohydrate, protein-preferred diet in the fasting state revealed no focal FDG uptake in the myocardium (B). Abnormally high FDG uptake wasdetected in the uterus with no metastatic sites (C).

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Iron Deﬁciency Anemia-Induced Cardiomyopathy and Multi-Imaging Modalities

activity of key enzymes of the citric acid cycle andslightly dilated after HF improvement, and thesereactiveenzymes.

ﬁndings were in line with cardiac indexes measured

Decreased levels of reactive oxygen species scav-by CMR imaging. Close observation to evaluate

enging enzymes in myocardial iron deﬁciency may

longer-term

intensify local oxidative stress, causing myocardial

warranted.

oxygenspecies

scavenging

damage (3). As noted earlier, compromised oxygen
delivery capacity may cause chronic tissue hypoxemia, which can lead to cardiomyocyte dysfunction.
In our case, the initial perfusion PET/CT revealed
signiﬁcantmicrovascular

dysfunction

that

may

reﬂect global myocyte dysfunction. Moreover, IDAinduced cardiomyopathy had no association withmyocardial inﬂammation, as shown by 18 F-FDG-PET/

cardiacfunction

andprognosis

is

FOLLOW-UP
The patient continues to take enalapril. LV function
by follow-up echocardiography and hemoglobin levelarewithinnormalranges12months

afterhospitalization.

CONCLUSIONSCT.
A further remarkable aspect of the present case is

To our knowledge, this is the ﬁrst case of severe IDA

the reversibility of IDA-induced cardiomyopathy

leading to LV dysfunction and congestive HF that wasconﬁrmed with several imaging modalities. At the 4-

properly diagnosed, managed, and followed withmonth follow-up, when the patient was asymptom-

multiple imaging modalities to explore the potential

atic and her hemoglobin, iron, and NT-proBNP levels

mechanisms. This case supports the reversibility ofwere normalized, we found remarkable improve-

IDA-induced cardiomyopathy if treated properly, butments in cardiac function parameters assessed byfurther research is required to determine the level oftransthoracic echocardiography, CMR, and perfusion

improvement.

PET/CT. This strongly suggests that IDA-induced
cardiomyopathy may be almost completely revers-ADDRESS FOR CORRESPONDENCE: Dr. Shiro Miura,

ible. However, it remains unclear whether complete

Department of Cardiology, Hokkaido Ohno Memorial

normalization of LV function occurs in severe cases.

Hospital, 2-1-16-1 Miyanosawa, Nishi-ku, Sapporo

Our present case showed that the LV remained

063-0052, Japan. E-mail: s.miura@ohno-kinen.or.jp.

REFERENCES
1. Grote Beverborg N, van Veldhuisen DJ, van derMeer P. Anemia in heart failure: still relevant?
J Am Coll Cardiol HF 2018;6:201–8.
2. Jankowska EA, Ponikowski P. Molecularchanges in myocardium in the course of anemia or
iron deﬁciency. Heart Fail Clin 2010;6:295–304.

3. Dai DF, Johnson SC, Villarin JJ, et al. Mitochondrial oxidative stress mediates angiotensin IIinduced cardiac hypertrophy and Galphaq
overexpression-induced heart failure. Circ Res
2011;108:837–46.

KEY WORDS cardiac magnetic resonance,
cardiomyopathy, iron deﬁciency anemia,
positron emission tomography

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