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DIAGNOSTIC DILEMMA

Aimee K. Zaas, MD, Section Editor

Like a House Afire: Cardiac SarcoidosisJames D. Richardson, MBBS,a,b Michael S. Cunnington, MBBS,a Adam J. Nelson, MBBS,a,b Julie A. Bradley, PhD,a

Karen S. L. Teo, PhD,a,b Stephen G. Worthley, PhD,a,b Matthew I. Worthley, PhDa,b

aCardiovascular Research Centre, Royal Adelaide Hospital and bDepartment of Medicine, University of Adelaide, Adelaide, South

ustralia, Australia.

PRESENTATIONIt seemed like an obvious case of acute coronary syn-drome—but was it really? A 36-year-old man of Sri Lankanorigin presented to his local rural emergency departmentwith severe central chest pain. He described persistent chesttightness radiating to his left arm. This had developed at restand was unaffected by inspiration or posture. Over thepreceding 24 hours, he had several short-lived episodes ofsimilar but milder pain that resolved spontaneously. Other-wise, the patient had been well with no recent viral illness.His medical history was significant for diet-controlled type2 diabetes mellitus and hypercholesterolemia. He was asmoker and had a strong family history of premature coro-nary artery disease.

ASSESSMENTOn examination, the patient was hemodynamically stable.His heart sounds were normal, with no pericardial rub, andhis lungs were clear on auscultation. An electrocardiogram(ECG) showed sinus rhythm with 1-mm ST elevation inleads I and aVL. A chest radiograph showed normal cardiacand mediastinal contours with clear lung fields. Serum tro-ponin T at admission was significantly elevated at 4.3 �g/Lnormal �0.02 �g/L). A random blood glucose measure-ent was 14.1 mmol/L, and hemoglobin A1c was raised at

.2%. The patient’s white cell count was mildly elevated at

.36 x103/mm3, and his C-reactive protein level was 23mmol/L.

A diagnosis of acute coronary syndrome was made.Treatment was initiated with aspirin and clopidogrel after aloading dose of clopidogrel, 300 mg. He also received a

Funding: None.Conflict of Interest: None.Authorship: All authors fully participated in the preparation of this

manuscript.Requests for reprints should be addressed to Matthew I. Worthley,

PhD, Cardiovascular Investigation Unit, Royal Adelaide Hospital, Level 6Theatre Block, North Terrace, Adelaide, South Australia, 5000, Australia.

E-mail address: matthew.worthley@adelaide.edu.au

0002-9343/$ -see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.amjmed.2012.09.002

therapeutic dose of subcutaneous low-molecular-weightheparin and opiate analgesia. He was not given thromboly-sis, and no catheterization laboratory facilities were avail-able at this rural location.

Over the next 24 hours, the patient had ongoing painrequiring opiate analgesia. A repeat ECG demonstrated an-terolateral and inferior T-wave inversion, with persisting STelevation in leads I and aVL (Figure 1). He was transferredto a tertiary cardiology center for further investigation.Echocardiography showed moderate septal hypertrophywith inferior hypokinesis and mild impairment of left ven-tricular systolic function. Coronary angiography revealedmild atherosclerosis with a noncontributory 30% stenosis inthe mid-left anterior descending artery. No provocative test-ing was undertaken for coronary spasm due to safety issuesassociated with performing this test in the setting of atroponin elevation.

DIAGNOSISThe etiology for this patient’s presentation remained uncer-tain, and cardiac magnetic resonance imaging (MRI) wasperformed. Transverse black-blood images showed medias-tinal lymphadenopathy with multiple enlarged lymph nodesmeasuring up to 18 � 16 mm (Figure 2A). Cine imagingdisplayed mild asymmetrical septal hypertrophy with nor-mal left ventricular volume and severe hypokinesia of themid-to-apical segments of the inferior, lateral, and anteriorwalls (ejection fraction, 52%).

T2-weighted images demonstrated an increased signal inthe same territories, indicating acute injury with edema(Figure 2B). Inversion recovery images showed patchymid-wall late gadolinium enhancement in the septum, withmore extensive late enhancement in the segments with re-gional wall-motion abnormalities (Figures 2C and D). Thepericardium appeared normal with no pericardial effusion.This pattern of late gadolinium enhancement, with sparingof the subendocardium, indicated myocardial fibrosis of

nonischemic etiology, and in association with the lymph-

22 The American Journal of Medicine, Vol 126, No 1, January 2013

Figure 1 An electrocardiogram (ECG) obtained during the 24 hours following presentation demon-

strated 1-mm ST-segment elevation in leads I and aVL with T-wave inversion in the inferolateral leads.

Figure 2 Cardiac magnetic resonance imaging was very useful. A, This transverse imageshowed mediastinal lymphadenopathy, marked here with an asterisk. B, A T2-weighted imagehad increased signal at the apex, indicating myocardial edema. C, An inversion recovery hori-zontal long-axis image exhibits late gadolinium enhancement in the septum and distal lateralwalls. Note the differing localization of late enhancement to that of the edema shown in2B—concomitant sarcoid involvement is reflected, but at different evolutionary stages. D, Ashort-axis image displays extensive late gadolinium enhancement of the distal anterior andinferior myocardium. Sparing of the subendocardium and the noncoronary distribution (anterior

wall involved with proximal septum-sparing) suggest a noncoronary etiology.

23Richardson et al Cardiac Sarcoid Mimicking an Acute Coronary Syndrome

adenopathy, led to a working diagnosis of acute cardiacsarcoidosis, a disease spurred by inflammation.

High-resolution computed tomography (CT) of the tho-rax confirmed the mediastinal lymphadenopathy noted on

Figure 3 A discrete well-formed granuloma composed ofepithelioid histiocytes was evident after hematoxylin and eosinstaining.

Figure 4 The patient’s progress was examined with ECG antreatment with prednisolone, the patient’s ECG showed new anextensive late gadolinium enhancement in the anteroseptum andMRI. This demonstrates the pathological evolution of cardiacimmunotherapy regimen, an ECG demonstrated marked improve

beginning more powerful treatment, a third cardiac MRI demonstrated

cardiac MRI but showed no evidence of pulmonary fibrosis.Abdominal CT demonstrated lymphadenopathy in the para-aortic, perigastric, epigastric and portacaval regions. Thor-ough clinical examination for peripheral lymphadenopathyidentified 1 palpable right femoral lymph node, which wasbiopsied. Histopathology showed discrete well-formedgranulomas composed of epithelioid histiocytes consistentwith sarcoidosis (Figure 3).

The incidence of sarcoidosis varies by ethnicity andgeographical region, from 10/100,000 in Caucasians to 40-80/100,000 in African Americans.1 Up to 40% also havecardiac involvement determined by cardiac MRI or positronemission tomography.2 The clinical manifestations of car-diac sarcoidosis depend on the activity, distribution, andextent of disease. The most common presentations relate toconduction abnormalities, arrhythmias (ventricular oratrial), sudden cardiac death, or heart failure. Presentationwith chest pain mimicking acute coronary syndrome, as inthis patient’s case, is rare.

Confirming the diagnosis of cardiac sarcoidosis can bechallenging. Diagnostic criteria consisting of histologicaland major/minor clinical criteria have been produced, butare most relevant in chronic disease.3 Tissue characteriza-tion by cardiac MRI is a useful diagnostic tool with reported

ac MRI. A, Almost 6 months after initial presentation, despiteeral T-wave inversion. B, A second cardiac MRI showed morethe same region where edema was identified on the first cardiacidosis. C, After the patient was placed on a more intensivewith residual abnormalities in aVL only. D, Three months after

d carditerolatapex—

sarcoment

improvement in late gadolinium enhancement.

Tbr

24 The American Journal of Medicine, Vol 126, No 1, January 2013

sensitivity of 100% and specificity of 78%.4 As with ourpatient, cardiac MRI can accurately assess wall thickness,regional wall-motion abnormalities, myocardial edema, andfibrosis in acute cardiac sarcoidosis. The thinned, scarredmyocardium of chronic disease also is readily detectable bycardiac MRI.

In fact, cardiac MRI has a valuable role in the investi-gation of patients with presumed acute coronary syndromewho have normal coronary arteries at angiography. Approx-imately 10% of patients with ST-elevation myocardial in-farction and 30% of biomarker-negative acute coronarysyndrome cases have nonobstructive coronary disease.5 Aroutine “structure and function” cardiac MRI with gadolin-ium contrast may establish a diagnosis in two-thirds ofcases, with exclusion of significant pathology in the remain-der.6 Diagnoses in such cases include myocarditis, Tako-

subo cardiomyopathy and other cardiomyopathies, em-olic and transient thrombotic events, as well as interestingarities, such as acute cardiac sarcoidosis.

MANAGEMENTTreatment is aimed at modifying the inflammatory diseaseprocess; other therapies deal with potential complications ofthe disease. Examples of the latter are antiarrhythmic ther-apy, implantable cardioverter-defibrillators, pacing, heartfailure therapy, or even cardiac transplantation. Medicaltherapy primarily consists of corticosteroid treatment. Theevidence for this is largely based on case series and expertopinion, with no published consensus guidelines. Highdoses of prednisolone—60-80 mg per day—are often initi-ated, though lower doses have been shown to be effective.7

Two small trials are ongoing: the Cardiac Sarcoidosis Re-sponse to Steroids Trial or NCT01210677, designed toexamine the effectiveness of a 3-month course of oral pred-nisolone, 0.5 mg/kg/day, and the Implantable Cardiac De-fibrillators for the Prevention of Sudden Death in Patientswith Cardiac Sarcoidosis trial or NCT01013311.

Our patient was treated with prednisolone, 25 mg daily,with initial symptomatic relief. An angiotensin-convertingenzyme inhibitor was prescribed for the left ventricularsystolic dysfunction, along with oral hypoglycemic drugs toimprove glycemic control. He was discharged with a plan toreview his progress in 6 weeks. Unfortunately, over thesubsequent month, he had ongoing chest pain and mildlyelevated troponin levels resulting in 3 admissions to hislocal rural hospital. His prednisolone dosage was increasedto 50 mg daily with some symptomatic improvement, butover the succeeding months, he developed steroid-related

adverse effects; specifically, significant weight gain, insom-

nia, hyperglycemia requiring insulin administration, andCushingoid appearance.

Nearly 6 months after the patient’s initial presentation,he re-presented with severe and prolonged chest pain, raisedtroponin levels, and an abnormal ECG, with deep arrowheadT-wave inversion across the anterior leads (Figure 4A). Re-peat coronary angiography was unchanged. Repeat cardiacMRI showed regional wall motion abnormalities as previ-ously identified, but with more extensive late gadoliniumenhancement in the septum and anterior wall and a reduc-tion in ejection fraction to 48% (Figure 4B).

In view of the patient’s progressive disease despite high-dose steroid therapy, he was placed on an intensified im-munosuppressive regimen of methotrexate and infliximab, amonoclonal antibody specific for tumor necrosis factor-�.This combination produced marked symptomatic relief ac-companied by near-normalization of his ECG (Figure 4D).Follow-up cardiac MRI, undertaken 3 months after escala-tion of immunotherapy, showed a reduction in late gadolin-ium enhancement and an improved ejection fraction of 67%(Figure 4C).

This case illustrates the rare presentation of acute cardiacsarcoidosis mimicking acute coronary syndrome; the utilityof cardiac MRI to diagnose disease, direct treatment, andmonitor the effect of treatment; and the potential difficultyin managing these challenging cases.

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3. Soejima K, Yada H. The work-up and management of patients withapparent or subclinical cardiac sarcoidosis: with emphasis on the asso-ciated heart rhythm abnormalities. J Cardiovasc Electrophysiol. 2009;20:578-583.

4. Smedema JP, Snoep G, van Kroonenburgh MP, et al. Evaluation of theaccuracy of gadolinium-enhanced cardiovascular magnetic resonance inthe diagnosis of cardiac sarcoidosis. J Am Coll Cardiol. 2005;45:1683-1690.

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