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C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

CASE REPORT

CLINICAL CASE

Cardiac AmyloidosisThe Importance of Surveillance in a Patient With an InitialNegative Cardiac Biopsy

Rajiv Ananthakrishna, MBBS, DM,a Rachael Lloyd, MBBS (HONS),a Bryone J. Kuss, MBBS, PHD,b

Joseph B. Selvanayagam, MBBS (HONS), DPHILa

ABSTRACT

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Cardiac amyloidosis is a progressive disorder and is sometimes difficult to diagnose even when suspected in the

appropriate clinical setting. This report presents an interesting case of rapidly progressive light-chain cardiac amyloidosis

and highlights the importance of close monitoring even when the initial biopsy and imaging findings are not

pathognomonic for amyloidosis. (Level of Difficulty: Beginner.) (J Am Coll Cardiol Case Rep 2020;-:-–-)

© 2020 The Authors. Published by Elsevier on behalf 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/).

HISTORY OF PRESENTATION

A 48-year-old female patient was referred to excludecardiac amyloidosis (CA). The patient was asymp-tomatic from a cardiac perspective. Results ofgeneral physical and systemic examinations wereunremarkable.

PAST MEDICAL HISTORY

The patient was diagnosed with monoclonal gamm-opathy of unknown significance (MGUS) 6 yearsearlier. In addition, she was evaluated for recentonset of numbness in both hands. The patient was

EARNING OBJECTIVES

Recognize the importance of close surveil-lance in the presence of red flags suggestingCA, even when the initial biopsy and imagingfindings are not diagnostic.Recall the clinical course and prognosis of ALamyloidosis.

N 2666-0849

m the aDepartment of Cardiovascular Medicine, Flinders Medical Cen

lecular Medicine (Haematology and Molecular Genetics), Flinders Univer

t they have no relationships relevant to the contents of this paper to dis

nuscript received October 1, 2019; revised manuscript received October 3

detected to have bilateral carpal tunnel syndrome,and conservative management was advised.

INVESTIGATIONS

Laboratory investigations revealed a cardiac troponinT level of 36 ng/l (normal: <30 ng/l) and an N-termi-nal pro-B-type natriuretic peptide (NT-proBNP) valueof 1,015 ng/l (normal: <125 ng/l). The concentration ofserum free light chains was 985 mg/l for the kappaisotype (normal: 3 to 19 mg/l) and 10 mg/l for thelambda isotype (normal: 6 to 26 mg/l). The kappa-to-lambda ratio was 98.5 (normal: 0.26 to 1.65). Althoughkappa light chains were elevated, they had been sta-ble over the past 6 years, with normal renal functionand serum calcium values. A comprehensive work-upfor multiple myeloma was negative. A bone marrowbiopsy was consistent with MGUS (plasmacytosis of9%). A rectal biopsy showed no deposits of amyloid.Echocardiographic evaluation revealed a mild in-crease in left ventricular wall thickness (involving thebasal inferior and basal inferolateral walls; maximumthickness of 13 mm) with normal left ventricular

https://doi.org/10.1016/j.jaccas.2019.11.041

tre, Adelaide, Australia; and the bDepartment of

sity, Adelaide, Australia. The authors have reported

close.

1, 2019, accepted November 2, 2019.

FIGURE 1 Initial CMR Imaging

(A and B) Cardiac magnetic reso

and basal inferolateral segments

endomyocardial biopsy samples

Gieson (VVG) stain. (E) Congo r

ABBR EV I A T I ON S

AND ACRONYMS

AL = light-chain

ATTR = transthyretin

CA = cardiac amyloidosis

CMR = cardiac magnetic

resonance

ECV = extracellular volume

MGUS = monoclonal

gammopathy of unknown

significance

NT-proBNP = N-terminal pro-

B-type natriuretic peptide

Ananthakrishna et al. J A C C : C A S E R E P O R T S , V O L . - , N O . - , 2 0 2 0

Cardiac Amyloidosis - 2 0 2 0 :- –-

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function. Cardiac magnetic resonance (CMR)confirmed the increased wall thickness, andthe time of inversion scout sequence showeda normal pattern of myocardial nulling.Phase-sensitive inversion recovery late gad-olinium enhancement imaging demonstratedsubepicardial hyperenhancement in the basalinferior and inferolateral segments. In addi-tion, there was hyperenhancement of the leftatrial and right ventricular free walls(Figures 1A and 1B). The CMR features raisedthe suspicion of CA. A right ventricularendomyocardial biopsy (6 samples from theregion of the right ventricular septum)

showed diffuse interstitial fibrosis with no evidenceof amyloid deposition (Figures 1C to 1F). The Congored–stained biopsy samples did not demonstrateapple-green birefringence on polarized microscopy.The immunoperoxidase studies showed lack of posi-tive labeling with antibodies to amyloid A protein,amyloid P protein, and transthyretin (ATTR). Aworking diagnosis of idiopathic nonischemic cardio-myopathy was considered, and the patient wasmonitored closely.

and Right Ventricular Endomyocardial Biopsy

nance (CMR) imaging: long-axis and short-axis views showing sub

of the left ventricle. In addition, there is hyperenhancement of the

demonstrating diffuse interstitial fibrosis and no evidence of amylo

ed (CR) stain. (F) Amyloid P immunoperoxidase (AMY P) stain.

FOLLOW-UP. At 9-month follow-up, clinical featuresof congestive cardiac failure developed in this pa-tient. Blood investigations showed a cardiac troponinT level of 290 ng/l and an NT-proBNP value of34,888 ng/l. The concentration of serum free lightchains was 1,105 mg/l for the kappa isotype and 6 mg/lfor the lambda isotype. The kappa-to-lambda ratiowas 184.17. Echocardiography revealed a marginalincrease in left ventricular wall thickness (basalseptal thickness of 15 mm) with obvious features ofgrade II left ventricular diastolic dysfunction. RepeatCMR showed a reversed nulling pattern on the time ofinversion scout sequence. Phase-sensitive inversionrecovery late gadolinium enhancement imagingexhibited extensive subendocardial hyperenhance-ment circumferentially, involving both the ventriclesand the left atrial wall, consistent with CA (Figures 2Aand 2B). A subsequent right ventricular endomyo-cardial biopsy confirmed the diagnosis of CA (light-chain [AL]) (Figures 2C to 2F). The amyloid fibrilsstained by Congo red showed apple-green birefrin-gence in polarized light. The immunoperoxidasestudies showed a strong positive labeling for anti-bodies to amyloid P protein and an absence of

epicardial late gadolinium enhancement involving the basal inferior

left atrial and right ventricular free walls. (C to F) Right ventricular

id deposition. (C) Hematoxylin and eosin (H&E) stain. (D) Elastic Van

FIGURE 2 Repeat CMR Imaging and Right Ventricular Endomyocardial Biopsy at 9 Months

(A and B) Cardiac magnetic resonance (CMR) imaging: long-axis and short-axis views illustrating global subendocardial late gadolinium enhancement involving both the

ventricles and the left atrial wall. (C to F) Right ventricular endomyocardial biopsy samples highlighting diffuse amyloid deposition. (C) Hematoxylin and eosin (H&E)

stain. (D) Elastic Van Gieson (VVG) stain. (E) Congo red (CR) stain. (F) Amyloid P immunoperoxidase (AMY P) stain.

J A C C : C A S E R E P O R T S , V O L . - , N O . - , 2 0 2 0 Ananthakrishna et al.- 2 0 2 0 :- –- Cardiac Amyloidosis

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labeling for antibodies to amyloid A protein andATTR. Bone marrow biopsy revealed an increase inplasma cells (15%) consistent with plasma celldyscrasia.

MANAGEMENT

The patient was started on anti–heart failure medi-cations and chemotherapy. She required an implant-able cardioverter-defibrillator for documentedventricular fibrillation. However, the patient had aprogressive downhill course with intractable heartfailure and died 6 months later.

DISCUSSION

CA is usually a progressive disorder resulting in earlymortality secondary to congestive cardiac failure andarrhythmias. Systemic AL amyloidosis and ATTRamyloidosis are the clinically relevant formsof amyloidosis affecting the heart. These 2 forms ofamyloidosis have differing clinical courses, thera-pies, and prognosis. A delay in establishing a diag-nosis is among the factors responsible for poor

outcomes. However, as illustrated by our case, thiscondition, even when suspected, is sometimeschallenging to diagnose. In our case, although effortswere made for an early definitive diagnosis, both theinitial CMR and the first endomyocardial biopsy werenot diagnostic and returned a yield of nonspecificnonischemic cardiomyopathy. However, as is oftentypical of CA of the AL type, the clinical course wasrapidly progressive, and the patient’s disorder waseventually diagnosed 9 months later on the basis ofboth CMR and endomyocardial biopsy. AL amyloid-osis has a poor long-term prognosis in comparisonwith ATTR amyloidosis. The median survival fromthe onset of heart failure in AL amyloidosis is6 months. Therefore, given the high mortality in ALamyloidosis, it is imperative to avoid a misdiagnosisor a delay in establishing the diagnosis. CA isgenerally considered a diffuse myocardial process,but patchy involvement is not uncommon, thusleading to an initial negative endomyocardial biopsyresult (1). The diagnosis of CA on CMR is based onthe characteristic late gadolinium enhancementpattern (global subendocardial or transmural

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hyperenhancement). Native T1 mapping has emergedas a useful CMR parameter in the assessment of pa-tients with suspected CA. In a recent study by Bag-giano et al. (2), the utility of noncontrast CMR (1.5-Tclinical scanner, Aera, Siemens Healthcare, Erlangen,Germany) for the diagnosis of CA was evaluated. Thenative T1 images were acquired using the modifiedLook-Locker inversion recovery sequence. A nativeT1 >1,164 ms was associated with a 98% positivepredictive value for the diagnosis of CA (2). Inaddition, T1 mapping (pre- and post-contrast) canalso be used to estimate the myocardial extracellularvolume (ECV) fraction. The ECV fraction is a surro-gate marker to quantify the burden of CA. CA isassociated with a higher ECV fraction (46.6 � 7.0%)than any other cardiomyopathy because of thewidespread extracellular deposition of amyloid fi-brils (3).

CONCLUSIONS

The diagnosis of CA can be difficult, and CA isoften an underdiagnosed cause of heart failure.The diagnosis cannot be solely based on a singleimaging modality; rather, a multiparametric assess-ment (biomarkers, imaging, and tissue biopsy) isnecessary for an early and prompt diagnosis. In theappropriate clinical setting (history of MGUS andcarpal tunnel syndrome), as highlighted, close moni-toring and imaging surveillance are recommendedeven when the initial biopsy and CMR results are notpathognomonic for CA.

ADDRESS FOR CORRESPONDENCE: Dr. Rajiv Anan-thakrishna, Department of Cardiovascular Medicine, Flin-ders Medical Centre, Flinders Drive, Bedford Park,Adelaide, Australia 5042. E-mail: rajiva.ms@gmail.com.

RE F E RENCE S

1. George JC, Katrapati P, Fang J. An unusual caseof biopsy-negative amyloid cardiomyopathy.Congest Heart Fail 2010;16:39–41.

2. Baggiano A, Boldrini M, Martinez-Naharro A,et al. Noncontrast magnetic resonance for thediagnosis of cardiac amyloidosis. J Am Coll

Cardiol Img 2019 Jun 7 [E-pub ahead ofprint].

3. Sado DM, Flett AS, Banypersad SM, et al. Car-diovascular magnetic resonance measurement ofmyocardial extracellular volume in health anddisease. Heart 2012;98:1436–41.

KEY WORDS amyloidosis, biopsy, cardiacmagnetic resonance