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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 Withan Initial Negative 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. We present 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;2:282–5)

© 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 Ce

lecular Medicine (Haematology and Molecular Genetics), Flinders Univer

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

ormed consent was obtained for this case.

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 cardiactroponin T level of 36 ng/l (normal: <30 ng/l) and anN-terminal pro-B-type natriuretic peptide (NT-proBNP) value of 1,015 ng/l (normal: <125 ng/l). Theconcentration of serum free light chains was 985 mg/lfor the kappa isotype (normal: 3 to 19 mg/l) and10 mg/l for the lambda isotype (normal: 6 to 26 mg/l).The kappa-to-lambda ratio was 98.5 (normal: 0.26 to1.65). Although kappa light chains were elevated,they had been stable over the past 6 years, withnormal renal function and serum calcium values. Acomprehensive work-up for multiple myeloma wasnegative. A bone marrow biopsy was consistent withMGUS (plasmacytosis of 9%). A rectal biopsy showedno deposits of amyloid. Echocardiographic evaluationrevealed a mild increase in left ventricular wallthickness (involving the basal inferior and basalinferolateral walls; maximum thickness of 13 mm)

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

ntre, Adelaide, Australia; and the bDepartment of

sity, Adelaide, Australia. The authors have reported

close.

1, 2019, accepted November 2, 2019.

AB BR E V I A T I O N S

AND ACRONYM S

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

J A C C : C A S E R E P O R T S , V O L . 2 , N O . 2 , 2 0 2 0 Ananthakrishna et al.F E B R U A R Y 2 0 2 0 : 2 8 2 – 5 Cardiac Amyloidosis

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with normal left ventricular function. Cardiac mag-netic resonance (CMR) confirmed the increased wallthickness, and the time of inversion scout sequenceshowed a normal pattern of myocardial nulling.Phase-sensitive inversion recovery late gadoliniumenhancement imaging demonstrated subepicardialhyperenhancement in the basal inferior and infero-lateral segments. In addition, there was hyper-enhancement of the left atrial and right ventricularfree walls (Figures 1A and 1B). The CMR features raisedthe suspicion of CA. A right ventricular endomyo-cardial biopsy (6 samples from the region of the rightventricular septum) showed diffuse interstitialfibrosis with no evidence of amyloid deposition(Figures 1C to 1F). The Congo red–stained biopsysamples did not demonstrate apple-green birefrin-gence on polarized microscopy. The immunoperox-idase studies showed lack of positive labeling withantibodies to amyloid A protein, amyloid P protein,and transthyretin (ATTR). A working diagnosis ofidiopathic nonischemic cardiomyopathy was consid-ered, and the patient was monitored closely.FOLLOW-UP. At 9-month follow-up, clinical featuresof congestive cardiac failure developed in this

FIGURE 1 Initial CMR Imaging and Right Ventricular Endomyocardia

(A and B) Cardiac magnetic resonance (CMR) imaging: long-axis and sho

and basal inferolateral segments of the left ventricle. In addition, there is

endomyocardial biopsy samples demonstrating diffuse interstitial fibrosis

Gieson (VVG) stain. (E) Congo red (CR) stain. (F) Amyloid P immunoper

patient. Blood investigations showed a car-diac troponin T level of 290 ng/l and an NT-proBNP value of 34,888 ng/l. The concentra-tion of serum free light chains was 1,105 mg/lfor the kappa isotype and 6 mg/l for thelambda isotype. The kappa-to-lambda ratiowas 184.17. Echocardiography revealed amarginal increase in left ventricular wallthickness (basal septal thickness of 15 mm)with obvious features of grade II left ven-tricular diastolic dysfunction. Repeat CMRshowed a reversed nulling pattern on thetime of inversion scout sequence. Phase-sensitive inversion recovery late gadolinium

enhancement imaging exhibited extensive sub-endocardial hyperenhancement circumferentially,involving both the ventricles and the left atrial wall,consistent with CA (Figures 2A and 2B). A subsequentright ventricular endomyocardial biopsy confirmedthe diagnosis of CA (light-chain [AL]) (Figures 2C to 2F).The amyloid fibrils stained by Congo red showedapple-green birefringence in polarized light. Theimmunoperoxidase studies showed a strong positivelabeling for antibodies to amyloid P protein and an

l Biopsy

rt-axis views showing subepicardial late gadolinium enhancement involving the basal inferior

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

and no evidence of amyloid deposition. (C) Hematoxylin and eosin (H&E) stain. (D) Elastic Van

oxidase (AMY P) stain.

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.

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

Cardiac Amyloidosis F E B R U A R Y 2 0 2 0 : 2 8 2 – 5

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absence of labeling for antibodies to amyloid A proteinand ATTR. Bonemarrow 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

J A C C : C A S E R E P O R T S , V O L . 2 , N O . 2 , 2 0 2 0 Ananthakrishna et al.F E B R U A R Y 2 0 2 0 : 2 8 2 – 5 Cardiac Amyloidosis

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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 5042, Australia. 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 CardiolImg 2020;13:69–80.

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