International Journal of Cardiology 177 (2014) e87–e89

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Letter to the Editor

Non-invasive imaging for cardiac amyloidosis — Delaying the obvious? Ashley Brogan c, Yanli Ding d, David R. Pimentel a,b, Flora Sam a,b,⁎ a

Cardiovascular Section and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, United States Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, United States c Evans Department of Internal Medicine, Boston University School of Medicine, Boston, MA, United States d Boston University Medical Campus Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, United States b

a r t i c l e

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Article history: Received 1 October 2014 Accepted 4 October 2014 Available online 13 October 2014 Keywords: Light chain Transthyretin Cardiac amyloidosis Heart failure

An 81 year old Hispanic man with a prior history of hypertension, atrial fibrillation, and heart failure (HF) with preserved ejection fraction presented to his cardiologist for followup after multiple hospitalizations for presyncope, COPD exacerbation and acute HF. He reported worsening pedal edema and dyspnea on exertion. On presentation, he was afebrile, heart rate was 90 bpm and blood pressure was 113/ 69 mm Hg. Oxygen saturation was 99% on room air. Physical examination was significant for lethargy and dyspnea upon standing. He had an elevated JVD, S3 gallop, II/VI systolic murmur at the left lower sternal border, cool extremities, ascites and bilateral leg edema. He was directly admitted to the Cardiomyopathy Service for further management. Two years prior to this index admission, he was admitted for suspected HF and an echocardiogram showed an LVEF of 65% and mild LVH. He was diuresed and discharged with outpatient followup. He remained out of the hospital for a year when he began to have recurrent hospitalizations for HF and hypotension. Furthermore, he developed atrial fibrillation. A repeat echocardiogram showed a slight decrease in LVEF from 65% to 55% and moderate LVH (Table 1). Admission laboratory results showed elevated creatinine, BNP, and Troponin I (Table 1). ECG revealed left axis deviation, inferior Q waves, poor R wave progression with a pseudo-infarction pattern, and low voltage in the limb leads. CXR was significant for bilateral pleural ⁎ Corresponding author at: Whitaker Cardiovascular Institute, Boston University School of Medicine, Evans Department of Medicine and Cardiovascular Section, 715 Albany Street, Room W507, Boston, MA 02118, United States. Tel.: +1 617 638 8072; fax: +1 617 638 4066. E-mail address: fl[email protected] (F. Sam). 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

effusions. Given his symptoms and echocardiography findings, amyloidosis was suspected. Serum immunofixation electrophoresis detected a kappa level of 999 mg/dl (574–1276) and an elevated lambda level of 655 mg/dl (269–638) with a kappa/lambda ratio 1.5. Urine immunofixation electrophoresis detected monoclonal free lambda protein with a total protein of b 60 mg/l. A fat pad biopsy was obtained which was highly positive for Congo red staining and immune gold testing was positive for the amyloid fibrils, lambda light chain (AL) immunoglobulins. There was no labeling observed for secondary (AA) or transthyretin (ATTR) and serum variant ATTR screening was negative. This was consistent with lambda positive AL amyloidosis. As worsening renal function precluded a cardiac magnetic resonance (CMR), a 99m technetium (Tc)-pyrophosphate scan was performed to differentiate between ATTR and AL amyloidosis. This showed increased uptake of the radiotracer in the heart compared to the chest at a ratio of 1.67, implying ATTR amyloidosis [1,2] (Fig. 1A). However, given the light chains detected in serum and urine, a bone marrow biopsy was performed which showed 60% cellularity. Immunohistochemistry (IHC) studies demonstrated CD138 staining of aggregated plasma cells (approximately 15% of cellularity) with a predominance for lambda AL immunoglobulin staining consistent with a plasma cell dyscrasia (Fig. 1B) and AL amyloid. Given these discordant findings, an endomyocardial biopsy was then performed showing Congo red staining of the myocardium with amyloid confined to the blood vessels without interstitial involvement (Fig. 1C and D). Electron microscopy (EM) was also consistent with amyloid. However, IHC assessment was untenable given the lack of amyloid present in the myocardial tissue sections. This case explores the challenges of differentiating the multiple forms of cardiac amyloidosis. ATTRwt cardiac amyloidosis (also known as senile systemic amyloidosis or age-related amyloidosis) was thought most likely, given the patient's age and persistent HF symptoms of 2 years. However, his echocardiogram did not reveal marked LVH, which is a common finding with ATTRwt [3,4]. Clinically, it was unlikely that he had either AA amyloidosis, which rarely affects the myocardium, or ATTRm, which typically occurs in younger individuals and oftentimes presents with peripheral and/or autonomic neuropathy followed by amyloid cardiomyopathy. Given the diagnostic complexity, there has been a surge of noninvasive imaging to help further differentiate the cardiac amyloidoses. Although the late gadolinium patterns seen with CMR have been reported to aid in the discrimination of the subtypes [5], our patient was unable to undergo this imaging modality given his worsening renal


A. Brogan et al. / International Journal of Cardiology 177 (2014) e87–e89

Table 1 (A) Admission laboratory results and (B) echocardiographic measurements. A. Laboratory test


Reference range

Hematocrit (%) Sodium (mmol/l) Potassium (mmol/l) BUN (mg/dl) Creatinine (mg/dl) Calcium (mg/dl) Alanine aminotransferase — ALT (U/L) Aspartate aminotransferase — AST (U/L) Alkaline phosphatase (U/L) Albumin (g/dl) Total Protein (g/dl) INR Creatine phosphokinase — CK (U/L) CK-MB (ng/ml) Troponin I (ng/ml) Brain natriuretic peptide (pg/ml)

44.3 149 3.6 40 1.31 9.9 98 63 143 3.3 6.6 2.59 27 2.6 0.457 1633

40.0–51.0 135–145 3.1–5.3 7.0–25 0.7–1.3 8.0–10.5 9.0–67.0 13–39 25–100 3.5–5.0 6.8–8.6 0.83–1.2 39–193 0.6–3.5 b0.033 0–176

B. Echocardiogram Left atrium (mm) Interventricular septum wall thickness (mm) LV posterior wall thickness (mm) LV end diastolic diameter (mm) LV end systolic diameter (mm) Fractional Shortening (%) LV ejection fraction (%) LV mass (gm) LV mass index (gm/m2)

35 15 12 32 27 16 55 144.21 82.41

b45 (7–11) (6–11) b 57 (21–40)

67–162 b130

function. The use of 99mTc-pyrophosphate to differentiate AL from ATTR using both semi-quantitative and quantitative methods has recently been described as well [1]. ATTR patients had a higher semi-quantitative visual score and quantitative score (97% sensitivity and 100% specificity) vs. AL amyloidosis patients [1]. Using these criteria, our patient had radionuclide

imaging suggestive of ATTR amyloid; however, his biomarkers, fat pad and bone marrow biopsy indicated AL amyloid. We believe that this is the first case, using these criteria, to demonstrate that significant 99mTcpyrophosphate tracer uptake can also occur in AL patients. Our finding is in keeping with Rappezi and colleagues who demonstrated that 99m technetium-dicarboxypropane diphosphonate, another calcium tracer, may aid in the diagnosis of cardiac ATTR, yet still results in cardiac uptake in nearly a third of AL patients [6]. This group proposed that higher calcium deposition in the myocardium resulted in serum hypocalcemia. However, unlike Rappezzi's cohort [6], our patient had normal serum calcium suggesting that this mechanism likely does not occur. AL amyloidosis is often associated with hypoalbuminemia and heavy proteinuria. This leads to hypocalcemia, which may be a marker of late disease, in most AL patients. However, despite normocalcemia, our patient had hypoalbuminemia. As hypothesized by Falk and colleagues [7], hypoalbuminemia may allow altered tracer dynamics and higher isotope availability for the myocardium leading to a false positive. Other false positive cases will need to be reported to help determine the importance of these parameters. Of course, a remote possibility also exists that these patients are afflicted with both ATTRwt and AL; as dual deposition of ATTRm and AL have been reported in non-cardiac tissue [8]. Unfortunately, no amyloid protein was present in the myocardium itself to definitively demonstrate a specific isotype in our patient. In conclusion, we present a case of a patient afflicted with AL cardiac amyloidosis with positive cardiac 99mTc-pyrophosphate imaging. This highlights the challenge in differentiating the forms of amyloid and in particular the difficulty of diagnosing ATTRwt.

Conflict of interest The authors report no relationships that could be construed as a conflict of interest.





Fig. 1. (A.) 99mTc-pyrophosphate scan demonstrating marked uptake in the heart of our patient. (B.) Bone marrow: CD138 stain of bone marrow showing plasma cells (black arrow) — 100× magnification. Right ventricle endomyocardial biopsy (light microscope): (C.) H&E stain and (D.) Congo red stain showing amyloid deposit in a blood vessel (white arrow) — 200× magnification for both.

A. Brogan et al. / International Journal of Cardiology 177 (2014) e87–e89

Acknowledgments None. References [1] Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. 99mTcpyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6(2):195–201. [2] Bokhari S, Shahzad R, Castaño A, Maurer M. Nuclear imaging modalities for cardiac amyloidosis. J Nucl Cardiol 2014;21(1):175–84. [3] Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 2005;165(12):1425–9.


[4] Biolo A, Ramamurthy S, Connors LH, et al. Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail 2008;1(4):249–57. [5] Kwong RY, Jerosch-Herold M. CMR and amyloid cardiomyopathy: are we getting closer to the biology? JACC Cardiovasc Imaging 2014;7(2):166–8. [6] Rapezzi C, Quarta C, Guidalotti P, et al. Usefulness and limitations of 99mTc-3,3diphosphono-1,2-propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;38(3):470–8. [7] Falk R, Dorbala S. Pursuing an underdiagnosed disease: a simple imaging test for increasing suspicion of cardiac amyloidosis. Eur J Nucl Med Mol Imaging 2011;38(3): 467–9. [8] Bergström J, Patrosso MC, Colussi G, et al. A novel type of familial transthyretin amyloidosis, ATTR Asn124Ser, with co-localization of kappa light chains. Amyloid 2007; 14(2):141–5.

Non-invasive imaging for cardiac amyloidosis - delaying the obvious?

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