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Amyloid, 2012; 19(2): 106–109© 2012 Informa UK, Ltd.ISSN 1350-6129 print/ISSN 1744-2818 onlineDOI: 10.3109/13506129.2012.660892

The main determinant of survival in amyloid light chain amyloidosis is cardiac involvement. The rate of change in wall thickness may be a strong predictor of survival. After treatment, some hematologic responders have had documented regression of wall thickness by echocardiography with resolution of heart failure symptoms. Herein, we demonstrate a case of treated immunoglobulin light chain cardiac amyloidosis with echocardiographic wall thinning and cardiac biopsies demonstrating complete histologic remission. This observation suggests a mechanism of treatment response and that with appropriately timed treatment, cardiac deposition of amyloid fibrils can be completely reversed.

Keywords: Biopsy, cardiac amyloid, histologic regression, echocardiography

Abbreviations: AL, amyloid light chain, FLC, free light chain

Introduction

The main prognostic determinant of survival in amyloid light chain (AL) amyloidosis is cardiac involvement [1]. Median survival from the time of diagnosis is 11 months [2] and 6 months if symptomatic heart failure is present [3]. The degree of wall thickness is felt to be due to the burden of amyloid fibril deposition within the intercellular spaces of the myocar-dium [4]. Amyloid fibrils in AL amyloidosis are hypothesized to have a direct toxic effect on the myocardial cells as those with senile amyloidosis (wild type) have thicker walls as com-pared to AL amyloidosis patients, but better outcomes [2]. The rate of change in wall thickness may be a strong predictor of survival [5]. Some hematologic responders have had docu-mented regression of wall thickness by echocardiography with resolution of heart failure symptoms [1,6–9].

Case

A 62-year-old Caucasian male presented with dyspnea with exertion. His history was significant for a recent biopsy con-firmed diagnosis of κ light chain positive AL amyloidosis of the kidney for which he underwent a 5 month course of tha-lidomide and dexamethasone at another institution. On our initial evaluation, his β-natriuretic peptide was 1050 pg/ml, and troponin-T 0.13 ng/ml. His electrocardiogram demon-strated low voltage in the limb leads (Figure 1). An echocar-diogram demonstrated a granular appearing left ventricular myocardium with increased thickness of the septal wall (17 mm), posterior wall (16 mm) and right ventricular free wall (9 mm) (Figure 2). An endomyocardial biopsy revealed pri-mary amyloidosis (AL type, κ immunoglobulin light chain positive) (Figure 3) with moderate interstitial deposits. This endomyocardial biopsy consisted of six 2–5 mm in diameter biopsy fragments obtained with a 7-French, 105 mm St. Jude bioptome. Three of six fragments were involved by amyloid as demonstrated in positive Congo red and positive sulfated Alcian Blue stains. Immunophenotyping of the amyloid deposits was accomplished by the immunohistochemical method; no further amyloid testing was performed.

He received three cycles of IV melphalan and dexametha-sone with subsequent clinical stabilization of the amyloido-sis. Pretreatment κ free light chains (FLCs) were 9.02 mg/dl (normal range: 0.33–1.94 mg/dl), λ FLCs were 2.95 mg/dl (normal range: 0.57–2.63 mg/dl) with a κ/λ (FLC) ratio of 3.06 (normal range: 0.26–1.65). The post treatment FLC ratio was improved at 2.67 with κ of 15.9 mg/dl.

Two years later, due to a rising free κ light chain (52.7 mg/dl) and FLC ratio (2.99), he underwent four cycles of cyclo-phosphamide, bortezomib and dexamethasone with resultant drop in the free κ light chain (12.9 mg/dl) and normalization

CASE REPORT

Histologic remission of cardiac amyloidosis: a case report

Matthew R. Nelson1, Louis A. Lanza2, Craig B. Reeder3, Robert L. Scott1, Ann E. McCullough4, Krishnaswamy Chandrasekaran1 & Roger L. Click5

1Division of Cardiovascular Diseases, Mayo Clinic Scottsdale, Arizona, USA, 2Division of Cardiothoracic Surgery, Mayo Clinic Scottsdale, Arizona, USA, 3Division of Hematology/Oncology, Mayo Clinic Scottsdale, Arizona, USA, 4Division of Pathology Mayo Clinic Scottsdale, Arizona, USA, and 5Division of Cardiovascular Diseases, Mayo Clinic Rochester, Minnesota, USA

Correspondence: Dr. Roger Click, MD, Ph.D., Division of Cardiovascular Diseases, Mayo Clinic, 201 W. Center St., Rochester, MN 55902, USA. E-mail: click.roger@mayo.edu(Accepted January 2012)

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Figure 1. ECG prior to treatment demonstrating low voltage in the limb leads. Other findings include sinus bradycardia (56 beats per minute), right bundle branch block and left anterior fascicular block.

Figure 2. Echocardiogram views of our patient prior to treatment. Top left is the parasternal long axis view with septal thickness 17 mm, and pos-terior wall thickness of 16 mm. Top right is the parasternal short axis, bottom left is the four chamber apical view, and bottom left is the long axis apical view.

Figure 3. Sulfated alcian blue stain (left), Congo red stain (right) from an endomyocardial biopsy of the right ventricle in 2006. Both images (mag-nification × 400) demonstrate the presence of amyloid deposits. The right image shows birefringent red/green material primarily in the interstitium under polarized light microscopy.

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of the FLC ratio to 1.3. The patient underwent a follow-up echocardiogram one year following treatment that demon-strated a marked reduction of left ventricular wall thickness (Figure 4). Wall thickness remained above the upper limits of normal for his age and gender due to the presence of mod-erately-severe aortic stenosis. The FLC ratio remained in the normal range for the next 2 years.

Two years after completing treatment, the patient unfor-tunately developed aortic valve endocarditis due to an infected dialysis catheter and he underwent an aortic valve replacement with a bioprosthesis. Multiple myocardial biop-sies (Figure  5) obtained intra-operatively demonstrated an absence of amyloid in the right and left ventricles by sulfated Alcian blue and Congo red stains. These intra-operative myocardial biopsies were generous needle biopsies from both ventricles: one Trucut needle biopsy, 15 mm in length and 1.5 mm in diameter, from the acute margin of the heart in the right ventricle, and two Trucut needle biopsies, each measuring 25 mm in length and 1.5 mm in diameter from

the left ventricular anterolateral wall. The previous diagnostic right ventricular endomyocardial biopsy and the subsequent intra-operative negative biventricular needle biopsies were processed and stained in the same laboratory using identi-cal histological procedures. The FLC ratio at the time of the intra-operative cardiac biopsies was still within the normal range.

Discussion

The salient feature of this case is the regression of wall thick-ness and the post treatment biopsy demonstrating histologic remission of amyloid deposition. Post treatment amyloid regression has been documented by serum amyloid P scin-tigraphy imaging and has been described in the liver and spleen [10]. However, in patients with cardiac amyloidosis, regression of ventricular wall thickness has been attrib-uted to remission without any histologic evidence. To our knowledge, this case for the first time, demonstrated that

Figure 4. Post treatment echocardiogram of our patient 4 years after diagnosis. Top left image of the parasternal long axis view showed a septal thickness of 13 mm and a posterior wall thickness of 12 mm. Top right is the parasternal short axis view, bottom left is the apical four chamber view and bottom right is the apical long axis view.

Figure 5. Sulfated alcian blue stain (left), Congo red stain (right) from an intra-operative myocardial biopsy in 2011. Both images (magnification × 400) demonstrate absence of amyloid deposition. The right image shows no birefringent material under polarized light microscopy. The pale white slightly refractile materials are collagen fibers.

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regression of wall thickness is due to histologic absence of cardiac amyloid fibrils after therapy. This observation sug-gests that during the disease process a gradient in favor of cardiac deposition of amyloid fibrils exists and this gradient is reversed in hematologic responders leading to the degra-dation and removal of protein deposits from the myocardial intercellular spaces. This reduction in amyloid deposition, we hypothesize, is demonstrated by a reduction of wall thickness on echocardiography.

The regression of cardiac wall thickening, documented by echocardiography, does occur in hematologic respond-ers and indicates a favorable response to treatment. A sur-vival advantage occurred in AL amyloid patients treated with melphalan and stem cell transplantation if arrested or slowed progression of myocardial wall thickness was observed [5]. The regression of wall thickening in AL amyloidosis, however, is not a common event in hemato-logic responders regardless of therapy type. An objective reduction in echocardiographic determined wall thickness occurred in only 2/90 patients randomized to a melphalan based regimen [11]. Two reports of a melphalan and stem cell transplantation regimen demonstrated that 1/8 patients [6] and 10/137 [7] patients with cardiac involvement had a ≥ 2 mm reduction in septal wall thickness. In patients unable to undergo stem cell transplantation treated with melphalan and high-dose dexamethasone, 6/32 with cardiac involve-ment underwent a ≥2 mm decrease in septal wall thickness with resolution of their heart failure symptoms [8]. More recently in patients treated with Bortezomib ± dexametha-sone, 20/69 had improvement in heart failure symptoms and/or a decrease in wall thickness [9].

In our case, the post treatment biopsy showing the absence of amyloid deposition demonstrates that the depo-sition of amyloid fibrils is completely reversible in hemato-logic responders. The aforementioned reports indicate that all those with a decreased wall thickness were hematologic responders but not all those with a hematologic response decreased their wall thickness. Further evaluation of demo-graphic and clinical characteristics of those who have a response to treatment with reduction in cardiac wall thick-ness is warranted.

Acknowledgements

The authors would like to thank Dr. Alan S. Cohen, Professor of Medicine at Boston University School of Medicine, for his critical appraisal of the manuscript.

Declaration of Interest: The authors report no conflicts of interest.

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8. Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, et al. Association of melphalan and high-dose dexa-methasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 2004;103:2936–2938.

9. Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 2010;28:1031–1037.

10. Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 2007;109:457–464.

11. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: col-chicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997;336:1202–1207.A

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