REVIEW Cardiac amyloidosis: from clinical suspicion to morphological diagnosis PAVLA FLODROVA 1 ,PATRIK FLODR 1 ,TOMAS PIKA 2 ,JIRI VYMETAL 3 , DUSAN HOLUB 4 ,PETR DZUBAK 4 ,MARIAN HAJDUCH 4 ,VLASTIMIL SCUDLA 2 1 Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic; 2 Department of Hemato-Oncology, University Hospital Olomouc, Olomouc, Czech Republic; 3 Department of Internal Medicine III – Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Olomouc, Czech Republic; 4 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic Summary Amyloidosis is a heterogeneous group of diseases charac- terised by extracellular accumulation of amyloid in various tissues and organs of the body, leading to alteration and destruction of tissues. Heart involvement is the most important prognostic factor in patients with systemic amyloidosis and the diagnosis and typing of amyloid must be made properly. The clinical picture shows congestive heart failure with predominant right-sided heart failure symptoms in fully developed disease, various types of arrhythmias and characteristic electrocardiography and echocardiography findings. Blood and urine monoclonal protein studies and cardiac biomarkers belong to the spectrum of standard lab- oratory examinations. Cardiac cardiomyopathy is connected with amyloid based on immunoglobulin light chains, serum amyloid A, transthyretin, atrial natriuretic factor or apolipoprotein A1. In the routine diagnostic algorithm, biopsy specimens are examined using special histological staining, immunohistochemistry and immunofluorescence; proteomic analysis is only performed in specialised centres. Key words: Amyloidosis; immunoglobulin light chains; transthyretin; AL amyloid; AA amyloid; echocardiography. Received 30 March, revised 8 August, accepted 16 October 2017 Available online: xxx INTRODUCTION Amyloidosis is a heterogeneous group of diseases charac- terised by extracellular accumulation of amyloid in various tissues and organs of the body, which leads to alteration and eventually destruction of tissues with impairment of organ function or even organ failure. Amyloid is defined as an insoluble or poorly soluble complex deposit composed of a principal proteinaceous part and other substances. The pro- teinaceous component is subtype-specific and is formed by normally soluble monomeric proteins, which are turned into a pathological fibrillar form due to gene mutation, production of a clonal B-cell neoplastic population, inherent instability of a wild-type protein, overproduction of the normal protein with reduced stability and an increased propensity to misfold. 1 The fibrillar form, amyloid fibrils, contains a high proportion of cross-b-sheet in the secondary conformation and is stabilised by intra- and intermolecular interactions. Besides others, these properties result in resistance to proteolytic degradation. Amyloid fibrils are rigid, non-branching fibrils with a diameter of approximately 10 nm. 2 The co-precipitated mol- ecules carry various chemical compounds, in particular pro- teoglycans, glycosaminoglycans and lipoproteins. The most frequent additional substances in amyloid are serum amyloid P component, apolipoprotein E, apolipoprotein A1 and apoli- poprotein A4. 3 – 6 According to the extent of involvement, amyloid disease may be systemic or localised; other classifications are based on heredity (acquired/inherited) or amyloidogenic proteins. The 2014 nomenclature of amyloid fibril proteins defines 31 known extracellular fibril proteins in humans. 2 THE ROLE OF ENDOMYOCARDIAL BIOPSY IN THE DIAGNOSIS OF AMYLOIDOSIS Endomyocardial biopsy (EMB) is an invasive diagnostic method usually performed by experienced teams in specialised medical centres to ensure a low rate of overall complications, ranging from 1% to 2%. 7 The technique of non-surgical car- diac biopsy was developed in dogs in the late 1950s using a transthoracic approach, which was superseded by the use of flexible catheter-tip biopsy forceps in the 1960s. 8 EMB is indicated for evaluation of specific heart involvement in a narrow spectrum of cases, for example in monitoring after cardiac transplantation, in patients with suspected myocarditis, cardiomyopathy, drug toxicity or in systemic conditions where heart disease is presumed such as various storage diseases (lipidosis, glycogen storage dis- eases and amyloidosis). Adequate biopsy sampling is necessary for an accurate diagnosis and multiple specimens of myocardial tissue of sufficient sizes are required, with a recommended diameter of 1 – 2 mm. 7 Recommendations for the number of biopsy sam- ples can be found in the Association for European Cardio- vascular Pathology guidelines. 9 Another three, or preferably four, formalin fixed tissue specimens and one or two snap- frozen or RNAlater treated tissue samples (tissue treated with RNA-preserving solution to prevent damage of RNA) should Print ISSN 0031-3025/Online ISSN 1465-3931 © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved. DOI: https://doi.org/10.1016/j.pathol.2017.10.012 Pathology (- 2018) -(-), pp. 1 – 8 Please cite this article in press as: Flodrova P, et al., Cardiac amyloidosis: from clinical suspicion to morphological diagnosis, Pathology (2018), https:// doi.org/10.1016/j.pathol.2017.10.012