Restrictive amyloid heart - the amyloidogenic proteins drive specific therapeutic choices 

Different proteins sharing the property of conforming as antiparallel -sheets may conform in insoluble amyloid fibrils that deposit in interstitium of organs/tissues and cause systemic amyloidosis. Cardiac involvement in systemic amyloidoses is frequent and constitutes a major predictor of poor outcome. The typical phenotype is that of restrictive cardiomyopathy.
The biochemical classification of amyloidogenic proteins drives different diagnostic and therapeutic work-ups.

In primary systemic amyloidosis (AL), the amyloidogenic protein is an abnormally conformed monoclonal immunoglobulin light chains (k or l) produced by clonal plasma cells. Fibrils deposite in kidneys, heart, liver, and other organs/tissues. Chemotherapy may reduce or even eradicate the amyloidogenic clone with consequent functional improvement of the affected organs. The key of success is early diagnosis. Heart transplantation with autologous stem cell transplantation is a potential option in patients younger than 60.

In the non-senile, autosomal dominant Transthyretin Amyloidosis (ATTR), amyloid fibrils are constituted of defective proteins synthesized by the mutated TTR allele (more than 70 known mutations, with different genotype-phenotype correlations). The treatment is based on transplantation of the TTR-producing liver; exceptionally, liver plus heart or kidney are transplanted. The severity of autonomic nervous system involvement is a key point for transplant decision.

In the autosomal dominant amyloidosis caused by ApoA1-apolipoprotein defects, the amyloid seems to deposits in the myocardial tissue at a low rate. Patients may successfully undergo transplantation of the most impaired organs, usually heart, liver or kidney, either single or combined.

In SAA-amyloidosis, the amyloidogenic protein is the acute-phase Serum Amyloid A protein that is produced in excess in chronic inflammatory diseases such as chronic infections, autoimmune disorders and familial mediterranean fever. Heart is rarely affected. The strategy is to treat underlying diseases. Trials with new molecules inhibiting amyloid formation and promoting amyloid resorption are in progress.

In dialysis-related amyloidosis caused by beta-2-microglobulin heart is not involved.

Diagnosis of the type of amyloidosis

• ApoA1- and TTR-amlyoidosis: positive family history, immunocharacterization of the amyloid fibrils in a tissue biopsy, gene defect detection and absence of light chains in serum and urines. In case of presence of light chains in urine or serum (about 10% of the population over 60ies) immunotyping of fibril is mandatory.
• Non-familial primary amyloidoses: k or l light chains identified with immunofixation in serum or urines, and tissue immunocharacterization of the amyloid protein.
• SAA amyloidosis: negative search for light chains, underlying inflammatory disease, positive immunostain with anti-SAA antibodies.

Diagnosis of amyloid cardiomyopathy

Heart involvement is diagnosed with a multiparametric approach that includes clinical, electrocardiographic and echocardiographic evaluation. Typically, the left ventricular thickness is increased and electrocardiographic voltages are decreased (echo-ECG mismatch).
Tissue diagnosis

The fine-needle biopsy of periumbelical fat is a preferral procedure for amyloid detection and immunochararcterization of amyloid protein. This approach excludes, with a few exceptions, the need of endomyocardial biopsy.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

1. Westermark P, Araki S, Benson MD, Cohen AS, Frangione B, Masters CL et al. Nomenclature of amyloid fibril proteins. Report from the meeting of the International Nomenclature Committee on Amyloidosis, August 8-9, 1998. Part 1. Amyloid 1999; 6:63-6.
2. Dubrey SW, Cha L, Anderson J, Chamarthi B, resinger J, Skinner M, Falk RH. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. Q J Med. 1998; 91: 141–157.
3. Obici L, Anesi E, Palladini G, Perfetti V, Arbustini E, Merlini G. Therapeutic advances demand better typing of amyloid deposits. Am J Med 2001; 111:243-4.