Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature

Abstract

Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. This has however dramatically improved in the last few years with the increased usage of the novel therapies such as proteasome inhibitors and haematopoietic cell transplantation, in the case of timely diagnosis and initiation of treatment. The treatment for AL is directed by the haematologist working closely with the cardiologist when there is a significant cardiac involvement. Transthyretin (TTR) is a protein that is produced by the liver and is involved in the transportation of thyroid hormones, especially thyroxine and retinol binding protein. ATTR results from the accumulation of transthyretin amyloid in the extracellular space of different organs and systems, especially the heart and the nervous system. Specific therapies for ATTR act at various levels of TTR, from synthesis to deposition: TTR tetramer stabilization, oligomer aggregation inhibition, genetic therapy, amyloid fibre degradation, antiserum amyloid P antibodies, and antiserum TTR antibodies. Treatment of systemic amyloidosis has dramatically evolved over the last few years in both AL and ATTR, improving disease prognosis. Moreover, recent studies revealed that timely treatment can lead to an improvement in clinical status and in a regression of amyloid myocardial infiltration showed by imaging, especially by cardiac magnetic resonance, in both AL and ATTR. However, treating cardiac amyloidosis is a complex task due to the frequent association between systemic congestion and low blood pressure, thrombo-embolic and haemorrhagic risk balance, patient frailty, and generally poor prognosis. The aim of this review is to describe the current state of knowledge regarding cardiac amyloidosis therapy in this constantly evolving field, classified as treatment of the cardiac complications of amyloidosis (heart failure, rhythm and conduction disturbances, and thrombo-embolic risk) and the disease-modifying therapy.

Keywords: Cardiac amyloidosis; Heart failure; Light chain; Systemic amyloidosis; Therapy; Transthyretin.

Figure 1

Diagnostic algorithm leading from the clinical suspicion for CA to the final diagnosis. *Except in genotype positive/phenotype negative mutant ATTR relatives or specific mutations with known low myocardial uptake like TTR Phe64Leu. FLC, free light chain; MGUS, monoclonal gammapathy of unknown significance. For all other abbreviations, see text. Reproduced with permission from Jurcut et al.

Figure 2

Amyloidosis pathophysiology and therapeutic implications. For abbreviations, see text.

Figure 3

Cardiac amyloidosis therapeutic options. ACEi, angiotensin‐converting enzyme inhibitor; ASO, antisense oligonucleotide; ATTR, transthyretin amyloidosis; BB, beta‐blocker; DOAC, direct anticoagulant; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; TTR, transthyretin; TUDCA, tauroursodeoxycholic acid; VKA, vitamin K antagonist.