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.

Anticoagulation in cardiomyopathy: unravelling the hidden threat and challenging the threat individually

“…However, anticoagulation with either VKA or NOACs can usually be safely prescribed to CA patients. 96 , 97 The American Heart Association (AHA) recommends anticoagulation (warfarin therapy with a target international normalized ratio of 2 to 3 or direct thrombin inhibitors) for CA patients with concomitant AF or history of thromboembolic stroke/TIA (transient ischaemic attack) in terms of a class I recommendation due to the high risk of intracardiac clot formation, even in the presence of sinus rhythm as both atria often present as ‘standstill’ secondary to amyloid infiltration. 15 , 94 On an empirical basis, anticoagulation is also recommended in patients with demonstrable atrial or ventricular clot.…”

“…However, the potential benefit of anticoagulant therapy has to be carefully weighed up against the increased risk of major haemorrhage in patients with vasculopathy secondary to amyloid deposition. However, anticoagulation with either VKA or NOACs can usually be safely prescribed to CA patients 96,97 . The American Heart Association (AHA) recommends anticoagulation (warfarin therapy with a target international normalized ratio of 2 to 3 or direct thrombin inhibitors) for CA patients with concomitant AF or history of thromboembolic stroke/TIA (transient ischaemic attack) in terms of a class I recommendation due to the high risk of intracardiac clot formation, even in the presence of sinus rhythm as both atria often present as ‘standstill’ secondary to amyloid infiltration 15,94 .…”

Cardiac Amyloidosis Treatment

“…Here we provide an overview of novel and experimental treatment strategies for the predominant types of CA, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA, or AL-CA ( Figure 1 , Table 1 ). 1 , 2 …”

“… Targets of treatment along the light chain and transthyretin amyloidogenic pathway. Reproduced with permission from @John Wiley & Sons Ltd on behalf of European Society of Cardiology, Adam et al 1 AL: amyloid light chain; TTR: transthyretin; siRNA: small interfering ribonucleic acid; ASO: antisense oligonucleotide; TUDCA: tauroursodeoxycholic acid …”

Assessment and Management of Older Patients With Transthyretin Amyloidosis Cardiomyopathy: Geriatric Cardiology, Frailty Assessment and Beyond

“…Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is caused by the deposition of misfolded transthyretin (TTR) proteins as amyloid fibrils in the myocardial extracellular space ( 1 ). TTR is a predominantly hepatic derived transport protein responsible for transporting thyroxin and retinal binding protein (hence the name ‘ trans-thy-retin' ) through the circulation and is also commonly referred to as prealbumin ( 2 ).…”