Promising new treatments for cardiac amyloidosis are expected in the near future.
Cardiac amyloidosis (CA) results from the deposition of misfolded proteins in the cardiac tissue. Its two main forms are light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), further classified as familial (vATTR) and wild-type (wtATTR). The treatments for AL, wtATTR, and vATTR differ greatly. An article in the European Heart Journal Supplements provides an overview of the present and future of CA treatment.
Light Chain Amyloidosis Treatment
This treatment is based on autologous stem cell transplantation and chemo/immunotherapy. Autologous stem cell transplantation is contraindicated in cases with significant cardiac involvement. The recommended chemotherapy regimen is cyclophosphamide, bortezomib, dexamethasone, and daratumumab as the first-line treatment in newly diagnosed patients. Although effective, these medications have numerous side effects and often require dose reduction or replacement with less effective, well-tolerated therapies. Isatuximab, birtamimab, CAEL-101, and AT-03 are currently under research for AL treatment.
Transthyretin Amyloidosis Treatment
ATTR has a better prognosis than AL, but only limited therapeutic options until a few years ago. Recent drug trials are showing promising results. Treatment guidelines include (a) specific therapies targeting the production and aggregation of amyloid fibrils; (b) symptomatic therapy for complications; (c) support; and (d) genetic counseling for the familial form.
Ø Specific ATTR Therapies
Liver transplantation is indicated in vATTR. The liver is the main source of serum transthyretin (TTR). Transplantation in the early stages of the disease in young patients is associated with a high 20-year survival rate. A combined liver and heart transplant is also possible.
TTR expression can be reduced with antisense oligonucleotides like inotersen and small-interfering RNA drugs like patisiran. Both drugs stabilize cardiac symptoms and are also effective for associated neuropathy. In recent trials, vutrisiran (a second-generation small-interfering RNA agent) effectively reduced TTR levels and improved cardiac and neurological symptoms. A phase III drug trial is ongoing.
TTR stabilizer drugs prevent TTR complex dissociation into amyloidogenic products. Diflunisal is beneficial for slowing the progression of ATTR CA with stable heart failure. Tafamidis effectively stabilizes cardiac ATTR (in both wATTR and vATTR), with a significant reduction in mortality and morbidity. Acoramidis is a new agent that is still under investigation and appears to be effective in vATTR.
CRISP–Cas9 is a novel therapeutic approach that modifies target DNA using a guide RNA to reduce TTR. NTLA2001 aims to cure ATTR with a single administration. Animal studies have shown promising results.
Monoclonal antibodies NI006 and NN6019-0001 are currently being studied to test the hypothesis of removal of amyloid deposits and the resultant improvement in cardiac function.
Ø Supportive Care
This involves attending to associated cardiac issues, such as treatment of heart failure with diuretics and mineralocorticoid receptor antagonists, the use of anticoagulants to prevent thromboembolism, pacemaker implantation for conduction disturbances, amiodarone for atrial fibrillation, and valve replacement in aortic stenosis.
Mallus, M. T., & Rizzello, V. (2023). Treatment of amyloidosis: present and future. European Heart Journal Supplements, 25(Supplement_B), B99–B103. https://doi.org/10.1093/eurheartjsupp/suad082