Table 4.

Grey zones and knowledge gaps in the current management of TTR-AC.

Reasonably indicated treatments and grey zones
Anti-neurohormonal therapy	No survival benefit is demonstrated in TTR-AC. Beta-blockers and ACE-i/ARB can be poorly tolerated, especially in advanced stages due to vasodilatation and reduced CO.
Atrial fibrillation and anticoagulation	Anticoagulation with VKAs and DOACs should be administered based on the usual indications and contraindications. Patients with TTR-AC in sinus rhythm can harbour thrombi in the left atrial appendage, especially when atrial function is severely impaired. Therefore, TEE should be routinely performed before a planned cardioversion.
Atrial fibrillation, rate or rhythm control and catheter ablation	There is no specific recommended strategy for the management of arrhythmias. Digoxin should be avoided or used at low dosages due to concerns about potential enhanced toxicity caused by binding to amyloid fibrils. Drugs with a negative inotropic effect should be avoided (i.e. verapamil and diltiazem). The efficacy of catheter ablation seems limited, but future studies are required.
Transcatheter aortic valve implantation	Percutaneous or surgical aortic valve replacement should not be denied only because of coexistent AC. Definitive PM implantation may be required due to a higher risk of persistent AV blocks.
Ventricular arrhythmias and implantable cardioverter defibrillator	Sudden death is not infrequent in patients with advanced HF, but it is generally due to electromechanical dissociation. The role of ICD for the purpose of: - primary prevention is currently limited; - secondary prevention can be considered in select non-advanced cases with sustained VT/VF.
Cardiac resynchronization therapy	Very limited data are available on this topic. CRT should be considered in patients eligible for PM implantation with an estimated time of RV pacing >40%.
Heart transplantation	Highly selected HF patients with TTRwt or TTRv and predominant cardiac phenotype without extra-cardiac organ damage could be eligible. Combined heart and liver transplantation could be considered in very selected cases with mixed phenotype and limited neurological involvement.

Legend: AC, Amyloid Cardiomyopathy; ACE-i, Angiotensin Converting Enzyme Inhibitors, ARBs, Angiotensin Receptor Blockers; AV, Atrio-Ventricular; CO, Cardiac Output; DOACs, Direct Oral Anticoagulants; HF, Heart Failure; LBBB, Left Bundle Branch Block; LVEF, Left Ventricular Ejection Fraction; PM, Pacemaker; RV, Right Ventricular; SCD, Sudden Cardiac Death; TEE, Transoesophageal Echocardiography; TTR-AC, Transthyretin Amyloid Cardiomyopathy; TTRv, variant Transthyretin; TTRwt, wild-type Transthyretin, VF, Ventricular Fibrillation; VKAs, Vitamin K Antagonists; VT, Ventricular Tachycardia.