Table 8.

Areas of investigation and uncertainty in cardiac amyloidosis

Pathophysiology

Amyloidogenesis Mechanism for tissue tropism Role of enzymatic cleavage Role of mechanical stress at tissue level

Determinants of phenotypic heterogeneity Gender Modifier genes Epigenetics Fibre composition

Diagnosis

Populations to screen for cardiac amyloidosis and optimal screening method

Expanded genetic testing in the overall population

Identification of a plasmatic biomarkers of unfolded TTR

Artificial intelligence tools to facilitate diagnosis (imaging, ECG, etc.)

Identification of the target of bone tracers within amyloid deposits

Validation of PET tracers for diagnosis of cardiac amyloidosis, differential diagnosis of ATTR vs. AL, and evaluation of amyloid burden

Natural history

Disease trajectories among carriers of different mutations

Definition and measurement of disease progression Ventricular thickness, mass, function Exercise capacity Biomarkers including monitoring of pre-albumin. TTR stability, kinetics, ligands as monitors of disease progression

Treatment of complications

Initiation of anticoagulation in patients without atrial fibrillation

Efficacy of heart failure drugs in patients with different degrees of heart failure

Efficacy of beta-blockers. Identification of patients who could benefit

Role of invasive heart failure monitoring devices

Identification of patients that benefit from prophylactic pacemaker

Identification of subgroups that can benefit from ICD and CRT

Disease-modifying treatments

New antiplasma cell therapy in AL

New stabilizers in ATTR

New gene silencers in ATTR

Early initiation of therapy: ATTRv mutation carriers without phenotype ATTR cardiac amyloidosis without heart failure

Comparison between diverse disease-modifying drugs in ATTR

Definition of disease progression despite therapy in ATTR

Criteria for switching from one drug to another

Early identification of responders/non-responders to specific therapies

Role of combined therapy

Antibodies to induce removal of tissue amyloid deposits

Genetic editing treatments

AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; PET, positron emission tomography; TTR, transthyretin.