Introduction
Epidemiology
AL amyloidosis
ATTR amyloidosis
ATTRv amyloidosis
ATTRwt amyloidosis
Key messages
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The most common types of amyloidosis include:
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AL amyloidosis
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ATTR amyloidosis.
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ATTR includes ATTRwt and hereditary ATTRv, which are predominantly found in Portugal, Japan, Sweden, and the USA.
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Cardiac amyloidosis is identified in:
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70% of patients with AL amyloidosis
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almost all patients with ATTRwt
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at different frequencies in ATTRv depending on the underlying mutation.
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Pathophysiology
AL amyloidosis
ATTR amyloidosis
ATTRv amyloidosis
ATTRwt amyloidosis
Key messages
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(Cardiac) amyloidosis is caused by accumulation of misfolded protein (i.e., amyloid) in the extracellular spaces of the heart.
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AL amyloidosis is caused by the depositing of misfolded immunoglobulin light chains, which are produced by a plasma cell clone.
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ATTR amyloidosis is based on the deposition of TTR, which is due to hereditary (ATTRv amyloidosis) or acquired (senile or wild-type; ATTRwt amyloidosis) changes to TTR.
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Hereditary cardiac ATTRv amyloidosis is based on mutations in the TTR gene that results in misfolded TTR protein. ATTRv amyloidosis commonly emerges considerably earlier than ATTRwt amyloidosis.
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The reason why unmutated TTR protein aggregates and deposits in the extracellular space in patients with cardiac ATTRwt amyloidosis has not been identified to date. ATTRwt amyloidosis usually emerges in men around the age of 70 years.
Clinical presentation
Amyloid subtype | Abbreviation | Precursor protein | Site of production | Organs involved | Clinical signs/predominant symptoms | Age at manifestation | Clinical course |
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Light chain amyloidosis | AL | Monoclonal light chain | Degenerate plasma cells in bone marrow | Heart, kidneys, liver, gastrointestinal tract, peripheral nervous system, soft tissue | Severe proteinuria; weight loss, constipation; periorbital hematoma; macroglossia; rapidly progressing cardiac amyloidosis (due to light chain toxicity) | Peak at 60–69 years | Cardiac involvement in 70% of patients; high mortality rate of up to 50% per year in patients after first cardiac decompensation |
Transthyretin wild-type amyloidosis | ATTRwt | Transthyretin | Liver | Primarily heart and peripheral nervous system | Primarily heart failure; bilateral carpal tunnel syndrome (usually 10 years before cardiac manifestation); rupture of the biceps tendon; spinal canal stenosis | Mainly males >60 years; early manifestations have been described | Average survival 6 years; more favorable prognosis than cardiac AL amyloidosis |
Hereditary transthyretin variant amyloidosis | ATTRv | Transthyretin | Liver | Heart and peripheral nervous system, autonomous nervous system, gastrointestinal tract | Clinically heterogeneous, from almost isolated neuropathy to cardiomyopathy overlap syndrome; most commonly peripheral sensorimotor neuropathy with motor impairment and neuropathic pain; gastrointestinal dysautonomia with weight loss and orthostatic hypotension; arrhythmia, syncope, sudden cardiac death | In adulthood due to age-associated comorbidities such as arterial hypertension, renal failure, and other biochemical processes | Organ manifestations and severity vary considerably; in patients with Val50Met, nervous system is mainly affected (familial amyloid polyneuropathy); Val142Ile frequently associated with cardiac amyloidosis |
Signs indicating the cause of cardiac amyloidosis
Reduction in longitudinal strain with apical sparing (cherry on the top) |
Discrepancy between left ventricular wall thickness and lack of left ventricular hypertrophy on electrocardiogram |
Atrioventricular block with hypertrophic phenotype |
Echocardiographic hypertrophic phenotype with associated infiltrative features, including increased thickness of atrioventricular valves, interatrial septum, and right ventricular free wall |
Marked extracellular volume expansion and/or diffuse late gadolinium enhancement on cardiac magnetic resonance tomography |
Symptoms of polyneuropathy and/or dysautonomia |
History of unilateral or bilateral carpal tunnel syndrome |
Mild increase in troponin levels on repeated occasions |
AL amyloidosis
ATTRwt amyloidosis
ATTRv amyloidosis
Key messages
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Patients with cardiac amyloidosis typically present with signs and symptoms of heart failure.
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Certain clinical signs are suggestive of distinct subtypes of cardiac amyloidosis (AL: periorbital hematoma, macroglossia; ATTRwt: carpal tunnel syndrome, rupture of the biceps tendon; ATTRv: peripheral sensorimotor neuropathy with motor impairment and neuropathic pain).
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The clinical picture and prognosis of patients with cardiac amyloidosis vary considerably according to amyloidosis subtype. The relative mortalities are: AL > ATTRv > ATTRwt (Table 1).
Diagnostic algorithm
Step 1 (first visit)
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Clinical assessment/patient history
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12-lead electrocardiography (ECG)
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Echocardiography
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Cardiac magnetic resonance imaging (CMR)
Step 2 (primary care provider and/or specialized center)
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Laboratory tests
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Scintigraphy
Step 3 (specialized center)
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Biopsy of the most affected or most easily accessible organ at a specialized center (this step is mandatory to confirm AL amyloidosis; in patients with ATTR amyloidosis, it is only necessary if the overall picture is not clear).
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Genetic testing (differentiation between ATTRwt and ATTRv).
Key messages
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In addition to clinical assessment, methods that provide evidence of cardiac amyloidosis include ECG, echocardiography, and CMR, provided that the latter is readily available.
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If the suspicion is substantiated, further evaluation should be carried out at or in close collaboration with a specialized center (i.e., laboratory testing, scintigraphy, biopsy, genetic testing).
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The red flags that can indicate cardiac amyloidosis are summarized in Table 2.
Diagnostic methods
Step 1: electrocardiography, echocardiography, and magnetic resonance imaging
12-lead electrocardiography
Holter ECG monitoring
Patient situation | AL amyloidosis | ATTR amyloidosis | ||||
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Frequency (months) | Assessment | Result | Frequency (months) | Assessment | Result | |
Receiving specific drug treatment | Every 3 (or after every 2 cycles) | NT-proBNPa; troponin T or I | Treatment success: >30% decrease; treatment failure, >30% increase; compared to previous result | Every 3‑6 | NT-proBNP, troponin T or I | Treatment success: depends on drugb |
Every 6 | ECG + Holter monitoring; transthoracic echocardiography including strain measurements; if available: heart CMR including LGE and T1 mapping | – | Every 12 | ECG + Holter monitoring; transthoracic echocardiography including strain measurements; if available: heart CMR including LGE and T1 mapping | – | |
After remission or in stable condition who does not receive specific treatment | Every 6 | ECG; NT-proBNPa; troponin T or I; transthoracic echocardiography including strain measurements | – | Every 6 | ECG; NT-proBNPa; troponin T or I; transthoracic echocardiography including strain measurements | – |
Every 12 | ECG + Holter monitoring; heart CMR including LGE and T1 mapping if laboratory tests or echocardiography suggest progression | – | Every 12 | ECG + Holter monitoring; heart CMR including LGE and T1 mapping if laboratory tests or echocardiography suggest progression | – |
Echocardiography
Cardiac magnetic resonance imaging
Key messages
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ECG findings, such as low voltage, pseudo-myocardial infarction pattern, and atrioventricular block, can provide important diagnostic clues for cardiac amyloidosis, although they are not pathognomonic.
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Characteristic echocardiographic results include small or regularly sized, hypertrophic ventricles, markedly enlarged atria, and some pericardial effusion. Also, preserved apical strain and diminished strain at the base are typical. Apical sparing (i.e., cherry on the top) can be visualized using the bull’s eye plot or the strain ratio.
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Cardiac CMR is very helpful to establish a diagnosis of cardiac amyloidosis. The use of CMR in the assessment of amyloidosis or LV hypertrophy of unknown origin depends on the local availability and the expertise of the examining physician.
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New cardiac CMR techniques, such as T1 mapping and assessment of ECV can facilitate the evaluation of disease severity and response to treatment.
Step 2: laboratory tests and scintigraphy
Laboratory tests
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Serum: electrophoresis, quantitative assessment of immunoglobulins, quantification of free light chains, and immunofixation;
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Urine: electrophoresis, immunofixation, quantification of immunoglobulins and free light chains; protein-to-creatinine ratio and albumin-to-creatinine ratio based on 24‑h urine samples.
Scintigraphy
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Grade 0: no cardiac uptake, regular osseous structures,
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Grade 1: minor cardiac uptake, with osseous structures appearing comparatively pale,
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Grade 2: moderate cardiac uptake, with osseous structures partly indistinct,
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Grade 3: strong cardiac update, markedly increased extracardiac retention in the soft tissue, with very indistinct osseous structures.
Positron emission tomography
Key messages
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Laboratory tests enable detection of amyloid precursor proteins (e.g., free light chains) and assessment of organ involvement and patient prognosis.
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Bone scintigraphy is mandatory in the evaluation of patients with suspected cardiac amyloidosis, provided that the diagnosis has not already been established by biopsy.
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Bone scintigraphy findings that are unequivocally positive (i.e., Perugini grade ≥2) are proof of ATTR amyloidosis and preclude AL amyloidosis in the absence of monoclonal gammopathy.
Step 3: biopsy and genetic testing
Biopsy/histology
Genetic testing
Key messages
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Cardiac ATTR amyloidosis can be diagnosed based on bone scintigraphy (Perugini score ≥2) and the absence of a monoclonal band in immunofixation/protein electrophoresis. The correct diagnosis of other types of amyloidosis requires evidence of amyloid in tissue biopsies (Congo red staining) and amyloid typing (immunohistochemistry staining, mass spectroscopy).
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Biopsies should be taken from the most severely affected organs after adequate benefit-risk assessment.
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In patients with cardiac ATTR amyloidosis, genetic testing is recommended to distinguish between ATTRwt and ATTRv, as this has prognostic and therapeutic implications. Presymptomatic testing of relatives of index patients with ATTR amyloidosis is reasonable (after genetic counseling) to identify the disease at an early stage or preclude the genetic defect.
Risk stratification
Staging according to: | Amyloidosis | Biomarker | Interpretation | Patient survival | ||||
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NT-proBNP (pg/mL) | Troponin T (ng/L) | FLC-diff. (mg/dL) | eGFR (mL/min) | 4‑year survival rates (%) | Mean (months) | |||
Grogan et al. [19] | ATTR | >3000 | >0.05 | – | – | Stage 1: both parameters < threshold | Stage 1: 57 | – |
Stage 2: one parameter > threshold | Stage 2: 42 | – | ||||||
Stage 3: both parameters > threshold | Stage 3: 18 | – | ||||||
Gillmore et al. [100] | ATTR | >3000 | – | – | <45 | Stage 1: both parameters < threshold | – | Stage 1: 69 |
Stage 2: one parameter > threshold | – | Stage 2: 47 | ||||||
Stage 3: both parameters > threshold | – | Stage 3: 24 | ||||||
Mayo Clinic staging system [85] | AL | ≥1800 | ≥25.0 | ≥18 | – | 1 point/elevated biomarker: stage I–IV | – | Stage I: 94 |
– | Stage II: 40 | |||||||
– | Stage III: 14 | |||||||
– | Stage IV: 6 |
Key messages
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Validated scoring systems have been implemented for risk stratification of patients with ATTR amyloidosis and AL amyloidosis. These are largely based on the biomarkers troponin T and NT-proBNP.
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T1 mapping and calculation of the ECV through CMR can also be used for prognostic assessment.
Which patients should be screened for cardiac amyloidosis?
All patients with established or suspected non-cardiac amyloidosis
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All patients with measurable paraprotein (cave: as pure light-chain paraproteins are not identified by electrophoresis, free light chains should always be tested in serum and urine). Screening should not be restricted to one occasion but should be performed at least once a year throughout the whole course of the disease. AL amyloidosis can develop at any time. It progresses over many months and should be recognized early on, as cardiac amyloidosis is a clear indication for early treatment.
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Patients with established or presumed AL amyloidosis.
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Patients with established or presumed amyloid-related polyneuropathy.
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Patients with established or presumed amyloid-related nephropathy.
Patients with a hypertrophic cardiac phenotype of unknown origin
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Older patients (men >65 years, women >70 years),
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Patients with HFpEF and a hypertrophic cardiac phenotype,
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Patients with (paradoxical) low-flow/low-gradient aortic stenosis.
Key messages
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Screening for cardiac amyloidosis is essential in all patients with established or suspected non-cardiac amyloidosis. Cardiac involvement generally determines the patient prognosis.
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Screening should be conducted in all patients with a hypertrophic cardiac phenotype of unknown origin, particularly in the presence of red flags.
Treatment options
Supportive therapies
Diuretics
Treatment of heart failure
Anticoagulation
Devices and ablation therapy
Key messages for supportive therapies
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Diuretics are a pillar of supportive treatment; however, dosing requires caution.
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Standard therapies established for heart failure have not been shown to provide distinct benefits for patients with cardiac amyloidosis, and their tolerability is low. These include beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors; however, these drugs can be considered in the setting of HFrEF.
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Anticoagulation therapy should be readily initiated after benefit-risk assessment.
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Conventional pacemaker therapy and cardiac resynchronization are helpful if indicated.
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Evidence supporting implantation of a cardioverter defibrillator as a primary prevention measure is lacking. For secondary prevention, the current ESC guidelines should be followed.
Amyloid-specific therapies
ATTR amyloidosis
AL amyloidosis
Transplantation
Heart transplantation
Liver transplantation
Stem cell transplantation
Key messages on specific therapies
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Specific agents have been developed for treatment of ATTR amyloidosis that either stabilize the TTR tetramer or suppress TTR synthesis in the liver. The timely use of tafamidis (Vyndaqel®) can improve prognosis of patients with cardiac amyloidosis.
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There is currently no specific treatment for patients with AL amyloidosis. Rapid treatment of the underlying clonal B‑cell disease or plasma cell dyscrasia of the bone marrow is essential.
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Autologous stem cell transplantation, possibly combined with heart transplantation, is an option in selected patients with AL amyloidosis.
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Heart transplantation can be considered in selected patients with ATTR amyloidosis, while liver transplantation is becoming less important.
Long-term care
Key message
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Follow-up assessments performed during long-term care of patients with cardiac amyloidosis are based on clinical evaluation, NT-proBNP or troponin T (or I) levels, ECG, and imaging parameters (Table 4).