Cardiac amyloidosis: AL vs ATTR, imaging, tafamidis

This page covers suspicion, AL versus ATTR, the diagnostic work-up, ATTR drug therapy and HF management in cardiac amyloidosis. The 2022 AHA/ACC/HFSA guideline reports important delays in diagnosing amyloid heart disease, perhaps not unexpectedly given the wide spectrum of possible presentations.^[4]

• Related topic: HFmrEF and HFpEF.
• Related topic: Hypertrophic cardiomyopathy.
• Related topic: Aortic stenosis: TAVI versus SAVR.
• Related topic: Atrial fibrillation.

Overview and definitions

Amyloid is misfolded protein deposited as fibrils outside the cells.^[2][1] ESC 2026 describes cardiac amyloidosis as an infiltrative cardiomyopathy in which extracellular amyloid fibril deposition increases myocardial thickness and stiffness, leading to a restrictive physiology.^[1]

The 2022 AHA/ACC/HFSA guideline calls it a restrictive cardiomyopathy with extracellular myocardial protein deposition, most commonly monoclonal immunoglobulin light chains (AL-CM) or transthyretin (ATTR-CM).^[4] In that guideline, ATTR can be caused by pathogenic variants in the TTR gene (ATTRv) or by wild-type transthyretin (ATTRwt).^[4]

Classification: AL versus ATTR

The ESC 2021 position statement describes a suspicious phase and a definite diagnosis phase, and says the latter includes typing of the amyloid, which is critical to guide specific treatment.^[3] The ESC 2021 position statement says identification of amyloid should be followed by classification of the amyloid fibril protein, and names mass spectrometry as the gold standard.^[3]

Amyloidosis subtypes that affect the heart (ESC 2021 position statement, Table 1; selected rows and columns)

^{[3] [3] [2] [1] [3] [2] [1]}

Epidemiology

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ESC 2023 says that, although once considered a rare disease, data from the last decade suggest cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes such as HFpEF, aortic stenosis or unexplained LV hypertrophy, particularly in the elderly.^[2] ESC 2023 also reports 7% in LV hypertrophy or HCM depending on age, and 7% in carpal tunnel syndrome undergoing surgery (higher if bilateral), mainly for the wild-type form.^[2]

ESC 2026 attributes a rising prevalence to greater awareness, streamlined diagnostic processes and new treatments, and notes that prevalence is higher in males.^[1] The 2022 AHA/ACC/HFSA guideline lists severe aortic stenosis, HFpEF, carpal tunnel syndrome, lumbar spinal stenosis and autonomic or sensory polyneuropathy as settings where ATTR-CM is prevalent.^[4]

Hereditary disease is not confined to the young.^[4][2] The 2022 AHA/ACC/HFSA guideline notes that the cardiac morphology and peripheral manifestations of hereditary amyloidosis may present in later life.^[4] ESC 2023 reports that 5% of ATTR-CM patients aged 70 years or more, and 10% of women in that group, have ATTRv.^[2]

Pathophysiology

Stabilisers act on the transthyretin tetramer, and silencers act on its production in the liver.^{[1][4][9][10][11][3]} The ATTR-ACT investigators describe deposition occurring when wild-type or variant transthyretin becomes unstable and misfolds, and tafamidis as binding transthyretin to prevent tetramer dissociation and amyloidogenesis.^[9] The 2022 AHA/ACC/HFSA guideline adds that tafamidis binds the thyroxin-binding site of TTR.^[4]

Each drug class targets one step of this pathway.^[1] ESC 2026 says ATTR therapies include drugs that inhibit hepatic synthesis of transthyretin, stabilise the tetramer or disrupt the amyloid fibrils.^[1]

How ATTR drugs act

^{[9] [10] [11] [4]}

ESC 2026 says patients with cardiac amyloidosis may poorly tolerate standard HF therapies.^[1] ESC 2026 lists restrictive physiology, autonomic dysfunction, atrioventricular conduction disturbance and kidney impairment as the reasons.^[1] For patients with ATTR-CM and EF 40% or less, the 2022 AHA/ACC/HFSA guideline says GDMT may be poorly tolerated, and that beta blockers may worsen HF symptoms because patients with ATTR-CM rely on heart rate response to maintain cardiac output.^[4]

^{[1] [9] [10] [11]}

Clinical presentation and red flags

Suspect it in an older patient with HF and a thick, non-dilated LV, especially when QRS voltage is low for the wall thickness.^[1][3][4] ESC 2026 says cardiac amyloidosis should be suspected in patients with HF and increased LV wall thickness in the presence of specific red flags, particularly in patients aged over 65 years.^[1]

The 2022 AHA/ACC/HFSA guideline says LV thickening (wall thickness of 14 mm or more) with fatigue, dyspnoea or oedema should trigger consideration of ATTR-CM.^[4] This applies especially with discordance between echocardiographic wall thickness and ECG QRS voltage, or with other findings such as apical sparing of longitudinal strain or diffuse late gadolinium enhancement (LGE) on CMR.^[4]

Red flags for the most common forms of cardiac amyloidosis (ESC 2026, Table 20)

^[1]

In ESC 2026 Table 20, skin bruising and macroglossia are marked for AL only, while deafness, bilateral carpal tunnel syndrome, ruptured biceps tendon and lumbar spinal stenosis are marked for TTR only.^[1] ESC 2026 marks vitreous deposits and family history as red flags of hereditary TTR-CA.^[1]

The ESC 2021 position statement adds cardiac-level red flags.^[3] They include HF that appears to be in disproportion to objective findings on the echocardiogram (including a disproportionately high NT-proBNP), unexplained right heart failure with ostensibly normal ventricular and valvular function, and idiopathic pericardial effusion.^[3] Persistent troponin elevation, disproportionally low QRS voltage and early conduction system disease are further signs that could evoke cardiac amyloidosis.^[3]

^[1]

Differential diagnosis

Amyloidosis can mimic HFpEF, and ESC 2023 lists it among the specific aetiologies suggested by echocardiography in hypertrophic cardiomyopathy.^[1][2] ESC 2026 stresses excluding conditions that might mimic the HFpEF syndrome, naming HCM and amyloidosis as examples.^[1]

Echocardiographic features that suggest specific aetiologies in hypertrophic cardiomyopathy (ESC 2023, Table 18; rows naming amyloidosis)

^[2]

A positive bone scan is not the same as ATTR.^[4][3] The 2022 AHA/ACC/HFSA guideline warns that PYP scans may be positive even in AL amyloidosis, so scintigraphy alone, without light-chain testing, cannot distinguish ATTR-CM from AL-CM.^[4]

Possible false positives and false negatives of bisphosphonate scintigraphy for ATTR (ESC 2021 position statement, Table 4)

^[3]

ESC 2023 gives a shorter version: false negatives may rarely occur in certain ATTRv genotypes, and false positives may be due to AL, recent myocardial infarction or long-term chloroquine use.^[2]

Investigations

The rows that start the work-up

Two ESC rows open the work-up, for overlapping groups of patients.^[1][2] For a patient with HF, the 2026 row is the newer one; it names light-chain tests alongside the scan, whereas the ESC 2023 scintigraphy row names the scan only.^[1][2]

• ESC 2026 HF, Recommendation Table 4 (patients with established HF): initial diagnostic testing with serum and urine immunofixation, serum free light chains assay and DPD/PYP/HMDP bone scintigraphy is recommended in patients with HF and a suspicion of cardiac amyloidosis (Class I, Level B).^[1]
• ESC 2023 cardiomyopathies, Recommendation Table 6: DPD/PYP/HMDP bone-tracer scintigraphy is recommended in patients with suspected ATTR-related cardiac amyloidosis to aid diagnosis (Class I, Level B); among the ESC guidelines checked for this topic, this is the current ESC row for suspected ATTR cardiac amyloidosis without HF, because the ESC 2026 row is limited to patients with established HF.^[2][1]
• 2022 AHA/ACC/HFSA, recommendations for diagnosis of cardiac amyloidosis: patients for whom there is a clinical suspicion for cardiac amyloidosis should have screening for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and serum free light chains (COR 1, LOE B-NR).^[14]
• 2022 AHA/ACC/HFSA, same table: in patients with high clinical suspicion for cardiac amyloidosis, without evidence of serum or urine monoclonal light chains, bone scintigraphy should be performed to confirm the presence of transthyretin cardiac amyloidosis (COR 1, LOE B-NR).^[14]
• Clinical suspicion, as the 2022 AHA/ACC/HFSA footnote defines it: LV wall thickness of 14 mm or more with fatigue, dyspnoea or oedema, especially with discordance between echocardiographic wall thickness and ECG QRS voltage, and in the context of aortic stenosis, HFpEF, carpal tunnel syndrome, spinal stenosis, and autonomic or sensory polyneuropathy.^[14]

The scan and the light-chain tests can be requested together.^[4] The 2022 AHA/ACC/HFSA guideline says both can be ordered at the same time for convenience, but the scan is interpreted only once the monoclonal light chain screen is negative.^[4]

Excluding a clonal dyscrasia

Serum and urine tests to rule out light-chain amyloidosis (ESC 2021 position statement, Table 3)

^[3]

• ESC 2021 position statement: the combination of SPIE, UPIE and serum free light chain quantification has a sensitivity of 99% for the abnormal pro-amyloidotic precursor in AL amyloidosis.^[3]
• 2022 AHA/ACC/HFSA: serum immunofixation, urine immunofixation and serum free light chains together are more than 99% sensitive for AL amyloidosis; immunofixation is preferred because serum and urine protein electrophoresis are less sensitive.^[4]
• ESC 2021 position statement: serum and urine protein electrophoresis should always be performed with immunofixation, to increase the sensitivity for monoclonal proteins.^[3]
• Kidney disease (ESC 2021 position statement): mild elevations of the kappa to lambda ratio are frequent; with normal SPIE and UPIE, a ratio up to 2.0 with eGFR of 45 mL/min/1.73 m2 or less (up to 3.1 on dialysis) can typically be considered normal; this correction does not apply to the Siemens N Latex assay.^[3]
• ESC 2021 position statement: low-level monoclonal protein or mild elevation of the ratio can be found in chronic kidney disease or monoclonal gammopathy of undetermined significance (MGUS); outside the kidney-disease allowance above, consultation with a haematologist is warranted.^[3]

Bone scintigraphy

• Grading (ESC 2021 position statement): Grade 0, no myocardial uptake and normal bone uptake; Grade 1, myocardial uptake lower than bone; Grade 2, myocardial uptake similar to bone; Grade 3, myocardial uptake greater than bone with reduced or absent bone uptake.^[3]
• Specificity (ESC 2021 position statement): without a detectable monoclonal protein or an abnormal free light chain ratio, the specificity of Grade 2 or 3 uptake for cardiac ATTR when the disease is suspected has been proposed to be almost 100%.^[3]
• SPECT: the ESC 2021 position statement says scintigraphy should always include SPECT, to confirm that uptake is myocardial and not from the cardiac chambers; ESC 2023 says tomographic scintigraphy should be considered to reduce misclassification (no class or level given).^[3][2]
• United States practice (2022 AHA/ACC/HFSA): PYP is the tracer used in the United States; without a light-chain abnormality, the PYP scan is diagnostic of ATTR-CM with Grade 2/3 cardiac uptake or a heart-to-contralateral chest (H/CL) ratio above 1.5, and SPECT is assessed in all positive scans to exclude blood pool or rib uptake.^[4]

^[3]

ECG, echocardiography and CMR

ECG, echocardiography and CMR supply many of the red flags in ESC 2026 Table 20.^[1] ESC 2026 notes that speckle-tracking echocardiography can show strain patterns that may be suggestive of amyloidosis or HCM, and that CMR tissue characterisation with parametric mapping enables classification of cardiac amyloid.^[1]

Echocardiographic and CMR criteria for non-invasive and invasive (with extracardiac biopsy-proven amyloidosis) diagnosis (ESC 2021 position statement, Table 2)

^[3]

The ESC 2021 position statement notes that the multiparametric score is not yet externally validated.^[3] Even so, a score of 8 or more with LV wall thickness of 12 mm or more and amyloid in an extracardiac biopsy could be considered diagnostic.^[3] In its HCM imaging table, ESC 2023 describes often global, subendocardial or segmental LGE in cardiac amyloidosis, with a highly specific pattern of myocardial and blood-pool gadolinium kinetics.^[2]

• ESC 2026 HF, Recommendation Table 4 (patients with established HF): contrast-enhanced CMR is recommended in patients with suspected cardiomyopathy, or where the underlying aetiology of HF is uncertain if further characterisation is likely to add value to patient care (Class I, Level C).^[1]
• ESC 2023 cardiomyopathies, Recommendation Table 5: contrast-enhanced CMR is recommended in patients with cardiomyopathy at initial evaluation (Class I, Level B), and contrast-enhanced CMR should be considered for the serial follow-up and assessment of therapeutic response in patients with cardiac amyloidosis, Anderson–Fabry disease, sarcoidosis, inflammatory cardiomyopathies and haemochromatosis with cardiac involvement (Class IIa, Level C); among the ESC guidelines checked for this topic, the initial-evaluation row is the current ESC CMR row for patients without HF, because the ESC 2026 row is limited to patients with established HF.^[2][1]
• 2022 AHA/ACC/HFSA: patterns of LGE or specific T1 and T2 techniques can suggest specific infiltrative and inflammatory cardiomyopathies, including amyloidosis.^[4]

Biopsy and genetic testing

To diagnose cardiac amyloidosis when the non-invasive criteria are not met, tissue is needed: invasive criteria apply to all forms.^[3] The ESC 2021 position statement confirms the diagnosis when endomyocardial biopsy shows amyloid after Congo red staining, irrespective of LV wall thickness.^[3] It also accepts amyloid in an extracardiac biopsy with characteristic echocardiographic features (with no alternative cause of the thick LV) or characteristic CMR features.^[3]

• ESC 2026 HF, Recommendation Table 4 (patients with established HF): endomyocardial biopsy should be considered to aid in diagnosis and management in patients with rapidly progressive HF despite standard therapy, or when other investigations suggest myocardial inflammation, infiltration or storage that cannot be identified by other means (Class IIa, Level C).^[1]
• ESC 2023 cardiomyopathies, Recommendation Table 7: in patients with suspected cardiomyopathy, endomyocardial biopsy should be considered when other investigations suggest myocardial inflammation, infiltration or storage that cannot be identified by other means (Class IIa, Level C); among the guidelines checked for this topic, this row is the one that covers patients without HF.^[2]
• ESC 2026 HF, Recommendation Table 4 (patients with established HF): genetic testing is recommended in patients fulfilling diagnostic criteria for cardiomyopathy where it enables diagnosis, prognostication, therapeutic stratification or reproductive management, or cascade evaluation of relatives who would otherwise be enrolled into long-term surveillance (Class I, Level C).^[1]
• ESC 2023 cardiomyopathies, Recommendation Table 8 (index patients): the same genetic testing row, for patients fulfilling diagnostic criteria for cardiomyopathy, carries Class I, Level B; among the ESC guidelines checked for this topic, this is the current ESC row for patients without HF, because the ESC 2026 row is limited to patients with established HF.^[2][1]
• ESC 2023: the scan cannot distinguish wild-type from mutated ATTR, so TTR genetic testing is required, and it is recommended in all ATTR-CM patients regardless of age (no class or level given).^[2]
• ESC 2021 position statement: once cardiac ATTR is confirmed, genetic counselling and testing should be performed to separate ATTRwt from ATTRv, even in elderly patients.^[3]
• 2022 AHA/ACC/HFSA: confirming ATTRv triggers genetic counselling and potential screening of family members, and therapies (inotersen and patisiran) then approved only for ATTRv with polyneuropathy.^[4]
• 2022 AHA/ACC/HFSA, recommendations for diagnosis of cardiac amyloidosis: in patients for whom a diagnosis of transthyretin cardiac amyloidosis is made, genetic testing with TTR gene sequencing is recommended to differentiate hereditary variant from wild-type disease (COR 1, LOE B-NR).^[14]

The non-invasive diagnostic algorithm

The ESC 2021 position statement builds its algorithm on scintigraphy and the three monoclonal protein tests performed together.^[3] ESC 2023 and ESC 2026 both describe the same split: invasive criteria for every form, non-invasive criteria only for ATTR.^[2][1]

^{[3] [3]}

Treatment overview

The ESC 2021 position statement divides the treatment of cardiac amyloidosis into two areas: treatment and prevention of complications, and stopping or delaying amyloid deposition by specific treatment.^[3]

^{[1] [5] [3]}

Treatment: AL cardiac amyloidosis

The ESC 2021 position statement notes that patients with AL amyloidosis have a haematological malignancy, and that multiorgan involvement makes them particularly susceptible to treatment toxicity.^[3] ESC 2026 says treatment includes chemotherapy or autologous stem cell transplantation, with careful monitoring of haematological response and of cardiac and organ function.^[1] It adds that management should be undertaken by a multidisciplinary team of oncohaematology specialists and cardiologists, with referral to specialised centres whenever possible.^[1]

• 2022 AHA/ACC/HFSA: AL amyloidosis is treatable, and patients with cardiac involvement should promptly be referred to haematology-oncology for timely treatment.^[4]
• ESC 2021 position statement: the cardiologist assesses the heart before initial haematological strategies (including consideration of autologous stem cell transplantation), evaluates for heart transplantation and monitors the heart during chemotherapy.^[3]
• ESC 2023: the prognosis of AL amyloidosis has improved significantly with very effective therapies that reduce production of the cardiotoxic light chains.^[2]

Treatment: ATTR cardiac amyloidosis

ESC 2026 recommends treatment with a TTR stabiliser or silencer with proven safety and efficacy on morbidity and mortality, in wild-type or hereditary ATTR-CA with a clinical history of HF in NYHA classes I–III.^[1] The drugs it names are the stabilisers tafamidis and acoramidis and the silencer vutrisiran.^[1]

Older documents are history on this point.^[1][4][3] In 2021 the ESC working group called tafamidis the only drug with randomised efficacy in ATTRwt and ATTRv cardiomyopathy, to be considered with reasonable expected survival.^[3] The 2022 AHA/ACC/HFSA text likewise called tafamidis the only therapy then shown to improve cardiovascular outcomes in ATTR-CM.^[4]

^{[9] [4] [1] [10] [1] [11] [1]}

ESC 2026 adds context that matters when you compare trials.^[1] It notes that placebo-arm survival in ATTRibute-CM was higher than survival in the treatment group of ATTR-ACT, possibly reflecting earlier disease stage and better access to diagnosis and specialist care.^[1] It also reports that in the open-label extension, early and continuous acoramidis significantly reduced death at 42 months compared with later initiation.^[1]

Patisiran has functional data, but ESC 2026 notes no morbidity and mortality data.^[1] APOLLO-B was a phase 3, double-blind trial of intravenous patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months in variant or wild-type ATTR cardiac amyloidosis.^[12][1] At month 12 the decline in 6-minute walk distance was smaller with patisiran (median difference 14.69 m; 95% CI 0.69 to 28.69).^[12][1] No significant benefit was observed for its second secondary end point, a composite of death from any cause, cardiovascular events and change in 6-minute walk distance over 12 months.^[12] ESC 2026 notes that no morbidity and mortality data are available for patisiran.^[1]

Tafamidis in the 2022 AHA/ACC/HFSA guideline

• Recommendation row (recommendations for treatment of cardiac amyloidosis): in select patients with wild-type or variant transthyretin cardiac amyloidosis and NYHA class I to III HF symptoms, transthyretin tetramer stabiliser therapy (tafamidis) is indicated to reduce cardiovascular morbidity and mortality (COR 1, LOE B-R).^[14]
• Value statement (low value, B-NR): at 2020 list prices, tafamidis provides low economic value (more than 180 000 US dollars per QALY gained) in patients with HF with wild-type or variant transthyretin cardiac amyloidosis.^[14]
• Doses: tafamidis meglumine 20 mg capsules, FDA-approved dose 80 mg (4 capsules) once daily; tafamidis 61 mg capsules, FDA-approved dose 61 mg once daily.^[4]
• Because tafamidis prevents but does not reverse amyloid deposition, greater benefit is expected when it is given early in the disease course.^[4]
• As the survival curves separate after 18 months, patients whose non-cardiac disease is not expected to limit survival should be selected.^[4]
• Benefit has not been observed in class IV symptoms, severe aortic stenosis or eGFR below 25 mL/min/1.73 m2.^[4]
• ATTR-ACT showed a higher rate of cardiovascular hospitalisation in NYHA class III, potentially attributable to longer survival during a more severe period of disease.^[4]
• Cost in its supportive text: at an annual cost of 225 000 US dollars, tafamidis had an incremental cost-effectiveness ratio above 180 000 US dollars per QALY gained, the guideline benchmark for low value, in one model-based analysis using ATTR-ACT results.^[4]

Heart failure and comorbidities: what changes

Standard HF care has to be adapted to the amyloid heart.^[1][4] ESC 2026 says evidence for foundational medical therapy in cardiac amyloidosis is still scarce and limited to post-hoc analyses of trials or retrospective studies.^[1]

Supportive HF treatment in cardiac amyloidosis

^{[1] [2] [4] [3]}

The 2022 AHA/ACC/HFSA guideline reminds clinicians that evaluation and management of autonomic dysfunction, volume status and arrhythmia are important.^[4]

Atrial fibrillation, flutter and thrombus

Intracardiac thrombus can form even without diagnosed AF, and the ESC AF row applies regardless of CHA2DS2-VA score.^[4][5] The 2022 AHA/ACC/HFSA guideline reports intracardiac thrombosis in approximately one-third of patients with cardiac amyloidosis, sometimes without diagnosed AF and regardless of CHA2DS2-VASc score.^[4]

• ESC 2024 AF: oral anticoagulation is recommended in all patients with AF and hypertrophic cardiomyopathy or cardiac amyloidosis, regardless of CHA2DS2-VA score, to prevent ischaemic stroke and thromboembolism (Class I, Level B).^[5]
• ESC 2023 cardiomyopathies, Recommendation Table 11: oral anticoagulation to reduce the risk of stroke and thromboembolic events is recommended in all patients with HCM or cardiac amyloidosis and AF or atrial flutter, unless contraindicated (Class I, Level B). For AF, the 2024 AF row above is the newer one; for atrial flutter, the 2024 AF flutter row recommends anticoagulation at elevated thromboembolic risk without naming amyloidosis (Class I, Level B), so among the guidelines checked for this topic the 2023 row is the one that names cardiac amyloidosis with atrial flutter.^[2][5]
• ESC 2026 HF (no class or level given): in cardiac amyloidosis with AF, anticoagulation is indicated regardless of CHA2DS2-VA score, because of the high thromboembolic risk; its AF section adds that patients with HCM and CA are at higher risk irrespective of CHA2DS2-VA score and that anticoagulation is recommended for all these patients with AF.^[1]
• ESC 2026 HF, Recommendation Table 15 (AF in patients with HF): oral anticoagulation is recommended in clinical AF at elevated thromboembolic risk as determined by CHA2DS2-VA score, to prevent ischaemic stroke and thromboembolism (Class I, Level A), and DOACs are recommended in preference to VKAs in patients with HF to prevent stroke and thromboembolism (Class I, Level B1), except in moderate or severe mitral stenosis and mechanical prosthetic heart valves, where VKAs are recommended. Neither row names amyloidosis, so the ESC 2024 AF row remains the one that does.^[1][5]
• ESC 2026 HF (no class or level given): transoesophageal echocardiography is necessary before cardioversion to exclude intracardiac thrombus, regardless of how long anticoagulation has been given.^[1]
• ESC 2024 AF (narrative): patients with AF and cardiac amyloidosis are among the subgroups with an increased risk of ischaemic stroke and intracardiac thrombus even if treated with adequate anticoagulation.^[5]
• 2022 AHA/ACC/HFSA, recommendations for treatment of cardiac amyloidosis: in patients with cardiac amyloidosis and AF, anticoagulation is reasonable to reduce the risk of stroke regardless of the CHA2DS2-VASc score (COR 2a, LOE C-LD).^[14]
• 2022 AHA/ACC/HFSA (supportive text): anticoagulation reduced the risk of intracardiac thrombus in a retrospective study; DOAC versus warfarin and left atrial appendage closure have not been studied in ATTR.^[4]
• 2022 AHA/ACC/HFSA (supportive text): the bleeding risk of anticoagulation in ATTR-CM with AF has not been established; patients with AL may have acquired haemostatic abnormalities (coagulation factor deficiencies, hyperfibrinolysis, platelet dysfunction), whereas TTR amyloidosis is not associated with haemostatic defects.^[4]

Conduction disease, pacing and defibrillators

ESC 2023 links the natural history of cardiac amyloidosis with conduction disease, symptomatic bradycardia and advanced AV block.^[2] The 2022 ESC ventricular arrhythmia guideline adds that ATTRwt is more often complicated by AV conduction delay and atrial arrhythmias.^[6]

• ESC 2023 (no class or level given): the clinical threshold for a pacemaker should be low, as the disease progresses and a device allows rate response to exercise and medication adjustment.^[2]
• ESC 2021 pacing guideline (no class or level given): conduction defects, tachyarrhythmias and sudden cardiac death are common in cardiac amyloid, and conventional indications should be used for pacing.^[7]
• ESC 2022 ventricular arrhythmias, Recommendation Table 32: an ICD should be considered in patients with light-chain or transthyretin-associated cardiac amyloidosis and haemodynamically not-tolerated VT (Class IIa, Level C). Its text calls the benefit of primary prevention ICDs in cardiac amyloidosis uncertain, and says an ICD should be considered in patients with haemodynamically not-tolerated VT after careful discussion of the competing risks of non-arrhythmic and non-cardiac death.^[6]
• ESC 2026 HF, general row for patients with HF (it does not name amyloidosis): an ICD is recommended in patients who have recovered from a ventricular arrhythmia causing haemodynamic instability (secondary prevention), who are expected to survive more than 1 year with good functional status, in the absence of reversible causes or unless the arrhythmia occurred less than 48 h after a myocardial infarction, to reduce the risk of sudden death and all-cause death (Class I, Level A).^[1]
• ESC 2023 (no class or level given): the role of the ICD in cardiac amyloidosis for sudden cardiac death prevention is not clearly known, and available data do not support primary prevention use.^[2]
• ESC 2023 writes its secondary-prevention ICD rows by phenotype: HCM, DCM and ARVC (Class I, Level B), and NDLVC and RCM (Class I, Level C), for survivors of cardiac arrest due to VT or VF or spontaneous sustained ventricular arrhythmia causing syncope or haemodynamic compromise without reversible causes. It names no amyloidosis-specific ICD row, and its gaps-in-evidence list for amyloid says SCD risk stratification and ICD indications should be carefully defined, taking into account estimated life expectancy, competitive non-cardiovascular mortality and the high rate of pulseless electrical activity.^[2]
• 2022 AHA/ACC/HFSA (supportive text): the benefit of ICDs in ATTR-CM has not been studied in randomised trials, a case-control study showed unclear benefit, and CRT has not been studied in ATTR-CM with HFrEF.^[4]

Aortic stenosis with ATTR

The 2025 ESC/EACTS valve guideline says ATTR cardiac amyloidosis may coexist with aortic stenosis in elderly patients, and the two conditions may causally interrelate.^[8] When ATTR is suspected, it says monoclonal protein should be excluded with immunofixation and quantitative free light chains, and the diagnosis ascertained by diphosphonate scintigraphy.^[8] Despite the limited long-term prognosis of ATTR, patients with concomitant severe aortic stenosis usually benefit from valve intervention.^[8]

Prognosis and follow-up

ESC 2023 calls cardiac amyloidosis a progressive disease with poor outcomes if left untreated.^[2] The 2022 ESC ventricular arrhythmia guideline says outcome is still poor in AL amyloidosis with manifest cardiac involvement, and names progressive HF, autonomic dysfunction and electromechanical dissociation as causes of death.^[6]

Two staging systems from the ESC 2021 position statement (Table 6; selected columns)

^[3]

The ESC 2021 position statement notes that these scores use parameters obtained at presentation, and that the prognostic impact of score changes during follow-up has not yet been validated.^[3] It describes a common follow-up scheme of 6-monthly visits with ECG and blood tests including NT-proBNP and troponin, plus a yearly echocardiogram and 24-h Holter ECG, while noting that no studies have addressed the optimal scheme.^[3]

Rising diuretic needs are a warning sign.^[1] ESC 2026 calls an increasing diuretic dose a signal of disease progression with worse outcomes.^[1]

Special populations

Families and carriers of ATTRv

• ESC 2021 position statement: genetic testing is recommended for relatives of patients with an inheritable form, with genetic counselling of patients and families; because all hereditary amyloidoses have adult onset, testing of minors is discouraged.^[3]
• ESC 2021 position statement: testing could be offered in young adulthood if it would guide professional choices or reproductive planning.^[3]
• ESC 2021 position statement: assessment of penetrance in carriers is generally recommended to start about 10 years before the age of onset in affected relatives (or others with the same mutation), or as soon as compatible symptoms develop.^[3]
• ESC 2021 position statement, Table 7 (asymptomatic ATTRv carriers): yearly ECG, blood tests including NT-proBNP and troponin, echocardiography, and neurological and ophthalmological evaluation; Holter ECG every 2 years; scintigraphy and CMR every 3 years or if any of the other tests is abnormal.^[3]

Older patients and those with kidney disease

Age does not exempt a patient with confirmed ATTR cardiac amyloidosis from TTR genetic testing.^[3][2] The ESC 2021 position statement says that once cardiac ATTR amyloidosis is confirmed, genetic testing should be performed even in elderly patients, as a significant number can have TTR mutations.^[3] In chronic kidney disease, interpret the free light chain ratio with the kidney-disease allowance given above, and note that ATTRibute-CM assessed efficacy only in patients with eGFR of at least 30 mL/min/1.73 m2.^[3][10]

Evidence, guidelines and regional differences

ESC 2026 HF supplies the current ESC rows on the amyloidosis work-up in HF and on ATTR therapy.^[1] The 2023 ESC cardiomyopathy guideline says specific recommendations for the assessment and management of cardiac amyloidosis are beyond its scope and highlights only key issues; its CMR, scintigraphy, biopsy, genetic testing and anticoagulation rows are given above.^[2]

^{[1] [5] [14] [4]}

Several questions remain open in ESC 2023: the efficacy and safety of tafamidis in NYHA class III, and whether patients with subclinical cardiac involvement need drug therapy.^[2] ESC 2026 lists ongoing studies of options acting on gene editing, RNA silencing or the repletion of amyloid deposits that might change the management of ATTR-CA in future.^[1]

ANZ practice

The 2024 Australia–New Zealand Expert Consensus Statement aims to update general physicians and cardiologists on diagnosis, investigation and management.^[13] It notes that the ESC and the ACC had updated their amyloidosis guidelines in the preceding 2 years, but that these guidelines do not reflect the Australian or New Zealand context.^[13]

• Delay: amyloidosis is frequently misdiagnosed, with a median diagnostic delay of more than 12 months and approximately 50% of patients visiting more than five physicians before diagnosis; specialised Australian Amyloidosis Network centres are limited in number and location, but their pathways triage urgent referrals.^[13]
• Work-up: it recommends simultaneous screening with technetium-99m PYP, DPD or HMDP bone scintigraphy and blood and urine testing for a monoclonal protein; non-invasive diagnosis of ATTR-CA is possible with Grade 2 or 3 uptake and no monoclonal protein in blood or urine.^[13]
• Suspected AL: where a monoclonal protein is detected and AL amyloidosis is suspected, urgent haematology referral for work-up, including bone marrow biopsy, is recommended.^[13]
• Scan technique: planar bone scintigraphy has a higher false positive rate because uptake is often by blood pool, whereas planar with SPECT imaging is more specific for myocardial tracer uptake.^[13]
• Genetics: all patients with confirmed ATTR-CA should have genetic testing for mutations.^[13]
• Rhythm: it states that anticoagulation is now indicated in ATTR-CA with AF, regardless of CHA2DS2-VASc, without naming a guideline recommendation row (the formal rows on cardiac amyloidosis with AF are ESC 2024 AF, Class I, Level B, and 2022 AHA/ACC/HFSA, COR 2a, LOE C-LD, above); standard pacing indications are recommended; ICDs have limited utility for primary prevention, but secondary prevention indications are accepted.^[13][5][14]
• Referral: it advocates referral to specialist amyloidosis centres with multidisciplinary teams for the assessment and management of ATTR-CA.^[13]
• Transplantation: cardiac transplantation for ATTR-CA is possible in select cases if patients are identified and referred early; the recommended age limit is about 70 years, so patients with ATTRwt-CA are often diagnosed too late.^[13]

The statement described drug access in Australia and New Zealand in 2024.^[13] The statement reported that tafamidis had received a positive Pharmaceutical Benefits Advisory Committee recommendation and would soon be available for ATTR-CA in NYHA class 1 and 2.^[13] It added that prescribing would be limited to cardiologists and amyloidosis specialists in Australia, and that tafamidis would not be readily available in New Zealand.^[13] Diflunisal was available through the Special Access Scheme at all Australian Amyloidosis Network centres; in New Zealand these treatments were accessible only through clinical trials.^[13] Acoramidis and TTR synthesis suppressors had proven benefit but were not yet available in Australia or New Zealand.^[13]

Guidelines checked

A row called the newer one, or the one covering a group, is so among the guidelines checked for this topic:

• Sources of the rows and statements used: ESC heart failure (2026), cardiomyopathies (2023), atrial fibrillation (2024), ventricular arrhythmias (2022), pacing (2021) and valvular heart disease (2025); the 2021 ESC working group position statement; the 2022 AHA/ACC/HFSA heart failure guideline (Circulation and JACC versions); the 2024 Australia–New Zealand consensus statement.^{[1][2][5][6][7][8][3][4][14][13]}
• Also swept for newer rows on the same questions (the guidelines checked for this topic): ESC cardiac rehabilitation (2026), pregnancy and dyslipidaemias (2025), chronic coronary syndromes, hypertension and peripheral arterial and aortic diseases (2024), acute coronary syndromes and endocarditis (2023) and non-cardiac surgery (2022); ACC/AHA aortic disease (2022), chronic coronary disease and atrial fibrillation (2023), hypertrophic cardiomyopathy (2024), acute coronary syndromes and blood pressure (2025), and pulmonary embolism and dyslipidaemia (2026).
• Not held as text, so not checked for this topic: ESC cardio-oncology and pulmonary hypertension (2022), diabetes (2023), myocarditis and pericarditis (2025), and cardiovascular disease and chronic kidney disease (2026); ACC/AHA adult congenital heart disease (2025), cardiovascular-kidney-metabolic syndrome (2026) and perioperative management (2026).

Exam pearls

• Non-invasive diagnosis is for ATTR only: typical echocardiographic or CMR findings, Grade 2 or 3 uptake on PYP, DPD or HMDP scintigraphy, and negative SPIE, UPIE and serum free light chains (ESC 2021 position statement).^[3]
• A positive scan with an abnormal light-chain test needs histology with typing, usually endomyocardial biopsy (ESC 2021 position statement).^[3]
• Grade 1 uptake with negative protein tests is not diagnostic; histological confirmation is required (ESC 2021 position statement).^[3]
• AL needs prompt referral to haematology-oncology (2022 AHA/ACC/HFSA); ESC 2026 stresses early therapy, particularly in AL.^[1][4]
• TTR genetic testing is recommended in all ATTR-CM regardless of age (ESC 2023).^[2]
• ESC 2026 recommends vutrisiran, tafamidis or acoramidis for variant or wild-type ATTR cardiac amyloidosis in NYHA classes I–III (Class I, Level A).^[1]
• ESC 2026 calls digoxin generally discouraged in cardiac amyloidosis because of a high risk of toxicity.^[1]
• Anticoagulate AF with cardiac amyloidosis regardless of CHA2DS2-VA score, to prevent ischaemic stroke and thromboembolism (ESC 2024 AF, Class I, Level B).^[5]

References14ShowHide

1. [1]Køber L, et al. 2026 ESC Guidelines for the management of heart failure. Eur Heart J, 2026.PMID 42661420
2. [2]Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J, 2023.PMID 37622657
3. [3]Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J, 2021.PMID 33825853
4. [4]Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 2022.PMID 35363499
5. [5]Van Gelder IC, et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J, 2024.PMID 39210723
6. [6]Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J, 2022.PMID 36017572
7. [7]Glikson M, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J, 2021.PMID 34455430
8. [8]Praz F, et al. 2025 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J, 2025.PMID 40878295
9. [9]Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med, 2018.PMID 30145929
10. [10]Gillmore JD, et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med, 2024.PMID 38197816
11. [11]Fontana M, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med, 2025.PMID 39213194
12. [12]Maurer MS, et al. Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis. N Engl J Med, 2023.PMID 37888916
13. [13]Bart NK, et al. 2024 Australia-New Zealand Expert Consensus Statement on Cardiac Amyloidosis. Heart Lung Circ, 2024.PMID 38570258
14. [14]Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol, 2022.PMID 35379503