#cardiomyopathy #amyloidosis #ATTR #TTR #infiltrative-cardiomyopathy #bone-scintigraphy

Transthyretin Amyloidosis (ATTR)

Details

Transthyretin amyloidosis is caused by dissociation of the transthyretin (TTR) tetramer, misfolding of the monomer and extracellular deposition of amyloid fibrils. When the deposits form in the myocardium the result is a restrictive/infiltrative cardiomyopathy — ATTR-CA — with concentric wall thickening, impaired diastolic filling and, ultimately, biventricular failure. TTR is a hepatic thyroxine- and retinol-binding protein, so the liver supplies the precursor and is the target of silencing and gene-editing therapies. (sources/imaging-amyloidosis-aha-2021, rating: very high; sources/esc-cmp-2023, rating: very high)

Two forms are recognised. ATTRwt (wild-type, formerly "senile systemic amyloidosis") arises from inherently unstable wild-type TTR in older adults and is almost always a cardiac-only phenotype. ATTRv (variant) is an autosomal dominant disease caused by one of more than 120 pathogenic TTR variants, with earlier onset and a mixed cardiac and polyneuropathic phenotype that varies by genotype. Cardiac involvement dominates ATTRwt and is present in up to 75% of AL amyloidosis. (sources/imaging-amyloidosis-aha-2021; sources/imaging-amyloidosis-2nd-aha-2021, rating: very high)

The phenotype overlaps HFpEF, hypertensive LVH, HCM and aortic stenosis, and the diagnosis was historically made at autopsy or biopsy. Bone scintigraphy plus exclusion of a monoclonal plasma cell process now establishes ATTR-CA non-invasively, but extra-cardiac red flags such as bilateral carpal tunnel syndrome usually precede cardiac symptoms by years, so most cases are still identified late. (sources/esc-cmp-2023; sources/imaging-amyloidosis-2nd-aha-2021)

Management changed substantially between 2018 and 2025: two stabilisers and one RNA interference agent have positive Phase 3 trials, ESC 2026 gives disease-modifying therapy Class I, Level A, and in vivo CRISPR editing has reached Phase 3. Prognosis remains limited — median survival 2–6 years from diagnosis — and no trial has established when therapy should start. (sources/HF-ESC-2026, rating: very high; sources/vutrisiran-attrcm-heliosb-nejm-2025, rating: very high)

Key Facts

Epidemiology and Natural History

ATTR-CA is found across the common cardiac phenotypes that it mimics, and the reported prevalence depends heavily on how the population was selected:

Setting	Prevalence of ATTR-CA	Source
HFpEF (screening and autopsy data)	5–13%; 14% in one prospective biopsy series	(sources/echo-hfpef-ase-2025, rating: very high)
Older patients with HFpEF or severe aortic stenosis	10–16%	(sources/imaging-amyloidosis-aha-2021, rating: very high)
Severe aortic stenosis	8%	(sources/esc-cmp-2023, rating: very high)
HFpEF with LVH	12%	(sources/esc-cmp-2023)
LVH/HCM cohorts	7%, age-dependent	(sources/esc-cmp-2023)
Carpal tunnel release surgery	7%	(sources/esc-cmp-2023)

Natural history is progressive and fatal. Until recently tafamidis was the only therapy that reduced mortality, while quality of life and functional capacity continued to decline. (sources/vutrisiran-attrcm-heliosb-nejm-2025)
ATTRwt dominates contemporary cardiac cohorts. It presents in older adults, usually with HFpEF and no family history; ATTRv presents earlier and, depending on variant, with neuropathy, cardiomyopathy or both. (sources/imaging-amyloidosis-aha-2021)
Extra-cardiac disease often precedes the cardiac phenotype. Bilateral carpal tunnel syndrome may precede cardiac symptoms by years and is a red flag for ATTRwt. (sources/esc-cmp-2023)

Pathophysiology

The rate-limiting step is tetramer dissociation. TTR circulates as a homotetramer whose thyroid-hormone-binding pockets sit at the dimer–dimer interface; tetramer dissociation releases monomers that misfold, oligomerise and deposit as amyloid. Stabilisers act by shifting the equilibrium back toward the tetramer; silencers remove the precursor altogether. (sources/acoramidis-attrcm-attributecm-nejm-2024, rating: very high)
ATTRwt and ATTRv destabilise the tetramer by different routes. In ATTRwt, wild-type TTR becomes structurally unstable with ageing; in ATTRv, pathogenic variants produce intrinsically unstable tetramers from birth. The protective T119M variant, which stabilises the tetramer, was the design template for acoramidis. (sources/esc-cmp-2023; sources/acoramidis-attrcm-attributecm-nejm-2024)
Deposition produces restrictive physiology. Amyloid infiltration thickens the walls and stiffens the myocardium, raising filling pressures and producing biatrial enlargement, diastolic dysfunction and a low stroke volume despite preserved ejection fraction. (sources/esc-cmp-2023; sources/echo-hfpef-ase-2025)
The left atrium is a target organ in its own right. LA strain is impaired regardless of LA size, reflecting both raised filling pressure and direct atrial infiltration, and LAA thrombus can form in normal sinus rhythm — the substrate for the anticoagulation recommendation even at low CHA₂DS₂-VA scores. (sources/imaging-amyloidosis-aha-2021; sources/HF-ESC-2026, rating: very high)
Extra-cardiac deposition explains the syndrome. Carpal tunnel syndrome, lumbar spinal stenosis and biceps tendon rupture reflect tenosynovial and ligamentous amyloid; ATTRv polyneuropathy is a length-dependent sensorimotor and autonomic neuropathy with its own licensed therapies. (sources/esc-cmp-2023; sources/imaging-amyloidosis-2nd-aha-2021, rating: very high)
ATTR and aortic stenosis interact. Amyloid co-exists with severe AS in the elderly and calcium–amyloid interaction in valve leaflets may contribute to AS progression, rather than the two being independent age-related diseases. (sources/vhd-esc-2025, rating: very high)

Genetics

ATTRv is autosomal dominant. Pathogenic variants in TTR (>120 described) are inherited dominantly and confer a mixed cardiac/neuropathic phenotype; ATTRwt by definition carries no TTR variant. Genetic testing is Class I in cardiomyopathy (ESC) and is required to separate ATTRv from ATTRwt once ATTR-CA is confirmed (AHA COR 1). (sources/esc-cmp-2023; sources/HF-ESC-2026; sources/HF-AHA-2022, rating: very high)
V122I (p.Val142Ile) is the commonest cardiac variant. It is carried by 3.4% of African Americans — roughly 2 million US carriers — and accounts for 10% of African Americans over 65 with severe heart failure, consistent with its predominantly cardiac phenotype; it made up 41% of the ATTRv subgroup in APOLLO-B. (sources/imaging-amyloidosis-aha-2021; sources/genetic-cmp-jcf-2018, rating: very high; sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
V30M is the archetypal polyneuropathic variant, the genotype in which T119M co-inheritance was shown to be protective. Genotype therefore determines whether a carrier presents to neurology or cardiology first. (sources/acoramidis-attrcm-attributecm-nejm-2024)
Penetrance is incomplete and age-dependent. The 1:230 population prevalence of ATTRv-CM implies that many carriers never develop clinically recognised disease, which complicates counselling and the interpretation of incidental genetic findings — TTR is on the ACMG secondary findings list. (sources/gene-editing-acc-2026, rating: very high)
ATTR can be found by a cardiomyopathy panel ordered for atrial fibrillation. In an early-onset AF genetics clinic, two of 48 positive results were TTR p.Val142Ile — patients investigated for AF, in whom a cardiomyopathy/arrhythmia panel returned a diagnosis with its own disease-modifying therapy. AF is a common and often early manifestation of ATTR-CM, and the finding is actionable in a way that most AF genetic results are not. (sources/genetic-eoaf-ehj-2026, rating: high)
Cascade testing is the point of genotyping a proband. Genetic testing enables cascade testing of relatives (ESC 2023), and carriers are then surveilled with echocardiography and bone scintigraphy. See concepts/Genetic-Testing-in-Cardiomyopathy. (sources/esc-cmp-2023; sources/imaging-amyloidosis-2nd-aha-2021)

When to Suspect

Domain	Red flags
Cardiac	HFpEF or unexplained HF with increased wall thickness; LV wall thickness ≥14 mm with fatigue, dyspnoea or oedema (AHA 2022 trigger); severe aortic stenosis, particularly low-flow/low-gradient; unexplained AV block or arrhythmia in an older adult
ECG–imaging discordance	Low QRS voltage — or normal voltage — relative to markedly increased LV mass; pseudoinfarction pattern
Extra-cardiac	Bilateral carpal tunnel syndrome (often years earlier); lumbar spinal stenosis; biceps tendon rupture without trauma; unexplained sensorimotor or autonomic polyneuropathy
Family	Known pathogenic TTR variant; family history of amyloidosis, unexplained HF or hereditary neuropathy
Imaging already done	Apical-sparing GLS, TDI 5-5-5 sign, ECV >0.40, diffuse LGE, myocardium nulling before blood pool

(sources/esc-cmp-2023, rating: very high; sources/HF-AHA-2022, rating: very high; sources/imaging-amyloidosis-2nd-aha-2021, rating: very high; sources/echo-hfpef-ase-2025, rating: very high)

Diagnosis

Non-invasive algorithm. Four steps, in order:

Suspect on the red-flag pattern above. (sources/esc-cmp-2023)
Exclude a monoclonal plasma cell process with serum free light chains plus serum and urine immunofixation — Class I in both AHA 2022 and ESC 2026, and non-negotiable before any scintigraphic diagnosis. (sources/HF-AHA-2022; sources/HF-ESC-2026)
Bone scintigraphy (99mTc-DPD/PYP/HMDP) with SPECT. Grade 2–3 myocardial uptake with a negative clonal screen and typical imaging establishes ATTR-CA without biopsy. (sources/esc-cmp-2023; sources/imaging-amyloidosis-2nd-aha-2021)
TTR gene sequencing to separate ATTRv from ATTRwt, which determines family screening and, in some systems, access to silencers. (sources/HF-AHA-2022)

Biopsy with fibril typing is required when the clonal screen is abnormal, uptake is Grade 1, or the imaging phenotype is atypical.

Formal non-biopsy criteria. All three conditions must be met:

Component	Requirement
1. Scintigraphy	99mTc-PYP/DPD/HMDP myocardial uptake Grade 2 or 3
2. Clonal screen	Absence of a clonal plasma cell process — serum FLC plus serum and urine immunofixation
3. Typical cardiac imaging	Any one of: echo LV wall thickness >12 mm; apical strain / (mid + basal strain) >1; grade ≥2 diastolic dysfunction; CMR LV wall thickness >upper limit of normal; global ECV >0.40; diffuse LGE; myocardium nulling before blood pool
Result	All three present → ATTR-CA diagnosed without biopsy

When Grade ≥2 uptake coexists with any abnormal FLC/immunofixation or MGUS the criteria are not met and the patient should be referred to a specialist amyloidosis centre. (sources/imaging-amyloidosis-2nd-aha-2021)

Bone scintigraphy. Uptake is graded visually against rib uptake (Perugini):

Grade	Myocardial uptake relative to ribs	Interpretation
0	None	Not ATTR — does not exclude AL
1	Less than ribs	Equivocal; reported in AL, AA and ApoA1 amyloidosis
2	Equal to ribs	Diagnostic of ATTR if clonal screen negative
3	Greater than ribs, with mild or absent rib uptake	Diagnostic of ATTR if clonal screen negative

Grade 2–3 uptake with a negative clonal screen is highly specific. In 1,498 patients with echo or CMR suggestive of amyloidosis and no monoclonal protein, positive predictive value was 100% (95% CI 98–100) — although the cohort came from expert centres and often had NYHA >II disease. (sources/imaging-amyloidosis-aha-2021)
SPECT is mandatory and timing has changed. The 2021 addendum made SPECT obligatory and moved imaging to 2–3 hours after injection; planar H/CL ratio alone at 1 hour produced false positives in lower-prevalence populations, and H/CL >1.5 was removed as a stand-alone "strongly positive" criterion. (sources/imaging-amyloidosis-aha-2021)
Scintigraphy cannot exclude AL. Grade 2–3 uptake occurs in more than 20% of AL patients, which is why immunofixation and FLC testing precede interpretation. (sources/imaging-amyloidosis-aha-2021)
Prognostic use is limited. Visual grade alone is not an independent outcome predictor, and serial scanning is not validated for monitoring. (sources/imaging-amyloidosis-aha-2021)

Echocardiography.

Morphology: LV wall thickness >1.2 cm without another explanation; biatrial enlargement; thickened interatrial septum and valves (>0.5 cm); pericardial effusion; normal or small LV cavity; sparkling myocardial texture. (sources/imaging-amyloidosis-aha-2021)
Apical sparing is the most specific sign. The "cherry-on-top" bullseye pattern is present in both AL and ATTR but not in HCM, hypertensive LVH or AS. Validated ratios: apical/(mid + basal) strain >1; septal apical-to-basal ratio >2.1; EF/strain ratio >4.1. (sources/echo-hfpef-ase-2025, rating: very high)
TDI 5-5-5 sign: s′, e′ and a′ all <5 cm/s at the mitral annulus, seen in advanced disease. (sources/echo-hfpef-ase-2025)
Diastolic progression: Grade 1 (impaired relaxation) → Grade 2 (pseudonormal) → Grade 3 (restrictive, associated with poor outcome). Advanced features are E/A >2.5, deceleration time <150 ms, IVRT <50 ms and septal/lateral e′ 3–4 cm/s. (sources/echo-hfpef-ase-2025)
Flow and prognosis: low stroke volume index with preserved LVEF, and paradoxical low-flow/low-gradient AS. RV involvement (reduced TAPSE, s′ <10 cm/s) confers worse prognosis; no formal echocardiographic staging system exists, so echo should not be used alone for risk stratification. (sources/echo-hfpef-ase-2025; sources/imaging-amyloidosis-aha-2021)

Cardiac magnetic resonance.

LGE: diffuse subendocardial enhancement is more typical of AL and transmural enhancement of ATTR, but the overlap is too great to subtype on pattern alone. (sources/esc-cmp-2023)
T1 mapping: native T1 is elevated (ShMOLLI sensitivity 92%, specificity 91%) and ECV >0.40 is highly suggestive; ECV rises before LGE is visible, making it an early disease marker and the most promising quantitative response biomarker. (sources/esc-cmp-2023; sources/imaging-amyloidosis-aha-2021)
Gadolinium kinetics: myocardium nulls before the blood pool on the TI scout — a characteristic finding. PSIR is mandatory and gadolinium-BOPTA must not be used. (sources/esc-cmp-2023; sources/imaging-amyloidosis-aha-2021)
Limitation: CMR cannot reliably distinguish AL from ATTR. (sources/esc-cmp-2023)

Biopsy and fibril typing.

Endomyocardial biopsy remains the gold standard — Congo red with apple-green birefringence under polarised light, reported as 100% sensitive but impractical as a screening test. (sources/imaging-amyloidosis-aha-2021)
Typing decides treatment. Mass spectrometry has 88% sensitivity and 96% specificity; immunohistochemistry is used at most centres with lower accuracy. Misclassification means plasma-cell-directed therapy instead of TTR-directed therapy, or the reverse. See entities/AL-Amyloidosis. (sources/lc-amyloidosis-nejm-2024, rating: very high)

Surveillance in asymptomatic carriers and monitoring. Appropriate-use ratings (A = appropriate, M = may be appropriate, R = rarely appropriate):

Scenario	Echo	CMR	Scintigraphy
Asymptomatic TTR carrier — initial	A (7)	M (6)	A (8)
Asymptomatic TTR carrier — recurrent	A (7)	M (6)	A (7.5)
Biopsy-proven ATTR-CA — every 12 months	A (7)	M (5)	R (2.5)
Biopsy-proven ATTR-CA — every 24 months	A (8)	A (8)	R (3)

Scintigraphy can detect pre-clinical ATTR-CA before echocardiographic or CMR changes in carriers, but is not validated for monitoring established disease. (sources/imaging-amyloidosis-2nd-aha-2021)

Management

Guideline position.

ESC 2026 gives disease-modifying therapy Class I, Level A in variant or wild-type ATTR-CA with NYHA I–III: a TTR silencer (vutrisiran) or a stabiliser (tafamidis or acoramidis). Patisiran is described but excluded because APOLLO-B reported no morbidity or mortality data. (sources/HF-ESC-2026, rating: very high)
Diagnosis is Class I, Level B: serum and urine immunofixation, serum free light chains and DPD/PYP/HMDP bone scintigraphy as initial testing, with genetic testing in cardiomyopathy Class I/C. (sources/HF-ESC-2026)
ESC 2023 named tafamidis as the approved therapy for both wild-type and hereditary ATTR-CM, and bone scintigraphy as the non-invasive gold standard. (sources/esc-cmp-2023)

Disease-modifying therapy.

Agent	Mechanism	Dose / route	Pivotal evidence	Headline result	Status
Tafamidis	Tetramer stabiliser, entropic binding, partial stabilisation	80 mg once daily, oral	ATTR-ACT, 30 months	All-cause mortality HR 0.70; CV hospitalisation HR 0.68; 30-month survival 70.5%	Approved; ESC I/A
Acoramidis	Tetramer stabiliser, enthalpic T119M mimicry, >90% stabilisation	800 mg twice daily, oral	ATTRibute-CM, n=632, 30 months	Win ratio 1.8; CV hospitalisation RR 0.50; 30-month survival 80.7% vs 74.3%, mortality not formally significant	Approved 2024 (Attruby); ESC I/A
Vutrisiran	GalNAc-conjugated siRNA silencing hepatic TTR mRNA	25 mg subcutaneously every 12 weeks	HELIOS-B, n=655, up to 42 months	Death or recurrent CV events HR 0.72; all-cause death HR 0.65; 81% TTR reduction	Approved for ATTR-CM; ESC I/A
Patisiran	LNP-formulated siRNA, intravenous	0.3 mg/kg every 3 weeks	APOLLO-B, n=360, 12 months	6MWT +14.7 m; KCCQ +3.7 points; hard composites not significant	Not approved for ATTR-CM; excluded from ESC 2026 recommendation
Nexiguran ziclumeran (nex-z)	CRISPR-Cas9 knockout of TTR in hepatocytes, single dose	Single intravenous infusion	Phase 1, n=36	TTR −90% at 12 months, durable to 24 months; 66% stable on all prognostic markers	Phase 3 MAGNITUDE paused October 2025

Tafamidis established the strategy. ATTR-ACT showed reduced all-cause mortality and cardiovascular hospitalisation over 30 months, and the long-term extension (median 58 months) found mortality reduction was dose-related, supporting the principle that more complete stabilisation produces better outcomes. (sources/acoramidis-attrcm-attributecm-nejm-2024, rating: very high)
Acoramidis met its four-step hierarchical endpoint and halved cardiovascular hospitalisation, with a 39.6 m 6MWT advantage and a 9.94-point KCCQ gain. The 30-month survival difference is not a formal mortality benefit — the Cox model violated proportional hazards and the log-rank sensitivity analysis was not significant. (sources/acoramidis-attrcm-attributecm-nejm-2024)
Vutrisiran is the first RNA interference agent with a mortality benefit in ATTR-CM: HELIOS-B reduced death or recurrent cardiovascular events and all-cause mortality through 42 months, with preserved 6MWT (+26.5 m) and KCCQ (+5.8 points), consistently on and off background tafamidis. The trial excluded NYHA IV and NYHA III with NAC stage 3 disease. (sources/vutrisiran-attrcm-heliosb-nejm-2025, rating: very high)
Patisiran achieved deeper knockdown than vutrisiran but, over 12 months, improved 6MWT and KCCQ without affecting hard endpoints (deaths 4 vs 10, HR 0.36, not significant). It is proof of concept for cardiac RNAi, not an approved ATTR-CM therapy. (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
Nex-z produces a one-time, permanent knockout rather than ongoing dosing: mean serum TTR fell 90% at 12 months and stayed suppressed through 24 months in all 11 patients completing follow-up, with 66% free of worsening on any prognostic marker. Phase 1 safety was manageable, but the Phase 3 MAGNITUDE trial paused screening and infusions in October 2025 after severe hepatotoxicity in a small percentage of participants, including one death from liver failure. (sources/nexz-crispr-attrcm-nejm-2024, rating: high; sources/gene-editing-acc-2026, rating: very high)
Other agents: inotersen is approved for ATTRv polyneuropathy and named in the ESC 2023 ATTR-CA pathway, without cardiac outcome data (sources/esc-cmp-2023); diflunisal is an older NSAID-class stabiliser, less potent than acoramidis in binding and stabilisation assays (sources/acoramidis-attrcm-attributecm-nejm-2024). Neither is named in the ESC 2026 recommendation.

Heart failure and atrial fibrillation.

Calcium channel blockers and digoxin should be avoided, and standard heart failure therapy otherwise applies. (sources/esc-cmp-2023; sources/HF-ESC-2026)
Anticoagulate AF regardless of CHA₂DS₂-VA score, and perform transoesophageal echo before cardioversion regardless of prior anticoagulation — the atrial myocardium is itself amyloidotic, so thromboembolic risk is not captured by clinical scores, and LAA thrombus can form in sinus rhythm. (sources/HF-ESC-2026; sources/imaging-amyloidosis-aha-2021)
Aetiology-specific HFpEF therapy is summarised in concepts/HFpEF-Management; ATTR-CA accounts for 5–13% of HFpEF. (sources/echo-hfpef-ase-2025)

Aortic stenosis.

Suspect ATTR when AS coexists with low ECG voltage relative to LV mass, a typical CMR pattern or a history of carpal tunnel syndrome, and screen with bone scintigraphy after excluding monoclonal protein. (sources/vhd-esc-2025, rating: very high)
Valve intervention remains indicated. Patients with concomitant severe AS and ATTR-CA usually benefit from valve intervention even when long-term prognosis is limited by amyloidosis. (sources/vhd-esc-2025)
Screening is not routine. Guidelines recommend testing only when ATTR is clinically suspected, despite the 8% prevalence reported in severe AS and 10–16% in older HFpEF or AS cohorts. (sources/vhd-esc-2025)

Monitoring.

Echocardiography every 12–24 months is appropriate for progression and for anticoagulation guidance (LA size and function, LAA assessment); every 6 months is only may-be-appropriate. (sources/imaging-amyloidosis-2nd-aha-2021)
CMR ECV is the most promising quantitative response marker, and NT-proBNP, troponin and eGFR are validated diagnostic and prognostic biomarkers. (sources/imaging-amyloidosis-aha-2021)
Serial scintigraphy is not recommended for progression or therapy response, and no imaging technique has been validated for therapy response against survival endpoints. (sources/imaging-amyloidosis-aha-2021)

Prognosis

Median survival is 2–6 years from diagnosis, although the figure predates silencer therapy. (sources/vutrisiran-attrcm-heliosb-nejm-2025, rating: very high)
Imaging predictors: RV involvement, impaired LV strain, short deceleration time, raised myocardial performance index and pericardial effusion; ECV and LGE pattern predict outcome in both AL and ATTR, whereas native T1 predicts in AL but not ATTR. (sources/imaging-amyloidosis-aha-2021)
Scintigraphic and autonomic predictors: H/CL >1.5 is associated with worse survival but visual grade alone is not independent; 123I-mIBG denervation precedes diphosphonate uptake in carriers, and late HMR <1.6 predicts poor prognosis, historically guiding transplant timing in ATTRv. (sources/imaging-amyloidosis-aha-2021)
No validated staging system guides therapy. HELIOS-B excluded NAC stage 3 with NYHA III, and the ESC I/A recommendation covers NYHA I–III, so both trial evidence and guideline scope stop short of advanced disease. (sources/vutrisiran-attrcm-heliosb-nejm-2025; sources/HF-ESC-2026)

Contradictions / Open Questions

AL versus ATTR misclassification — mass spectrometry is not universally available. Grade 2–3 scintigraphy occurs in >20% of AL patients, and both diseases can co-present with monoclonal gammopathy (for example V122I ATTR in Black patients), so imaging and clinical features cannot separate them without fibril typing. Mass spectrometry (sensitivity 88%, specificity 96%) is confined to reference laboratories and immunohistochemistry is less accurate, yet the two diagnoses require entirely different treatment. (sources/lc-amyloidosis-nejm-2024, rating: very high)
Prevalence estimates come from selected cohorts. The same phenotype yields 5–13% (HFpEF screening and autopsy), 8% (severe AS), 12% (HFpEF with LVH) and 10–16% (older HFpEF or severe AS) depending on source and population, so community burden is unknown — yet guidelines still decline to screen AS patients routinely despite that range. (sources/echo-hfpef-ase-2025; sources/esc-cmp-2023; sources/imaging-amyloidosis-aha-2021; sources/vhd-esc-2025)
The wall-thickness trigger and the diagnostic threshold disagree. AHA 2022 triggers investigation at ≥14 mm, whereas the consensus diagnostic criteria and the ESC definition of increased wall thickness use >12 mm. The reason for the gap is not stated, and a patient at 12–13 mm can satisfy the diagnostic criteria while falling below the screening trigger. (sources/HF-AHA-2022; sources/imaging-amyloidosis-2nd-aha-2021; sources/esc-cmp-2023)
Bone scintigraphy versus CMR — complementary but neither definitive alone. Scintigraphy establishes the subtype; CMR with native T1 and ECV quantifies fibrosis and prognosis. The roles differ, but the choice and sequence are not standardised, and CMR is preferred whenever AL is suspected. (sources/esc-cmp-2023; sources/imaging-amyloidosis-2nd-aha-2021)
Tafamidis timing is undefined. The optimal point of initiation relative to disease stage is unestablished: efficacy is limited in advanced disease with irreversible organ damage, yet no validated staging system guides prescribing, and early initiation is advocated without prospective comparison. (sources/esc-cmp-2023)
Acoramidis has no formal mortality benefit. In ATTRibute-CM the Cox model for death violated proportional hazards — curves crossed repeatedly before separating at about 19 months — and the prespecified log-rank analysis was not significant. The 30-month survival difference (80.7% vs 74.3%) is numerically favourable but cannot be claimed as a mortality benefit. (sources/acoramidis-attrcm-attributecm-nejm-2024, rating: very high)
Acoramidis versus tafamidis — no head-to-head comparison. Preclinical assays show superior potency and more complete stabilisation, and 30-month survival was numerically better than in ATTR-ACT, but the trials differ in era, NT-proBNP threshold (≥300 versus any) and population. Whether replacing one stabiliser with the other improves outcomes is untested. (sources/acoramidis-attrcm-attributecm-nejm-2024)
Silencer versus stabiliser, and whether to combine them, is unstudied. Tafamidis, acoramidis and vutrisiran each have positive Phase 3 trials and ESC 2026 gives the class I/A, but HELIOS-B allowed rather than randomised tafamidis use; the 40% of patients on tafamidis had HR 0.79 (95% CI 0.51–1.21), underpowered for any comparison. No trial has tested combination therapy, so sequencing and additivity remain unknown. (sources/vutrisiran-attrcm-heliosb-nejm-2025; sources/HF-ESC-2026)
All three positive trials show delayed curve separation. ATTRibute-CM separated at about 19 months — recapitulating the delayed tafamidis pattern — and HELIOS-B at about 6 months, and every trial enrolled established HF. This implies the benefit of treating pre-clinical or early disease — the population most likely to gain — has never been measured. (sources/acoramidis-attrcm-attributecm-nejm-2024; sources/vutrisiran-attrcm-heliosb-nejm-2025)
Patisiran versus vutrisiran — duration or drug? APOLLO-B (12 months) failed its hard endpoints, whereas HELIOS-B (up to 42 months) showed a mortality benefit, even though patisiran achieved deeper knockdown (87% versus 81%). Whether the difference reflects trial duration, subcutaneous delivery and adherence, or pharmacology cannot be resolved without an adequately powered comparison. (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
Permanent TTR knockout is unproven and now carries a hepatotoxicity signal. Nex-z suppresses TTR more deeply than any RNAi agent and does so permanently, but the evidence is a 36-patient open-label Phase 1 against Phase 3 mortality data for vutrisiran and tafamidis. The October 2025 MAGNITUDE pause — severe hepatotoxicity in a small percentage of participants, including one death from liver failure — was not seen in Phase 1, leaving open whether lifelong TTR deficiency is tolerable at scale. (sources/nexz-crispr-attrcm-nejm-2024, rating: high; sources/gene-editing-acc-2026, rating: very high)

Connections

Differential diagnosis: entities/AL-Amyloidosis · entities/RCM · entities/HCM · entities/Fabry-Disease · concepts/Fabry-Cardiomyopathy · concepts/Constrictive-vs-Restrictive — ATTR-CA can produce restrictive haemodynamics mimicking constrictive pericarditis
Imaging: concepts/Cardiac-Amyloidosis-Imaging · concepts/Late-Gadolinium-Enhancement · concepts/LV-Diastolic-Function · concepts/Phenotypic-Approach-to-Cardiomyopathy
Therapy: concepts/TTR-Stabilizer-Therapy · entities/Vutrisiran · entities/Patisiran · entities/Nexiguran-Ziclumeran · concepts/Gene-Silencing-Therapy · concepts/Gene-Editing-Risk-Benefit-Framework · concepts/Lipid-Gene-Therapy
Heart failure and valves: entities/Heart-Failure · entities/HFpEF · concepts/HFpEF-Management · concepts/Aortic-Stenosis · concepts/Valvular-Heart-Disease · entities/Atrial-Fibrillation
Genetics: concepts/Genetic-Testing-in-Cardiomyopathy · concepts/Incidental-Cardiovascular-Variants · concepts/DTC-Genetic-Testing — TTR is an ACMG secondary-findings gene
Other: concepts/Sudden-Cardiac-Death · concepts/AL-Amyloidosis-Staging — AL uses dFLC-based staging, distinct from anything used in ATTR