#cardiomyopathy #amyloidosis #genetics #multimodality-imaging

Transthyretin Amyloidosis (ATTR)

Details

Transthyretin amyloidosis (ATTR) is caused by misfolding and extracellular deposition of transthyretin (TTR) protein in the myocardium, producing a restrictive/infiltrative cardiomyopathy. Two main forms exist: ATTRwt (wild-type, previously "senile amyloidosis") affecting primarily men >65 years, and ATTRv (hereditary, TTR gene mutation) presenting earlier. ATTR is significantly underdiagnosed; cardiac ATTR (ATTR-CA) is increasingly recognized in patients with HFpEF, LVH, and aortic stenosis.

Epidemiology

ATTR-CA found in 8% of patients with severe aortic stenosis, 12% of HFpEF with LVH, 7% of LVH/HCM patients depending on age, and 7% of carpal tunnel syndrome patients undergoing surgery. (sources/esc-cmp-2023)
Carpal tunnel syndrome (often bilateral) is a red flag for ATTRwt — may precede cardiac symptoms by years. (sources/esc-cmp-2023)

Pathophysiology

TTR tetramer destabilization → monomer misfolding → extracellular amyloid deposition in myocardium → restrictive/infiltrative cardiomyopathy with progressive diastolic dysfunction and eventual biventricular failure. (sources/esc-cmp-2023)
LA dysfunction and a thrombogenic milieu develop even in normal sinus rhythm due to amyloid infiltration of the atrial wall — LAA thrombus can form in the absence of AF. (sources/imaging-amyloidosis-aha-2021)
In ATTRwt, wild-type TTR becomes structurally unstable with aging; in ATTRv, pathogenic TTR gene variants produce intrinsically unstable tetramers. (sources/esc-cmp-2023)
Co-existing AS and ATTR-CA may be causally interrelated — ATTR may contribute to AS progression through calcium-amyloid interaction in valve leaflets. (sources/vhd-esc-2025, rating: very high)

Clinical Presentation

Clinical red flags: Bilateral carpal tunnel syndrome (often preceding cardiac symptoms by years); severe aortic stenosis in elderly; HFpEF with LVH; unexplained LVH. (sources/esc-cmp-2023)
ECG findings: Low QRS voltage (especially in absence of other explanations); AV block; pseudoinfarction pattern. Low ECG voltage relative to LV mass is a specific clue — discordance between voltage and wall thickness. (sources/esc-cmp-2023, sources/vhd-esc-2025, rating: very high)
Echocardiographic red flags: LV wall thickness >1.2 cm; biatrial enlargement; thickened interatrial septum and valves; pericardial effusion; sparkling myocardial texture; "cherry-on-top" apical sparing GLS pattern on bullseye map (most specific echo sign — present in both AL and ATTR but not HCM/AS); TDI "5-5-5 sign" (s', e', a' all <5 cm/s); low stroke volume index with preserved LVEF. (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
Diastolic dysfunction progression: Early stage → Grade 1 (impaired relaxation); intermediate → Grade 2 (pseudonormal); advanced → Grade 3 (restrictive), associated with poor outcome. Advanced disease features: E/A >2.5, E velocity deceleration time (DT) <150 ms, IVRT <50 ms, septal and lateral e' velocities 3–4 cm/s. (sources/echo-hfpef-ase-2025, rating: very high)
Apical sparing pattern on LV GLS (speckle-tracking): Distinctive LV longitudinal strain phenotype with relative apical sparing compared with mid and basal segments; distinguishes amyloidosis from hypertensive LVH, HCM, and AS. Validated ratios: apical strain / (mid + basal strain) >1; septal apical-to-basal ratio >2.1; EF/strain ratio >4.1. (sources/echo-hfpef-ase-2025, rating: very high)

Diagnosis

Bone Scintigraphy (DPD/PYP/HMDP)

Gold standard for non-invasive diagnosis of ATTR-CA (Class I, Level B). Grade 2–3 tracer uptake in the absence of monoclonal protein establishes ATTR-CA diagnosis without biopsy (PPV 100% [95%CI 98–100], n=1,498 multicenter). (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
Visual grading system (vs rib uptake): Grade 0 = no uptake; Grade 1 = uptake < ribs; Grade 2 = uptake equal to ribs; Grade 3 = uptake > ribs with mild/absent rib uptake. Grade ≥2 = diagnostic of ATTR-CA if monoclonal protein excluded. Grade 1 may occur in AL, AA, or ApoA1 amyloidosis. Grade ≥2 reported in >20% of AL patients — serum/urine immunofixation + FLC assay is non-negotiable before ATTR diagnosis. (sources/imaging-amyloidosis-aha-2021)
Formal non-biopsy ATTR-CA diagnostic criteria: Requires ALL three: (1) 99mTc-PYP/DPD/HMDP Grade ≥2; (2) absence of clonal plasma cell process (FLC + serum/urine immunofixation); (3) typical imaging features — any one of: LV wall thickness >12 mm on echo, apical sparing GLS ratio (apical/mid+basal) >1, Grade ≥2 diastolic dysfunction on echo; CMR LV thickness >ULN, global ECV >0.40, diffuse LGE, or myocardium-before-blood-pool gadolinium nulling. When Grade ≥2 scintigraphy co-exists with any abnormal FLC/immunofixation or MGUS → NOT diagnostic; refer to specialist amyloid centre. (sources/imaging-amyloidosis-2nd-aha-2021)
SPECT protocol update (2021): SPECT is now mandatory in all scintigraphy studies (was optional). Preferred scan timing is 2–3 hours post-injection (1-hour planar-only imaging not recommended). H/CL ratio ≥1.5 alone is insufficient — myocardial uptake must be confirmed on SPECT first. H/CL criterion >1.5 as "strongly positive" has been removed from reporting. (sources/imaging-amyloidosis-aha-2021)

Cardiac Magnetic Resonance

LGE patterns: Diffuse subendocardial LGE (AL-predominant) or transmural LGE (ATTR-predominant). (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
T1 mapping: Elevated native T1 (ShMOLLI sensitivity 92%/specificity 91%); ECV >0.40 highly suggestive (elevated even before LGE apparent = early disease marker). (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
TI scout: Myocardium nulls before blood pool — a characteristic finding. PSIR technique mandatory; gadolinium-BOPTA must not be used. (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
Limitation: CMR cannot reliably distinguish AL from ATTR subtype. (sources/esc-cmp-2023)

Echocardiography

LV wall thickness >1.2 cm; biatrial enlargement; thickened interatrial septum and valves; pericardial effusion; sparkling myocardial texture. (sources/esc-cmp-2023, sources/imaging-amyloidosis-aha-2021)
Apical sparing GLS pattern on bullseye map — most specific echo sign (present in both AL and ATTR but not HCM/AS). (sources/esc-cmp-2023)
TDI "5-5-5 sign": s', e', a' all <5 cm/s — seen in advanced disease. (sources/echo-hfpef-ase-2025, rating: very high)
Diastolic dysfunction staging: Grade 1 (impaired relaxation) → Grade 2 (pseudonormal) → Grade 3 (restrictive, poor outcome). Advanced features: E/A >2.5, DT <150 ms, IVRT <50 ms. (sources/echo-hfpef-ase-2025, rating: very high)
Low stroke volume index with preserved LVEF; paradoxical low-flow/low-gradient AS pattern. (sources/echo-hfpef-ase-2025, rating: very high)

Genetic Testing

TTR gene sequencing identifies ATTRv and guides family screening. (sources/esc-cmp-2023)

Imaging Surveillance in Asymptomatic TTR Carriers

Echo: Appropriate (A, score 7) for both initial and recurrent evaluation. (sources/imaging-amyloidosis-2nd-aha-2021)
Scintigraphy: Appropriate (A, score 8 initial; 7.5 recurrent) — can detect pre-clinical ATTR-CA before echocardiographic or CMR changes. (sources/imaging-amyloidosis-2nd-aha-2021)
CMR: May Be Appropriate (M, score 6) — ECV may identify disease earlier than echo, but panel lacked consensus. (sources/imaging-amyloidosis-2nd-aha-2021)
Monitoring biopsy-proven ATTR-CA: Echo every 12 months Appropriate (A, 7); every 24 months Appropriate (A, 8); every 6 months only May Be Appropriate. CMR every 24 months Appropriate (A, 8). Serial scintigraphy Rarely Appropriate for monitoring. (sources/imaging-amyloidosis-2nd-aha-2021)

Management

Disease-Modifying Therapy

Tafamidis: First approved TTR stabilizer for ATTR-CM (ATTRwt and ATTRv). ATTR-ACT (NEJM 2018, 30 months): all-cause mortality HR 0.70; CV hospitalization HR 0.68; 30-month survival 70.5% in combined tafamidis groups. Dose-related mortality reduction with higher stabilization confirmed in long-term extension (median 58 months). Entropic (hydrophobic) binding mode; dose 80 mg OD. (sources/esc-cmp-2023)
Acoramidis (ATTRibute-CM, NEJM 2024): Second TTR stabilizer; BridgeBio Pharma. Phase 3 double-blind RCT (n=632; 90.3% ATTRwt; 30 months; acoramidis 800 mg BID vs placebo). Mimics the T119M natural protective TTR variant through enthalpic hydrogen bonding; achieves >90% TTR stabilization across the dosing interval. Primary 4-step hierarchical endpoint (death/CV hosp/NT-proBNP/6MWT) met: win ratio 1.8 (95% CI 1.4–2.2; P<0.001). CV hospitalization RR 0.496 (P<0.001); 6MWT +39.6 m (P<0.001); KCCQ-OS +9.94 pts (P<0.001); serum TTR +7.01 mg/dL (P<0.001). 30-month survival 80.7% vs 74.3%; curves diverged at ~19 months; Cox model violated proportional hazards; log-rank sensitivity analysis NS. Serious adverse events less frequent (54.6% vs 64.9%). FDA-approved 2024 (Attruby). (sources/acoramidis-attrcm-attributecm-nejm-2024 — very high)
Vutrisiran (HELIOS-B, NEJM 2025): Phase 3 double-blind RCT (n=655); subcutaneous GalNAc-siRNA (25 mg Q12W) silencing hepatic TTR mRNA — achieves 81% serum TTR reduction. In ATTR-CM (both ATTRwt and ATTRv): reduced composite of all-cause death + recurrent CV events (HR 0.72; 95% CI 0.56–0.93; P=0.01), reduced all-cause mortality through 42 months (HR 0.65; 95% CI 0.46–0.90; P=0.01), preserved 6MWT (+26.5 m vs placebo; P<0.001) and KCCQ-OS (+5.8 points; P<0.001). Benefits consistent on and off background tafamidis. First RNAi therapy proven to reduce mortality in ATTR-CM. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Patisiran (APOLLO-B, NEJM 2023): LNP-formulated siRNA (IV Q3W); 86.8% TTR knockdown in ATTR-CM. Phase 3 RCT (n=360; 12 months): primary 6MWT +14.69 m (P=0.02) and KCCQ-OS +3.7 pts (P=0.04) met; hard composite endpoints (death/CV events win ratio 1.27 NS; death/hospitalisation HR 0.88 NS) not significant; deaths 4 (2.2%) vs 10 (5.6%), HR 0.36 NS — underpowered. Exploratory signals favourable: LV mass −9.45 g, NT-proBNP ratio 0.80, troponin I ratio 0.87. Patisiran is not approved for ATTR-CM; results served as proof-of-concept for RNAi in cardiac amyloid. (sources/patisiran-attrcm-apollob-nejm-2023 — high)
Inotersen (ASO): approved for ATTRv polyneuropathy; limited ATTR-CM evidence. See concepts/TTR-Stabilizer-Therapy for detailed class comparison. (sources/esc-cmp-2023)
Nexiguran ziclumeran / nex-z (NEJM 2024, Phase 1): CRISPR-Cas9 in vivo gene editing via hepatotropic lipid nanoparticle; single IV infusion induces permanent NHEJ-mediated TTR gene knockout in hepatocytes. Phase 1 open-label trial (n=36; 50% NYHA III; 31% ATTRv; no concurrent TTR therapy; single site UK; median follow-up 18 months): mean serum TTR −89% at 28 days, −90% at 12 months, maintained through 24 months in all 11 patients completing 2 years. Disease appeared to stabilize at 12 months: 66% no worsening on any prognostic marker; NYHA improved in 47%; KCCQ +8 pts; 6MWT +5 m; cardiac imaging stable. Safety manageable: 5 infusion-related reactions (1 severe/self-limiting); 2 transient AST/ALT elevations; vitamin A persistently low (expected; no clinical deficiency); 1 unrelated death. Phase 3 MAGNITUDE trial (NCT06128629) ongoing. Unlike RNAi agents, nex-z delivers a one-time permanent knockdown rather than requiring ongoing dosing. (sources/nexz-crispr-attrcm-nejm-2024 — high)

Heart Failure Management

Standard HF guidelines apply; calcium channel blockers and digoxin should be used cautiously or avoided due to risk of toxicity/adverse haemodynamics in amyloidosis. (sources/esc-cmp-2023)

Anticoagulation

LAA thrombus can form in cardiac amyloidosis even in normal sinus rhythm due to LA dysfunction and thrombogenic milieu — some centres perform TEE before cardioversion even in anticoagulated patients. (sources/imaging-amyloidosis-aha-2021)

Serial Imaging for Monitoring

Serial echocardiography is reasonable for disease progression and anticoagulation guidance (LA size/function; TEE for LAA thrombus). (sources/imaging-amyloidosis-aha-2021)
CMR ECV is the most promising quantitative response biomarker — retrospective data show ECV and LV mass decrease with deep haematologic response in AL amyloidosis. (sources/imaging-amyloidosis-aha-2021)
Serial SPECT scintigraphy (99mTc-PYP/DPD/HMDP) is NOT recommended for monitoring — not validated for this purpose. (sources/imaging-amyloidosis-aha-2021)

Coexistence with Aortic Stenosis

ATTR-CA co-exists with AS in elderly patients and the two conditions may causally interrelate — ATTR may contribute to AS progression through calcium-amyloid interaction in the valve leaflets. (sources/vhd-esc-2025, rating: very high)
Screen with bone scintigraphy (after excluding monoclonal protein by immunofixation + free light chains) if ATTR is suspected in patients with AS: low ECG voltage relative to LV mass, typical CMR pattern, carpal tunnel syndrome history. (sources/vhd-esc-2025, rating: very high)
Valve intervention remains indicated despite co-existing ATTR-CA: patients with concomitant severe AS and ATTR-CA usually benefit from valve intervention, even if long-term prognosis is limited by amyloidosis. (sources/vhd-esc-2025, rating: very high)
ATTR screening is not yet routine in AS workup — current guidelines recommend it only when clinically suspected. (sources/vhd-esc-2025, rating: very high)

Contradictions / Open Questions

AL vs ATTR misclassification risk — mass spectrometry not universally available: Bone scintigraphy Grade ≥2 is reported in >20% of AL amyloidosis patients. Both AL and ATTR can co-present with monoclonal gammopathy (e.g., V122I ATTR variant in Black patients), making clinical and imaging distinction unreliable without fibril typing. Mass spectrometry (sensitivity 88%, specificity 96%) is the gold standard but limited to reference laboratories. Immunohistochemistry is used at most centres but has lower accuracy. Misclassification leads to entirely wrong treatment (plasma-cell-directed therapy vs TTR-stabilizer/silencer). See entities/AL-Amyloidosis. (sources/lc-amyloidosis-nejm-2024, rating: very high)
Prevalence estimates from selected screening populations — community burden unclear: The 8% rate of ATTR-CA in severe aortic stenosis and 12% in HFpEF with LVH derive from specialized screening programs and referral cohorts, not unselected community populations. These estimates may substantially overstate the true community prevalence of ATTR-CA and influence the threshold for routine bone scintigraphy screening in less selected patients. (sources/esc-cmp-2023)
Bone scintigraphy vs. CMR — complementary but neither definitive alone: Bone scintigraphy (Grade 2–3 uptake without monoclonal protein) is listed as Class I non-invasive diagnostic standard for ATTR-CA. However, CMR with native T1 and ECV provides unique information (fibrosis burden, prognosis) not available from scintigraphy. The two modalities serve different diagnostic roles, and the choice between them is not standardized. (sources/esc-cmp-2023)
Tafamidis — timing of initiation undefined: Tafamidis is recommended as disease-modifying therapy for ATTR-CM but the optimal timing of initiation relative to disease stage is not established. It has limited efficacy in advanced disease with irreversible organ damage (parallel to ERT in AFD), yet no validated staging system guides prescribing. Early initiation is advocated but not prospectively validated against late initiation. (sources/esc-cmp-2023)
Acoramidis mortality benefit not formally significant: In ATTRibute-CM, the Cox model for death from any cause violated proportional hazards assumptions (curves crossed multiple times early before separating at ~19 months). The prespecified log-rank sensitivity analysis was not significant. Numerical 30-month survival favored acoramidis (80.7% vs 74.3%), but formal mortality benefit cannot be claimed. (sources/acoramidis-attrcm-attributecm-nejm-2024 — very high)
Acoramidis vs tafamidis — no head-to-head clinical comparison: Pre-clinical assays show superior potency and stabilization with acoramidis. The 30-month survival was numerically better in ATTRibute-CM (80.7%) than ATTR-ACT (70.5%), but trials enrolled in different eras with different baseline NT-proBNP thresholds (≥300 vs any) and population characteristics. Whether acoramidis is clinically superior to tafamidis is unknown. (sources/acoramidis-attrcm-attributecm-nejm-2024 — very high)
Three disease-modifying classes but no class comparison data: Tafamidis (tetramer stabilizer), acoramidis (tetramer stabilizer), and vutrisiran (RNAi TTR knockdown) each have positive Phase 3 trials. The optimal agent, sequencing, and whether combining a stabilizer with RNAi provides additive benefit is entirely unstudied. (sources/acoramidis-attrcm-attributecm-nejm-2024, sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Vutrisiran vs tafamidis — no head-to-head comparison: HELIOS-B allowed but did not randomize tafamidis use; it cannot establish whether vutrisiran monotherapy is superior, equivalent, or inferior to tafamidis monotherapy. The subgroup on tafamidis (40% of patients) showed HR 0.79 (95% CI 0.51–1.21) — statistically underpowered. The optimal first-line disease-modifying agent, and whether combining both classes provides additive mortality benefit, remains unknown. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Delayed mortality benefit pattern shared across all three trials: ATTR-ACT (tafamidis), ATTRibute-CM (acoramidis), and HELIOS-B (vutrisiran) all show delayed curve separation (~19 months, ~19 months, ~6 months respectively). This implies optimal timing of therapy initiation — potentially in pre-clinical or early disease — has not been established by any of these trials, which enrolled patients with established HF. (sources/acoramidis-attrcm-attributecm-nejm-2024, sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Patisiran vs vutrisiran — is the difference trial duration or drug?: APOLLO-B (patisiran, 12 months) failed hard endpoints; HELIOS-B (vutrisiran, up to 42 months) demonstrated mortality benefit (HR 0.65). Patisiran achieves higher TTR knockdown (87% vs 81%) yet no mortality signal was demonstrated. Whether vutrisiran's superiority reflects the longer trial duration, the SC delivery enabling more consistent use, or a genuine pharmacological advantage is unknown; the two agents have not been compared in a head-to-head or adequately powered trial. (sources/patisiran-attrcm-apollob-nejm-2023 — high)
CRISPR gene editing (nex-z) vs RNAi — permanent knockdown without established efficacy AND new hepatotoxicity signal: Nex-z achieves −90% TTR suppression with a single IV dose (deeper than vutrisiran −81% and patisiran −87%), and this suppression is permanent. However, nex-z has only Phase 1 data (n=36, no control, open-label); vutrisiran and tafamidis each have Phase 3 mortality benefit data. In October 2025, the MAGNITUDE Phase 3 trial paused new screening and infusions due to severe hepatotoxicity in a very small percentage of participants, including one death from liver failure — a signal not observed in the Phase 1 cohort. Whether deeper, permanent TTR knockdown translates to greater clinical benefit in ATTR-CM, and the long-term safety of lifelong TTR deficiency, remains unresolved and now complicated by this Phase 3 safety concern. (sources/nexz-crispr-attrcm-nejm-2024 — high; sources/gene-editing-acc-2026 — very high)

Connections

Related to entities/HCM
Related to entities/RCM
Related to concepts/Constrictive-vs-Restrictive — ATTR-CA can produce restrictive haemodynamics mimicking constrictive pericarditis
Related to concepts/Late-Gadolinium-Enhancement
Related to concepts/Phenotypic-Approach-to-Cardiomyopathy
Related to concepts/Sudden-Cardiac-Death
Related to concepts/Aortic-Stenosis
Related to concepts/Valvular-Heart-Disease
Related to concepts/LV-Diastolic-Function — diastolic progression and echo features in amyloidosis
Related to concepts/Cardiac-Amyloidosis-Imaging — full multimodality imaging framework
Related to entities/Vutrisiran — RNAi therapeutic for ATTR-CM (HELIOS-B mortality benefit)
Related to entities/Patisiran — first RNAi agent tested in ATTR-CM (APOLLO-B); proof-of-concept; not approved for ATTR-CM
Related to entities/Nexiguran-Ziclumeran — CRISPR-Cas9 one-time TTR gene knockout; Phase 1 data; Phase 3 MAGNITUDE trial ongoing
Related to concepts/TTR-Stabilizer-Therapy — detailed comparison of tafamidis vs acoramidis as a class
Related to concepts/CRISPR-Cas9-in-Channelopathies — gene editing platform; first clinical application to ATTR
Related to entities/AL-Amyloidosis — key differential; plasma cell dyscrasia vs TTR misfolding; mass spectrometry critical for distinction
Related to concepts/AL-Amyloidosis-Staging — Mayo 2004/2012/European/renal staging for AL (distinct from ATTR staging)
Related to sources/echo-hfpef-ase-2025
Related to sources/imaging-amyloidosis-aha-2021
Related to sources/imaging-amyloidosis-2nd-aha-2021
Related to sources/vutrisiran-attrcm-heliosb-nejm-2025
Related to sources/acoramidis-attrcm-attributecm-nejm-2024