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: Approved for ATTR-CM (both ATTRwt and ATTRv) — stabilizes the TTR tetramer and reduces cardiac amyloid deposition. Recommended as disease-modifying therapy. (sources/esc-cmp-2023)
- Novel therapies: patisiran and inotersen (approved for familial polyneuropathy ± cardiomyopathy); second-generation RNA interference agents. (sources/esc-cmp-2023)
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
- 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)
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 sources/echo-hfpef-ase-2025
- Related to sources/imaging-amyloidosis-aha-2021
- Related to sources/imaging-amyloidosis-2nd-aha-2021