ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis — Part 1

Authors, Journal, Affiliations, Type, DOI

• Lead Author: Sharmila Dorbala (Brigham and Women's Hospital / Harvard Medical School)
• Co-Chair: Jamieson M. Bourque (University of Virginia)
• Journal: Circulation: Cardiovascular Imaging
• Year: 2021; 14:e000029
• Societies: ASNC, AHA, ASE, EANM, HFSA, ISA, SCMR, SNMMI (8 societies)
• Type: Multi-society expert consensus (Part 1 of 2)
• DOI: https://doi.org/10.1161/HCI.0000000000000029

Overview

This is the first 8-society expert consensus establishing evidence-based standards and standardized imaging protocols for multimodality imaging in cardiac amyloidosis using echocardiography, CMR, and radionuclide imaging. Part 1 reviews the evidence base and defines standardized acquisition, interpretation, and reporting. Part 2 (separate document) addresses diagnostic criteria and appropriate utilization indications. A key addendum updated SPECT to mandatory status and revised 99mTc-PYP timing to 2–3 hours after findings of false-positive diagnoses based on planar H/CL ratio alone at 1 hour in lower-prevalence populations.

Keywords

Cardiac amyloidosis, AL amyloidosis, ATTR amyloidosis, echocardiography, cardiovascular magnetic resonance, radionuclide imaging, multimodality imaging, 99mTc-PYP, DPD, HMDP, late gadolinium enhancement, T1 mapping, extracellular volume, speckle-tracking, global longitudinal strain

Key Takeaways

Overview of Cardiac Amyloidosis

• Two main types: AL amyloidosis (monoclonal light chain from bone marrow plasma cells) and ATTR amyloidosis (transthyretin protein; wild-type ATTRwt or hereditary ATTRv from TTR gene variants)
• ATTRwt prevalence: 10–16% of older patients with HFpEF or severe aortic stenosis; Val122Ile variant in 3.4% of African Americans (~2 million US carriers)
• AL amyloidosis: median survival <6 months untreated; anti-plasma cell therapy now extends median survival >5 years
• Cardiac amyloidosis is the dominant clinical feature in ATTRwt (100% cardiac) and common in AL (up to 75%)
• Tafamidis (TTR stabilizer) received FDA approval for ATTR cardiomyopathy following randomized trial demonstrating reduced all-cause mortality

Biomarkers and Biopsy

• Endomyocardial biopsy remains gold standard (100% sensitive) but impractical as screening test
• Serum/urine immunofixation + serum FLC assay required to exclude AL amyloidosis
• In ATTR-CA, NT-proBNP, cardiac troponin, and eGFR validated as diagnostic and prognostic markers
• TTR gene sequencing required to distinguish ATTRwt from ATTRv

Echocardiography — Diagnosis

• Morphological red flags: LV wall thickness >1.2 cm without other explanation; biatrial enlargement; thickened interatrial septum and valves (>0.5 cm); pericardial effusion; normal/small LV cavity; sparkling myocardial texture
• Tissue Doppler "5-5-5 sign": All TDI velocities (s', e', a') <5 cm/s at mitral annulus — highly suggestive in advanced disease
• Global longitudinal strain (GLS): Reduced GLS (absolute value <–15%) with preserved LVEF and radial shortening is characteristic; apical sparing is key differentiator
• "Cherry-on-top" sign on bullseye map: Apical preservation with severely impaired basal and mid-LV longitudinal strain — the most specific echocardiographic sign for cardiac amyloidosis (does not distinguish AL vs ATTR)
• Myocardial contraction fraction (MCF): Ratio of stroke volume to myocardial volume; independent of chamber geometry; correlates strongly with LV longitudinal strain
• Stroke volume index: Prognostic in AL cardiac amyloidosis independently of biomarker staging; routinely calculable
• Left atrial strain (reservoir + pump) frequently impaired regardless of LA size — reflects raised filling pressures AND direct atrial amyloid infiltration; may predispose to LAA thrombus even in sinus rhythm
• Right ventricular involvement: Reduced TAPSE, TDI s' <10 cm/s, RV longitudinal strain; RV involvement confers worse prognosis
• Echocardiographic reporting categories: Not suggestive / Strongly suggestive / Equivocal

Echocardiography — Prognosis

• LV longitudinal strain, E-wave deceleration time, myocardial performance index, pericardial effusion all predict worse outcomes
• No formal echocardiographic staging system for ATTR or AL exists; echocardiography should not be used in isolation for risk stratification

Cardiac Magnetic Resonance (CMR) — Diagnosis

• LGE patterns: Diffuse subendocardial (more prevalent in AL) and transmural (more prevalent in ATTR); global and biventricular in advanced disease; basal predilection progressing to transmurality
• PSIR technique (phase-sensitive inversion recovery) is recommended over standard mag-IR LGE — eliminates need to optimize null-point settings; more robust and operator-independent
• Diagnostic accuracy of LGE: Sensitivity 85–90%, specificity ~92% (meta-analysis, 7 studies)
• TI scout sign: Myocardium nulls before or concurrent with blood pool — confirmatory sign visible on TI scout (reflects ECV approximating plasma volume)
• Native T1 mapping: ShMOLLI method sensitivity 92%, specificity 91%; composite extracellular + intracellular signal; utility when contrast contraindicated
• ECV mapping: ECV >0.40 highly suggestive of cardiac amyloidosis; isolates extracellular signal; elevated even when LGE and conventional testing suggest no involvement (early disease marker); tracks amyloid burden over time
• T2 mapping: Independent prognostic factor in AL cardiac amyloidosis; reflects myocardial oedema; not part of standard clinical protocol
• CMR CANNOT definitively distinguish AL from ATTR cardiac amyloidosis
• Cyclic gadolinium agents required; partially protein-bound agents (gadolinium-BOPTA/MultiHance) must NOT be used — ECV technique and characteristic LGE pattern unreliable with these agents
• Reporting categories: Not suggestive / Strongly suggestive / Equivocal

CMR — Prognosis

• LGE pattern is independent predictor of prognosis in both AL and ATTR after adjustment for echo and biomarkers; progression from normal → subendocardial → transmural correlates with disease staging
• Higher native T1 stratifies prognosis in AL (not ATTR); ECV predicts prognosis in both AL and ATTR
• T2 mapping (myocardial oedema) independent predictor in AL

Radionuclide Imaging (99mTc-PYP/DPD/HMDP) — Diagnosis

• Preferential ATTR uptake mechanism (vs AL): proposed calcium-mediated; also modulated by TTR fibril proteolysis (full-length vs C-terminal fragments)
• Visual grading scale:
  • Grade 0: No myocardial uptake, normal bone uptake
  • Grade 1: Myocardial uptake < rib uptake
  • Grade 2: Myocardial uptake = rib uptake
  • Grade 3: Myocardial uptake > rib uptake with mild/absent rib uptake
• Grade ≥2 + exclusion of monoclonal protein = ATTR-CA without biopsy (specificity and PPV >98%; multicenter, n=1,498, PPV 100% [95%CI 98–100])
• Grade 1 may be seen in AL, AA amyloidosis, and ApoA1 amyloidosis; not diagnostic of ATTR
• Grade ≥2 has been reported in >20% of AL amyloidosis patients — thus excluding monoclonal protein is mandatory before ATTR diagnosis
• H/CL (heart/contralateral lung) ratio: ≥1.5 at 1 hour or ≥1.3 at 3 hours supports ATTR-CA — but ONLY when myocardial uptake is confirmed on SPECT; H/CL ratio alone is insufficient
• 99mTc-PYP, DPD, and HMDP appear interchangeable (no direct head-to-head comparison); DPD/HMDP limited in USA; PYP limited in Europe
• Extra-cardiac amyloid (skeletal muscle, lung) detectable on DPD/HMDP whole-body imaging

Radionuclide — Addendum (Critical Protocol Update)

• SPECT is now mandatory in ALL studies (regardless of timing) — required to confirm myocardial vs blood pool/bone uptake
• Preferred timing revised to 2–3 hours post-injection (was 1 hour in original); 1-hour imaging is optional only
• 1-hour planar-only imaging is NOT recommended
• If excess blood pool activity at 1 hour → repeat SPECT at 3 hours
• H/CL ratio criterion >1.5 as "strongly positive" has been REMOVED from reporting (no longer listed in Part 2 diagnostic criteria)
• Errors that prompted addendum: (1) diagnosing ATTR based on H/CL ratio without SPECT confirmation; (2) blood pool activity misread as positive; (3) missing AL amyloidosis by not ordering FLC/immunofixation

Radionuclide — Prognosis

• Degree of cardiac uptake (H/CL ratio, H/WB ratio) correlates with LV wall thickness, troponin, NT-proBNP, ECV, LV EF, and overall mortality
• H/CL >1.5 associated with worse survival in ATTR-CA (multicenter)
• Visual grade alone NOT shown to be independent predictor of outcomes
• 123I-mIBG: cardiac sympathetic denervation precedes diphosphonate uptake in TTR mutation carriers; late HMR <1.6 predicts poor prognosis; guides liver transplant timing in ATTRv

Management Imaging

• Serial transthoracic echocardiography: reasonable for disease progression monitoring and anticoagulation guidance (LA function, LAA assessment)
• CMR ECV: emerging tool to assess amyloid burden response to therapy; retrospective data show LV mass and ECV decrease with complete/very good partial chemo response in AL
• Serial SPECT 99mTc-PYP/DPD/HMDP: NOT recommended for disease progression or therapy response monitoring (not validated for this purpose)
• No imaging technique has been validated for assessing therapy response in prospective studies with survival endpoints

Standardized Protocols Summary

• Echo: ASE/EACVI guidelines; report wall thickness + texture, TDI velocities, GLS bullseye map, diastolic function, hemodynamics, RV wall thickness
• CMR protocol (steps 1–7): Cine → Native T1 map → T2 → Contrast (cyclic gadolinium) → ECV T1 map (≥10 min post-contrast) → TI scout → PSIR LGE
• Scintigraphy: 10–20 mCi IV; 2–3h preferred (1h optional); anterior + lateral planar; SPECT mandatory; CT attenuation correction recommended; SPECT/CT fusion helpful

Limitations of the Document

• Predominantly single-centre small studies; multicenter larger studies limited
• No prospective randomised clinical trial data for imaging-based diagnostic or treatment strategies
• Most evidence from patients with NYHA Class >II (advanced disease); early/pre-clinical ATTR detection yield not validated
• Verification bias limits true specificity of LGE (only CMR-positive cases typically referred for biopsy)
• No imaging technique validated against survival for therapy response monitoring
• Diagnostic accuracy data comes predominantly from expert centers with high disease prevalence — PPV may be lower in general practice settings

Key Concepts Mentioned

• concepts/Cardiac-Amyloidosis-Imaging — primary concept page for this source
• concepts/Late-Gadolinium-Enhancement — LGE patterns in amyloidosis; PSIR technique; ECV
• concepts/LV-Diastolic-Function — restrictive filling pattern; 5-5-5 sign; diastolic staging

Key Entities Mentioned

• entities/ATTR-Amyloidosis — ATTR diagnosis, scintigraphy grading, imaging protocols, prognosis
• entities/Heart-Failure — HFpEF as presentation phenotype; ATTR prevalence in HFpEF
• entities/HCM — differential diagnosis of increased LV wall thickness; apical sparing differentiates amyloidosis
• entities/Atrial-Fibrillation — LAA thrombus risk in amyloidosis even in sinus rhythm; anticoagulation guidance

Wiki Pages Updated

• Created: wiki/sources/imaging-amyloidosis-aha-2021.md (this file)
• Created: wiki/concepts/Cardiac-Amyloidosis-Imaging.md
• Updated: wiki/entities/ATTR-Amyloidosis.md
• Updated: wiki/concepts/Late-Gadolinium-Enhancement.md
• Updated: wiki/wikiindex.md
• Updated: wiki/sourceindex.md