ATTR cardiac amyloidosis found during aortic stenosis work-up — case discussion

Presentation

Practice case (not a real patient). An 82-year-old man in Australia is referred with heart failure in NYHA class II and severe aortic stenosis for consideration of transcatheter aortic valve replacement.^[3] His echocardiogram shows a non-dilated left ventricle with increased wall thickness, and his ECG shows low QRS voltage relative to that thickness.^[3][1] He had bilateral carpal tunnel syndrome some years ago.^[1]

Step 1 — Should amyloidosis be considered?

Discussion:

• The ESC 2021 position statement says increased wall thickness in a non-dilated LV should trigger further evaluation in elderly patients with severe aortic stenosis, particularly those undergoing transcatheter aortic valve replacement.^[3]
• ESC 2023 reports ATTR cardiac amyloidosis in 8% of patients with severe aortic stenosis screened with bone scintigraphy.^[2]
• 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]
• ESC 2026 Table 20 lists low QRS voltage relative to LV thickness (TTR and AL) and bilateral carpal tunnel syndrome (TTR only) as red flags.^[1]

Step 2 — Which tests, and in what order?

Discussion:

• ESC 2026: in patients with HF and a suspicion of cardiac amyloidosis, initial testing with serum and urine immunofixation, a serum free light chain assay and DPD/PYP/HMDP bone scintigraphy is recommended (Class I, Level B).^[1]

• The 2025 ESC/EACTS valve guideline says that when ATTR is suspected, monoclonal protein should be excluded with immunofixation and quantitative free light chains, and the diagnosis ascertained by diphosphonate scintigraphy.^[8]

• The 2022 AHA/ACC/HFSA guideline says a technetium pyrophosphate (99mTc-PYP) scan and the light-chain screen can be ordered at the same time for convenience, but the PYP scan is interpreted only in the context of a negative monoclonal light chain screen.^[4]

• Result: DPD scintigraphy shows Grade 3 myocardial uptake, confirmed as myocardial on SPECT. SPIE and UPIE show no monoclonal protein, and the serum free light chain ratio is within the normal range.^[3]

Step 3 — Can the diagnosis be made without a biopsy?

Discussion:

• Yes. The ESC 2021 position statement allows ATTR cardiac amyloidosis to be diagnosed without histology when typical echocardiographic or CMR findings accompany Grade 2 or 3 uptake and a clonal dyscrasia is excluded by all of serum free light chains, serum immunofixation and urine immunofixation.^[3]

• The next step it names is genetic testing to differentiate between ATTRv and ATTRwt.^[3]

• His age does not remove the need: ESC 2023 says TTR genetic testing is recommended in all ATTR-CM patients regardless of age, and the 2022 AHA/ACC/HFSA guideline recommends TTR gene sequencing once transthyretin cardiac amyloidosis is diagnosed (COR 1, LOE B-NR).^[2][14]

• Result: no pathogenic TTR variant is found, so he has wild-type ATTR cardiac amyloidosis.^[4]

Step 4 — Does the amyloid change the valve decision?

Discussion:

• The 2025 ESC/EACTS valve guideline says that despite the limited long-term prognosis of ATTR cardiac amyloidosis, patients with concomitant severe aortic stenosis usually benefit from valve intervention.^[8]
• The choice of valve procedure is covered in the aortic stenosis topic.

Step 5 — Disease-specific treatment and referral

Discussion:

• ESC 2026: a TTR silencer (vutrisiran) or stabiliser (tafamidis or acoramidis) is recommended in variant or wild-type ATTR cardiac amyloidosis with NYHA classes I–III, to reduce progression of symptoms and the risk of cardiovascular hospitalisation and all-cause death (Class I, Level A); his NYHA class II lies within that range.^[1]
• 2022 AHA/ACC/HFSA: benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis or eGFR below 25 mL/min/1.73 m2; his severe aortic stenosis is relevant to that statement.^[4]
• The 2024 ANZ consensus statement advocates referral to specialist amyloidosis centres with multidisciplinary teams for the assessment and management of ATTR-CA.^[13]
• In 2024 it reported that tafamidis had a positive Pharmaceutical Benefits Advisory Committee recommendation and would soon be available in Australia for ATTR-CA in NYHA class 1 and 2, with prescribing limited to cardiologists and amyloidosis specialists; his NYHA class II is within that group.^[13]

Step 6 — Six months later he develops atrial fibrillation

Discussion:

• ESC 2024 AF: oral anticoagulation is recommended in all patients with AF and cardiac amyloidosis, regardless of CHA2DS2-VA score, to prevent ischaemic stroke and thromboembolism (Class I, Level B).^[5]
• ESC 2026 HF: transoesophageal echocardiography is necessary before cardioversion to exclude intracardiac thrombus, regardless of how long anticoagulation has been given.^[1]
• ESC 2026 HF: digoxin is generally discouraged in cardiac amyloidosis because of a high risk of toxicity.^[1]

Learning points

• Think of ATTR in older patients with severe aortic stenosis and a thick, non-dilated LV, particularly before transcatheter valve replacement (ESC 2021 position statement).^[3]
• Read a positive bone scan only alongside SPIE, UPIE and serum free light chains; non-invasive diagnosis is for ATTR only (ESC 2021 position statement).^[3]
• Patients with ATTR and severe aortic stenosis usually benefit from valve intervention (ESC/EACTS 2025).^[8]