cardiac amyloidosis
Contents
Infiltrative cardiomyopathy caused by misfolded protein deposition in the myocardium. Two types: AL (light chain, from clonal plasma cell disorder — haematological emergency) and ATTR (transthyretin, wild-type or hereditary — now treatable with TTR stabilisers). ATTR-wt may account for >1 in 8 HFpEF cases.
when to suspect
Workup warranted when LV wall thickness >12 mm + ≥1 red flag:
- voltage-mass mismatch — low/normal voltage on ECG despite thick walls on echo (low voltage seen in only 25–40% of ATTR; voltage-to-mass ratio is more sensitive)
- apical sparing on strain imaging (bull’s-eye pattern)
- bilateral carpal tunnel — may precede cardiac disease by 5–10 years (ATTR); biceps tendon rupture, spinal stenosis are other harbingers
- persistent troponin elevation with clean coronaries
- unexplained AV block or prior pacemaker
- low-flow low-gradient AS with EF >40% — ATTR present in ~16% of patients with severe calcific AS undergoing TAVR
- normotensive HFpEF in a previously hypertensive patient (“disappearing hypertension”)
- macroglossia, periorbital purpura — pathognomonic for AL
- unexplained neuropathy or dysautonomia
Increased wall thickness from infiltration should not be called “LVH” — this causes premature closure and delays the diagnosis of amyloidosis.
classification
| feature | AL amyloidosis | ATTR wild-type | ATTR hereditary |
|---|---|---|---|
| protein | immunoglobulin light chains | native transthyretin | mutant transthyretin |
| cause | clonal plasma cell dyscrasia | age-related misfolding | TTR gene mutation (AD) |
| typical age | 50–70 | >70 (mostly men) | 30–80 (varies by mutation) |
| extracardiac | renal (nephrotic syndrome), neuropathy, liver, soft tissue | carpal tunnel, spinal stenosis | neuropathy (often dominant), carpal tunnel |
| prognosis untreated | median ~6 months (cardiac) | median 3–5 years | variable |
| treatment | chemotherapy (treat the clone) | TTR stabiliser | TTR stabiliser ± gene silencer |
AL is a haematological emergency. Every patient with suspected cardiac amyloidosis needs a clonal workup before anything else.
diagnostic workup
step 1 — rule out AL (mandatory)
Order all three:
- serum free light chains (sFLC) — kappa/lambda ratio
- serum immunofixation (IFE) — more sensitive than SPEP; prefer IFE
- urine immunofixation
Combined sensitivity ~99%. If any abnormal → urgent haematology referral + tissue biopsy (fat pad aspirate first; organ biopsy if negative with high suspicion). Congo red staining + mass spectrometry for typing.
step 2 — Tc-99m PYP scan (if clonal screen negative)
| PYP grade | interpretation |
|---|---|
| 0 | no uptake — amyloid unlikely |
| 1 | mild uptake < bone — indeterminate; biopsy needed |
| 2–3 | uptake ≥ bone — diagnostic for ATTR (if clonal screen negative) |
Grade 2–3 + negative clonal workup: specificity >99%, PPV 100% — no biopsy needed.
step 3 — genetic testing (if ATTR confirmed)
- TTR gene sequencing — wild-type vs hereditary
- key variants: Val122Ile (also Val142Ile; 3–4% of Black Americans, cardiac-predominant), Val30Met (neuropathy-predominant), Thr60Ala (mixed)
- first-degree relatives with positive screen → echo starting 10 years before the index patient’s age at diagnosis
cardiac MRI
Not required for diagnosis. Useful when the differential is broad (hypertrophic cardiomyopathy, Fabry, sarcoidosis) or when haematology needs to confirm cardiac involvement in biopsy-proven AL.
management
AL amyloidosis — treat the clone
Urgent haematology referral. Treatment is chemotherapy analogous to multiple myeloma:
- first-line: D-VCd (daratumumab + bortezomib + cyclophosphamide + dexamethasone) — ANDROMEDA (2021)
- ASCT in selected patients (Mayo stage I–II)
- goal: rapid normalisation of dFLC → organ response follows over months
ATTR amyloidosis — TTR stabilisers
| agent | trial | result |
|---|---|---|
| tafamidis (Vyndamax) 61 mg daily | ATTR-ACT (2018) | ↓all-cause mortality (HR 0.70, 95% CI 0.51–0.96), ↓CV hospitalisations; NNT ~8 at 30 months |
| acoramidis (Attruby) 712 mg BID | ATTRibute-CM (2024) | ↓composite of mortality + CV hospitalisation (HR 0.64, 95% CI 0.50–0.83) over 30 months |
Both are approved TTR stabilisers for ATTR-CM (2025 ACC Concise Clinical Guidance). Benefit greatest when started early (NYHA I–II).
TTR stabilisers are expensive (~$200,000/year). Provincial coverage criteria vary.
ATTR — gene silencers
| drug | route | indication | key trial |
|---|---|---|---|
| vutrisiran (Amvuttra) | SC q3 months | ATTR-CM (wt and hereditary) — FDA-approved cardiac indication | HELIOS-B (2024) — ↓CV mortality, CV hospitalisations, and urgent HF visits |
| patisiran (Onpattro) | IV q3 weeks | hATTR polyneuropathy (cardiac subgroup benefit in APOLLO) | APOLLO (2018) |
Vutrisiran is the first gene silencer with a dedicated cardiac approval. Patisiran showed cardiac benefit in APOLLO subgroup analysis but the APOLLO-B co-administration trial with tafamidis did not gain approval.
supportive care
- loop diuretics — mainstay of volume management; narrow therapeutic window (easily too dry or overloaded); tolerate mild oedema
- low threshold to stop vasodilators (ACEi/ARB, ARNi) and beta-blockers — no demonstrated benefit in amyloid cardiomyopathy; often harmful due to fixed stroke volume and autonomic dysfunction
- beta-blockers: low-dose bisoprolol (≤2.5 mg/d) may be cautiously considered if EF ≤40% or for AF rate control, but discontinue if not tolerated (2025 ACC guidance)
- SGLT2 inhibitors and MRAs — options for congestion relief; a multicenter propensity-matched cohort (n=440) showed SGLT2i associated with reduced all-cause mortality (HR 0.57) and HF hospitalisation (HR 0.57) in ATTR-CM (Porcari, JACC. 2024); 2025 ACC guidance lists both as options but notes routine use not yet supported by RCT data
- AF: anticoagulate all patients regardless of CHA₂DS₂-VASc — high thromboembolic risk from atrial infiltration and stasis; amiodarone is best tolerated for rate/rhythm control
- neuropathy: ATTRv with neuropathy → neurology referral (gene silencer eligible); symptomatic: pregabalin, gabapentin, duloxetine; autonomic: midodrine, droxidopa, fludrocortisone
what NOT to do
| drug | concern |
|---|---|
| non-DHP CCBs (verapamil, diltiazem) | in AL: bind amyloid fibrils → heart block, cardiogenic shock; in ATTR: negative inotropy/chronotropy in preload-dependent heart. Avoid entirely in both types |
| digoxin | binds amyloid fibrils (AL) → toxicity at “therapeutic” levels; avoid or use extreme caution |
| beta-blockers | ↓CO in rate-dependent physiology; low-dose may be tolerated in select patients (see above) |
| ACEi / ARBs / ARNi | worsen orthostatic hypotension; discontinue if symptomatic |
- do not call increased wall thickness “LVH” without considering infiltration
- do not apply standard HFrEF GDMT — these patients are preload-dependent
- do not biopsy if PYP grade 2–3 and clonal screen is negative
extracardiac manifestations
- renal: AL → glomerular light chain deposition → nephrotic syndrome; AA → chronic inflammation (RA, TB, FMF); ATTR rarely affects kidneys
- neurological: peripheral neuropathy (hATTR > AL), autonomic dysfunction (orthostatic hypotension, gastroparesis, erectile dysfunction), bilateral carpal tunnel, lumbar spinal stenosis (ATTR-wt)
- AL soft tissue clues: macroglossia (nearly pathognomonic), periorbital purpura, hepatomegaly, acquired factor X deficiency
- AL diagnosis requires all 4: clonal plasma cell disorder + systemic syndrome + Congo red positive biopsy + light chain typing
key trials
| trial | year | drug | result |
|---|---|---|---|
| ATTR-ACT | 2018 | tafamidis | ↓mortality (HR 0.70), ↓CV hospitalisations; NNT ~8 at 30 months |
| ATTRibute-CM | 2024 | acoramidis | ↓mortality + CV hospitalisation composite (HR 0.64) |
| HELIOS-B | 2024 | vutrisiran | ↓primary composite (HR 0.72); all-cause mortality HR 0.65 through 42 months |
| ANDROMEDA | 2021 | D-VCd | deeper haematological and organ response in AL amyloidosis |
| APOLLO | 2018 | patisiran | improved neuropathy; cardiac subgroup benefit |