cardiac amyloidosis

Infiltrative cardiomyopathy caused by extracellular deposition of misfolded protein fibrils. Two main types: AL (light-chain, cancer-associated) and ATTR (transthyretin — wild-type or hereditary). Increasingly recognised as a cause of HFnrEF and “low-flow low-gradient” aortic stenosis. Non-invasive diagnosis of ATTR is now possible with Tc-99m-PYP scintigraphy. Traditional HF drugs (BB, CCB, digoxin) are often harmful.

types

	AL amyloidosis	ATTR wild-type	ATTR hereditary
protein	immunoglobulin light chains	normal transthyretin (misfolded)	mutant transthyretin
underlying disease	plasma cell dyscrasia (myeloma spectrum)	age-related (>65, M > F)	autosomal dominant (TTR gene variants)
organ involvement	heart, kidney, liver, nerves, soft tissue	primarily heart	heart + neuropathy (varies by variant)
prognosis (untreated)	median ~6 months with cardiac involvement	median ~3–5 years	variable by variant
treatment	chemotherapy targeting plasma cells	tafamidis (TTR stabiliser)	tafamidis, inotersen, patisiran (TTR silencers)

when to suspect cardiac amyloidosis

red flags — think amyloid

LVH on echo with low voltage on ECG (voltage-mass mismatch)
low-flow low-gradient aortic stenosis with LVEF >40%
bilateral carpal tunnel syndrome (especially pre-dating cardiac symptoms)
unexplained peripheral/autonomic neuropathy
HFnrEF with disproportionate diastolic dysfunction
speckle-tracking echo showing apical sparing pattern (relative apical preservation of longitudinal strain)

diagnostic workup

step 1 — screening

Test	Finding
ECG	low voltage (limb leads <5 mm) or pseudo-infarct pattern; AF common
echo	concentric LVH, biatrial enlargement, diastolic dysfunction, pericardial effusion, thickened valves, granular/sparkling myocardium
cardiac MRI	diffuse subendocardial or transmural LGE; elevated native T1; difficulty nulling myocardium
BNP / troponin	disproportionately elevated relative to clinical presentation

step 2 — AL vs ATTR differentiation

Test	Purpose
serum free light chains + SPEP/UPEP with immunofixation	rule out AL amyloidosis — must be done in ALL patients before diagnosing ATTR
Tc-99m-PYP bone scintigraphy	grade 2–3 uptake with negative light chain studies = non-invasive ATTR diagnosis — Gillmore (2016)

must exclude AL first

Tc-99m-PYP can be positive in AL amyloidosis. A positive scan is only diagnostic of ATTR if light chain studies are negative. Missing AL has catastrophic consequences — it requires urgent chemotherapy.

step 3 — if ATTR confirmed

TTR gene sequencing — distinguish wild-type from hereditary
hereditary variants: Val122Ile (common in African descent, cardiac-predominant), Thr60Ala (mixed cardiac + neuro)

when biopsy is needed

discordant results (e.g. PYP grade 1, or positive light chains + positive PYP)
high clinical suspicion with non-diagnostic non-invasive workup
endomyocardial biopsy with Congo red staining (apple-green birefringence) + mass spectrometry for typing

management

drugs to use with caution or avoid

Drug	Concern
beta-blockers	reduce CO in stiff, rate-dependent ventricle — use lowest dose if needed for rate control
CCBs (verapamil, diltiazem)	negative inotropy in infiltrated myocardium → haemodynamic collapse
digoxin	binds amyloid fibrils → toxic levels at therapeutic doses
ACEi / ARBs	worsen orthostatic hypotension / dysautonomia — use cautiously
nitrates	preload-dependent → hypotension

digoxin in amyloidosis

Amyloid fibrils bind digoxin, leading to tissue toxicity even at “normal” serum levels. Avoid unless no alternative for rate control.

AF management

anticoagulate regardless of CHA₂DS₂-VASc — high thromboembolic risk from atrial infiltration and stasis (similar principle to HCM)
rate control: cautious BB at lowest effective dose; avoid CCBs and digoxin
rhythm control often attempted but AF recurrence rate is high

disease-modifying therapy

Agent	Type	Mechanism	Evidence
tafamidis	ATTR (both WT and hereditary)	TTR tetramer stabiliser	ATTR-ACT (2018) — reduced mortality + CV hospitalisation
inotersen	ATTR hereditary (neuropathy)	TTR antisense oligonucleotide	reduces hepatic TTR production
patisiran	ATTR hereditary (neuropathy)	TTR siRNA	reduces hepatic TTR production
chemotherapy	AL	target underlying plasma cell clone	regimen based on haematology (e.g. VCD, DRd) — urgent referral

tafamidis — key points for practice

start early (NYHA I–III) — less benefit in advanced disease
expensive — access may require special authorisation
does not reverse existing amyloid deposition — stabilises and slows progression
monitor with serial echo and biomarkers (BNP, troponin)