Cardiac amyloidosis
Description
- Extracellular deposition of misfolded protein as beta-pleated sheet amyloid fibrils in the myocardium -> infiltrative, restrictive cardiomyopathy
- Presents as HFpEF with increased wall thickness, not a dilated ventricle
The two types that matter
| AL (light chain) | ATTR (transthyretin) | |
|---|---|---|
| Precursor | Monoclonal free light chains from a plasma cell clone | Transthyretin (liver-derived) |
| Subtypes | - | Wild-type (ATTRwt) - elderly men; hereditary (ATTRv) - V122I, T60A, V30M |
| Age | 50-70 | ATTRwt >70; ATTRv variable |
| Cardiac wall thickness | Modest | Often marked (>15-18 mm) |
| Troponin/NT-proBNP | Disproportionately high for wall thickness | Raised |
| Extracardiac | Macroglossia, periorbital purpura, nephrotic proteinuria, hepatomegaly, autonomic neuropathy | Carpal tunnel, lumbar spinal stenosis, biceps tendon rupture, polyneuropathy |
| Tempo | Rapidly progressive | Indolent over years |
| Untreated median survival with HF | ~6 months | 2-6 years |
- *AL is a haematological emergency; ATTR is a chronic cardiology problem*
Clinical picture
- HFpEF with right heart failure often predominating - raised JVP, ascites, congestive hepatomegaly, peripheral oedema
- Atrial fibrillation and conduction disease - very common
- Hypotension, or "normalisation" of previously hypertensive blood pressure - a hypertensive patient whose BP drifts down and whose antihypertensives are being stopped is a classic presentation
- Exertional syncope (fixed stroke volume, autonomic failure)
- Angina with unobstructed coronaries (microvascular amyloid)
- Advanced: low output, cachexia
Epidemiology
- Far commoner than historically recognised - increasingly diagnosed since bone scintigraphy became routine
- ATTRwt found in ~13-16% of HFpEF patients with wall thickness >=12 mm
- Also found in: ~5-16% of severe aortic stenosis referred for TAVI, ~5% of "hypertrophic cardiomyopathy" phenotypes
- ATTRwt: M >> F (~90% male), typically >70 yrs
- ATTRv V122I (p.V142I) carried by ~3-4% of people of West African ancestry - presents in the 60s with cardiomyopathy
- AL amyloidosis: ~10 per million/yr; cardiac involvement in ~50-70%, and is the dominant prognostic determinant
Aetiopathogenesis
AL
- Clonal plasma cell dyscrasia (usually small, often not meeting myeloma criteria) -> monoclonal free light chains (lambda > kappa)
- Light chains are directly cardiotoxic in addition to depositing as fibrils
- Explains the disproportionately high troponin and the rapid decline - and why reducing light chain production produces improvement
ATTR
- Transthyretin is a liver-synthesised tetramer transporting thyroxine and retinol-binding protein
- Tetramer dissociation -> monomer misfolding -> fibril deposition
- Wild-type: age-related destabilisation
- Hereditary: autosomal dominant point mutation destabilising the tetramer
- V122I (p.V142I) - cardiac, West African ancestry
- T60A - cardiac + neuropathy, Irish ancestry
- V30M (p.V50M) - neuropathy-predominant, Portuguese/Swedish/Japanese
- Therapeutic logic follows directly: stabilise the tetramer (tafamidis, acoramidis, diflunisal) or silence hepatic production (patisiran, vutrisiran, eplontersen)
Other types
- AA (serum amyloid A) - chronic inflammation; cardiac involvement rare
- Dialysis-related (beta-2 microglobulin), isolated atrial (ANP)
Mechanism of the haemodynamics
- Interstitial infiltration -> increased wall thickness with a small cavity -> impaired relaxation, high filling pressures, restrictive physiology
- Atrial infiltration -> atrial mechanical failure -> thrombus even in sinus rhythm
- Conduction system infiltration -> AV block
- Autonomic infiltration (AL, ATTRv) -> postural hypotension - which collides head-on with the need for diuretics
Diagnosis
When to suspect
- Unexplained increased LV wall thickness in a patient >60 with heart failure
- HFpEF intolerant of ACE inhibitors/beta blockers because of hypotension
- Low-voltage or normal-voltage ECG despite thick walls
- Bilateral carpal tunnel syndrome (often years earlier), lumbar spinal stenosis, spontaneous biceps tendon rupture
- Aortic stenosis with disproportionate symptoms or wall thickness
- AF with conduction disease and heart failure in an elderly man
ECG
- Low QRS voltage (or voltage that is merely normal) in the presence of a thick-walled heart is the diagnostic hallmark
- Sensitivity ~72-79%, specificity ~91-100% for the discordance
- Pseudo-infarct pattern - poor R wave progression, pathological Q waves anteriorly
- AF, first-degree AV block, bundle branch block
Echocardiography
- Increased wall thickness of all chambers ("pan-cardiac") - LV, RV free wall, interatrial septum, valves
- Small LV cavity, biatrial enlargement, pericardial effusion
- Granular sparkling myocardium (classic but insensitive and machine-dependent)
- Apical-sparing ("cherry on top") longitudinal strain pattern - reduced basal and mid strain with preserved apical strain
- The most useful echo sign; sensitivity and specificity both ~85-90%
- Restrictive filling: E/A >2, short deceleration time, raised E/e'
CMR
- Diffuse or global subendocardial late gadolinium enhancement with abnormal gadolinium kinetics (difficulty nulling the myocardium)
- Increased extracellular volume (ECV) - quantifies amyloid burden and tracks response
The diagnostic algorithm - the single most examinable part
Step 1 - ALWAYS exclude AL first, in parallel
- Serum free light chain assay + serum and urine immunofixation electrophoresis
- All three. Serum protein electrophoresis alone is insufficient
- Any monoclonal protein -> haematology referral and tissue biopsy for typing (mass spectrometry); do NOT rely on the bone scan
Step 2 - bone scintigraphy (99mTc-DPD / PYP / HMDP)
- Perugini grade 2 or 3 cardiac uptake (>= rib uptake)
- Grade 2-3 uptake + NO monoclonal protein = ATTR cardiac amyloidosis, diagnosed non-invasively - no biopsy required
- Specificity ~100% in that combination; this changed the field
- AL can also take up tracer (~20% of AL show grade 1-2) - hence the absolute requirement to exclude a paraprotein first
Step 3 - genotype
- TTR gene sequencing in every confirmed ATTR case - distinguishes wild-type from hereditary; determines family cascade screening
Biopsy when needed
- Endomyocardial biopsy (near 100% sensitive) if imaging is equivocal or a paraprotein is present
- Typing by mass spectrometry or immunohistochemistry is mandatory - treating AL as ATTR, or vice versa, is a catastrophic error
- Abdominal fat pad aspirate: sensitive in AL (~70-80%), poor in ATTRwt
Biomarkers
- NT-proBNP and troponin - diagnosis, staging and monitoring
- Mayo staging in AL (NT-proBNP, troponin, free light chain difference); NAC/Gillmore staging in ATTR (NT-proBNP, eGFR)
Management
A. Disease-modifying therapy - by type
AL - treat the plasma cell clone urgently
- Daratumumab + bortezomib + cyclophosphamide + dexamethasone (Dara-CyBorD) is the standard of care (ANDROMEDA)
- Autologous stem cell transplant in selected patients with limited cardiac involvement
- Haematology referral the same week - do not wait for a cardiology work-up to complete
- Response measured by haematological response (free light chain difference) and organ response (NT-proBNP)
ATTR - stabilise or silence
- Tafamidis (TTR tetramer stabiliser) - reduces mortality and cardiovascular hospitalisation (ATTR-ACT); the only disease-modifying therapy approved in Australia for ATTR-CM, with restricted access criteria
- Benefit is greatest in NYHA I-II - treat early; it does not rescue advanced disease
- Acoramidis - stabiliser, positive phase 3 (ATTRibute-CM); not yet available in Australia
- Vutrisiran (siRNA) - reduced mortality and cardiovascular events in HELIOS-B; FDA-approved for ATTR-CM; check current TGA/PBS status in Australia
- Other silencers: patisiran, eplontersen (established in ATTR polyneuropathy)
- Diflunisal - off-label stabiliser; NSAID toxicity (renal, GI, fluid retention) limits use in heart failure
- CRISPR-based TTR knockout (nexiguran ziclumeran) - in trials
B. Heart failure management - and how it differs from ordinary HFpEF
- Loop diuretics +/- an MRA are the mainstay - titrate carefully against postural BP and renal function
- *Standard heart failure drugs are poorly tolerated and are not beneficial here*
- Beta blockers - the stiff ventricle depends on heart rate for output; bradycardia reduces cardiac output. Usually not tolerated unless needed for AF rate control
- ACE inhibitors/ARB/ARNI - hypotension, especially with autonomic involvement
- Digoxin - historically avoided (binds amyloid fibrils, toxicity); may be used cautiously at low dose with monitoring in AF
- Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) - avoid (bind fibrils, profound hypotension and bradycardia)
- SGLT2 inhibitors - increasingly used, generally well tolerated, with supportive observational data
C. Arrhythmia and conduction
- Anticoagulate all patients with AF regardless of CHA2DS2-VA score
- Atrial mechanical failure means thrombus forms even in sinus rhythm; exclude LA appendage thrombus with TOE before cardioversion
- Rate vs rhythm: rhythm control often preferred (loss of atrial kick is poorly tolerated); amiodarone is the usual agent
- Pacemaker for high-grade AV block - common; low threshold for monitoring
- ICD: primary prevention is of limited value - death is frequently from electromechanical dissociation rather than a shockable rhythm; consider for secondary prevention or in AL with ventricular arrhythmia
D. Other
- Postural hypotension: compression stockings, midodrine, fludrocortisone (carefully - fluid retention)
- Aortic stenosis + ATTR - TAVI is reasonable; the amyloid, not the valve, then determines prognosis
- Cardiac transplantation - selected patients; in AL, only after haematological response; combined heart-liver in ATTRv
- Genetic counselling and cascade screening for ATTRv - first-degree relatives, with a defined age to begin surveillance
- Palliative care and advance care planning - particularly in AL with advanced cardiac stage
- Australian Amyloidosis Network referral for multidisciplinary care
Associations
- Bilateral carpal tunnel syndrome - precedes ATTR cardiac disease by 5-10 years; the single most useful historical clue
- Lumbar spinal stenosis, spontaneous biceps tendon rupture ("Popeye sign"), rotator cuff tears, trigger finger
- Severe aortic stenosis - ATTR found in 5-16% of TAVI candidates
- HFpEF - ATTRwt in 13-16% with increased wall thickness
- Peripheral and autonomic neuropathy - prominent in AL and ATTRv
- Macroglossia and periorbital purpura - specific for AL, present in only ~15%, but diagnostic when seen
- Nephrotic syndrome, hepatomegaly, factor X deficiency and bleeding (AL)
- Multiple myeloma and MGUS
- Atrial fibrillation, conduction disease, intracardiac thrombus
- Previously well-controlled hypertension that "resolves"
- A "hypertrophic cardiomyopathy" phenotype in an elderly patient with no family history
Natural history & complications
- AL with cardiac involvement has the worst prognosis of the cardiac amyloidoses
- Untreated, median survival ~6 months once heart failure develops
- Modern therapy has transformed this for those who survive the first months - early mortality remains high, so diagnostic delay is lethal
- ATTRwt: median survival ~3.5-5 years untreated; more indolent
- ATTRv: depends on the variant; V122I is aggressive and cardiac-predominant
- Tafamidis reduces mortality ~30% at 30 months, with benefit concentrated in NYHA I-II - reinforcing early diagnosis
Prognostic markers
- NT-proBNP and troponin (Mayo stage in AL, NAC stage in ATTR)
- eGFR, systolic BP, NYHA class, 6-minute walk distance
- ECV on CMR, degree of longitudinal strain impairment
Complications
- Progressive right and left heart failure with diuretic-refractory congestion
- Hypotension and cardiorenal syndrome - the practical limit on treatment
- Atrial fibrillation, intracardiac thrombus and stroke even in sinus rhythm
- High-grade AV block and sudden death (often electromechanical dissociation)
- Syncope with exertion - an ominous sign
- Cardiac cachexia, malnutrition
- AL-specific: nephrotic syndrome, bleeding from acquired factor X deficiency, autonomic failure, hepatic involvement
- ATTRv: progressive polyneuropathy and gastrointestinal dysfunction
- The central message: suspect it, exclude AL with free light chains and immunofixation before anything else, and diagnose early enough for stabiliser therapy to matter
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