Infiltrative cardiomyopathy and cardiac amyloidosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Infiltrative cardiomyopathy includes amyloid, sarcoid, iron and storage disease. In cardiac amyloidosis, misfolded light chain (AL) or transthyretin (ATTR) fibrils cause wall thickening, restrictive physiology, arrhythmia and conduction disease.

The diagnostic sequence matters more than any single image. Monoclonal-protein testing determines whether bone scintigraphy can support a non-biopsy ATTR diagnosis; ambiguous or discordant cases require expert biopsy and mass-spectrometry typing.

Treatment combines careful congestion control, rhythm/conduction management and disease-specific therapy. AL is a haematological emergency; ATTR treatment and hereditary-family care should begin through an amyloidosis service.

Key points

Think amyloid when increased wall thickness is paired with low-voltage discordance, restrictive physiology, apical-sparing strain or systemic red flags.
ATTR red flags include bilateral carpal tunnel, lumbar spinal stenosis, biceps rupture, neuropathy and unexplained HFpEF or aortic stenosis in later life.
First exclude a monoclonal process with serum free light chains plus serum and urine immunofixation; electrophoresis alone is insufficient.
Grade 2-3 DPD cardiac uptake can establish ATTR non-invasively only when AL has been excluded and SPECT confirms myocardial uptake.
A monoclonal protein does not prove AL and a positive DPD scan does not override it: obtain urgent haematology input and tissue typing.
After ATTR diagnosis, sequence TTR even in an older patient because hereditary disease changes family counselling.
Diuretics are central for congestion, but hypotension, autonomic dysfunction and a small stiff ventricle often limit conventional HF drugs.
NICE-funded ATTR-CM stabilisers now include tafamidis and acoramidis; confirm subtype and eligibility before prescribing.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

AL amyloidosis

A clonal plasma-cell disorder produces unstable immunoglobulin light chains that misfold and deposit in myocardium and other organs. Cardiac involvement may progress rapidly and makes specialist assessment time-critical.

Wild-type transthyretin amyloidosis

Age-related instability of normal transthyretin permits amyloid formation, commonly affecting the heart in later life. Earlier carpal tunnel, lumbar stenosis or biceps rupture may precede cardiac symptoms.

Hereditary transthyretin amyloidosis

A pathogenic TTR variant destabilises the protein and can cause cardiomyopathy, neuropathy or both. Age alone cannot exclude hereditary disease; TTR sequencing distinguishes hereditary from wild-type ATTR, and a pathogenic variant has implications for relatives.

Other infiltrative or storage disease

Sarcoid inflammation, iron overload and lysosomal storage disorders affect myocardium through granuloma, toxic accumulation or intracellular storage. Their imaging, systemic features and disease-specific tests differ from amyloid.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Pathological material accumulates
Misfolded light-chain or transthyretin fibrils deposit extracellularly between cardiac cells; other infiltrative disorders accumulate different material or inflammatory lesions. Normal myocardial architecture becomes progressively disrupted.
2
Ventricular walls stiffen
Infiltration increases apparent wall thickness and reduces compliance without necessarily increasing true muscle mass. A normal-sized or small, stiff ventricle often requires higher pressure to fill.
3
Restrictive heart failure develops
Rising diastolic pressure enlarges both atria and causes pulmonary and systemic venous congestion. Stroke-volume reserve becomes constrained, so tachycardia or excessive preload reduction may be poorly tolerated.
4
Electrical tissue is involved
Atrial and conduction-system infiltration promotes atrial fibrillation, sinus-node dysfunction and atrioventricular block. Patchy scar may also support ventricular arrhythmia, although sudden death can be electromechanical.
5
Systemic disease limits compensation
Autonomic neuropathy can lower vascular tone, while renal or neurological involvement complicates volume control and function. The resulting hypotension makes conventional vasodilating heart-failure treatment difficult to tolerate.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Cardiac phenotype

HFpEF or restrictive failure with increased wall thickness, biatrial enlargement, small cavity, valve/interatrial-septal thickening and pericardial effusion.

Electrical discordance

Low or relatively modest QRS voltage despite thick walls, pseudo-infarct pattern, AF and progressive AV conduction disease are clues, not mandatory criteria.

ATTR extracardiac clues

Bilateral carpal tunnel often years earlier, lumbar stenosis, spontaneous biceps rupture, peripheral/autonomic neuropathy and family history.

AL systemic clues

Nephrotic proteinuria, macroglossia, periorbital purpura, bruising, weight loss or a known plasma-cell disorder increases urgency.

Time-critical ALRed flag

Rapid HF progression, hypotension and disproportionate troponin/NT-proBNP with any monoclonal abnormality requires urgent specialist assessment.

Electrical instabilityRed flag

Syncope, symptomatic bradycardia, high-grade block or ventricular arrhythmia needs monitored assessment; sudden death may be electromechanical as well as tachyarrhythmic.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serum free light-chain ratio plus serum and urine immunofixationFirst step
Why
Screen sensitively for a monoclonal protein and possible AL.
Interpretation and limitations
Any abnormality needs haematology correlation; renal impairment can alter the light-chain ratio. All three tests being negative is required before a non-biopsy ATTR pathway.
02
ECG and ambulatory monitoring
Why
Assess voltage, pseudo-infarct pattern, AF, pauses and conduction disease.
Interpretation and limitations
Normal voltage does not exclude amyloid; symptom-linked bradyarrhythmia may require device assessment.
03
TTE with strain
Why
Define wall thickness, restrictive filling, valves, atria, RV and longitudinal strain.
Interpretation and limitations
Relative apical sparing supports amyloid but is not specific enough to type or exclude disease.
04
CMR
Why
Identify diffuse infiltration, abnormal gadolinium kinetics, LGE and extracellular-volume expansion.
Interpretation and limitations
A characteristic pattern strengthens suspicion but does not determine AL versus ATTR.
05
99mTc-DPD scintigraphy with SPECT
Why
Identify myocardial ATTR tracer uptake after monoclonal screening.
Interpretation and limitations
Grade 2-3 myocardial uptake plus a negative monoclonal screen can establish ATTR-CM; grade 0-1 or monoclonal positivity requires further evaluation.
06
Tissue biopsy with amyloid typing and TTR sequencing
Why
Resolve uncertain/monoclonal cases and distinguish hereditary from wild-type ATTR.
Interpretation and limitations
Congo-red positivity confirms amyloid, but treatment requires protein typing; sequence TTR after ATTR is identified.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Hypertensive left-ventricular hypertrophy

Longstanding pressure overload can create thick walls and diastolic dysfunction. A convincing hypertension history and ECG voltage proportionate to wall thickness support hypertensive remodelling, but neither feature alone excludes amyloid.

Hypertrophic cardiomyopathy

Sarcomeric HCM is a separate disease that often produces asymmetric hypertrophy, dynamic obstruction or a familial phenotype. Restrictive physiology, voltage–wall-thickness discordance and characteristic extracardiac red flags instead raise suspicion of amyloid.

Aortic stenosis

Valve obstruction causes concentric hypertrophy, exertional symptoms and heart failure. Restricted calcified cusps and a valve-level Doppler gradient identify the loading lesion, although amyloid may coexist.

Constrictive pericarditis

Pericardial restraint also causes high filling pressure, biatrial enlargement and right-sided congestion. Respiratory ventricular interdependence and characteristic venous-flow changes support constriction; pericardial thickening or calcification may be present but is not required.

Other storage or inflammatory cardiomyopathy

Fabry disease, iron overload and cardiac sarcoidosis can mimic wall thickening, scar or conduction disease. Targeted systemic examination, CMR pattern and specific laboratory or genetic testing discriminate.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SuspectedAmyloid diagnostic forkFirst stepCardiac imaging plus clinical red flags.

1Obtain ECG/echo and send serum free light chains, serum immunofixation and urine immunofixation together; arrange CMR where it will refine phenotype.
2If any monoclonal test is abnormal, refer urgently to haematology/amyloidosis specialists for clonal evaluation and biopsy typing; do not declare ATTR from DPD alone.
3If all monoclonal tests are negative, perform DPD scintigraphy with SPECT; grade 2-3 myocardial uptake can support non-biopsy ATTR-CM.
4AlternativeIf DPD is grade 0-1, imaging is discordant or the clinical suspicion remains high, pursue expert biopsy/alternative infiltrative diagnoses rather than closing the case.

02ALPossible light-chain amyloidosisMonoclonal abnormality or tissue suggesting AL.

1Contact haematology/amyloidosis services urgently and stage cardiac/renal involvement; cardiac AL should not wait for a routine clinic slot.
2Obtain the safest informative tissue sample and type deposits definitively; MGUS can coexist with ATTR, so clonality alone is not protein typing.
3Use cautious diuresis and manage arrhythmia/conduction disease while haematology initiates clone-directed treatment; avoid hypotension and nephrotoxins.
4EscalationEscalate rapidly progressive HF or low output to a centre experienced in amyloid and advanced support.

03ATTRConfirmed transthyretin cardiomyopathyValidated non-biopsy or tissue-typed ATTR-CM.

1Sequence TTR and provide genetic counselling; cascade-test relatives if a pathogenic variant is found.
2Refer to a specialist service for a NICE-approved TTR stabiliser: tafamidis under TA984 or acoramidis under TA1121, choosing an appropriate funded option.
3Treat congestion with the minimum effective diuretic and assess AF anticoagulation, conduction/device needs, autonomic hypotension and neuropathy.
4Continue longitudinal assessment; stabilisers slow progression and do not reverse advanced deposits immediately.

04OtherNon-amyloid infiltrationAmyloid pathway negative or imaging suggests sarcoid, iron or storage disease.

1Use phenotype-specific tests: FDG-PET/CMR and extracardiac biopsy for suspected sarcoid, iron indices and T2* CMR for iron, or enzyme/genomic testing for storage disease.
2Treat the underlying process through the relevant specialist team while managing HF and arrhythmia phenotype.
3Revisit tissue diagnosis when empirical treatment would be toxic or when imaging and systemic findings conflict.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

TTR stabiliser for eligible adult wild-type or hereditary ATTR-CM under NICE TA984.

Tafamidis

61 mg orally once daily (tafamidis free acid); this corresponds to 80 mg tafamidis meglumine and the formulations are not interchangeable mg-for-mg.

Confirm ATTR and exclude AL first; specialist initiation. Limited evidence in very advanced NYHA IV disease; reassess around transplantation and pregnancy.

TTR stabiliser for eligible adult wild-type or variant ATTR-CM under NICE TA1121.

Acoramidis

712 mg orally twice daily (two 356 mg tablets twice daily).

Specialist initiation after subtype confirmation; limited data if CrCl below 30 mL/min and none on dialysis, so use caution. Not recommended in hepatic impairment; an early eGFR change may reflect haemodynamics.

Symptom relief from systemic or pulmonary congestion.

Furosemide

Common oral starting dose 20-40 mg once daily, then individualise to weight and congestion.

A stiff small ventricle is preload-sensitive; excessive diuresis can cause hypotension, renal injury and low output. Monitor potassium and renal function.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Restrictive heart failure and low output

Progressive stiffness causes pulmonary and systemic congestion while fixed stroke volume produces fatigue, hypotension and organ hypoperfusion. A narrow volume margin makes both overload and over-diuresis hazardous.

Atrial fibrillation and thromboembolism

Atrial infiltration and enlargement promote fibrillation and mechanical atrial dysfunction. Blood stasis and amyloid-related atrial disease can create substantial intracardiac thrombus and embolic risk.

Conduction block

Progressive infiltration of the sinus node and atrioventricular conduction system causes bradycardia or high-grade block. Syncope may result and pacing assessment is often required.

Sudden cardiac death

Ventricular arrhythmia can occur, but electromechanical dissociation or severe bradyarrhythmia may also cause sudden death. This mixed mechanism limits reliance on ejection fraction alone for risk assessment.

Extracardiac organ failure

AL may involve kidneys and other organs, while hereditary ATTR may cause progressive peripheral and autonomic neuropathy. Multisystem disease worsens frailty, treatment tolerance and overall prognosis.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track weight, orthostatic BP, congestion, renal function and electrolytes during diuretic changes.
Follow NT-proBNP/troponin trends in context; interpret renal changes and AF before assuming amyloid progression.
Repeat ECG/ambulatory monitoring for syncope, palpitations or progressive conduction disease.
Assess function and structure with interval echo/CMR according to specialist plan, symptoms and treatment.
For ATTR therapy, review adherence, adverse effects, NYHA trajectory, admissions and transplant suitability.
For hereditary ATTR, document genetic counselling and cascade-testing progress.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The monoclonal screen is three-part

Serum electrophoresis without immunofixation, or serum testing without urine, is not an adequate AL exclusion.

MGUS complicates interpretation

Older patients may have both a monoclonal gammopathy and ATTR; tissue typing prevents the wrong disease-specific treatment.

DPD requires SPECT

Planar blood-pool activity can mimic cardiac uptake; SPECT confirms that tracer is in myocardium.

Apical sparing is a clue

It raises suspicion but also occurs in other hypertrophic states and cannot type amyloid.

Wild-type cannot be assumed by age

TTR sequencing after ATTR diagnosis identifies variant disease and changes family care.

11Common pitfallsFrequent interpretation and management errors.

01
Ordering DPD without a complete monoclonal screen and calling any uptake ATTR.
02
Treating a monoclonal protein as proof that deposits are AL without amyloid typing.
03
Delaying suspected cardiac AL in a routine cardiology queue.
04
Using high-dose diuresis or vasodilators without regard to preload sensitivity and autonomic hypotension.
05
Starting a TTR stabiliser before confirming ATTR and excluding AL.