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Inherited Cardiac Conditions reference

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Cardiac Amyloidosis

Quick Summary

Definition: Deposition of misfolded protein as amyloid fibrils in the myocardium (most commonly transthyretin or light-chain), producing an infiltrative, restrictive cardiomyopathy.[1]

  • Prevalence: Increasingly recognized (often misdiagnosed as HCM/HFpEF), ATTRwt most common in elderly males[1]
  • Key types: ATTRwt (wild-type, elderly), AL (light chain, plasma cell), ATTRv (hereditary, TTR mutations)
  • Hallmark: LVH + HFpEF + low QRS voltage despite thick walls + carpal tunnel/neuropathy + bone scan uptake
  • High-risk markers: AL type, advanced stage, severe LV dysfunction, troponin/BNP elevation
  • First-line Mx: ATTR-CM: TTR stabilizers (tafamidis, acoramidis) and/or TTR gene silencers (vutrisiran) where licensed and available (availability and licensing differ by jurisdiction); AL: urgent haematology-led, plasma-cell-directed treatment (chemotherapy-based regimens), with transplantation reserved for carefully selected patients; non-dihydropyridine calcium-channel blockers generally avoided, digoxin used cautiously if at all

Aetiology

Monogenic (Mendelian): hereditary ATTRv, from TTR variants (e.g. V122I, T60A, V30M)[1]

Acquired: AL (plasma-cell dyscrasia) and ATTRwt (age-related); ATTRwt is the commonest cardiac form in the elderly[5]

Complex (likely polygenic): not a recognised mechanism

Genetics

ATTRv (hereditary): Autosomal dominant, TTR gene mutations

  • V122I most common in Black patients (~3-4% carrier frequency)
  • V30M common in Portuguese, Japanese populations
  • Screen first-degree relatives if ATTRv identified

ATTRwt: Not inherited, age-related

AL amyloidosis: Not inherited, acquired plasma cell disorder

Prevalence

ATTRwt (wild-type): Commonest form; predominantly men aged >65. An increasingly recognised cause of HFpEF in the elderly, present in ~13% of patients hospitalised with HFpEF and up to ~16% of severe aortic stenosis referred for TAVI[1][5].

AL (light chain): Incidence ~10–12 per million person-years; cardiac involvement occurs in roughly half of cases and is the dominant prognostic factor[5].

ATTRv (hereditary): Autosomal dominant TTR variants. p.Val142Ile (V122I) is cardiac-predominant and carried by ~3–4% of people of West-African ancestry; p.Thr80Ala (Irish) is mixed phenotype; p.Val50Met (V30M) is neuropathy-predominant[1].

Under-recognised: frequently mislabelled as HCM or hypertensive/HFpEF heart disease, actively consider it in any unexplained LV thickening, especially with the red flags below.

Diagnosis

Red flag features suggesting amyloidosis:

  • LV wall thickness >12 mm with HFpEF
  • Low QRS voltage despite thick walls on echo (voltage–mass mismatch)
  • Carpal tunnel syndrome, especially bilateral; lumbar canal stenosis
  • Autonomic dysfunction, peripheral neuropathy
  • Intolerance to ACEi/ARB or beta-blockers; persistently elevated troponin

Diagnostic pathway:

  1. Monoclonal protein screen (essential before any non-biopsy ATTR diagnosis): serum free light-chain assay plus serum and urine immunofixation. Protein electrophoresis alone is insufficient[1].
  2. Bone scintigraphy (Tc-99m DPD/PYP/HMDP): grade cardiac uptake using the Perugini score (0–3).
  3. Definitive non-biopsy diagnosis of ATTR-CM: Perugini grade 2–3 myocardial uptake with absence of a monoclonal protein confirms ATTR-CM without biopsy (Gillmore criteria; near-100% specificity)[1][5].
  4. Endomyocardial biopsy required if: a monoclonal protein is present (to diagnose/exclude AL) or scintigraphy is grade 0–1 with persistent suspicion. Biopsy with typing (mass spectrometry/immunohistochemistry) is the gold standard for AL[5].
  5. Confirm the subtype: once ATTR is established, TTR gene sequencing is required to separate ATTRwt from ATTRv and to trigger genetic counselling and family screening[5].

Key rule: a monoclonal protein MUST be excluded (steps 1 and 3) before grade 2–3 bone-scan uptake can be called diagnostic of ATTR-CM. Bone scintigraphy can also be positive in AL amyloidosis, so a positive scan with a monoclonal protein present does NOT confirm ATTR and mandates biopsy[1].

Investigations

ECG: Low voltage, pseudo-infarct pattern (Q waves)

Echo: Concentric LVH, restrictive filling, apical sparing, sparkling myocardium

Cardiac MRI: LGE (global subendocardial), abnormal gadolinium kinetics, elevated ECV

Bone scintigraphy (DPD/PYP/HMDP): grade 2-3 uptake supports a non-biopsy ATTR-CM diagnosis only after AL amyloidosis has been excluded with serum free light chains plus serum and urine immunofixation; if a monoclonal protein is present, biopsy with amyloid typing is required

Blood: NT-proBNP, troponin (both elevated), serum free light chains, immunofixation

Biopsy: If AL suspected or diagnosis unclear

Treatments

1. General measures:

  • Genetic counselling and family screening where ATTRv (hereditary) is identified, see the Genetic Testing page

2. Medical therapy:

  • ATTR-CM, disease-modifying therapy (start early; benefit is greatest in NYHA I–II): agent selection rests with a specialist amyloidosis centre and depends on current licensing and NICE or local funding. The classes below are alternative options rather than interchangeable equivalents, and are not routinely used in combination.
    1. TTR stabiliser (first-line): tafamidis 61 mg free-acid (≡ 80 mg meglumine) once daily, reduced all-cause mortality and CV hospitalisation in ATTR-ACT[2][4]. Acoramidis is a newer stabiliser (positive ATTRibute-CM trial[6]), NICE-recommended for ATTR-CM[9].
    2. TTR gene silencers: patisiran/vutrisiran (siRNA) and eplontersen (antisense), established in ATTRv polyneuropathy, with vutrisiran showing cardiovascular benefit in ATTR-CM (HELIOS-B)[7] and now NICE-recommended for ATTR-CM[10].
  • AL amyloidosis, oncological emergency (urgent haematology referral):
    1. Anti-plasma-cell therapy: daratumumab-based regimens (e.g. dara-VCd) are first-line (ANDROMEDA)[8].
    2. Mayo stage (troponin, NT-proBNP, difference in free light chains) drives prognosis and transplant eligibility; cardiac involvement is the main determinant of survival.
  • Supportive heart-failure management (both types):
    • Mainstay: loop diuretics ± MRA for congestion, often at high doses[3].
    • Use with caution or avoid: beta-blockers, ACEi/ARB, calcium-channel blockers and digoxin are frequently poorly tolerated (fixed stroke volume, hypotension; digoxin binds amyloid fibrils)[1].
    • Anticoagulation: low threshold in AF or flutter given the high thromboembolic risk. In sinus rhythm it is not routine, but may be considered where there is atrial mechanical dysfunction, demonstrated thrombus or prior embolism.

3. Device therapy:

  • Permanent pacemaker for high-grade conduction disease; routine prophylactic ICD is not recommended

4. Advanced heart failure and/or transplant referral:

  • Autologous stem-cell transplant in eligible AL patients[5]; heart (or combined-organ) transplant in selected younger patients with controlled systemic disease

Complications

  • Progressive restrictive heart failure: with low output, and standard heart failure drugs (beta-blockers, ACE inhibitors, digoxin) are often poorly tolerated[1]
  • Atrial fibrillation and flutter: carrying high thromboembolic risk and normally anticoagulated. Intracardiac thrombus can also occur in sinus rhythm, so anticoagulation may be considered in specific high-risk situations (atrial mechanical dysfunction, demonstrated thrombus, or prior embolism) rather than routinely for sinus rhythm alone
  • Conduction disease and AV block: needing pacing, with bradyarrhythmia
  • Pulseless electrical activity: a common mode of death, limiting ICD benefit
  • Extracardiac associations and red flags: coexisting low-flow aortic stenosis, carpal tunnel syndrome, lumbar spinal stenosis and biceps tendon rupture

Risk Stratification

Prognosis without treatment:

  • AL amyloidosis: Median survival 6 months if untreated cardiac involvement
  • ATTRwt: Median survival 3-5 years from diagnosis (improved with tafamidis)
  • ATTRv: Variable depending on mutation

Poor prognostic markers:

  • NT-proBNP >3000 ng/L
  • Troponin elevation
  • NYHA III-IV
  • Reduced LVEF

Pregnancy Management

Pregnancy in cardiac amyloidosis - exceptionally rare, individualized

Pregnancy in cardiac amyloidosis is exceptionally rare: most cardiac amyloidosis presents after typical reproductive age (AL median age ~65, ATTR wild-type generally older, ATTRv variable and occasionally younger depending on the specific variant). Because of this, the evidence base is limited to case reports and small series, and there is no validated disease-specific pregnancy risk algorithm (no reliable disease-specific mWHO classification, and no validated biomarker or LVEF cut-off that defines an absolute contraindication).

AL amyloidosis: AL requires urgent haematology-led, plasma-cell-directed treatment (chemotherapy regimens are generally teratogenic), which is difficult to reconcile with an ongoing pregnancy; this makes pregnancy very high risk in AL but the individual circumstances (disease activity, response to prior treatment, organ involvement) should still be assessed by a haematology-amyloidosis-obstetric team rather than applying a blanket rule.

ATTR (wild-type or variant): risk depends on the degree of cardiac involvement, functional status and, for ATTRv, the specific variant; management must be individualized through a joint Pregnancy Heart Team and amyloidosis team, covering cardiac assessment, monitoring plan, medication review and delivery planning specific to that patient. There is no validated fixed review interval, echo frequency, delivery week, or requirement for arterial-line or ICU monitoring that applies to all cases; these should be set by the MDT based on the individual's condition.

Medications: AL chemotherapy regimens are generally teratogenic and require specialist discussion. Tafamidis, acoramidis and vutrisiran have no established pregnancy safety data; continuing or stopping ATTR-directed therapy in pregnancy should be an individualized decision weighing disease progression risk against the absence of safety data. Non-dihydropyridine calcium-channel blockers are generally avoided in amyloid; beta-blockers may be poorly tolerated given fixed stroke-volume physiology but are not universally prohibited; digoxin is generally avoided but may be used cautiously with monitoring if considered necessary.

Contraception: discuss the full range of options, including long-acting reversible contraception and permanent methods, through non-directive counselling; the decision, including whether to consider a future pregnancy, is led by the patient.

Follow-up

Based on the ESC cardiac amyloidosis position statement[1][5].

Advanced / complicated = higher disease stage (elevated NT-proBNP/troponin), NYHA III–IV symptoms, conduction disease or arrhythmia, or AL amyloidosis on active haematological therapy. For AL amyloidosis, cardiac surveillance is additional to, and paced by, the haematology treatment protocol.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

Genotype+ / Phenotype−Uncomplicated / StableAdvanced / Complicated
FrequencyEvery 1–2 yrs (from ~10 yrs before predicted onset)Every 6–12 monthsEvery 3–6 months
Clinical reviewCardiac + neuropathy symptom reviewSymptoms, NYHA, fluid status, orthostatic BPAs above + device check
ECGPeriodicAnnual (low voltage, conduction disease)Each visit
EchocardiographyEvery 1–2 years (wall thickness, GLS)Annual (wall thickness, GLS, diastology)6-monthly
BiomarkersNT-proBNP / troponin (baseline trend)NT-proBNP + troponin (staging/prognosis)Each visit
Holter / ambulatoryAs indicatedAnnual (AF, conduction, arrhythmia)6-monthly
AL-specific–Haematology review + free light chainsPer oncology protocol

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

  • Suspect in elderly with HFpEF and thick walls, especially if low voltage ECG[1]
  • Must exclude monoclonal protein before diagnosing ATTR on bone scan alone[1]
  • DPD/PYP scan is key diagnostic test for ATTR[1]
  • Screen family if ATTRv (hereditary) identified
  • TTR-directed therapy improves outcomes in ATTR-CM and should be started early in eligible patients, with the choice of agent and eligibility determined by a specialist amyloidosis centre under current licensing and funding[1]
  • AL amyloidosis requires urgent haematology referral
  • Pregnancy EXTREMELY RARE (age >50 typical); likely high to very high risk, particularly with restrictive physiology, heart failure, arrhythmia, autonomic dysfunction or systemic AL disease; manage only with expert cardio-obstetric, haematology and amyloid MDT input
  • Restrictive physiology poorly tolerates pregnancy volume load - very high decompensation risk

References & Review Date

Last reviewed: July 2026

  1. Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554–1568. doi:10.1093/eurheartj/ehab072
  2. Maurer MS, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-ACT). N Engl J Med. 2018;379(11):1007–1016. doi:10.1056/NEJMoa1805689
  3. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. doi:10.1093/eurheartj/ehab368
  4. NICE Technology Appraisal TA984 (2024). Tafamidis for treating transthyretin amyloidosis with cardiomyopathy (updates and replaces TA696). nice.org.uk/guidance/ta984
  5. Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. J Am Coll Cardiol. 2023;81(11):1076–1126. doi:10.1016/j.jacc.2022.11.022
  6. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy (ATTRibute-CM). N Engl J Med. 2024;390(2):132–142. doi:10.1056/NEJMoa2305434
  7. Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy (HELIOS-B). N Engl J Med. 2025;392(1):33–44. doi:10.1056/NEJMoa2409134
  8. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis (ANDROMEDA). N Engl J Med. 2021;385(1):46–58. doi:10.1056/NEJMoa2028631
  9. NICE Technology Appraisal TA1121 (2026). Acoramidis for treating transthyretin amyloidosis with cardiomyopathy. nice.org.uk/guidance/ta1121
  10. NICE Technology Appraisal TA1115 (2025). Vutrisiran for treating transthyretin amyloidosis with cardiomyopathy. nice.org.uk/guidance/ta1115