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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: Tafamidis (ATTR stabilizer), patisiran/inotersen (ATTRv), chemotherapy (AL), avoid digoxin/CCBs, transplant if AL

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 (mandatory): 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 mandatory 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): Grade 2-3 cardiac uptake diagnostic for ATTR

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

Biopsy: If AL suspected or diagnosis unclear

Treatments

ATTR-CM, disease-modifying therapy (start early; benefit is greatest in NYHA I–II):

  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]. 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]; autologous stem-cell transplant in eligible patients[5].
  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, high thromboembolic risk, even in sinus rhythm with atrial mechanical dysfunction.
  • Devices: permanent pacemaker for high-grade conduction disease; routine prophylactic ICD is not recommended.
  • Advanced disease: 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: with high thromboembolic risk; intracardiac thrombus can occur even in sinus rhythm, so anticoagulation is considered broadly
  • 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 (mWHO Class III-IV)

PRECONCEPTION COUNSELLING:

  • General considerations:
    • Cardiac amyloidosis in pregnancy is EXTREMELY RARE
    • Most amyloidosis presents age >50 (post-reproductive age)
    • AL amyloidosis: Younger onset possible; median age 65
    • ATTRv (hereditary): Can present younger (30s-40s depending on mutation)
    • Limited published data - case reports only
  • Risk stratification by type and severity:
    • AL amyloidosis (light chain): mWHO IV - PREGNANCY CONTRAINDICATED
      • Rapidly progressive multi-organ disease
      • Median survival 4 months untreated, 2-3 years with treatment
      • Chemotherapy required - highly teratogenic
      • Cardiac involvement = very poor prognosis
    • ATTR wild-type: mWHO IV - pregnancy contraindicated (age >65, post-menopausal)
    • ATTRv (hereditary): mWHO III-IV depending on severity
      • Early/minimal cardiac involvement: mWHO III (high risk)
      • Moderate-severe involvement: mWHO IV (contraindicated)
      • Some mutations present young (V30M Portuguese, Swedish mutations)
  • Pregnancy feasibility by cardiac function:
    • LVEF >50%, NYHA I, NT-proBNP <1000: Pregnancy possibly feasible (mWHO III)
    • LVEF 40-50%, NYHA II, NT-proBNP 1000-3000: Very high risk (mWHO IV)
    • LVEF <40%, NYHA III-IV, NT-proBNP >3000: ABSOLUTE CONTRAINDICATION
  • ATTRv-specific genetic counselling:
    • Autosomal dominant: 50% transmission risk
    • Age of onset varies by mutation (V30M: 30s-40s; V122I: 60s-70s)
    • Prenatal testing available
    • Pre-implantation genetic diagnosis option
  • Medications - MAJOR CHALLENGES:
    • AL amyloidosis chemotherapy: All regimens teratogenic (cyclophosphamide, bortezomib, dexamethasone, melphalan)
    • Tafamidis (ATTR): NO pregnancy data; likely must discontinue (Category C)
    • Patisiran/inotersen (ATTRv RNAi therapies): NO pregnancy data
    • Diuretics: Essential for volume management; use cautiously (can reduce placental perfusion)
    • ACE-I/ARBs: STOP pre-conception
    • Beta-blockers: Generally poorly tolerated in amyloid (fixed stroke volume, rely on HR for cardiac output)

IF PREGNANCY PROCEEDS (ATTRv with early disease ONLY):

  • Monitoring frequency:
    • Fortnightly cardiology review from 20 weeks
    • Echo monthly (LVEF, wall thickness, diastolic function, RV function)
    • NT-proBNP fortnightly (rising trend = decompensation)
    • Extremely low threshold for admission
  • Physiological challenges:
    • Amyloid heart = restrictive cardiomyopathy: Rigid, non-compliant ventricles
    • Cannot tolerate volume load (pregnancy plasma volume ↑40-50%)
    • Fixed stroke volume → rely on heart rate → poorly tolerate beta-blockers/bradycardia
    • Very high risk of acute decompensation
  • Heart failure management:
    • Diuretics ESSENTIAL (furosemide) - balance preload carefully
    • Avoid beta-blockers if possible (worsen fixed stroke volume physiology)
    • ACE-I contraindicated in pregnancy; no good replacement for afterload reduction
    • Digoxin CONTRAINDICATED in amyloid (binds to amyloid fibrils → toxicity)
  • Tafamidis in pregnancy (ATTRv/wild-type):
    • No human pregnancy data
    • Animal studies: no teratogenicity but limited data
    • If patient on tafamidis and becomes pregnant: Discuss risk vs benefit of continuing
    • Discontinuing may lead to disease progression
    • Individual decision with full informed consent

LABOUR & DELIVERY:

  • Delivery planning:
    • Tertiary centre MANDATORY (advanced heart failure, potential for rapid decompensation)
    • Early delivery 34-36 weeks (do NOT allow to term)
    • Cardiology, obstetrics, cardiac anaesthetics, ICU involvement
  • Mode of delivery:
    • Elective caesarean section preferred (control timing, avoid unpredictable labour stress)
    • Vaginal delivery possible if LVEF >45% and stable, but high risk
    • Assisted second stage if vaginal (minimize maternal effort)
  • Anaesthesia - VERY HIGH RISK:
    • Restrictive cardiomyopathy = preload-dependent
    • Epidural/spinal: Risk of hypotension (vasodilation) → reduced preload → cardiovascular collapse
    • GA: Risk of cardiovascular collapse with induction
    • Both options very high risk - senior cardiac anaesthetist essential
    • Invasive BP monitoring (arterial line) MANDATORY
    • Central line consider (CVP monitoring, inotrope access)
  • Intrapartum haemodynamic management:
    • Careful fluid balance - avoid overload AND hypovolaemia
    • Maintain preload (amyloid heart very preload-dependent)
    • Avoid sudden drops in SVR (epidural/spinal)
    • Have inotropes ready (dobutamine) if needed

POSTPARTUM:

  • Critical period 48-72 hours:
    • ICU monitoring MANDATORY for 48-72 hours minimum
    • Autotransfusion from uterine contraction + third-space mobilization = acute volume load
    • Very high risk pulmonary oedema/cardiovascular collapse
  • Diuresis:
    • Aggressive diuresis to remove pregnancy volume load
    • Daily weights, strict fluid balance
    • Target return to pre-pregnancy weight
  • Resume medications:
    • Tafamidis if ATTRv (if was on pre-pregnancy)
    • Consider ACE-I/ARB if needed (enalapril compatible with breastfeeding)
    • Continue diuretics
  • Contraception:
    • Permanent contraception STRONGLY RECOMMENDED
    • Tubal ligation if patient consents
    • If not: LARC (Mirena preferred, minimal systemic hormone)
    • Counsel AGAINST any future pregnancy - risk unacceptable
  • Breastfeeding: Not contraindicated but patient may be too unwell; support formula feeding if needed

ABSOLUTE CONTRAINDICATIONS TO PREGNANCY:

  • AL (light chain) amyloidosis - requires chemotherapy
  • LVEF <40%
  • NYHA Class III-IV
  • NT-proBNP >3000 ng/L
  • Elevated troponin (indicates advanced disease)
  • Multi-organ amyloid involvement (renal, hepatic)

CRITICAL SUMMARY:
Cardiac amyloidosis in pregnancy is EXTREMELY RARE and carries VERY HIGH maternal mortality risk. AL amyloidosis: pregnancy absolutely contraindicated (requires chemotherapy). ATTRv: pregnancy generally contraindicated except possibly early disease with minimal cardiac involvement. Restrictive physiology poorly tolerates pregnancy volume load. If pregnancy proceeds: early delivery 34-36 weeks, elective CS, ICU monitoring postpartum. Permanent contraception essential. Limited evidence - case-by-case decision-making required.

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]
  • DPD/PYP scan is key diagnostic test for ATTR[1]
  • Must exclude monoclonal protein before diagnosing ATTR on bone scan alone[1]
  • Tafamidis improves survival in ATTR - start early[1]
  • AL amyloidosis requires urgent haematology referral
  • Screen family if ATTRv (hereditary) identified
  • Pregnancy EXTREMELY RARE (age >50 typical); AL: mWHO IV contraindicated; ATTRv: mWHO III-IV high risk
  • Restrictive physiology poorly tolerates pregnancy volume load - very high decompensation risk

References & Review Date

Last reviewed: June 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 J Heart Fail. 2021;23(4):512–526. doi:10.1002/ejhf.2135
  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 (2025). 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