Cardiac Amyloidosis

1. Clinical Overview

Summary

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins (amyloid fibrils) in the myocardium, leading to progressive diastolic dysfunction and restrictive physiology. [1,2] Previously considered rare and largely a post-mortem diagnosis, improved recognition and advances in non-invasive diagnostic techniques have revealed cardiac amyloidosis to be a significantly under-diagnosed cause of heart failure with preserved ejection fraction (HFpEF), particularly in elderly patients.

The two clinically important types are:

• Light-chain (AL) amyloidosis: Caused by misfolded immunoglobulin light chains from clonal plasma cell disorders
• Transthyretin (ATTR) amyloidosis: Subdivided into hereditary (ATTRv, variant/mutant) and wild-type (ATTRwt, formerly senile cardiac amyloidosis)

Early diagnosis is critical as prognosis differs markedly between types and disease-modifying therapies are now available. The ATTR-ACT trial demonstrated that tafamidis reduces all-cause mortality by 30% in ATTR cardiac amyloidosis. [3] The classic presentation of low-voltage ECG despite increased wall thickness on echocardiography should prompt immediate investigation.

Key Clinical Facts

Clinical Pearls

Diagnostic Pearl - Voltage-Mass Discordance: The combination of increased LV wall thickness (> 12mm) on echocardiography with low-voltage QRS complexes (less than 0.5mV in limb leads or less than 1.0mV in precordial leads) on ECG is highly suggestive of infiltrative cardiomyopathy. This discordance occurs because amyloid deposits increase mass without contributing to electrical signal generation. Request cardiac MRI and bone scintigraphy immediately.

Examination Pearl - Carpal Tunnel as Early Sign: Bilateral carpal tunnel syndrome preceding heart failure symptoms by 5-10 years is characteristic of ATTR amyloidosis due to amyloid deposition in the flexor retinaculum. Always ask about carpal tunnel surgery in patients presenting with HFpEF, especially males > 65 years. [9]

Treatment Pearl - Tafamidis Impact: Tafamidis reduces mortality and cardiovascular hospitalisation in ATTR cardiac amyloidosis by 30% (ATTR-ACT trial, NNT 7.5 over 30 months). [3] Ensure ALL patients with suspected ATTR are evaluated for this therapy. Do not delay diagnosis.

Pitfall Warning - Type Matters: Do not assume all amyloidosis is AL. ATTR is more common than previously thought and requires different treatment (TTR stabilisers, not chemotherapy). Misdiagnosis leads to inappropriate and potentially harmful treatment.

Imaging Pearl - Bone Scintigraphy Interpretation: Grade 2-3 cardiac uptake on Tc-99m PYP/DPD/HMDP scintigraphy, combined with absence of monoclonal protein (negative serum/urine immunofixation AND normal free light chain ratio), allows diagnosis of ATTR cardiac amyloidosis WITHOUT endomyocardial biopsy. This has revolutionised diagnosis. [8]

ECG Pearl - Pseudo-Infarct Pattern: Look for pseudo-infarct patterns (Q waves in anterior or inferior leads without coronary artery disease) which occur in 50% of cardiac amyloidosis cases due to replacement of myocardium with electrically inert amyloid.

Mnemonic - ATTR Features: Aged (wild-type predominantly elderly), Transthyretin protein, Tafamidis treats it, Runs in families (variant/hereditary form)

Why This Matters Clinically

Cardiac amyloidosis is increasingly recognised as a treatable cause of HFpEF. The convergence of improved awareness, non-invasive diagnostic algorithms, and effective disease-modifying therapy has fundamentally changed the landscape:

1. Under-diagnosis is the norm: Autopsy studies suggest ATTRwt is present in 25% of those > 85 years, yet clinical diagnosis remains rare
2. Misdiagnosis leads to harm: Patients treated for hypertensive heart disease receive medications (digoxin, CCBs) that are contraindicated in amyloidosis
3. Treatment changes prognosis: Early tafamidis in ATTR, or chemotherapy in AL, significantly improves survival
4. This is a high-yield MRCP topic: Reflects advances in cardiac imaging and therapeutics, ideal for examination scenarios

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2. Epidemiology

Incidence and Prevalence

Demographics and Risk Factors

Risk Factor Table

Geographic Variation

ATTRv has distinct endemic populations due to founder effects:

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3. Pathophysiology

Molecular Mechanisms

Step 1: Amyloid Precursor Protein Production

AL Amyloidosis:

• Clonal plasma cells produce excess monoclonal immunoglobulin light chains (typically lambda > kappa)
• Light chains have inherent amyloidogenic properties based on amino acid sequence
• Certain light chain subtypes (lambda VI, lambda III) are particularly amyloidogenic
• The degree of amyloidogenicity correlates with clinical severity [10]

ATTR Amyloidosis:

• Transthyretin (TTR) is a 55 kDa homotetrameric protein synthesised primarily in the liver
• TTR normally transports thyroxine (T4) and retinol-binding protein
• ATTRwt: Age-related post-translational modifications destabilise the tetramer
• ATTRv: Point mutations in the TTR gene destabilise the tetramer structure
• Over 130 TTR mutations are described; V122I and V30M are most common [7]

Step 2: Protein Misfolding and Fibril Formation

The amyloid cascade proceeds through defined steps:

1. Tetramer dissociation (ATTR) or light chain misfolding (AL)
2. Monomer formation with exposed hydrophobic regions
3. Oligomer aggregation into intermediate toxic species
4. Beta-pleated sheet configuration - characteristic cross-beta structure
5. Fibril elongation into insoluble fibrils (7.5-10nm diameter, rigid, unbranched)
6. Fibril deposition in extracellular matrix

All amyloid fibrils share:

• Characteristic apple-green birefringence under polarised light with Congo red staining
• Binding of serum amyloid P component (SAP)
• Resistance to proteolytic degradation

Step 3: Cardiac Infiltration and Toxicity

Amyloid causes cardiac dysfunction through multiple mechanisms:

Structural Effects:

• Progressive accumulation in myocardial interstitium
• Wall thickening WITHOUT true myocyte hypertrophy
• Disruption of myocyte architecture and contractile function
• Deposition in coronary arteries (microvascular dysfunction)
• Deposition in conduction system (arrhythmias, AV block)
• Atrial infiltration (AF, atrial thrombus formation)

Direct Toxicity (particularly AL):

• Light chain oligomers are directly cardiotoxic [10]
• Induction of oxidative stress
• Activation of p38 MAPK pathway
• Mitochondrial dysfunction
• Cellular apoptosis
• This explains the rapid progression in AL compared to ATTR

Step 4: Haemodynamic Consequences

The infiltrated heart develops restrictive physiology:

Step 5: Systemic Involvement (Type-Specific)

AL Amyloidosis - Multi-organ:

• Kidney (nephrotic syndrome, renal failure)
• Liver (hepatomegaly, elevated ALP)
• Gastrointestinal tract (malabsorption, bleeding)
• Peripheral nerves (sensorimotor neuropathy)
• Autonomic nerves (orthostatic hypotension)
• Soft tissues (macroglossia, periorbital purpura)

ATTR Amyloidosis:

• Heart (cardiomyopathy - predominant in ATTRwt)
• Peripheral nerves (polyneuropathy - predominant in some ATTRv mutations)
• Autonomic nerves (orthostatic hypotension, GI dysmotility)
• Soft tissues (carpal tunnel syndrome, lumbar stenosis)
• Eyes (vitreous opacities in some ATTRv)

Classification Systems

Classification by Amyloid Type

Cardiac Staging Systems

Mayo Staging for AL Cardiac Amyloidosis (2004, Revised 2012): [11]

European Modification for AL (2015): Incorporates dFLC (difference between involved and uninvolved free light chain):

• Stage I: NT-proBNP less than 332, cTnT less than 0.035, dFLC less than 180
• Stage IV: NT-proBNP > 332, cTnT > 0.035, dFLC > 180

NAC Staging for ATTR Cardiac Amyloidosis: [12]

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4. Clinical Presentation

Cardinal Symptoms

Heart Failure Symptoms (Present in > 80%):

Cardiac Symptoms Beyond Heart Failure:

Extracardiac Symptoms (Critical Diagnostic Clues)

Symptoms Suggesting AL Amyloidosis:

Symptoms Suggesting ATTR Amyloidosis:

Red Flag Presentations

[!CAUTION] RED FLAGS - SUSPECT CARDIAC AMYLOIDOSIS

ECG-Echo Discordance:

• Low-voltage ECG (limb leads less than 5mm, precordial less than 10mm) with increased LV wall thickness (> 12mm)
• This voltage-mass discordance is highly specific for infiltrative disease

Clinical Combinations:

• HFpEF + bilateral carpal tunnel syndrome history
• HFpEF + unexplained LVH in elderly without hypertension
• HFpEF + nephrotic syndrome (suggests AL)
• HFpEF + peripheral neuropathy
• HFpEF + orthostatic hypotension

Alarm Features:

• Syncope in HFpEF patient (poor prognosis; consider arrhythmia)
• Macroglossia (pathognomonic for AL - urgent haematology referral)
• Periorbital purpura (pathognomonic for AL)
• Rapidly progressive symptoms (suggests AL)

ECG Red Flags:

• Pseudo-infarct pattern (Q waves without CAD)
• AV conduction disease with thick ventricles
• Low voltage in a "thick heart"

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5. Clinical Examination

Structured Cardiovascular Examination

General Inspection

Cardiovascular Examination

Jugular Venous Pressure:

• Elevated (often > 10 cmH2O)
• Kussmaul's sign: Paradoxical rise on inspiration (restrictive physiology)
• Prominent x and y descents (restrictive pattern)

Apex Beat:

• Non-displaced (normal LV cavity size)
• Difficult to palpate (thick but non-compliant)
• No sustained heave despite wall thickening

Auscultation:

• S1: Soft (reduced contractility)
• S2: Normal or soft
• S4: Present (atrial contraction against stiff ventricle)
• S3: May be present in advanced disease
• Murmurs: Usually absent; may have functional MR/TR

Peripheral Signs of Heart Failure:

• Peripheral oedema (often pitting, bilateral)
• Hepatomegaly (may be pulsatile with TR)
• Ascites (late sign)
• Elevated JVP as above

Systemic Examination for Extra-Cardiac Involvement

Special Tests at Bedside

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6. Investigations

First-Line Investigations

ECG Findings [13]

Critical ECG Interpretation: The combination of low-voltage QRS with echocardiographic LVH (voltage-mass discordance) is nearly pathognomonic for cardiac amyloidosis and distinguishes it from hypertensive heart disease or HCM.

Echocardiography [14]

Strain Imaging (Speckle Tracking):

• Global longitudinal strain (GLS) is reduced (< -18%)
• Apical sparing pattern: Relative preservation of apical strain with reduced basal and mid-wall strain
• This "cherry on top" or "bullseye" pattern is characteristic and helps distinguish from other causes of LVH [15]

Laboratory Investigations

Advanced Imaging

Cardiac MRI [16]

Characteristic CMR Pattern:

• LGE showing diffuse subendocardial enhancement progressing to transmural
• "Zebra stripe" appearance in some cases
• T1 mapping is more sensitive than LGE for early disease
• ECV correlates with amyloid burden and prognosis

Nuclear Imaging - Bone Scintigraphy [8]

This is the key investigation that allows non-invasive diagnosis of ATTR without biopsy.

Technique:

• Tc-99m labelled bone-seeking tracers: PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), or HMDP (hydroxymethylene diphosphonate)
• Planar and SPECT imaging at 1-3 hours post-injection
• Comparison with rib uptake (Perugini grading)

Perugini Grading System:

Critical Diagnostic Algorithm: [8] Grade 2-3 uptake + Negative serum/urine immunofixation + Normal free light chain ratio = ATTR cardiac amyloidosis confirmed WITHOUT biopsy

This algorithm has > 99% specificity and positive predictive value for ATTR when rigorously applied.

Important Caveats:

• If monoclonal protein IS present, biopsy is required (may be AL with incidental MGUS, or mixed AL+ATTR)
• Grade 1 uptake is indeterminate and requires further evaluation
• Bone scintigraphy does NOT distinguish ATTRwt from ATTRv (requires genetic testing)

Tissue Diagnosis

Indications for Biopsy

Biopsy is required when:

• Bone scintigraphy is negative or Grade 1
• Monoclonal protein is present (cannot exclude AL)
• Alternative amyloid types suspected
• Diagnosis uncertain after non-invasive workup

Biopsy Sites

Histopathology

Diagnostic Algorithm

SUSPECTED CARDIAC AMYLOIDOSIS
(HFpEF + LVH + low-voltage ECG or other red flags)
                    |
                    v
    ┌───────────────────────────────────┐
    │   STEP 1: Initial Workup         │
    │   - ECG + Echocardiography       │
    │   - NT-proBNP, Troponin          │
    │   - Serum free light chains      │
    │   - Serum + urine immunofixation │
    └───────────────┬───────────────────┘
                    |
                    v
    ┌───────────────────────────────────┐
    │   STEP 2: Bone Scintigraphy      │
    │   (Tc-99m PYP/DPD/HMDP)          │
    └───────────────┬───────────────────┘
                    |
        ┌───────────┼───────────┐
        |           |           |
        v           v           v
    Grade 0     Grade 1     Grade 2-3
        |           |           |
        v           v           v
   Not ATTR    Indeterminate  Potential ATTR
        |           |           |
        v           v           v
                    |     Check for monoclonal protein
                    |           |
                    |    ┌──────┴──────┐
                    |    |             |
                    v    v             v
              Biopsy  NEGATIVE      POSITIVE
              required     |             |
                          v             v
                    ATTR CONFIRMED   BIOPSY REQUIRED
                    No biopsy needed  (may be AL or mixed)
                          |
                    ┌─────┴─────┐
                    |           |
                    v           v
              Genetic Testing  If positive
              for TTR mutations   → ATTRv
                    |           If negative
                    v              → ATTRwt
              Management based on type

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7. Management

General Principles

1. Confirm diagnosis and type - AL vs ATTR has fundamentally different treatment
2. Multidisciplinary approach - Cardiology, Haematology (AL), Neurology (if neuropathy), Genetics (ATTRv), specialist amyloid centre
3. Refer to specialist centre - National Amyloidosis Centre (UK) or equivalent
4. Avoid harmful medications - Digoxin, CCBs, negative inotropes
5. Supportive care while pursuing disease-specific treatment
6. Prognostic staging - guides treatment intensity

Conservative/Supportive Management

Lifestyle Modifications

Heart Failure Medications - CAUTION REQUIRED

Disease-Modifying Therapy: ATTR Amyloidosis

TTR Stabilisers

Tafamidis (Vyndaqel/Vyndamax): [3]

Diflunisal: (Off-label)

• NSAID with TTR-stabilising properties
• Evidence: Observational data suggesting slower progression
• Dose: 250mg BD
• Issues: NSAID side effects (GI, renal, CV risk); contraindicated in heart failure

Gene Silencing Therapies

Patisiran (Onpattro): [18]

Inotersen (Tegsedi):

Vutrisiran (Amvuttra):

• Next-generation siRNA; more convenient dosing (every 3 months)
• HELIOS-A trial showed sustained neuropathy improvement
• Cardiac outcomes data from HELIOS-B expected

Disease-Modifying Therapy: AL Amyloidosis

Treatment is directed at the underlying plasma cell clone - managed by Haematology.

Chemotherapy Regimens [19]

Treatment Goals:

• Achieve haematological response (normalisation of free light chains)
• Organ response follows haematological response
• Complete response (CR): Normal FLC ratio, negative immunofixation
• Very good partial response (VGPR): dFLC less than 40mg/L

Autologous Stem Cell Transplantation

Management of Arrhythmias

Atrial Fibrillation

Ventricular Arrhythmias

Management of Conduction Disease

Advanced Heart Failure Therapies

Disposition and Follow-Up

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8. Complications

Cardiovascular Complications

Systemic Complications (AL Amyloidosis)

Treatment-Related Complications

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9. Prognosis and Outcomes

Natural History (Untreated)

Outcomes with Modern Treatment

Prognostic Biomarkers

Favourable vs Adverse Prognostic Factors

Favourable:

• Early diagnosis and treatment initiation
• ATTR type (vs AL)
• Low-stage disease (Mayo Stage I for AL; NAC Stage I for ATTR)
• Haematological complete response (AL)
• NYHA Class I-II
• Normal or mildly elevated biomarkers
• Younger age
• Good renal function

Adverse:

• Advanced cardiac stage (Mayo Stage III/IIIb; NAC Stage III)
• AL type without haematological response
• NYHA Class III-IV
• Markedly elevated biomarkers (NT-proBNP > 8500, troponin elevated)
• Syncope
• Ventricular arrhythmias
• Poor functional capacity
• Renal impairment
• Multi-organ involvement (AL)

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10. Evidence Base and Guidelines

Key Guidelines

Landmark Trials

ATTR-ACT Trial (2018) [3]

APOLLO Trial (2018) [18]

Gillmore Non-Biopsy Diagnosis Study (2016) [8]

ANDROMEDA Trial (2021) [19]

Key Supporting Studies

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11. Patient Information

What is Cardiac Amyloidosis?

Cardiac amyloidosis is a condition where abnormal proteins build up in your heart muscle. These proteins are called amyloid. They make your heart stiff, so it cannot relax properly and fill with blood effectively. This leads to a type of heart failure.

There are two main types:

• AL amyloidosis: The abnormal protein comes from bone marrow cells. This type can affect many organs and needs chemotherapy treatment.
• ATTR amyloidosis: The abnormal protein is called transthyretin, normally made by the liver. This type mainly affects the heart and can be treated with a medication called tafamidis.

Why is Early Diagnosis Important?

Without treatment, amyloid continues to build up in the heart, causing progressive heart failure. However, we now have effective treatments that can slow or stop the disease:

• For AL type: Chemotherapy to stop the abnormal cells making the protein
• For ATTR type: Tafamidis, a tablet that stabilises the protein and reduces heart damage

The earlier we diagnose and treat, the better the outcome.

What Tests Will I Need?

• Blood tests: Including tests for the abnormal proteins and heart strain markers (NT-proBNP, troponin)
• Heart ultrasound (echocardiogram): To see how thick and stiff your heart is
• ECG: To check your heart rhythm
• Nuclear scan (bone scintigraphy): A special scan that can diagnose ATTR type without needing a biopsy
• Heart MRI: To see detailed images of your heart
• Genetic testing: If ATTR is confirmed, to check for inherited forms
• Occasionally, a biopsy (small tissue sample) may be needed

How is it Treated?

1. Water tablets (diuretics) to remove excess fluid
2. Disease-specific treatment:
   • ATTR: Tafamidis (a tablet taken daily to stabilise the protein)
   • AL: Chemotherapy to stop the abnormal protein being made
3. Avoiding certain medications that can make the condition worse (like digoxin and certain blood pressure tablets)
4. Lifestyle changes: Salt and fluid restriction, compression stockings
5. Regular monitoring with scans, blood tests, and clinic visits

Living with Cardiac Amyloidosis

• Keep to your daily fluid allowance (usually 1.5-2 litres)
• Reduce salt in your diet
• Take your medications regularly
• Wear compression stockings if advised
• Keep active within your limits
• Attend all clinic appointments

When to Seek Urgent Help

Contact your medical team or seek emergency help if you experience:

• Worsening breathlessness, especially at rest or lying flat
• Increasing swelling of ankles, legs, or abdomen
• Dizziness or fainting
• Palpitations (awareness of your heartbeat)
• Chest pain or pressure
• Weight gain of more than 2kg in 2-3 days

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12. Examination Focus

High-Yield Examination Topics

1. Diagnostic approach to HFpEF with LVH - when to suspect amyloidosis
2. Differentiating AL from ATTR amyloidosis
3. Role of bone scintigraphy in non-invasive diagnosis
4. Interpretation of cardiac MRI in infiltrative disease
5. Medications to avoid in cardiac amyloidosis
6. Tafamidis - mechanism, evidence, indications
7. Staging systems for prognosis
8. Multidisciplinary management approach

Common Exam Questions

1. "A 72-year-old man presents with HFpEF and a history of bilateral carpal tunnel syndrome. What is your differential diagnosis and approach?"
2. "How would you differentiate AL from ATTR cardiac amyloidosis?"
3. "What is the significance of bone scintigraphy in cardiac amyloidosis, and how do you interpret the results?"
4. "Which medications should be avoided in cardiac amyloidosis, and why?"
5. "A patient with suspected cardiac amyloidosis has Grade 2 uptake on Tc-99m PYP scan. What additional test determines your next step?"
6. "Describe the ATTR-ACT trial and its implications for practice."
7. "What are the characteristic echocardiographic and ECG findings in cardiac amyloidosis?"

Viva Framework

Opening Statement:

"Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded amyloid proteins. The two clinically important types are AL amyloidosis from light chains and ATTR from transthyretin. ATTR is more common than previously recognised, found in 13-25% of HFpEF patients over 60 years. The diagnosis is important because disease-modifying therapy now exists: tafamidis for ATTR reduces mortality by 30%."

Key Facts to Quote:

• Incidence: AL 10-12 per million; ATTRwt in 13-25% HFpEF > 60 years
• V122I mutation in 3-4% African Americans
• ATTR-ACT: 30% mortality reduction with tafamidis (NNT 7.5 over 30 months)
• Non-invasive diagnosis: Grade 2-3 bone scan + no monoclonal protein = ATTR confirmed
• Avoid digoxin and CCBs

Classification to Know:

• Mayo Staging (AL): I, II, III, IIIb based on NT-proBNP, troponin, dFLC
• NAC Staging (ATTR): I, II, III based on NT-proBNP and eGFR
• Perugini grading for bone scintigraphy: 0, 1, 2, 3

If Asked About Investigations:

"I would structure investigations as: first, screening with ECG looking for low voltage and pseudo-infarct pattern, echocardiography for wall thickness and diastolic dysfunction. Second, typing with serum and urine immunofixation plus free light chains to identify any monoclonal protein. Third, imaging confirmation with Tc-99m bone scintigraphy - if Grade 2-3 uptake with no monoclonal protein, ATTR is confirmed without biopsy. CMR provides additional tissue characterisation. Genetic testing follows to distinguish ATTRwt from ATTRv."

If Asked About Management:

"Management has two components: supportive and disease-modifying. Supportive care includes careful diuresis, avoiding harmful drugs like digoxin and calcium channel blockers, and managing arrhythmias with anticoagulation for AF given high stroke risk. Disease-modifying therapy depends on type: for ATTR, tafamidis stabilises the TTR tetramer and has Level I evidence from ATTR-ACT showing mortality reduction. For AL, the goal is haematological response through chemotherapy, typically daratumumab-CyBorD based on ANDROMEDA trial results."

Common Mistakes to Avoid

Model Answer Example

Q: "Describe your approach to a 68-year-old man with HFpEF and bilateral carpal tunnel syndrome."

"This presentation raises significant concern for cardiac amyloidosis, specifically ATTR given the demographic and carpal tunnel history. I would approach this systematically.

First, I would confirm features suggestive of infiltrative disease: on ECG, looking for low-voltage QRS complexes with pseudo-infarct pattern; on echo, increased wall thickness with diastolic dysfunction and potentially apical sparing on strain imaging.

Second, I would type the amyloid by checking serum free light chains and serum/urine immunofixation to exclude AL amyloidosis with a monoclonal protein.

Third, I would arrange Tc-99m bone scintigraphy. If this shows Grade 2-3 cardiac uptake and there is no monoclonal protein, I can diagnose ATTR without biopsy. I would then arrange TTR gene sequencing to distinguish wild-type from hereditary ATTR.

Management would include initiating tafamidis, which the ATTR-ACT trial showed reduces mortality by 30%. I would avoid digoxin and calcium channel blockers, carefully manage diuretics for congestion, and anticoagulate if atrial fibrillation develops. I would refer to a specialist amyloid centre for ongoing care."

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13. References

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6. Castaño A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017;38(38):2879-2887. doi:10.1093/eurheartj/ehx350 PMID: 29019612

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19. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021;385(1):46-58. doi:10.1056/NEJMoa2028631 PMID: 34192431

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Last Reviewed: 2026-01-09 | MedVellum Editorial Team

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