What is the recommended algorithm for a cardiac amyloidosis workup and management?

Cardiac Amyloidosis Workup Algorithm

The recommended diagnostic workup for cardiac amyloidosis begins with screening for serum and urine monoclonal light chains, followed by bone scintigraphy for those without evidence of monoclonal proteins, with subsequent genetic testing to differentiate between amyloid types. 1

Clinical Suspicion: When to Consider Cardiac Amyloidosis

Suspect cardiac amyloidosis in patients with:

• Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema
• Discordance between wall thickness on echocardiogram and QRS voltage on ECG
• Unexplained heart failure, especially with preserved ejection fraction (≥40%)
• Low-flow aortic stenosis
• History of carpal tunnel syndrome (especially bilateral)
• Spinal stenosis
• Autonomic or sensory polyneuropathy
• Unexplained biceps tendon rupture
• Family history of amyloidosis

Diagnostic Algorithm

Step 1: Initial Screening

• Obtain ECG, echocardiography, and consider cardiac MRI
• Look for: increased wall thickness >12mm, biatrial enlargement, "granular sparkling" appearance of myocardium, and preserved ejection fraction 2

Step 2: Laboratory Testing

• Screen for monoclonal light chains:
  • Serum and urine immunofixation electrophoresis
  • Serum free light chain assay 1

Step 3: Imaging Based on Light Chain Results

• If monoclonal proteins present:

  • Hematology-oncology consultation
  • Consider heart or other tissue biopsy
  • If biopsy positive → AL amyloidosis

• If NO monoclonal proteins present:

  • Proceed to bone scintigraphy (99mTc-PYP/DPD/HMDP)
  • Positive scan without monoclonal proteins → ATTR amyloidosis 1, 3

Step 4: Genetic Testing

• For patients diagnosed with ATTR amyloidosis:
  • Perform TTR gene sequencing to differentiate:
    • ATTRv (variant/hereditary)
    • ATTRwt (wild-type) 1
  • If ATTRv identified → refer to genetic counselor and consider family screening

Treatment Approach

• For AL amyloidosis:

  • Refer to hematologist-oncologist for anti-plasma cell therapy 4

• For ATTR amyloidosis:

  • NYHA class I-III symptoms: Tafamidis (VYNDAQEL 80mg or VYNDAMAX 61mg once daily) to reduce cardiovascular mortality and hospitalization 1, 5
  • TTR silencer therapy if neuropathy present

• For patients with atrial fibrillation:

  • Anticoagulation is reasonable regardless of CHA₂DS₂-VASc score 1

Pitfalls to Avoid

1. Delayed diagnosis: Cardiac amyloidosis is often misdiagnosed as other forms of heart failure or hypertrophic cardiomyopathy
2. Incomplete screening: Always perform both serum AND urine testing for monoclonal proteins
3. Missing AL amyloidosis: A positive bone scan does not exclude AL amyloidosis - always check for monoclonal proteins first
4. Inadequate follow-up: Patients with ATTRv require genetic counseling and family screening
5. Overlooking non-cardiac manifestations: Bilateral carpal tunnel syndrome, spinal stenosis, and peripheral neuropathy can precede cardiac symptoms by years 1

Imaging Considerations

• Echocardiography: First-line imaging but lacks specificity
• Cardiac MRI: Provides tissue characterization with late gadolinium enhancement pattern (avoid if GFR <30 ml/min/1.73m²) 1
• Bone scintigraphy: Highly specific for ATTR when grade 2-3 cardiac uptake is present in the absence of monoclonal proteins 3
• Endomyocardial biopsy: Consider when imaging findings are equivocal or discordant 4

Early diagnosis is crucial as effective treatments are now available that can significantly improve survival and quality of life, particularly for ATTR amyloidosis where tafamidis has been shown to reduce cardiovascular mortality 1, 5.